diff --git "a/notes/Ghai-Essential-Pediatrics_17.txt" "b/notes/Ghai-Essential-Pediatrics_17.txt" new file mode 100644--- /dev/null +++ "b/notes/Ghai-Essential-Pediatrics_17.txt" @@ -0,0 +1,2141 @@ +x. Bisphosphonates, both intravenous and oral, have been useful in cases of osteogenesis imperfecta. +xi. Stem cell transplantation is recommended for many genetic disorders like thalassemia major, severe form + +of Hurler syndrome and some primary immuno­ deficiencies. The benefit is maximized if the trans­ plantation is done early in the course of disease. +xii. Gene therapy is possible in patients with adenosine deaminase deficiency, familial hypercholesterolemia and some cancers. The normal gene is introduced in affected individuals using viral or nonviral vectors. As the exact regulation of gene function of single gene disorders is very complex, the implementation of gene therapy is complicated. +I + +PREVENTION OF GENETIC DISORDERS Carrier Screening +It is now possible to detect the carrier state in a large num­ ber of autosomal recessive or X-linked recessive disorders. Female carriers of Ouchenne muscular dystrophy may show high serum levels of the enzyme creatinine phospho­ kinase, but can be tested more precisely using molecular techniques. Female carriers of glucose-6-phosphate dehydrogenase deficiency are detected by demonstrating relatively low level of enzymes in their erythrocytes. HbA2 levels are useful in identifying carriers of p thalassemia trait in high-risk communities. Molecular techniques are increasingly used for detection of individuals who are m ore likely to give birth to offspring with hereditary dis­ orders. + +Newborn Screening +This is an example of secondary prevention by early diagnosis and treatment. Newborn infants are screened routinely for some endocrine disorders and inborn errors of metabolism in developed countries. This is of special value for detecting the affected cases during the newborn period, so that the handicap can be prevented or ized by early treatment, e.g. in cases of congenital hypo­ thyroidism, congenital adrenal hyperplasia, phenylketo­ nuria, galactosemia and tyrosinemia. + +Prevention of Neural Tube Defects (NTD) +Folic acid supplementation is recommended at a dose of 0.4 mg daily from one month before to three months after conception to prevent NTD. Expectant mothers at high­ risk of NTD (e.g. previous fetus with NTD) should con­ sume 4 mg of folic acid daily to prevent recurrence of neural tube defects. + +Prenatal Diagnosis and Selective Termination of Affected Fetuses +This is a successfully used modality for preventing birth of affected babies and reducing the load of lethal, chronically disabling, untreatable or difficult-to-treat genetic disorders in the community. The prenatal screening or diagnostic modalities can be noninvasive or invasive. Noninvasive techniques include fetal ultrasono­ graphy and maternal serum screening. +_ Ess__en__t_l_ _Pe_d__t__c __________________________________ +r +i +_ +s_ +i +a +i +a +_ +_ + + +Maternal Serum Screening +Estimation of pregnancy associated plasma protein A (PAPP-A) and free P-human chorionic gonadotropin (hCG) in the first trimester and serum alpha-fetoprotein, hCG, w1conjugated estriol and inhibin A in second trimester are useful biochemical markers to detect aneuploidies. If the risk of bearing a child with Down syndrome is more than 1:250, prenatal fetal karyotyping can be offered. Fetal ultrasonography helps to detect fetuses who are at high­ risk for chromosomal abnormalities. Important findings in the second trimester which are markers of Down syndrome include increased nuchal fold thickness (measured over the occiput and not the spine), short femur and humerus length and duodenal atresia. In the first trimester, nuchal trans­ lucency and nasal bone are robust markers. Ultrasound findings help in cow1seling, particularly if the parents have opted for initial screening with maternal serum markers. Both maternal serum screening and fetal ultrasound are screening techniques and cannot rule out Down syndrome. The detection rate of triple test in the second trimester is about 65% with a false positive rate of 5%. First trimester screening using dual markers have high detection rates, which improves further if ultrasound markers are com­ bined. Alpha-fetoprotein and estriol are low, whereas hCG is high, in pregnancies with Down syndrome fetuses. All three markers are reduced in fetuses with trisomy 18. Elevated alpha-fetoprotein level in maternal blood is also a very sensitive marker for fetuses affected with open neural tube defects. + +Invasive Prenatal Testing +This includes chorionic villus biopsy (done at 10-12 weeks of gestation or later), amniocentesis (16-20 weeks) and + +cord blood sampling (after 18 weeks). Procedure related risk is lowest with amniocentesis (- 0.5%), while chorionic villus biopsy carries a risk of fetal loss in about 2%. These samples can be used for chromosomal studies, DNA based tests or enzyme assays. Amniotic fluid is the preferred sample for chromosomal studies and chorionic villus tissue for DNA based tests. Single gene disorders with a known gene can be diagnosed prenatally. Some common examples are thalassemia, sickle cell anemia, hemophilia, Duchenne muscular dystrophy and cystic fibrosis. + +Genetic Counseling +Genetic counseling is a communication process, which deals with problems associated with the occurrence and recurrence of a genetic disorder in a family. Counseling should be undertaken by a physician with proper under­ standing of the genetic mechanisms. Some important indi­ cations for genetic counseling are as follows: (i) known or suspected hereditary disease in a patient or family; (ii) birth defects in previous children; (iii) unexplained mental retar­ dation, dysmorphism, multiple malformations in a child; (iv) consanguinity; (v) exposure to a teratogen during pregnancy; and (vi) identification of malformation(s) by ultrasonography during pregnancy. + +Suggested Reading +Cassidy SB, Allanson JE Management of genetic syndromes, 3rd edition, Wiley Blackwell, USA,2010 +Harper PS. Practical Genetic Cow1seling, 5th edn. Wright Publishers, Bristol, 2004 +Reardon W. The Bedside Dysmorphologist. Oxford University Press, 2008 +Rimori DL, Cooner JM, Pyeritz RE, Korf BR. Principles and Practice of Medical Genetics, 5th edn., Churchill Livingstone, Philadelphia, 2006 + +Inborn Errors of Metabolism + + + + + + + +Neerja Gupta, Madhulika Kabra + + + + + + + +Inborn errors of metabolism (IEM) are conditions caused by genetic defects related to synthesis, metabolism, transport or storage of biochemical compounds. The metabolic error usually results in the deficiency of one or more enzymes required for the formation or transport of proteins. The worldwide incidence of IEMs is 3-4/1000 live births; most are inherited in an autosomal recessive manner. + +SUSPECTING AN INBORN ERROR OF METABOLISM +IEMs may present in the newborn period, in early or late childhood, or in adults. The diagnosis is often delayed, and requires a high index of suspicion, since symptoms are nonspecific, leading to evaluation for other pediatric illnesses like sepsis and hypoxic ischemic encephalopathy. +Features of Metabolic Disorders +• Sudden and rapid illness in a previously normal baby precipitated by fever, vomiting or fasting +• Nonspecific, unexplained features such as poor feeding, lethargy, vomiting, hypotonia, failure to thrive, respi­ ratory abnormalities, hiccups, apnea, bradycardia and hypothermia, with normal sepsis screen +• Rapidly progressive encephalopathy of unknown etiology +• Persistent or recurrent hypoglycemia, intractable metabolic acidosis, unexplained leukopenia or throm­ bocytopenia +• Hyperammonemia • E. coli sepsis +• Organomegaly +• Peculiar odor (musty in phenylketonuria; cabbage like in tyrosinemia; maple syrup like in maple syrup urine disease; like sweaty feet in isovaleric acidemia, or glutaric acidemia type II; like cat urine: in 3-methyl-crotonyl CoA carboxylase or multiple carboxylase deficiency) +• Family history of unexplained neonatal deaths or progressive neurological disease, HELLP (hemolysis, + +elevated liver enzymes, low platelet counts) syndrome in mother +• Parental consanguinity + +Classification +Based on the pathophysiology, IEMs can be classified as follows: +Intoxication group includes disorders of intermediary metabolism, with accumulation of toxic compounds resulting in acute or progressive symptoms. Amino­ acidopathies (e.g. phenylketonuria and maple syrup urine disease), organic aciduria, urea cycle defects, disorders of carbohydrate and copper metabolism and porphyrias belong to this category. Symptoms are often precipitated by catabolic state (fever, infections, immunization, dehydration or fasting). +Defects in energy metabolism include conditions associated with deficient energy production or utilization within liver, muscle, heart and brain, e.g. mitochondrial disorders, disorders of glycolysis, glycogen metabolism and gluco­ neogenesis and hyperinsulinism. Failure to thrive, hypo­ glycemia, hepatomegaly, hypotonia, cardiomyopathy, myopathy, high lactate, neurological symptoms, circulatory collapse or sudden death may be seen. +Disorders of complex molecules include lysosomal storage diseases, peroxisomal disorders, a,-antitrypsin deficiency and congenital disorders of glycosylation. Symptoms are usually progressive and permanent and do not have precipitating factors. +Metabolic disorders can have either acute or chronic presentation (Table 23.1). + +Acute Presentation +Neonates with metabolic disorders appear normal at birth since the small intermediary metabolites are eliminated by the placenta during fetal life. Disorders of glucose, protein and fat breakdown usually present early, although + +647 +_ E_s_s_e_n_ ti_ al_ _P_e_d_ i_a _tr-ic_ --------------------------------- +s +_ +_ + + +Table 23.1: Classification of inborn errors of metabolism +Acute Chronic encephalopathy encephalopathy + +Age at Neonatal or early Late infancy, presentation infancy childhood, adolescence +Metabolite and Small molecule; Large or complex type of defect intoxication or molecule(s) +energy metabolism defects +Presentation Seizures, Spasticity, hyperreflexia, respiratory ataxia; dementia, abnormalities, vision and hearing, vomiting, lethargy, impairment, liver unexplained coma dysfunction, +cardiomyopathy + +premature neonates with transient hyperammonemia of newborn (THAN) and term babies with glutaric acidemia type II or pyruvate carboxylase deficiency may present on the first day of life. In general, an early onset of clinical symptoms is associated with severe disease. The onset of +illness is delayed in the intermittent or milder forms. +An important clue to diagnosis is unexpected deterioration after normal initial period in a full term baby. Neonates with organic +acidurias, urea cycle disorders and some inoacidurias may present with lethargy, poor feeding, persistent vomiting, seizures, tachypnea, floppiness and body or urine odor. Common conditions such as sepsis, hypoxic ischemic +encephalopathy and hypoglycemia should be excluded. Older children show acute unexplained, recurrent +episodes of altered sensorium, vomiting, lethargy pro­ gressing to coma, stroke or stroke like episodes, ataxia, psychiatric features, exercise intolerance, abdominal pain, quadriparesis or arrhythmias. The symptom free period may be prolonged, often longer than a 1 yr and patients are normal in between the episodes. Intercurrent illnesses, high protein intake, exercise, fasting and drug intake (enzyme inducers) may precipitate symptoms. Encephalo­ pathy occurs with little warning in previously healthy individuals; progresses rapidly, may be recurrent and show fluctuating consciousness and is not associated with focal neurological deficits. +Physical examination may show altered sensorium, apnea or hyperpnea and hypotonia. Facial dysmorphism, structural anomalies of brain, cataract, retinopathy, deaf­ ness, hypertrophic or dilated cardiomyopathy, hepato­ megaly, multicystic dysplastic kidneys, myopathy and peculiar urine odor suggest specific diagnoses. +Laboratory Investigations +Biochemical tests may be normal when the child is asymptomatic. The initial screening investigations include total and differential counts and blood levels of sugar, electrolytes, bicarbonate, calcium, transinases, ammonia, lactate and pyruvate. During neonatal period, ammonia +levels are <200 µg/ dl; beyond neonatal age, levels + +<80 µg/dl are considered normal. In urea cycle disorders, blood ammonia levels exceed 1000 µg/ dl and cause respiratory alkalosis with compensatory metabolic acidosis. In organic acidurias, ammonia levels are <500 µg/ dl and in fatty acid oxidation defects <250 µg/ dl. Urine metabolic screen includes pH, ketones, reducing substances and ferric chloride, dinitrophenylhydrazine (DNPH) and nitroprusside tests. +Specialized tests such as quantitative urinary and plasma amino acids analysis by high performance liquid chroma­ tography (HPLC), plasma carnitine and acylcarnitine by tandem mass spectrometry (TMS) and urinary organic acids by gas chromatography and mass spectrometry (GCMS) are helpful in reaching a conclusive diagnosis. Cerebrospinal fluid, chest X-ray, echocardiography, ultra­ sound abdomen, computed tomography (CT) head, magnetic resonance imaging of brain and electroence­ phalogram (EEG) are useful in specific cases. +Acutely presenting IEMs are classified into five major categories (Table 23.2). Figure 23.1 describes the initial approach in such patients. + +Biochemical Autopsy +In a severely ill or dying child, where an IEM is suspected, parents should be advised about the need for a bio­ chemical autopsy for confirmation of diagnosis. Following informed written consent, the following samples should +be obtained postmortem to facilitate diagnosis. +Blood: 5-10 ml each in heparin (for plasma) and EDTA (leukocytes); store at -20°C +Urine: Store at -20°C Cerebrospinal fluid: Store at -20°C +Skin biopsy (including dermis: Store at 37°C in culture +medium or saline with glucose). +Liver, muscle, kidney, heart biopsy: Tissue frozen Clinical photograph and infantogram + +Management +Treatment is often instituted empirically; prompt manage­ ment may be lifesaving. Dietary or parenteral intake of potentially toxic compounds (such as protein, fat, galac­ tose, fructose) is eliminated; adequate calories are pro­ vided using 0.2% saline in 10% dextrose intravenously. lntralipids (2-3 g/kg/ day) may be infused if fatty acid oxidation defect is not suspected. Metabolic acidosis (pH <7.30, bicarbonate <15 mEq/1, anion gap >16 mEq/1) should be corrected. Blood levels of sugar, pH and electro­ lytes should be monitored. +The excretion of toxic metabolites is enhanced by hemo­ dialysis or using alternative pathways for nitrogen excre­ tion. Immediate measures to decrease plasma levels of ammonia are necessary as the risk for irreversible cerebral damage is related to its concentration. IV phenylacetate and sodium benzoate with L-arginine (Table 23.3) are used as detoxifying agents. Dialysis is initiated if plasma +ammonia levels exceed 500-600 µg/dl, or if levels do not +Inborn Errors of Metabolism - + +Table 23.2: Differential diagnosis of metabolic disorders with acute presentation + +Group Acidosis + +I ± + +II +++ + +III ++ + + + + +IV N + + +V ± + + +Ketosis + + ++ + ++ + +± + + + + +N + + +N + + +Plasma lactate + +N + +i + +i i i + + + + +N + + +± + + +Plasma NH3 + +N + +ii + +N + + + + +i i i + + +i + + +Plasma glucose + +N/t + +H + +N + + + + +N + + +Ht + +Diagnosis + +Aminoacidopathies + +Organic acidurias + +Mitochondrial disorders + + + + +Urea cycle disorder + +Fatty acid oxidation defects, glycogen storage disorders + + +Special test + +Plasma or urine amino +acid and blood spot for TMS Urine GCMS and blood +spot for TMS +Lactate: pyruvate ratio, blood spot for TMS, urine GCMS; testing for mitochondrial mutations; muscle biopsy +Plasma amino acid, urine GCMS; urinary orotic acid excretion +Blood spot for TMS for acylcarnitines and urine organic acids + + +GCMS Gas chromatography and mass spectrometry; TMS Tandem mass spectrometry; + present; N normal; i increased + +Suspected metabolic disorder +Poor feeding, persistent vomiting, seizures, floppiness, encephalopathy ++ + +Plasma ammonia + + +High + +Normall ++ +Blood pH, HC03 and anion gap + + + +[ No acidosis or ketosis + +High lactate Hypoglycemia ± ketosis ++ +.'e�e d�fect� �nic aciduria +l + +Lu" Fatty acid oxidation defect Glycogen storage disease +type 1 +Hereditary fructose intolerance + + +Acidosis + +High lactate Normal lactate Normoglycemia Normo- or hypoglycemia Ketosis Ketosis + ++ +Pyruvate carboxylase Maple syrup urine disease deficiency Short chain acyl CoA +Multiple carboxylase dehydrogenase deficiency deficiency +Respiratory chain or mitochondrial defects + + +No acidosis +l + + + + +Aminoacidopathies Nonketotic hyperglycinemia Galactosemia +Peroxisomal disorders + + +Fig. 23.1: Approach to a case with a suspected metabolic disorder + + +fall within 2 hr after initiation of IV treatment. Hemo­ dialysis is preferred to peritoneal dialysis and exchange transfusion. +Carnitine eliminates organic acids as carnitine esters. Carnitine may be used in life-threatening situations associated with its deficiency, at a dose of 25-50 mg/kg IV given over 2-3 minutes, followed by 25-100 mg/kg/ day orally. L-carnitine should not be administered with sodium benzoate. Intractable seizures without metabolic acidosis or hyperammonemia are treated with pyridoxine 100-200 mg IV. +If clinical improvement is observed and a final diagnosis is not established, some amino acid intake should be + + +provided after 2-3 days of complete protein restriction. Essential amino acids or total protein is provided orally or IV at an initial dose of 0.5 g/kg/ day and gradually increased to 1.0-1.5 g/kg/day, until diagnostic evaluation is complete and plans are made for longterm therapy. Appropriate amino acid formula (free of precursor amino acids) or protein free infant formula with breast milk is gradually introduced with careful clinical and laboratory monitoring. Expressed human milk is preferred as it can be measured and total protein intake quantified. +Empiric cofactor or coenzyme therapy may be adminis­ tered (Table 23.4) to maximize residual enzyme activity awaiting final diagnosis. Longterm strict adherence to +___ s_se___tia_l_P_ed_ita.ri_c _________________________________ +n +s +_ +E +_ + + +Table 23.3: Management of hyperammonemia Drug Loading dose Maintenance dose +Sodium benzoate 250 mg/kg 250-500 mg/kg in and/or sodium (2.5 ml/kg) IV in 24 hr (2.5 ml/kg/ +phenylacetate 10% glucose over 24 hr) IV as continuous 2 hr infusion +L-Arginine* 600 mg/kg 600 mg/kg/day IV +(6 ml/kg) IV in as continuous +10% glucose over infusion +2 hr +* The dose of arginine hydrochloride can be decreased to 200 mg/kg for carbamoyl phosphate synthetase or ornithine transcarbamylase deficiency; IV intravenous + +dietary and pharmacologic regimen is recommended. Prompt recognition and avoidance of physiologic stresses (fever, infection, trauma, surgery, fasting) and changes in diet that may precipitate symptoms is important in pre­ venting metabolic decompensation. + +Chronic and Progressive Presentation +This group of metabolic disorders is characterized by variable but insidious onset from birth to adulthood. Unexplained developmental delay with or without seizures, organomegaly, coarse facies, cataract, dislocated lens, chronic skin lesions, abnormal hair, abnormal urine color on standing and failure to thrive are important clues. These forms are divided into subgroups depending upon the involvement of specific system. The approach to a patient with chronic encephalopathy is shown in Fig. 23.2. +Neurologic findings are developmental delay or progressive psychomotor retardation, seizures, ataxia, spasticity, variable hearing and visual impairment, and extra- + + +Table 23.4: Cofactor and adjunctive therapy +Disorder Therapy Oral dose, +mg/kg/day +Maple syrup Thiamine 5 urine disease +Methylmalonic Vitamine B12 1-2 mg/day +aciduria L-carnitine 50-100 +Metronidazole 10-20 +Propionic acidemia L-carnitine 50-100 +Metronidazole 10-20 +Isovaleric acidemia L-carnitine 50-100 +L-glycine 150-300 +Multiple carbo- Biotin 10-40 mg/day +xylase or biotinidase +deficiency + + +pyramidal symptoms. Psychomotor or developmental delay is the chief manifestation and tends to be global and progressive. History of regression of milestones may be present. Severe irritability, impulsivity, aggressiveness and hyperactivity and behavioral patterns such as auto­ matism, stereotypes, compulsive chewing of thumbs and fingers, self-mutilation and nocturnal restlessness are com­ mon. Complex partial or myoclonic seizures occur early in course of the disease and are often resistant to therapy. Signs include change in tone and pyramidal or extra­ pyramidal deficit. Differentiating between involvement of either gray matter or white matter is helpful in narrowing the differential diagnosis (Table. 23.5). Movement disorders are intermittent or progressive, in form of ataxia, dystonia, choreoathetosis and Parkinsonism. Underlying conditions include organic acidurias, late-onset neuronal + + +Chronic encephalopathy Psychomotor regression Seizures +Neurological signs +l +Isolated neurological features + + +Yes No + + +Gray matter diseas +Seizures +Impaired vision ej Dementia +• + +Pyridoxine dependency Biotinidase deficiency Neuronal ceroid lipofuscinosis +GM2 gangliosidosis (early onset) Mitochondrial, e.g. Leigh disease, +MELAS + +White matter disease Motor difficulties +Tone abnormalities + + +Central only: Canavan disease, Alexander disease, GM2 and GM1 gangliosidosis (late), adrenoleukodystrophy, aminoacidopathies, organic aciduria +Central and peripheral: Metachromatic leukodystrophy, Krabbe disease, peroxisomal disorders + + +Visceromegaly +± skeletal changes Gaucher disease Niemann Pick disease Mucopolysaccharidoses +types I, II, Ill, VII GM1 gangliosidosis Sialidosis II Zellweger syndrome + + +Muscle Changes in skin ± Mitochondrial connective tissues +disorders Homocystinuria Menkes disease Fucosidosis Galactosialidosis + + +Fig. 23.2: Initial approach to a chronic encephalopathy. MELAS myopathy, encephalopathy, lactic acidosis and stroke like episodes; MLD metachromatic leukodystrophy +Inborn Errors of Metabolism -- + + + +Table 23.5: Differentiating features of gray matter and white matter disorders +Clinical features Gray matter White matter disease disease (leukodystrophy) (poliodystrophy) +Age of onset Early Usually late childhood +Head size Microcephaly is May have common macrocephaly +Seizures Early, severe Late, uncommon +Cognitive Progressive Initially normal functions decline +Spasticity At a later stage Early, severe Reflexes Normal or brisk Absent +(neuropathy) or +brisk (long tract involvement) +Eye Retinal degene- Optic atrophy, ration or cherry- cataract or cherry-red spot red spot +Peripheral Late Early demyelination neuropathy +Electromyography Usually normal Slowed nerve conduction velocity +Visual evoked Usually normal Prolonged or absent potentials +Electroretinography Abnormal Normal +MRI brain Cerebral or White matter cerebellar involvement atrophy (demyelination or +dysmyelination) + + + +ceroid lipofuscinosis, lysosomal storage disorders and urea cycle disorders. +Muscular disorders presenting with myopathy are usually due to defects in energy metabolism. Myopathy can be progressive (glycogen storage disease, GSD types II and III), exercise intolerance with cramps and myoglobinuria (GSD V, VI), or as part of multisystem disease (mito­ chondrial myopathies). +Hepatic presentations include the presence of unconju­ gated or conjugated jaundice, hypoglycemia and hepato­ megaly with or without hepatocellular dysfunction. Coexisting deranged lipid profile is seen in GSD type I and hepatosplenomegaly a feature of GSD III and lyso­ somal storage disorders. Hepatocellular dysfunction is seen in galactosemia, GSD IV and III, Niemann-Pick type B, ai-antitrypsin deficiency. Disorders leading to cirrhosis include tyrosinemia, galactosemia, hereditary fructose intolerance and Wilson disease. +Cardiac manifestations may occur in fatty acid oxidation defects, mitochondrial disorders, GSD type II, methylma­ lonic acidemia, Fabry disease, Kearns-Sayre syndrome, + +familial hypercholesterolemia, mucopolysaccharidoses and GMl gangliosidosis. +Dysmorphic features are present in patients with Zellweger syndrome, glutaric aciduria type 2 and storage syndromes. +Renal manifestations are seen in patients with cystinosis, galactosemia, hereditary fructose intolerance and tyro­ sinemia (renal tubular acidosis); progressive renal failure is common in patients with cystinosis. Enlarged kidneys are seen in patients with GSD type I. +Ocular findings often provide a clue to the underlying IEM. The presence of cataract(s) suggests galactosemia, peroxi­ somal disorders, Lowe syndrome and Wilson disease. Corneal abnormalities are seen inmucopolysaccharidoses, Wilson disease and Fabry disease. Patients with homo­ cystinuria show lens dislocation. Cherry-red spots are found in various lysosomal storage diseases, such as Tay­ Sachs disease, GMl gangliosidosis and Niemann-Pick disease. +Skin may show an eczematous rash associated with alopecia in biotinidase deficiency. Angiokeratoma are characteristic of Fabry disease, but can be seen in fucosi­ dosis and �-mannosidosis. +Evaluation +Investigations should include complete hemogram, liver and renal function tests and serum electrolytes. Pancyto­ penia may be seen in patients with methylmalonic acidemia and propionic acidemia. The peripheral smear may show vacuolated lymphocytes in neuronal ceroid lipofuscinosis, fucosidosis and sialidosis; acanthocytosis in abetalipoproteinemia and Hallervorden-Spatz disease (pantothenate kinase associated neurodegeneration). Adrenal insufficiency is frequent in patients with adrenoleukodystrophy. Metabolic acidosis and evidence of proximal renal tubular dysfunction is present in patients with Lowe syndrome, cystinosis, Wilson disease and galactosemia. Investigations that enable specific diagnosis include neurological imaging and electrophysiological studies and skeletal survey. Specific enzyme assays and estimation of plasma levels of lactate, ammonia, very long chain fatty acids and amino acids are useful in certain cases. +Management +A multidisciplinary team of metabolic specialists, pediatric neurologists, clinical geneticist, cardiologist, orthopedic surgeon and physiotherapist is required to maximize the supportive care in these patients. Other treatment options include cofactor and megavitamin therapy, special diets, enzyme replacement therapy and organ transplantation. Most IEMs are inherited in autosomal recessive manner and risk of recurrence in subsequent pregnancy is 25%. Few disorders are X-linked, autosomal dominant and mitochondrial in inheritance. Prenatal diagnosis is possi­ ble by enzyme assays or mutation testing in fetal DNA in chorionic villus biopsy metabolites in amniotic fluid and using fetal DNA (Chapter 22). +___ _s_s_e_ n_ t_ a_i_P_e_d_ ia_ _tr-ic_ _________________________________ +i +s +E + + +SPECIFIC DISORDERS +Aminoacidopathies +These disorders do not have a common phenotype but have unique features depending upon the site of defect. + +Phen ylketonuria +Phenylketonuria (PKU) is a disorder of phenylalanine metabolism and occurs due to deficiency of phenylalanine hydroxylase (PAH). + +Clinical features. Affected individuals have profound and irreversible intellectual disability, microcephaly, epilepsy and behavioral problems. These patients often have a musty body odor and skin conditions such as eczema caused by excretion of excessive phenylalanine and its metabolites. Decreased skin, hair and eye pigmentation may also be present due to associated inhibition of tyrosinase and reduced melanin synthesis (Fig. 23.3). + +Diagnosis. Modalities include (i) newborn screening: PKU can be detected in virtually 100% of cases by various methods of newborn screening such as Guthrie card bacterial inhibition assay (BIA), fluorometric analysis and tandem mass spectrometry. In classic PKU, plasma phenylalanine level is > 1000 µmol/1 with <1% residual PAH activity, (ii) molecular genetic testing of the PAH gene. +Treatment. A low-protein diet and use of phenylalanine­ free medical formula as soon as possible afterbirth to achieve plasma concentrations 120-360 µmol/1 (2-6 mg/ dl) is recommended. A significant proportion of patients with PKU may benefit from adjuvant therapy with single daily dose of 5-10 mg/kg tetrahydrobiopterin. + +Maple Syrup Urine Disease (MSUD) +MSUD is due to decreased activity of branched chain alpha ketoacid dehydrogenase (BCKAD) complex, a mito- + + + + + + + + + + + + + + + + +Fig. 23.3: Blond hair in a child with phenylketonuria + +chondrial enzyme involved in degradation of branched chain amino acids (leucine, isoleucine and valine). There are five different phenotypes based on clinical findings and response to thiamine. This enzyme has four subunits: ElXf Eip, E2 and E3. +Clinicalfeatures. The first sign of classic MSUD in untreated neonates is maple syrup odor in cerumen at 12-24 hr afterbirth. By 48-72 hr, poor feeding, ketonuria, irritability and drowsiness develops followed by unexplained progressive coma. The characteristic urine smell develops on day 5-7 of life. In advanced stage, intermittent apnea, bradycardia, hypothermia, generalized hypertonia, opisthotonus and involuntary movements such as fencing and bicycling may appear. Individuals with acute intermittent late onset forms of MSUD can have recurrent episodes of severe metabolic decompensation and encephalopathy during any catabolic stress. Chronic progressive forms can present with variable manifestations such as developmental delay or progressive psychomotor retardation, seizures, failure to thrive, sleep disturbances, hyperactivity, mood swings and movement disorders. +Diagnosis. (i) Urine 2,4-dinitrophenylhydrazine (DNPH) test to detect ketonuria by adding DNPH to urine which produces a yellow-white precipitate due to presence of branched chain ketoacids, (ii) elevated plasma levels of leucine, isoleucine, valine (5 to 10-fold greater than normal) and alloisoleucine, (iii) enzymatic and/or genetic testing are useful for confirming the diagnosis. +Treatment. Treatment during acute stage should follow the abovementioned principles along with rapid removal of branched chain amino acids from body tissues and fluids using either peritoneal or hemodialysis. Cerebral edema is a common complication should be treated promptly in an intensive care setting with mannitol, hypertonic saline and diuretics. During recovery high calorie, branched chain amino acid free formula is initiated early with regular plasma amino acid monitoring. Some patients with milder forms may respond to thiamine. Orthotopic liver transplantation is effective therapy for classic MSUD. + +Hepatorenal Tyrosinemia Type I +The condition is caused by deficiency of enzyme fumaryl­ acetoacetate hydrolase (FAH), encoded by FAH gene. Enzyme is mainly expressed in liver and kidney. +Clinical features. It is a disorder of tyrosine metabolism, classically presents as severe liver disease in young infants. Severe forms present during infancy with vomiting, diarrhea, bleeding diathesis, hepatomegaly, jaundice, hypoglycemia, ascites and coagulopathy. Children older than six months of age may come to medical attention with variable degree of renal dysfunction, hypophosphatemic rickets and aminoaciduria. Untreated children may have repeated, often unrecognized, neurologic crises lasting 1-7 days that can include change in mental status, abdominal +Inborn Errors of Metabolism - + + + +pain, peripheral neuropathy, autonomic dysfunction and/ or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis or hepatocellular carcinoma. + +Diagnosis The following tests are useful: (i) Deranged liver function tests; prolonged prothrombin and partial thromboplastin times, (ii) generalized aminoaciduria; radiological evidence of rickets, (iii) markedly elevated serum concentration of alpha-fetoprotein (average 160,000 ng/ml) (normal: <1000 ng/ml for infants 1-3 months; <12 ng/ml for age 3 months to 18 yr), (iv) increased succinylacetone concentration in the blood and excretion in the urine. Elevated plasma concentration of tyrosine, methionine and phenylalanine, (v) enzyme assay, and (vi) molecular genetic studies for FAH gene. + +Treatment Nitisinone or 2-(2-nitro-4-fluoromethyl­ benzoyl)- 1,3-cyclohexanedione (NTBC) treatment should begin as soon as the diagnosis of tyrosinemia type I is confirmed. It blocks tyrosine degradation at an early step to prevent the production of downstream metabolites such as fumarylacetoacetate and succinylacetone. It is given at doses of 1 mg/kg/day. Dietary restriction of phenylalanine and tyrosine is required to prevent tyrosine crystals from forming in the cornea. In Western countries, prior to the availability of nitisinone, the only definitive therapy for tyrosinemia type I was liver transplantation, which now is reserved for those children who have severe liver failure at presentation and fail to respond to nitisinone therapy or have documented evidence of malignant changes in hepatic tissue. Nitsinone is not readily available in India and is expensive. + +Classic Homocystinuria +This occurs due to cystathionine �-synthase deficiency leading to accumulation of homocysteine, which has deleterious effects on the central nervous system, vessels, skin, joints and skeleton. Two clinical variants exist: B6 (pyridoxine)-responsive homocystinuria and B6-non­ responsive homocystinuria. B6-responsive homocystinuria is typically, but not always, milder than the nonresponsive variant and has a better outcome than the nonresponsive ones. +Clinical features. Patients typically present with ocular, skeletal, CNS and vascular manifestations usually after 3--4 yr of age. Developmental delay, seizures, psychiatric problems and extrapyramidal signs such as dystonia, downward lens dislocation and/ or severe myopia, marfanoid habitus, osteoporosis with or without thromboembolic complications are the usual presenting features. They can also have hypopigmentation and pancreatitis. Ectopia lentis occurs by age eight years. Thromboembolism is a major cause of early death and morbidity. + +Diagnosis. Quantitative plasma amino acid analysis showing increased levels of methionine, homocysteine with no cystathionine confirms the diagnosis. Plasma total homocysteine levels are important for monitoring the treatment (normal levels <15 µmol/1; homocystinuria >200 µmol/1). Confirmation can be done by CBS enzyme acti­ vity or molecular testing for CBS gene. Urine nitroprusside test is a good screening test. + +Treatment. Treatment is directed towards lowering the plasma homocysteine levels as close to normal as possible. About half of all patients respond to vitamin B6 therapy (200-1000 mg/ day). In patients with folate and vitamin B12 deficiency, folic acid (5 mg/day) and hydroxy­ cobalamin (1 mg intramuscularly per month) is also given. Patients nonresponsive to pyridoxine require lifelong methionine restricted diet with frequent biochemical monitoring. Oral betaine at 150 mg/kg/day (in two divided doses) is effective in lowering homocysteine levels. Vitamin C supplementation (1 g/day) ameliorates endothelial dysfunction. + +Alkaptonuria +This was the first inborn error of metabolism described by Garrod in 1902 and is caused by defect of the enzyme homogentisate 1,2-dioxygenase (homogentisic acid oxidase). The most prominent symptoms are related to connective tissues and joints. These manifestations are rarely noticed before the age of 20 to 30 yr. + +Clinical features. The disorder comes to attention due to change in color of urine to brownish black or staining of diapers. Pigment deposits irritate the articular cartilage, resulting in degeneration and osteoarthritis like changes. Intervertebral disks are degenerated, spaces are narrowed and calcification occurs. Ochronotic arthritis commonly involves shoulders and hips. Pigment deposits in the kidney manifest as renal stones. A grayish discoloration of sclera and the ear and nose cartilage (ochronosis) usually occurs after 30 yr. The pigment in ochronosis is a polymer of homogentisic acid. + +Diagnosis. The urine becomes dark on standing, especially if the pH of urine is alkaline. Excessive urine homo­ gentisate results in positive reducing substances. Organic acid analysis by GCMS can identify and quantify homo­ gentisic acid. + +Treatment. No specific therapy is known. Administration of vitamin C prevents deposits of the ochronotic material in cartilage but has no effect on the basic metabolic defect. Nitisinone inhibits the enzyme that produces homo­ gentisic acid and may prove useful. + +Urea Cycle Defects +The urea cycle is the main pathway for the removal of highly toxic ammonia, derived from the catabolism of +E s s e n t i t P e d iat ris __________________________________ +_ +_ +_ +_ +_ +_ +_ +c +_ +a +_ +g s +te yase +Fumara Ar ino uccinate l (4) +________ + +amino acids, in the form of urea. It is basically composed of six enzymes as demonstrated in Fig. 23.4. Defects of any of these enzymes are characterized by hyperam­ monemia and deranged amino acid metabolism. + +Clinical Features +Presentation is highly variable. In the classical forms, neonates present within first few days of life with poor feeding, recurrent vomiting, tachypnea, hypothermia, irritability, seizures and lethargy progressing to coma. Partial deficiencies of these enzymes represent milder forms and have symptoms that are often subtle and may not occur for months or years. These are usually diagnosed by hyperammonemic episodes manifesting as poor appetite, vomiting, lethargy and behavioral problems and are often triggered by stress or illness. These patients are intolerant to and dislike protein food. Arginase deficiency has more specific symptoms such as spastic diplegia, dystonia and ataxia. + +Diagnosis +The diagnosis of a urea cycle disorder is based on clinical suspicion and biochemical screening. Presence of hyperammonemia (plasma ammonia >80 µg/dl after neonatal period) associated with normal anion gap and normal glucose level suggests a urea cycle defect. Plasma amino acid analysis and urinary erotic acid can distinguish the specific defects (Fig. 23.5). A definitive diagnosis of a urea cycle defect depends on either DNA analysis or measurement of enzyme activity. + +Management +Treatment is based on the principles highlighted in the section on management of acute presentation and includes rapid removal of ammonia and inhibition of its + + +Glutamic acid + Acetyl CoA + +N-acetyl glutamate synthase +l + +N-acetyl glutamate +1� +! +Carbamoyl phosphate Ammonia synthase ( 1) + +Carbamoyl phosphate ----� Oralie acid + + +Ornithine +transcarbamoylase (2) +Citrulline +Aspartate + + + +Arginosuccinate +Ng� + + + + +Fig. 23.4: Pathways for ammonia disposal and ornithine metabolism. Deficiency of enzymes results in the following: (1) CPS deficiency, (2) OTC deficiency, (3) citrullinemia, (4) arginosuccinic aciduria and (5) argininemia + + +production along with treatment of any intercurrent illness and correction of dehydration or electrolyte imba­ lance. Maintenance therapy includes nutritional manage­ ment with restriction of protein, pharmacological therapy with sodium benzoate/phenylacetate (250-500 mg/kg/ day), essential amino acids (0.25 g/kg/day) and arginine (200-600 mg/kg/day). + + + +Hyperammonemia without acidosis ++ + + +Plasma amino acids + + + +No specific amino acid elevation + + +Urine erotic acid* ++ +i Normal or low High +! +Low plasma citrul/ine + +Deficiency of carbamoyl phosphate Ornithine transcarbamoy/ase l +synthase or N-acetylg/utamate synthase deficiency + + +Elevation of specific amino acid +l + + + +Elevated arginine: Argininemia Elevated citrulline: Citrullinemia Elevated ornithine: Hyperammonemia, +hyperornithinemia, homocitrullinemia + + +Fig. 23.5: Algorithm to distinguish different urea cycle defects +• Transient hyperammonemia of the newborn is characterized by hyperammonemia, normal levels of urine orotic and normal or high plasma citrulline +Inborn Errors of Metabolism - + + +Organic Acidurias +The term "organic acidemia" or "organic aciduria" (OA) applies to a group of disorders characterized by the excre­ tion of nonamino organic acids in urine. This group of disorders results from enzyme deficiencies in pathways of amino acid degradation. Defects in the metabolism of the branched-chain amino acids (leucine, isoleucine, valine) as well as tyrosine, homocysteine, methionine, threonine, lysine, hydroxylysine and tryptophan are responsible for most of these disorders. They have two types of clinical presentations: an insidious onset with few to no acute crises and an acute metabolic encephalopathy that is precipitated by illness and increased catabolism. + +Clinical Features +Neonates with OA are well at birth and for the first few days of life. The presenting features are that of toxic encephalopathy and includes vomiting, poor feeding, neurologic symptoms such as seizures and abnormal tone, and lethargy progressing to coma. An early diagnosis and treatment results in improved outcome. In the older child or adolescent, OA present with loss of intellectual function, ataxia or focal neurologic signs, Reye like syndrome, recurrent ketoacidosis or psychiatric symptoms. Specific features of some OA are listed below. + +Cutaneous abnormalities. Perioral eruption (multiple carboxylase deficiency). + +Abnormal urinary or body odor. Maple syrup/burnt sugar (maple syrup urine disease), sweaty feet (isovaleric acidemia, glutaric aciduria type 2), cat urine (multiple carboxylase deficiency). + +Hair abnormalities. Alopecia or sparse hair suggests biotinidase deficiency (Fig. 23.6). + +Dysmorphic features. Mevalonic aciduria, glutaric aciduria type 2,3(0H)isobutyric aciduria. + + + + + + + + + + + + + + + + + +Fig. 23.6: Alopecia in a child with biotinidase deficiency + +Hypoglycemia and neurological symptoms. Organic acidurias, including late onset MSUO. + +Acute ataxia. Late onset MSUD, methylmalonic acidemia, isovaleric acidemia, multiple carboxylase deficiency. + +Acute metabolic encephalopathies. Glutaryl-CoA dehydro­ genase deficiency, isovaleric acidemia, MSUD, methyl­ malonic acidemia, multiple carboxylase deficiency and propionic acidurias. +I + +Acute hemiplegia and metabolic stroke. Methylmalonic acidemia and propionic acidemia, glutaric aciduria type 1, methylcrotonyl-CoA carboxylase deficiency. + +Diagnosis +Patients with OA can have acidosis, ketosis, hyper­ ammonemia, abnormal liver function tests, hypoglycemia and neutropenia. Analysis of urine for organic acids using gas chromatography with mass spectrometry (GCMS) enables diagnosis and plasma or serum acylcarnitine prole tested by TMS is often helpful. The urinary organic acid profile is nearly always abnormal in the presence of acute illness with decompensation. However, it may be normal when the affected individual is not acutely ill; in certain disorders, the analytes are present in small amounts. +Urine samples should be obtained during the acute phase of illness and frozen at -20°C. Confirmation of diagnosis is possible by measuring the activity of the deficient enzyme in lymphocytes or cultured fibroblasts and/or DNA analysis. + +Management +The management of OA during acute crises follows above­ mentioned principles. Adjunctive therapy with cofactors or vitamins, such as thiamine to treat thiamine-responsive MSUD and hydroxycobalamin to treat methylmalonic acidemia is useful. For disorders of propionate metabolism, intermittent administration of metronidazole (10-15 mg/ kg/day for 10-15 days) reduces the production of pro­ pionate by gut bacteria. Various cofactors and adjunctive therapy are detailed in Table 23.4. + +Defects of Carbohydrate Metabolism Galactosemia +There are three disorders of galactose metabolism (Fig. 23.7), but it is the deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT), that is referred to as galactosemia. Deficiency of GALT results in accumu­ lation of galactose-1-phosphate and metabolites (e.g. galactitol) that might have toxic effect on the, e.g. liver and other organs. +Clinical features Patients appear normal at birth, but by 3-4 days of breast milk or formula feeding show life­ threatening disease with vomiting, diarrhea, poor weight gain, predominant hepatic and renal manifestations and +___ _s_s__n_t_iai_P_ed_iat_rics __________________________________ +E +e +_ +_ +_ +_ +_ +5 +d + +Galactitol + - - �1!9 ! '!. !91�.. - - - . Galactose ATP +Glucose-1-phosphate + UDP � Galactokinase +""·••= �-�°"� ADP-1 +' +"" " ' +p +p +hos hat +DP-gluco +=� se +� Glalaotooe-::,:::,h::.�,• + +Hereditary Fructose Intolerance +The condition occurs due to deficiency of the enzyme, +aldolase B. Symptoms occur following ingestion of fructose or sucrose and present with intractable vomiting and symptomatic hypoglycemia. Prolonged exposure results in failure to thrive, irritability, hepatomegaly, abdominal distension, edema and jaundice. Milder +variants are common and present with bloating, abdominal + + + + +4'wep1merase undyltransferase +( + +UDP-galactose +Glucose-1-phosphate + +1 Phosphoglucomutase + +Glucose-6-phosphate + +distension and diarrhea. Investigations show hypo­ glycemia, marked lactic acidosis, hyperuricemia, hypo­ phosphatemia, hyperchloremic metabolic acidosis, generalized aminoaciduria and deranged prothrombin and partial thromboplastin time and liver function tests. Confirmation is done by demonstration of deficiency of aldolase B in fresh liver biopsy sample. Fructose free diet +is therapeutic. + + + +Fig. 23. 7: Disorders of galactose metabolism + +cataract. Jaundice and liver dysfunction are progressive and appear at the end of first or during second week of life. The disease may present initially with indirect hyperbilirubinemia due to hemolysis secondary to high levels of galactose-1-phosphate in erythrocytes. Many +affected infants die of Escherichia coli sepsis in the neonatal period. Untreated infants, if surviving the neonatal period, have persistent liver disease, cataracts and severe mental +retardation. Alternatively, the effects of acute galactose toxicity may rarely cause predominant neurologic symptoms. Renal tubular disease presents with metabolic acidosis, galactosuria, glucosuria and aminoaciduria (Fanconi syndrome). +Diagnosis The diagnosis is confirmed by either enzyme or specific mutational analysis. In case of suspected galactosemia, the urine should be tested simultaneously with Benedict reagent and by glucose oxidase method. A negative dipstick by glucose oxidase method with positive Benedict reaction indicates nonglucose reducing substances, +e.g. galactose or fructose. A negative test does not eliminate the possibility of these disorders, especially if the patient has received intravenous glucose for more than +a few hours. If the diagnosis of galactosemia is suspected, whether or not urinary reducing substances are found, galactose-containing feedings should be discontinued and replaced by soy based or lactose free formula pending results of confirmatory enzyme assay or genetic studies. +Galactokinase deficiency Galactosemia due to galactokinase deficiency is rare and has mild mani­ festations. The only significant abnormality is cataract due to accumulation of galactitol. Liver, kidney and brain damage are not seen. Galactose free diet, if started early, leads to clinical improvement and prevents further damage. Mental retardation, if already present does not improve with therapy. Galactose restricted diet is required +throughout life. + + +Glycogen Storage Diseases +Glycogen is an extensively branched polysaccharide macromolecule formed by thousands of glucose units +joined into chains by o:-1-4 and :-1-6 bond. Ingested carbohydrate is absorbed as glucose via the portal system. The glucose is phosphorylated to intermediate compounds (glucose-6-phosphate and glucose-1-phosphate) and is stored as glycogen. Glycogen is the main glucose reservoir in the liver and provides energy between meals or during fasting. In muscle, it provides energy for contraction. When peripheral glucose is utilized and glucose levels fall, glycogen is depolymerized, bonds at branch points are split and free glucose is released into blood by hydrolytic dephosphorylation. The final reaction is mediated by the enzyme glucose-6-phosphatase. The series of reactions causing release of glucose are called glycogenolysis (Fig. 23.8). Any defect in the synthesis and degradation of glycogen causes glycogen storage disease (GSD). Several disorders of glycogen metabolism are described; these are subdivided into liver and muscle glycogenoses (Table 23.6). +Hepatic glycogenoses GSD Ia (von Gierke disease), lb, type IIIa (Cori/Forbes), IIIb, IV (Anderson), VI (Hers) and IX present with hepatomegaly and hypoglycemia. Figure 23.9 shows a child with GSD I with' doll like fades' with protuberant abdomen due to marked hepatomegaly. +GSD I is distinguished from other disorders that primarily affect liver by markedly elevated lactic acid as well as elevated uric acid and cholesterol concentrations. GSD III is characterized by normal or slightly increased +concentrations of lactic acid, normal uric acid, but a greater elevation of triglycerides and cholesterol than GSD I. Creatine phosphokinase may be elevated in older children +and adolescents if there is muscle involvement. GSD III is subdivided into patients who have no muscle involvement (IIIb) and those who develop muscle weakness by their teenage years (Illa). GSD VI and IX have more benign +courses than GSD I and III. Hypoglycemia is less severe, +Inborn Errors of Metabolism -- + + + +Table 23.6: Enzymatic deficiencies in common glycogenoses Type Enzyme defect Common name +Liver glycogenoses +Ia Glucose-6-phosphatase von Gierke lb Glucose-6-phosphate +translocase +Illa Liver and muscle Cori/Forbes debrancher deficiency +(amylo-1, 6-glucosidase ) Illb Liver debrancher +deficiency only +IV Brancher enzyme Anderson (a-1, 4 glucan: +a-1, 4 glucan-6-a glucosyl transferase) +VI Liver phosphorylase Hers IX Phosphorylase kinase +Muscle glycogenoses +II Lysosomal alpha-1, Pompe 4-glucosidase (acid +maltase) +V Muscle phosphorylase McArdle VII Phosphofructokinase Tarui + + +and hepatomegaly resolves after puberty. GSD IV (Anderson amylopectinosis-brancher enzyme deficiency) leads to formation of an abnormal glycogen that appears to be noxious to the liver. Severe liver disease develops in the Ist few months afterbirth, leading to cirrhosis. Unlike the other primarily liver disorders, it often causes severe liver failure. Liver failure with portal hypertension sug­ gests GSD IV. +Work up should be done in patients with hypoglycemia and hepatomegaly. Concentrations of glucose, uric acid, lactic acid, liver transaminases and lipids (cholesterol and triglycerides) are helpful in differentiating type I and III. Enzyme assay in fresh liver tissue confirms the diagnosis of the liver GSD. DNA testing is increasingly available for these disorders, alleviating the need for liver biopsy. +Muscle glycogenoses GSD V (McArdle disease), VII (Tarui) and II (Pompe) primarily involve muscle. GSD V and VII often present in adolescence with exercise intolerance and myoglobinuria. These patients may have +muscular hypotonia, weakness, easy fatigability and muscle +cramps. A muscle biopsy may be necessary to confirm the diagnosis. DNA testing now offers an alternative and helps to distinguish between type V and type VII. +Type II (Pompe), disease results from lysosomal storage of glycogen in skeletal muscles, cardiac muscles and cen­ tral nervous system. There is progressive cardiomyopathy. Electrocardiogram shows left axis deviation, short PR interval and large QRS. Heart failure with dyspnea and cyanosis may occur. Skeletal muscles show hypotonia and marked weakness (Figs 23.lOA to D). The tongue is large + +and protruding. Death usually occurs before the age of 1 yr. The diagnosis is suggested by low levels of the enzyme acid maltase in leukocytes, liver, muscles and fibroblasts. +Treatment Therapy of hepatic glycogenoses is targeted to maintain normoglycemia and is achieved by continuous nasogastric infusion of glucose or uncooked starch. Depend­ ing on response, frequent daytime feeds and continuous nasogastric feeding at night may be given. Uncooked starch acts as a slow release form of glucose. This is especially useful in type I, III and IV but most demanding in type I. The intake of lactose, fructose and sucrose should be restricted, except fruits, vegetables and small amounts of milk products. Enough nutrients, vitamins and minerals should be given. If despite optimizing dietary treatment, serum triglyceride levels remain above 900 mg/ dl, trigly­ ceride-lowering drugs (nicotinic acid, fibrates) should be recommended to reduce risk of cholelithiasis and pancreati-tis. Allopurinol (10 mg/kg per day, divided into 3 dosages) should be given for hyperuricemia. Enzyme replacement therapy (ERT) is available and very effective for type II GSD but the cost is prohibitive. +I + +Mitochondrial Fatty Acid Oxidation Defects Pathogenesis +Fatty acid oxidation plays a major role in energy production during fasting or periods of high-energy demand leading to glycogen depletion. It involves three processes: +a. Mobilization of fatty acids into mitochondria. Long chain fatty acids (C14-20) undergo active transport through carnitine shuttle; whereas short (C4 to 6) and medium chain (Cl2) fatty acids enters independently of canitine and are activated to coenzyme A (CoA) esters. Disorders of canitine cycle includes canitine palmitoyl transferase I and II deficiency. +b. �oxidation.This involves removal of 2-carbon fragments (i.e. acetyl-CoA) from the transported saturated fatty acids via a four-step enzymatic reaction. Each enzyme has different chain length specificity. Deficiency of various acyl-CoA dehydrogenases (AD) results in short chain AD (SCAD) deficiency, medium chain AD (MCAD) deficiency, long chain AD (LCHAD) and very long chain AD (VLCAD) deficiency. +c. Electron transfer to the respiratory chain. Acetyl-CoA is utilized as energy substrate in muscle and liver. Exam­ ple glutaric acidurias type II (multiple acyl-CoA dehy­ drogenase or MAD deficiency). + +Clinical Features +Features may have varying severity and present at any age. Symptoms are precipitated by fasting, exercise or intercurrent illness leading to episodes of metabolic decompensation. +i. Presence of acute hypoketotic hypoglycemia and ence­ phalopathy, associated with Reye like illness, hepato­ megaly and liver dysfunction. +___ _s s_e_n_t_ia_P_e d_i_atic__________________________________ +ll r GSD +ive VIII +s +E +_ +i +_ +r +- +_ +_ + + + + + + +Lysosom .,,--� +_ +e +Glycogen +I I +: a-1, 4-glucosidase +4, GSD 11 + + +Glycogen + + + +GSDIV Glycogen synthetase +Uridine diphosphoglucose + +Phosphorylase kinase + ++ Muscle GSD IX +Phosphory ase +l +Liver GSDVI + +Glucose Pyrophosph� Glucose -1-phosphate Limit dextrins +I +) +I +I +I +a,v +I UTP Phosphoglucomutase 1 Debranching DIll +I +I +.. +enzyme +[GS + +Glucose ____ lucose-6_-_Pspha_se _ Glucose-6-phosphate Glucokinase Glucose +t +a +_ +_ +h +_ +o +_ +_ +G +_ +_ +_ +_ +GSDI +Phosphoglucoisomerase + +Fructose-6-phosphate +Phosphofructokinase GSDVI I + +Fructose-1 -phosphate r + +Pyruvate-----. Lactate + +Fig. 23.8: Glycogen storage disorders Schematic glucose and glycogen metabolism in the liver and lysosome Fig. 23.9:Achildwithglycogen storage disease type I. Note +the doll like facies and protu­ berant abdomen) + + + + + + + + + + + + +Figs 23.10A to D: A child with Pompe disease showing (A to C) signs of marked hypotonia and (D) cardiomegaly + + + +ii. Cardiomyopathy (hypertrophic more common than dilated) and conduction defects including arrhythmias causing sudden early death. +iii. Myopathy + +Diagnosis +This is usually made by performing organic acid analysis on urine and plasma acylcarnitine prole, which is later confirmed by enzyme assay, or mutation analysis. + + +Treatment +Acute decompensation is managed as mentioned in the above section. Prolonged fasting should be avoided. Medium chain triglyceride (MCT) rich formula can be given in VLCAD, LCHAD and CPT I and II deficiency, but not in MCAD and MAD deficiency. +Mitochondrial Disorders +Mitochondria are mainly involved in the energy production pathway of oxidative phosphorylation (OXPHOS). +Inborn Errors of Metabolism - + + +Mitochondrial disorders refer to defects in the OXPHOS pathway. Mitochondria are mainly derived from the ovum; hence, mitochondrial DNA (mtDNA) disorders are maternally inherited. Tissues such as brain, liver and kidney have high-energy requirements and are susceptible to injury. +Mitochondrial disorders can occur due to either alterations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutations. The mutant mtDNA produce less energy; symptoms are apparent when energy production is less than energy requirements. Disorders that are due to nDNA mutations are autosomal recessive, autosomal dominant or X-linked. A mitochondrial disorder is often suspected with multisystem involvement such as stroke, hearing loss, muscle weakness, cardio­ myopathy and/ or endocrine dysfunction. The disorders due to mt DNA deletion/ duplication mutations are chronic progressive external ophthalmoplegia, Kearns­ Sayre syndrome, Pearson syndrome. Disorders caused by mtDNA point mutations include (Leber hereditary optic neuropathy LHON), (maternally inherited Leigh syn­ drome MILS), (mitochondrial encephalopathy, lactic acidosis and stroke MELAS), (myoclonic epilepsy with ragged red fibres MERRF ), (neurogenic weakness, ataxia and retinitis pigmentosa NARP), hypertrophic cardio­ myopathy, mitochondrial myopathy and (nonsyndromic aminoglycoside-induced sensory neural hearing loss SNHL). + +Diagnosis +A markedly elevated lactate level raises the possibility of a mitochondrial disorder. An elevated lactate-to-pyruvate ratio of greater than 30 suggests an OXPHOS defect. CSF lactate and pyruvate values also are helpful in some patients. The definite method is muscle biopsy where presence of ragged red bers as well as subsarcolernal accumulation of mitochondria confirms mitochondro­ pathy. Staining for succinate dehydrogenase and cytochrome C oxidase is useful. + +Treatment +No specific therapy is available. Supportive treatment includes symptomatic therapy, supplementation with cofactors such as riboflavin, Co-Q, folinic acid, vitamin E, vitamin C, carnitine, high lipid, low carbohydrate diet and avoiding mitochondrial toxins such as sodium valproate and statins. + +Lysosomal Storage Disorders +Lysosomes are one of the important cellular organelles responsible for degradation of complex cellular molecules using various acid hydrolases. Deficiency of these enzymes results in the accumulation or storage of an intermediate compound. Deposition of this stored material in several body tissues leads to cellular damage and disease symptoms. Common categories of lysosomal storage disorders are discussed below. +Enzyme deficiencies in the degradation pathway of glycosaminoglycans cause mucopolysaccharidoses. In some glycolipid storage disorders, neurological functions are impaired due to abnormal deposition in the brain. The second category of oligosaccharidoses is the result of defici­ encies of enzymes responsible for degradation of glyco­ proteins with a less complex polysaccharide (oligo­ saccharides) than glycosainoglycans. The third category, sphingolipidoses is caused by deficiency of sphingolipid degrading enzymes. Accumulation of lipid inside the cells gives them a foamy appearance. Foamy cells appear in liver, spleen, lungs and marrow, resulting in enlargement of these organs. All conditions have autosomal recessive inheritance except mucopolysaccharidosis II and Fabry disease which are (X-linked). Common disorders are discussed below and summarized in Table 23.7. +Mucopolysaccharidoses +Mucopolysaccharides constitute a major part of connective tissue and consist of units of disaccharides, nitrogen and esters. In mucopolysaccharidoses, acid mucopoly- + + + +Table 23.7: Clinical features of common lysosomal storage disorders + +Disorder +Gangliosidosis GMl Gaucher disease Krabbe disease Metachromatic +leukodystrophy Multiple sulfatase +deficiency Niemann-Pick +disease Sandhoff disease + +Tay-Sachs disease + + +Cherry-red spot + + + +Rare + ++ + ++ + ++ + ++ + + +Visceromegaly ++ + + + + ++ + ++ + ++ + +Skeletal changes ++ (Variable) + + + + ++ + + + ++ (Variable) + + +Mental retardation ++ + + + + ++ + ++ (Type A, C) + ++ + ++ + + +Bu/bar signs + ++ (in types II, III) + + + + + + ++ (in late stages of infantile forms) ++ (in late stages of infantile forms) +essent iaiPed iatric _________________________________ +_ +s +_ +_ +_ +_ +_ +_ +_ +_ +_ +_ +_ +_ +_ +_ _ +_ + +saccharides are deposited in the tissues and excreted in the urine. Due to lack of degradation, mucopolysaccharides accumulate in the lysosomes causing disorganization of the cell structure and function. Partially degraded muco­ polysaccharides are excreted in urine. At least 8 genetic variants of mucopolysaccharidoses are recognized (Table 23.8) with phenotypic differences (Figs 23.llA to H). + +Mental retardation is severe in type III (Sanfilippo) and VII (Sly), moderate in type I (Hurler, IH), mild in type II (Hunter), rare in type IV (Morquio) and type I (Scheie, IS) and not seen in type VI (Maroteaux Lamy). +Cloudy cornea is observed in types I, IS and VI but it may occur in some cases of type IV, cloudiness of cornea is minimal in type III and is not seen in type II. + + + +LJ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +Figs 23.11 A to H: Mucopolysaccharidoses. (A) Patient with type IH disease showing corneal clouding and coarse facial features; (B) patient with MPS type II without corneal clouding but with facial coarseness; (C) patient with MPS IHS (milder phenotype) demonstrating restriction of joint movements; (D) mild facial coarseness in a child with MPS Ill; (E) chest deformity in a patient with MPS IV (Morquio disease); (F) patient with MPS VI (Maroteux-Lamy) with abnormal skull and facial coarseness; (G) beaking of the inferior margins of vertebrae and proximal pointing of metacarpals in MPS type I; CH) central beaking of the lumber vertebrae along with proximally pointed metacarpals and short ulnae in MPS IV +Inborn Errors of Metabolism - + +Table 23.8: Clinical features of mucopolysaccharidoses +MPS type Mental retardation Coarse facies Visceromegaly Joint contractures Dysostosis multiplex Corneal clouding + +Hurler/IH + + + Scheie/IS + (Mild) Hunter/II + + + Sanfilippo/III + + (Mild) ± Morquio/IV + (Mild) Maroteaux- + + +Lamy/VI +Sly/VII + + + + + +Skeletal changes are most marked in type IV, marked in type I, II, VI and VII but are mild in types III and IS. Skeletal changes observed include thickening of the skull, marked deformity of sella turcica, broad spatula like ribs, beak shaped vertebrae (around Ll vertebra) and proximal tapering of metacarpals; these abnormalities are referred to as dysostosis multiplex. In Morquio disease (type IV) the trunk is short with flattened narrow vertebrae, barrel shaped chest with sternum protruding forwards. Other features include short neck, broad mouth, widely spaced teeth, prominent maxilla and joint laxity. +Facies are coarse in type IH. Lips are thick, tongue is enlarged and teeth are peg-like and separated; nasal bridge is depressed. The features are coarse and often mistaken for cretinism. +Hepatosplenomegaly is present in types I, II, VI and VII and multiple sulfatase deficiency. +Diagnosis Urinary excretion of glycosaminoglycans (GAG) by 2D electrophoresis is a useful screening test. Specific enzyme assays and DNA analyses confirm the diagnosis. +i. Accumulation of dermatan sulfate and heparan sulfate in tissues and their urinary excretion occurs in Hurler syndrome (type IH), Scheie syndrome (type IS), Hunter syndrome (type II) and type VII. +ii. Heparan sulfate accumulates in tissues and is excreted in urine in Sanfilippo disease (all varieties of MPS III). +iii. Keratan sulfate and chondroitin sulfate are excreted in Morquio syndrome (type IV). +iv. Derma tan sulfate is excreted in the urine in Maroteaux­ Lam y syndrome (type VI). +v. Keratan sulfate like material accumulates in tissue and is excreted in urine in type VIII. +Treatment Palliative care and multidisciplinary manage­ ment are important. Enzyme replacement therapy is avail­ able for type I, II and type VI but the cost is prohibitive. Trials are underway for other types of MPS. Bone marrow transplantation has been found to be effective in MPS I. +0/igosaccharidoses +This group is characterized by developmental delay with or without regression, facial coarsening, enlarged liver and +spleen, and ocular (cherry-red spot, corneal clouding) + ++ + + + ± + + + +± +- (Laxity) + + + + + +I + ++ + ± + +changes. Oligosaccharidoses include-pyknodysostosis, p, P mannosidosis, fucosidosis, aspartyl glucosaminuria, Schindler disease and sialidosis I and II. Urine screening +for oligosaccharides provides clue for diagnosis. Radio­ logical evidence of dysostosis multiplex may be present. Enzyme assay and DNA analysis is confirmatory. + +Sphingo/ipidoses +These are clinically heterogeneous disorders and include GMl and GM2 gangliosidoses, Gaucher disease, Niemann-Pick diseases, Fabry disease, Farber disease, and Krabbe and metachromatic leukodystrophies. The most consistent feature is enlarged liver and spleen, with or without neurological involvement (Gaucher disease I and II, Niemann-Pick disease A and B, and GMl gangliosidosis). Metachromatic leukodystrophy and Krabbe disease are caracterized by white matter involvement and demyelination. +Gaucher disease Gaucher disease is the commonest lysosomal storage disease. Inherited in an autosomal +recessive manner, there is deficiency of the tissue enzyme glucocerebrosidase that splits glucose from glucosyl­ ceramide, resulting in accumulation of the latter in cells +of the reticuloendothelial system. The cerebroside-laden cells are large and have eccentric nuclei with vacuolated cytoplasm and 'wrinkled tissue paper' appearance (Gaucher cells). +The spleen is markedly enlarged and there are signs of hypersplenism, e.g. leukopenia and thrombocytopenia. The liver is enlarged and the marrow cavity is widened, due to deposits of Gaucher cells. Expansion of the bone is prominent, especially at the lower end of the femur and humerus. It manifests as a spectrum and has two variants: non-neuronopathic (type I) and neuronopathic (type II: acute; type III: chronic form). +Non-neuronopathic (type I) is the commonest form and characterized by absence of neurological symptoms. Signs and symptoms can develop at any age and include anemia, fatigue, poor growth, delayed puberty, easy bleeding and bruising, weak bones, bone and joint pain, fractures and enlarged liver and spleen (Fig. 23.12A). The earlier the onset of first symptoms, the more severe is the disease +and rapid progression if left untreated. +_ E_ssen_t iaiP_ed_ iatric_ _________________________________ +s +_ +_ +_ +_ +_ +_ +_ +_ +_ +_ +_ + +Neuronopatlzic forms show involvement of the central nervous system. Two types are distinguished by the rate of neurological progression. Type II (acute neuronopathic) presents early in fetal life as hydrops (excess accumulation of fluid in subcutaneous tissue and other cavities) or in early infancy. Infants are normal during first few months of life before showing neurological signs and involvement of spleen and liver. They can also have skin involvement. Course is rapidly progressive leading to early death by 2-4 yr. Type III Gaucher disease (chronic neuronopathic, Fig. 23.12B) represents a chronic form with a more indolent course and manifestations in early childhood before the age of 2 yr. Signs and symptoms are the same as in type 1 except that neurological involvement is slowly progressive and leads to death by 2nd or 3rd decade. Neurological symptoms include developmental delay, stridor, squint and swallowing difficulty, opisthotonus, head retroflexion, spasticity and trismus, abnormal eye movements, oculomotor apraxia (trouble in moving eyes to look side­ to-side, need to turn head to see things on the side), saccadic initiation failure (failure in starting fast eye movements) and optokinetic nystagmus, dementia and ataxia, generalized tonic-clonic seizures and progressive myoclonic epilepsy. + +Diagnosis is made by measuring glucocerebrosidase levels in leukocytes or skin fibroblasts. Serum chitotriosidase levels are elevated. Volume assessment of liver and spleen by MRI or ultrasound is advised. Neuro-ophthalmological investigations, hearing assessment by brain evoked response audiometry, EEG and neuropsychometry tests are required. DNA analysis is helpful in assessment of phenotype and prenatal diagnosis. +Treatment. This was the first storage disorder for which treatment was available. Options include: enzyme replacement therapy (ERT) and substrate reduction therapy. + + + + + + + + + + + + + + + + +Figs 23.12A and B: (A) Gaucher Type 1: Note protuberant abdo­ men due to hepatosplenomegaly; (B) Gaucher Type Ill. Note trismus and ophthalmoplegia + + +ERT means providing deficient enzyme through IV route to allow breakdown of fat in cerebroside laden cells, so that they function normally and size of spleen and liver is restored, with improved quality of life. While ERT does not have much effect on neurons, it is efficacious first line of therapy for the hematological, visceral and skeletal manifestations. The dose of ERT is 60 IU/kg/every 2 weeks, but dose is individualized depending upon the clinical status. Substrate reduction therapy (SRT) means reducing the production of fatty material, thereby avoiding cellular accumulation. Miglustat is oral treatment for adult patients with type I Gaucher disease with mild to moderate manifestations for which enzyme therapy is not an option. Both forms of treatment are expensive. Splenectomy increases the risk of progressive skeletal and pulmonary disease. Stem cell transplantation is another option. +Metachromatic leukodystrophy Sulfated glyco­ sphingolipids accumulate in white matter of the central nervous system, peripheral nerves, liver and kidney. The myelin degenerates but neuronal cells are affected to lesser degree. Granular masses accumulate in the white matter of the brain. Acidified cresyl violet stains them purple with a brown background, resulting in metachromatic staining. +Clinical features. This disorder has infantile and juvenile forms. Early manifestations including disturbances of gait, incoordination and progressive mental deterioration appear in the second year of life. Knee jerk is brisk but ankle reflex and plantar response may be absent because of involvement of peripheral nerves. Death occurs before the age of 10 yr. Diagnosis is confirmed by level of the enzyme, arylsulphatase A in white cells. +Treatment. There is no effective treatment; bone marrow transplantation has been used. + +GM1 gang/iosidosis In type I, the onset is at birth. There is severe cerebral degeneration. Facial features resemble +mucopolysaccharidosis type IH. Hepatosplenomegaly and cherry red spot on the macular region are present. X­ ray of the bones show mild dysostosis. These children die of respiratory infections before the age of 2 yr. In type II, the onset of illness is between 1 and 2 yr and death occurs before the age of 10 yr. Liver and spleen are not enlarged. Radiological abnormalities are minimal but psychiatric and motor disturbances are severe. + +GM2 gang/iosidosis Inborn errors of GM2 ganglioside metabolism result in accumulation of the metabolite within lysosomes of nerve cells. Most infants with Tay­ Sachs form (type I) of the disease have severe deficiency +of �-N-acetylhexosaminidase A (hexosaminidase A). Hexosaminidase A and B are deficient in Sandhoff disease (type II). +Tay-Sachs disease is an autosomal recessively inherited defect, common in Ashkenazi Jews, but reported from all +Inborn Errors of Metabolism - +I + + + +over the world including India. A history of consanguinity is obtained. Deficiency ofhexosaminidase leads to accumu­ +lation of ganglioside GM2 within ganglion cells of the nervous system; myelin is degenerated. The disorder mani­ +fests by 6 months. Apathy, hypotonia, visual defects and developmental retardation occur early. The child pro­ gressively becomes spastic, blind and demented. Fundus shows cherry-red spot over the macular region. Death occurs within 3-4 yr. In Sandhoff disease, visceral involvement is present in addition to features of Tay-Sachs disease. +Niemann-Pick disease This is an autosomal recessive disorder of sphingomyelin and cholesterol in the lysosomes. In the classical form (type A), clinical features begin in early life with feeding difficulties, failure to thrive and developmental delay and later neuroregression. There is protuberant abdomen with hepatosplenomegaly. Cherry-red spot on fundus examination is seen in about half the cases. Diagnosis is confirmed by measurement of sphingomyelinase levels. Type B disease is a milder form with hepatosplenomegaly but no neurological involve­ ment. Late onset variants (type C) are associated with extrapyramidal manifestations. There is no specific treatment. Table 23.7 summarizes the clinical features of common sphingolipidosis. +Neuronal ceroid /ipofuscinosis (NCL) These are one of the most frequent and progressive neurodegenerative disorders of childhood. It is characterized by progressive psychomotor retardation, seizures, visual loss and early death. Depending upon the age of onset and severity, it can be divided into infantile, late infantile, juvenile and adult NCL. Confirmation is done by enzyme assay and mutation analysis. No specific therapy is available at present. Antiepileptic such as lamotrigine and leveti­ racetam are preferred. + +Peroxisomal Disorders +Peroxisomes are involved in the oxidation (P-oxidation of phytanic acid and p oxidation of very long-chain fatty acids, VLCFAs) as well as synthesis of plasmalogens. Based upon their functioning, peroxisomal disorders can be divided into two major groups. +Disorders of peroxisomal biogenesis or importation are caused by defects in the transfer of proteins produced in the cytosol into the peroxisomes. This includes Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease and rhizomelic chondrodysplasia punc­ tata. These disorders have autosomal recessive inheritance and are caused by defects in genes coding for peroxins (PEX). Defects in these genes interfere with peroxisomal biogenesis and import of proteins into peroxisome. +Approximately 65% of the patients harbor mutations in PEXl gene. + +Zellweger syndrome (Fig. 23.13), also known as cerebro­ hepa torenal syndrome is characterized by dysmorphic + +facies (high forehead, large anterior fontanelle, at occiput, hypoplastic supraorbital ridges, broad nasal bridge, epicanthal folds, anteverted nostrils, micrognathia), central nervous system defects (neuronal migration defect, dysmyelination, seizures), hepatic dysfunction and cirrhosis, adrenal insufficiency and renal microcysts. Prognosis is poor and patients usually die in infancy. Diagnosis is suggested by high plasma levels of very long chain fatty acids (VLCFA) and phytanic acid, and low erythrocyte plasmalogen levels. + + + + + + + + + + + + + + + + +Fig. 23.13: An infant with Zellweger syndrome. Note flat facial profile + +Rhizomelic chondrodysplasia punctata is characterized by altered phytanic acid a-oxidation and plasmalogen synthesis. Type 1 is a peroxisomal biogenesis defect, while types 2 and 3 are disorders of individual peroxisomal enzymes. Patients show rhizomelia and joint contractures along with extensive epiphyseal stippling of long bones (Figs 23.14A and B). They have congenital cataract, developmental delay and growth failure. In contrast to Zellweger syndrome, patients with this disorder have normal VLCFA concentrations and low red blood cell plasmalogens. Phytanic acid concentrations are either elevated (in type 1) or normal (type 2 or 3). + + + + + + + + + + + + + +Figs 23.14A and B: (A) Child with rhizomelic chondrodysplasia punctata; CB) epiphyseal stippling +Essent iaiPed iatric _________________________________ +_ +s +__ +_ +_ +_ +_ +_ _ _ _ _ _ _ _ _ _ + + + + + + + + + + + + + +Fig. 23.15: Brain MRI findings in X-linked adrenoleukodystrophy. T2 weighted axial images show symmetrical hyperintense signal changes in the bilateral parieto-occipital white matter and splenium of corpus callosum (Courtesy: Dr. Atin Kumar, Deptt. of Radiodiagnosis, AIIMS, New Delhi) + + +Disorders of individual peroxisomal enzymes include X-linked adrenoleukodystrophy and classical Refsum disease. +X-linked adrenoleukodystrophy (ALO) is an X-linked recessive disorder caused by tissue accumulation of VLCFA with a carbon chain length of 24 or more due to deficient peroxisomal degradation of fatty acids. The defective gene (ABCDl gene) is located on Xq28. The three neurological forms are: +The childhood cerebral form usually manifests between 4 and 8 yr of age with subtle initial manifestations of worsening school performance and behavioral problems such as hyperactivity and emotional !ability. Auditory and visual disturbances may be associated. Seizures are often the initial manifestation. In most patients, adrenal dysfunction is noticed after the cerebral symptoms. Soon rapid neurological progression ensues causing increasing spasticity, visual and hearing impairment. Progression is due to an inflammatory response, which is most intense +in the parieto-occipital areas. MRI brain typically shows demyelination in these areas (Fig. 23.15). In adolescents, the usual age of manifestation is between 10 and 21 yr +and progression is much slower than the above form. Adrenomyeloneuropathy is a milder form with onset in late + + +adolescence or adulthood and is characterized by progressive paraparesis due to long tract degeneration in the spinal cord. +Elevated plasma levels of VLCFA can identify patients and 85% of female carriers of X-adrenoleukodystrophy. Mutation analysis is the most reliable method to identify carriers. Corticosteroid replacement should be given for adrenal insufficiency. Bone marrow transplantation can be considered in neurologically asymptomatic or mildly involved patients. Lorenzo oil is recommended in neurologically asymptomatic and boys who are less than 8-yr-old with normal MRI. +Suggested Reading +Burton BK. Inborn errors of metabolism in infancy: A guide to diagnosis. Pediatrics 1998;102:£69 +Clarke JTR. General principles. In: A clinical guide to inherited metabolic diseases, 3rdedn. New York: Cambridge University Press, 2006 Lyon G, Kolodny EH, Pastores GM. Neurology of Hereditary Metabolic Diseases of Children, 3rd edn New York. McGraw Hill, 2006 Saudubray JM, Chappentier C. Clinical phenotypes: diagnosis/ algorithms. In: Scriver CR, Beaudet AL, Sly WS, et al. eds. Metabolic and molecular bases of inherited disease, 8th edn. New York: McGraw­ +Hill, 2001;pp 1327-403 +Saudubray JM, van den Berghe G, Walter JH. Inborn metabolic diseases: Diagnosis and treatment, 5th edn. Springer Medizin; 2011 + +Eye Disorders + + + + + + +Radhika Tandon + + + + + + + +Children may present to pediatricians with various primary eye problems. Several systemic diseases have ocular manifestations, some of which are very useful in making the correct diagnosis and instituting appropriate management. Finally, therapies for some diseases are known to have ocular side effects which need to be recognized. + +PEDIATRIC EYE SCREENING +The concept of screening children for eye diseases is based on the awareness that infants and young children cannot communicate their symptoms and visual difficulties. In addition, several potentially blinding diseases manifest in this age group; their early detection and treatment can limit ocular morbidity and prevent irreversible blindness. +The goal of pediatric eye screening is to detect eye and visual disorders in children or identify their risk factors so that the child can be referred for detailed ophthalmic evaluation, confirmation of diagnosis and appropriate medical management. + +Comprehensive Pediatric Eye Evaluation +Presence of any of the following risk factors is an indication for referral for comprehensive ophthalmic evaluation. +I. General health condition, systemic disease or use of medications associated with eye disease +• Extreme prematurity (gestational age s;30 weeks); suspected retinopathy of prematurity +• Intrauterine growth retardation • Perinatal complications +• Neurological disorders +• Juvenile rheumatoid arthritis • Thyroid disease +• Craniofacial abnormalities • Diabetes mellitus +• Syndromes with known ocular manifestations +• Chronic steroid therapy; use of hydroxychloroquine or other medications known to affect eyes +• Suspected child abuse + +II. Family history of any of the following • Retinoblastoma +• Childhood cataract +• Childhood glaucoma +• Refractive errors in early childhood • Retinal dystrophy or degeneration • Strabismus and/ or amblyopia +• Sickle cell disease +• Syndromes with ocular manifestations • Nontraumatic childhood blindness +III. Signs or symptoms reported by the family, health care provider or school teacher +• Defective ocular fixation or visual interactions • Abnormal appearance of the eye(s) +• Squinting or tendency to close one eye in certain situations +• Any obvious ocular alignment, movement abnor-mality, head tilt or nystagmus +• Large and/or cloudy eye(s) • Drooping of the eyelid(s) +• Lumps or swelling around the eye(s) +• Persistent or recurrent tearing, sticky discharge, redness, itching or photophobia +• Learning disabilities or dyslexia + +Guidelines for Examination +Children are best examined in a comfortable and friendly environment. Very young children can remain in the lap of their mother while older children can be distracted with toys and colorful objects. When the child first enters the room, simple observation of behavior, fixation, movement and general awareness of the surroundings are good indicators of the child's visual status, and gross abnor­ malities can be detected. +Steady fixation and uniform steady alignment of the eyes develop in the first 4-6 weeks. Visual acuity assessment in children less than 6 months of age is limited to seeing if the child attempts to fix and follow light. A child 6-12 months + +665 +. E_s_s_e_ _t_ a_l_P_e_d_ i_a _tr_ic_ _________________________________ +s +i +n +- +. + + +of age can follow and even reach out towards colorful objects, and this permits a very crude assessment of gross visual ability. A more objective assessment can be made with electrophysiological tests using a pattern-induced visual evoked response (pattern VER) using chequered patterns of varying degrees of resolution or by observing the optokinetic response or nystagmus induced by the child's attempt to view a striped pattern on a moving drum (OKN). Both these tests are an assessment of the resolution acuity or power of the eye to distinguish patterns of varying degrees of separation or width. These tests are expensive and not readily available in routine clinics. For most preverbal children up to the age of 3 yr, a simple obser­ vation of fixation pattern and behavior, ability to see, follow or pick-up small objects like toys or candy beads, preferen­ tial looking tests using Teller acuity cards or preferential looking cards are used to estimate the visual status. Unilateral loss is also tested for by observing if the child resists closure or occlusion of one eye over the other. +Vision of children 3-5 yr of age can be assessed using picture tests and symbols with matching cards such as the Kays symbols, tumbling E or HOTV card tests where one relies on the child's ability to recognize the shape and match the shape with a similar one on a card. Children 5 yr or older can be tested with more conventional vision testing methods using a Snellen visual acuity chart with either alphabets or tumbling E or Landoldts C symbols. +Ocular movements and external examination of the eye can be performed by using adequate illumination with a torch and aided by toys or colorful pictures to capture the child's attention and interest to cooperate with the exa­ miner. Pupillary reactions must be tested and fundus examination should be attempted with a direct ophthal­ moscope through the undilated pupil to view the disc and macula. In case required, more detailed examination of the fundus and retinal periphery can be carried out after dila­ ting the pupils with mydriatic eye drops such as 2.5% phenylephrine or short-acting cyloplegic-mydriatic drops such as 0.5% tropicamide or 1 % cyclopentolate eye drops. The retina is best viewed with an indirect ophthalmoscope as this gives the maximum field of view and the exami­ nation can be completed efficiently. In general, as far as possible, most of the examination should be completed without touching or going too close to the child so that the child is comfortable and does not feel intimidated. Digital assessment of the intraocular pressure, eversion of the lids and slit lamp examination are occasionally required. In certain situations, an examination under anesthesia is required and should be done only after obtaining the parents' informed consent. + +CONGENITAL AND DEVELOPMENTAL ABNORMALITIES + +This group of diseases may or may not manifest at birth. If the disease is detected at birth, it is 'congenital' such as lid coloboma, severe corneal opacity or total cataract with +a white opaque lens. Sometimes the disease is present at + + +birth, but is detected later on, for example, a partial cataract or mild congenital glaucoma. Sometimes the disease is a defect of development but manifests later, such as deve­ lopmental cataract or juvenile glaucoma. + +Disorders in Development of the Whole Eyeball (Globe Abnormalities) +A child may be born with a small eye (microphthalmos or nanophthalmos), absent eyeball (anophthalmos) with or without an orbital cyst, or more complex abnormalities associated with craniofacial dysgenesis. + +Abnormalities of Development of the Orbit, Eyelids and Adnexa (Lacrimal Drainage System and Glands) +Children are sometimes born with the eyes completely covered by the eyelids so that the globe is not apparent or visible (cryptophthalmos). A blocked nasolacrimal duct may manifest at birth as a dacryocystocele, or later as dacryocystitis. Lacrimal diverticulae or fistula are other abnormalities which may or may not be apparent at birth. Telangiectasias and vascular abnormalities such as capillary or cavernous hemangioma, lymph hemangioma, arteriovenous malformations and orbital varices may be present as isolated abnormalities or as part of syndromes such as the phakomatoses. +Other abnormalities of the lids include abnormal shape and position such as blepharophimosis, ptosis, prominent epicanthic folds, lid coloboma, congenital ichthyosis, entropion and ectropion. Early oculoplastic reconstruction needs to be undertaken if the visual axis is covered or the cornea is at risk of exposure keratopathy due to lago­ phthalmos or inadequate lid closure. + +Diseases Affecting the Conjunctiva and Anterior Segment +Some of the important conditions that may be seen include conjunctiva} telangiectasia, hazy or opaque cornea (causes of which can be memorized using the mnemonic STUMPED, i.e. sclerocornea, birth trauma, ulcer, muco­ polysaccharidosis, Peter anomaly, endothelial dystrophy or endothelial dysfunction secondary to congenital glaucoma, and dermoid); flat cornea (cornea plana), anterior segment dysgenesis, aniridia, iris coloboma, primary congenital or juvenile developmental glaucoma, lens opacity or cataract, lens coloboma, displaced or subluxated lens or ectopia lentis, abnormal shape of lens such as microspherophakia, lens coloboma, lenticonus and persistent hyperplastic primary vitreous (Fig. 24.1). + +Retinopathy of Prematurity +This condition is seen in preterm babies due to early exposure to oxygen and other environmental factors by a premature, underdeveloped retinal vascular system. The chief risk factors are prematurity, especially birth before 32 weeks of gestation, birth weight less than 1500 g and +presence of other contributory risk factors such as +------------------------------------E_y_e _D_is_o_rd_ e_ r_s.... + + + + + + + + + + + + + + + +Fig. 24.1: Child with bilateral congenital corneal opacity. Differential diagnoses include all causes of congenital corneal opacity, congenital glaucoma with buphthalmos and corneal edema due to raised intraocular pressure + + +supplemental oxygen therapy, hypoxemia, hypercarbia and concurrent illnesses like septicemia. The clinical features are graded in stages of severity depending on the retinal signs and the zone of retina involved. Children at risk should be screened periodically to look for evidence of developing what is considered as 'threshold' disease, i.e. requiring ablative laser treatment of the avascular zone of the retina to check further progression and prevent blinding stages of the disease which would then require surgical intervention to treat the ensuing retinal detachment and other complications. + +ACQUIRED EYE DISEASES + +Nutritional Disorders +The most important condition in this category is vitamin A deficiency which can be catastrophic in young children if severe enough to produce keratomalacia. Up to the age of six months, children have adequate hepatic reserves of vitamin A. However, if the mother's nutrition is poor or the infant is not properly fed afterbirth, severe vitamin A deficiency may be precipitated by an attack of acute respiratory infection such as measles, pneumonia or acute gastroenteritis, which could lead to bilateral blindness due to severe keratomalacia. Milder forms of vitamin A defi­ ciency may manifest with xerosis of the conjunctiva, Bitot spot and nyctalopia or night blindness. Adequate nutri­ tional advice to the pregnant and lactating mother and proper weaning with vitamin A rich fruits and vegetables is advised. Keratomalacia is treated with oral vitamin A 200,000 IU stat followed by a second dose after 24 hr and a third dose after 2 weeks. In case the child is vomiting and cannot retain oral supplement, an intramuscular injection of vitamin A may be given instead. For children less than 1 yr of age and those weighing less than 10 kg, half the dose is given to avoid vitamin A toxicity and +vitamin A induced intracranial hypertension. + +Infections +Preseptal cellulitis and orbital cellulitis manifest as swelling and inflammation of the eyelids, are differentiated clini­ cally, and often occur due to spread of infection from the lids, adnexa or paranasal sinuses or following trauma. These are potentially dangerous infections as they involve the anatomical'dangerous area of the face' and if not trea­ ted promptly and adequately, can spread intracranially, resulting in meningitis or cavernous sinus thrombosis. Ultrasonography is required to detect an orbital abscess, which has to be drained. CT scan or MRI is required if involvement of adjacent paranasal sinuses or intracranial involvement is suspected. Treatment requires systemic antibiotics and anti-inflammatory agents, supplementation with topical antibiotics, and supportive measures, inclu­ ding lubricating eyedrops to prevent corneal damage. +Other infections involving the eyelids include blepha­ ritis, hordeolum externum (stye), hordeolum internum (infected chalazion), molluscum contagiosum and phthiri­ asis of the eyelashes. Lid hygiene, hot fomentation and local antibiotic ointments are useful along with instructions for personal hygiene. Phthiriasis will require mechanical removal of nits adhering to the eyelashes, local application of 20% fluorescein sodium to the lid margins and systemic ivermectin therapy for recalcitrant cases, along with advice on hygiene and treatment of other affected family members. +Common infections of the ocular surface include con­ junctivitis which could be bacterial, viral or chlamydial. +Conjunctivitis occurring within the first month after birth is called ophthalmia neonatorwn. Every effort should be made to identify the etiologic agent, especially in cases of ophthalmia neonatorum, since gonococcal conjunctivitis can cause loss of vision in the newborn. Conjunctiva! smears +and swabs can be sent for microbiological evaluation. Mucopurulent conjunctivitis is treated with topical anti­ biotic eyedrops and supportive measures such as cleansing the eye with clean water, lubricating eyedrops and cold compresses. +More severe infections include keratitis and corneal ulcers (Fig. 24.2). Trauma is the most common underlying predisposing factor, but poor hygiene and lowering of local immunity secondary to chronic inflammation, viral infections or use of topical steroids are other risk factors for bacterial and fungal infections of the cornea. Trauma with vegetative matter, such as a thorn, tree branch or wooden broomstick (often used for making 'bows and arrows' for playing), predisposes to fungal infections. Corneal ulcers require an examination under anesthesia for detailed evaluation and corneal scraping for micro­ biological analysis. Empirical therapy for bacterial corneal ulcers is started with a combination of freshly prepared fortified topical antibiotics such as 5% cephazolin and 1.3% tobramycin eye drops hourly and half hourly alternately round the clock for the first 48 hr. After 48 hr, the culture +report and clinical response are reviewed. If there is no +_ E_ssen_ t_ a1P_ed_ ia tric_ _________________________________ +s +i +_ +_ +_ +_ _ +_ +_ +_ +_ _ + + + + + + + + + + + + + + + + + + +Fig. 24.2: A partially treated hypopyon corneal ulcer. The overlying epithelial defect has healed, but there is a deep corneal abscess, corneal edema and purulent fluid, i.e. hypopyon in the anterior chamber + +substantial clinical improvement, the antibiotic is changed based on microbiology results. If clinically responding to therapy, the frequency of antibiotics can be reduced to use during waking hours only, followed two days later by two hourly application, then reduced to 4 hourly or 6 hourly, and discontinued a week after the ulcer has healed. Supportive measures include topical cycloplegics, hot fomentation, analgesics, antiglaucoma medication if secondary glaucoma is present, and antibiotic ointment at night. Fungal keratitis is treated with topical natamycin (5%) 1 hourly with supportive measures. Herpes simplex viral keratitis is treated with topical acyclovir 3% eye ointment for epithelial involvement and systemic acyclovir for herpetic keratouveitis or recurrent disease. +Other infections include endophthalmitis (traumatic, metastatic, or iatrogenic following intraocular surgery) and parasitic infestations, such as toxoplasmosis, toxo­ cariasis, and cysticercosis of the eye, extraocular muscles or orbit. + +Allergic and Inflammatory Diseases +Children may develop allergic diseases of the skin around the eye and the ocular surface and conjunctiva. Dermatitis may be an allergic reaction to local ophthalmic medication or sometimes secondary to insect bite, application of traditional eye medicines or herbal remedies and use of local creams or lotions. In addition, a variety of environ­ mental and hereditary factors may interplay to produce a variety of allergic conjunctival manifestations such as seasonal allergic conjunctivitis, hay fever conjunctivitis, perennial or chronic allergic conjunctivitis, atopic allergic conjunctivitis and vernal keratoconjunctivitis. Itching, redness, discomfort, gritty or foreign body sensation, watering, mucoid or thick ropy discharge, photophobia + +and blepharospasm are all seen in different combinations and varying degrees of severity. Treatment includes cold compresses, topical antihistnic eyedrops for mild cases and counseling to avoid rubbing the eyes. Topical corticosteroid eyedrops give quick relief but are best avoided in mild cases because of the danger of self-medi­ cation and unsupervised chronic topical use complicated by steroid induced glaucoma and secondary corneal infection and ulceration. More severe allergies may have secondary consequences in the form of dry eye, kerato­ pathy and corneal ulceration. These are best referred to ophthalmologists for expert management and careful followup. +Other inflammatory diseases include phlyctenular conjunctivitis or keratoconjunctivitis (believed to be an 'allergic' immunological reaction to tubercular antigen); interstitial keratitis secondary to infections like rubella, syphilis, leprosy and tuberculosis; and uveitis, either idiopathic or associated with juvenile chronic arthritis, psoriasis, tuberculosis, sarcoidosis and toxoplasmosis. Acute anterior uveitis (iritis, cyclitis and iridocyclitis) usually presents with a red inflamed eye with photophobia and diminution of vision. Chronic uveitis may be less symptomatic with decreased vision due to complicated cataract. Intermediate and posterior uveitis (pars planitis, vitritis, retinitis, choroiditis and retinochoroiditis) are usually painless with symptoms of decreased vision (due to hazy media and retinal or optic nerve swelling and inflammation) and floaters (due to inflammatory cells in the vitreous). Treatment is with topical cycloplegic agents and steroids, supplemented with systemic steroids and specific therapy for any underlying disease, such as tuberculosis. Patients with uveitis need detailed exami­ nation with a slit lamp biomicroscope to identify the inflammatory response, ophthalmoscopy to view the fundus and specialist ophthalmic care and followup to control the inflammation and minimize the morbidity related to the disease and its treatment. +Intraocular (retinoblastoma or juvenile xanthogranu­ loma) or systemic malignant disorders may sometimes mimic uveitis syndrome due to malignant cells in the eye and vascular uveal tracts. +Optic neuritis is another important inflammatory disease which could be idiopathic, secondary to infections or associated with demyelinating disorders. Classical features include a rapid drop in vision, usually in one eye, which is accompanied by a relative afferent pupillary defect and normal fundus (retrobulbar neuritis) or inflam­ matory swelling of the optic disc (papillitis) and retinal edema and/ or exudates (neuroretinitis). Patients need to be treated in consultation with a neuroophthalmologist after investigations to identify the cause. + +Metabolic and Endocrine Disorders +Homocystinuria is associated with subluxation of the lens, and secondary glaucoma can be seen as a complication. +-------------------------------------E_y_e_D_is_o_r_d_e_rs__ + + +The lens is usually subluxated downwards which causes poor vision due to displacement and astigmatism. Surgical lens removal has to be done under general anesthesia taking suitable precautions, as the patients are prone to thromboembolism. Optical rehabilitation is usually done with spectacles or contact lenses, though in some cases intraocular lenses can be fitted using scleral or bag fixation augmented with bag fixation devices. +Various storage disorders such as cerebral storage disease, lipidosis and gangliosidosis may be associated with a 'cherry red spot' due to abnormal deposition in the retina, corneal clouding as in some of the mucopoly­ saccharidoses, and Kayser-Fleischer ring in peripheral cornea in Wilson disease. Juvenile diabetes mellitus may be associated with cataract and diabetic retinopathy and thyroid dysfunction with dysthyroid eye disease. Tyro­ sinase deficiency might be associated with ocular albinism with foveal hypoplasia and poor vision. + +Musculoskeletal and Neurodegenerative Diseases and Phakomatoses +Marfan and Ehlers Danlos syndromes may be associated with subluxated lens and consequent secondary glaucoma. Marfan syndrome is usually associated with upward and outward displacement of the lenses and myopia with blurred vision. Retinal detachment is not connected also common. Surgical lens removal becomes necessary if the vision is not corrected with spectacles or contact lenses. Leukodystrophies and demyelinating diseases may be associated with extraocular muscle weakness, ptosis and optic neuropathy. Phakomatoses like neurofibromatosis, Sturge-Weber syndrome and nevus of Ota may be associated with cafe au lai t spots, plexiform neurofibromas of the lids and orbit and Lisch nodules on the iris and glaucoma. +Muscular dystrophies or degenerations such as chronic progressive external ophthalmoplegia result in ptosis and restriction of eye movements. Duchenne muscular dystrophy may be associated with cataracts. + +Tumors and Neoplastic Diseases +Benign tumors include dermoids of orbit, lids or on cornea, hamartomas, osteoma, vascular malformations or heman­ giomas of various types and neurofibromas. Malignant intraocular tumors are confined to retinoblastoma (Fig. 24.3), juvenile xanthogranuloma, medulloepithe­ lioma and metastatic lesions from neuroblastomas, Ewing sarcoma, leukemias and lymphomas. Orbital tumors include rhabdomyosarcoma, Langerhans cell histiocytosis, extraocular spread of retinoblastoma, metastatic spread of Ewing sarcoma, neuroblastoma, leukemia and lymphoma. + +Refractive Errors +An abnormality in the refractive and focusing apparatus makes it difficult for parallel rays of light from the distance + + + + + + + +Fig. 24.3: 'Leukocoria' or white pupil in an infant secondary to retinoblastoma. Note the white appearance that appears to be from a structure located more posteriorly, has a slight yellowish pinkish tinge due to vascularization and has an appearance that is unlike that seen with to a cataract. Ultrasonography of the orbits helps confirm the diagnosis + +to be accurately focused on the retina. This deviation from the normal emmetropic state is termed as 'ametropia' or refractive error. This manifests as poor or blurred vision which may be noticed by parents, relatives, friends, school teachers or reported by the child as a difficulty in viewing clearly. Sometimes, indirect evidence is reported as eye rubbing, 'squinting', 'going too close to the television' or holding objects too close to the eyes. An assessment of visual acuity is followed by cycloplegic refraction; fundus evaluation is required in addition to routine ophthalmic +evaluation. Refractive errors include myopia, hypermetropia +and astigmatism, and spectacles must be prescribed accordingly. Associated amblyopia or strabismus must be taken care of and any additional features like nystagmus or extraocular muscle imbalance ruled out. Patients need to be carefully counseled with respect to improvement of vision with spectacles and need for compliance with followup. Failure to show an improvement of vision warrants investigations to rule out any associated subtle pathology such as microstrabismus, retinal macular degeneration, retinitis pigmentosa, congenital hereditary cone dystrophy, delayed visual maturation, dyslexia or Leber amaurosis. + +Strabismus and Amblyopia +Strabismus is defined as the condition when the visual axes of the two eyes do not meet at the point of regard. In other words, the motor and sensory alignment of the two eyes and their images in the brain are not synchronized. The cause may be a basic abnormality of development as in essential esotropia or exotropia (concomitant squint when the angle of deviation or separation of the two eyes is uniform, irrespective of the direction or position of gaze) or secondary to extraocular muscle paralysis, e.g. paralytic squint, orbital space occupying lesion, myositis or orbital inflammation as in orbital pseudornor syndrome, orbital musculofascial abnormality like Duane retraction syn­ drome or Brown's superior oblique tendon sheath syndrome (causing an incomitant or nonconcomitant squint, where the deviation is more in certain positions and less or even absent in some positions of gaze). +An inward deviation of the eye is termed esotropia and outward deviation is termed exotropia. The child initially suffers diplopia due to the different images being pre- +__ E_s_s_ _n_t_iai_P_ed_iat_rics __________________________________ +e +_ +_ +_ +_ +_ +_ + +sented to the visual cortex by the two eyes, but learns to suppress one image, eventually developing amblyopia or a 'lazy eye' with loss of binocularity and stereopsis. In very young children, the presence of an intermittent or constant squint or misalignment of the eyes should be indications for referral to an ophthalmologist. +Amblyopia or 'lazy eye' is a condition of subnormal vision defined as two lines less than normal or less than the fellow eye on the visual acuity chart with no anato­ mical cause detectable on examination, i.e. no media opacity and a normal fundus. Amblyogenic factors have their maximum impact on the immature developing visual system, i.e. during the first 6 yr of life and include sensory deprivation or abnormal binocular interaction. The former would refer to a corneal opacity or cataract which, even if taken care of surgically, do not indicate good chances of restoration of normal vision. Similarly, abnormal bin­ ocular interaction occurs in the presence of strabismus or anisometropia (difference in the refractive power of the two eyes), in which case one eye takes over and the visual cortical neurons meant to receive stimuli from the other eye are unable to develop normally, leading to a 'lazy eye'. These changes are potentially reversible with appropriate therapy in the first decade, but become irreversible and permanent later. Treatment involves restoration of vision with correction of refractive error, removal of media opacity if present (such as corneal opacity or cataract), patching therapy by part time patching of the 'good' eye to enable the 'lazy' eye to catch up, and strabismus surgery to restore ocular alignment if required. + +Cataract +A visible lenticular opacity in the eye is termed as a cataract. It is congenital if present since birth, develop­ mental if appearing later on, and traumatic if occuring after an episode of eye trauma. A central opacity is consi­ dered visually significant if it impairs visual acuity, and on clinical assessment obstructs a clear view of the fundus. A cataract may be unilateral or bilateral and symmetric or asymmetric. In view of the risk of sensory deprivation amblyopia, visually significant cataract should be treated surgically as soon as possible after birth. Functional success is highest if operated within the first few weeks after birth, provided the child is medically fit to undergo general anesthesia. Unilateral cataracts must be supple­ mented with postoperative patching therapy to take care of any amblyopic effect. Optical and visual rehabilitation for the aphakic state resulting from lens removal includes the implantation of an intraocular lens (IOL) for children above two years of age. Generally, intraocular lenses are avoided for children less than two years old as there are significant problems of change in lens power requirements as the maximum growth of the eyeball takes place during the first two years of life and the risk of complications of glaucoma and intraocular inflammation and fibrosis are higher. In very young children, therefore, a capsule rim is + +left for subsequent secondary IOL implantation, and temporary optical rehabilitation is provided with spectacles or contact lenses supplemented with patching for amblyopia in unilateral cases (Fig. 24.4). + + + + + + + + + + + + + + + + + + + +Fig. 24.4: A child with bilateral developmental cataract. The cataract is partial and the condition was detected late. Also note that the child has a convergent squint. The child also has impaired hearing and congenital heart disease, suspected to be due to congenital rubella syndrome + +Glaucoma +Primary congenital and developmental juvenile glaucoma are now recognized to be inherited diseases. Primary congenital glaucoma is associated with CYPlBl gene, (2p21) with a predominantly autosomal recessive mode of inheri­ tance, and mutations in the myocillin (MYOC) gene. Photophobia, blepharospasm, watering and an enlarged eyeball are classic symptoms. Suspicion of glaucoma or buphthalmos warrants urgent referral to an ophthal­ mologist. An examination under anesthesia is required to measure the corneal diameter and intraocular pressure, and to visualize the optic disc. Once glaucoma is confirmed, medical therapy is started to lower the pressure and patient prepared for surgery. If the cornea is clear enough to allow visualization of the angle structures, a goniotomy is attemp­ ted. If the glaucoma is more severe or the cornea very edema­ tous, a drainage procedure is undertaken to open alternative aqueous drainage channels such as trabeculectomy and trabeculotomy. If the cornea fails to clear after adequate control of the intraocular pressure, corneal transplantation is required to restore vision and prevent irreversible sensory deprivation amblyopia. +Children can also develop secondary glaucoma due to chronic use of topical corticosteroid eyedrops, following eye trauma particularly if associated with traumatic hyphema (blood in the anterior chamber) or angle +-------------------------------------E_y_e _D_i_s_o_rd_ e_r__s _ + + +recession, after surgery for developmental cataract and after chronic uveitis. + +Eye Trauma and Related Problems +Eye injuries are common in children (Figs 24.SA and 8). Eye injuries are considered to be an important cause of preventable blindness. Effort must be made to educate the community in general, and mothers in particular, about the importance of not allowing children to play with sharp pointed toys like bows and arrows, firecrackers, chemicals including colors during Holi festival or other chemicals like edible 'chuna'. Sharp and dangerous household objects like knives, scissors and needles, and chemicals like cleaning liquid, acid, whitewash paint and edible 'chuna' should be kept out of reach of children. +In case an injury is sustained, the eyes should be immediately washed thoroughly with locally available drinkable water, and the child should be rushed to the nearest hospital. +Perforating injuries of the globe require surgical repair under general anesthesia along with administration of systemic and topical antibiotics and tetanus prophylaxis. The child should be told not to rub the eyes and given only fluids while rushing the child to hospital so that there is no unnecessary delay in preparing the patient for general anesthesia and planning surgery. Meticulous repair of the wounds is undertaken as soon as possible to mize the risk of secondary complications such as endophthalrnitis, expulsion of intraocular contents and later risk of sympa­ thetic ophthalmitis or an inflammatory panuveitis in the normal eye due to sensitization of the immune system to the sequestered antigens in the exposed uveal tissue. + +Retinal Diseases +Children may be affected by a wide variety of retinal diseases. Retinal detachment can occur secondary to trauma or spontaneously in cases with high or pathological myopia. Classical symptoms such as sudden loss of vision with floaters and photopsia may not be reported by children and the detachment may not be detected till much later. Retinal detachment requires surgical treatment and the sooner the surgery is performed, the greater are the chances of functional recovery of vision. Other diseases that can affect the retina in childhood include degenerative and hereditary conditions like retinitis pigmentosa and different forms of macular degeneration such as Stargardt disease. These diseases lead to gradual, painless, bilateral diminution of vision in the first or second decade of life which may be accompanied by defective dark adaptation or abnormal color vision. No specific treatment modalities are available, but refractive correction, low vision aids, visual rehabilitation and genetic counseling are ancillary measures. + + + + + + + + + + + + + + + + +Fig. 24.SA: The sequelae of ocular trauma. Following injury with a wooden stick, the child had corneal perforation, which was repaired. Traumatic cataract was surgically removed. Note the irreversible anatomical damage with corneal scar, distorted iris and pupil and lens capsular opacification + + + + + + + + + + + + + + + + +Fig. 24.58: The sequelae of chemical injury, due to edible 'chuna'. Despite aggressive management, longterm sequelae include residual conjunctiva! inflammation with limbal stem cell deficiency and a scarred, irregular and opacified corneal surface + +Vascular abnormalities of the retina such as heman­ giomas, arteriovenous malformations and exudative vi treoretinopa thies like Coats disease may be seen. Retinal vasculitis may be seen in Eales disease and other inflam­ matory disorders. Diabetic retinopathy and hypertensive retinopathy can occur if these systemic disorders are present in sufficient grade of severity and for an adequate duration of time. + +Suggested Reading +Sihota R, Tandon R. Parsons' diseases of the eye, 21st edn, 2011 Elsevier India, Delhj, + +Skin Disorders + + + + + + + +Neena Khanna, Seemab Rasool + + + + + + + +Skin disorders account for nearly one-third of ailments in children. The prerequisite for dermatological diagnosis is identification of the different skin lesions as well as the various patterns formed by them. + +surface, e.g. molluscum contagiosum) or verrucous (with multiple closely packed firm elevations, e.g. verrucous warts). A papule which is >0.5 cm in size and with the major part in the skin is called a nodule (Fig. 25.28). + + +BASIC PRINCIPLES +Morphology of Lesions Macules +Macule is a circumscribed area of change in skin color without any change in consistency (Fig. 25.1). A macule may be hyperpigmented, e.g. cafe au lait macule, hypopigrnented, e.g. leprosy, depirnented, e.g. vitiligo or erythematous, e.g. drug rash. + +Papu/es and Nodules +Pa pule is a solid lesion< 0.5 cm in diameter with major part of it projecting above the skin (Fig. 25.2A). Papules may be dome shaped (e.g. trichoepithelioma), flat topped (e.g. verruca plana), conical (e.g. condyloma acuminata), filiform (e.g. filiform warts) or umblicated (with crater on + + + + + + + + + + + + + + + + +Fig. 25.1: Macule, Circumscribed area of change in skin color without any change in consistency + +Figs 25.2A and B: (A) Papule: Solid lesion, <0.5 cm; (B) Nodule: Solid lesion, >0.5 cm + +672 +--------------------------------------5-k_in__Di_so_r_d_e_r_s___ + + +Plaque +Plaque is an area of altered skin consistency, the surface area of which is greater than its depth (Fig. 25.3). A plaque can be elevated, depressed or flat. + +Wheal +Wheal, the characteristic lesion in urticaria, is an evanescent, pale or erythematous raised lesion which disappears within 24-48 hr (Fig. 25.4). Wheals are due to dermal edema, and when the edema extends into subcutis, they are called angioedema. When the wheals are linear, the phenomenon is called dermographism. + +Blisters +Blister is a circumscribed elevated, superficial fluid filled cavity (Fig. 25.5). If <0.5 cm, it is a vesicle and if >0.5 cm, a bulla. + + + + + + + + + + + + + + + + + +Fig. 25.3: Plaque: Area of altered skin consistency with a surface area of which is greater than its depth + + + + + + + + + + + + + + + + +Fig. 25.4: Wheal: Evanescent, pale eythematous raised lesion which disappears within 24-48 hr + + + + + + + + + + + + + + + + + + + +Fig. 25.5: Blister: Circumscribed, elevated, superficial fluid filled lesion +I + +Scales +Scales are flakes of stratum corneum (Fig. 25.6) and are diagnostic in certain dermatoses, e.g. silver easily detachable flakes (psoriasis), branny (pityriasis versicolor) and fish-like scales ichthyosis). + +Crusts +Crusts are formed when serum, blood or pus dries on the skin surface (Fig. 25.7). + +Erosions and Ulcers +A defect, which involves only the epidermis and heals without a scar (Fig. 25.8A) is called an erosion, while an ulcer is a defect in the skin which extends into the dermis or deeper, and heals with scarring (Fig. 25.8B). + + + + + + + + + + + + + + + + + + +Fig. 25.6: Scale: Flakes of stratum corneum +E s s n t i l P ed iat rics __________________________________ +e +a +_ +__ +_ +_ +_ +_ +_ _ _ _ _ _ _ _ _ _ +Atrophy +Atrophy is the reduction of some or all layers of skin. In epidermal atrophy, ting of the epidermis leads to loss of skin texture and cigarette-paper like wring without depression. In dermal atrophy, loss of connective tissue of the dermis leads to depression of the lesion. +Lichenification +Lichenification consists of a triad of skin thickening, hyperpigmentation and increased skin markings (Fig. 25.9). It is caused by repeated scratching. + +Burrow +Burrow is a dark serpentine, curvilinear lesion with a minute papule at one end and is diagnostic of scabies (Fig. 25.10). +Fig. 25. 7: Crust: Yellow brown collection of keratin and serum Comedones +Comedones are due to keratin plugs that form within follicular ostia and they can be open or closed (Fig. 25.11). + + + + + + + + + + + + + + + + +Fig. 25.9: Lichenification, Thickening and hyperpigmentation of skin with increased skin markings + + + + + + + + + + + + + + +Figs 25.8A and B: Erosions and ulcers, (A) Erosions are due to complete or partial loss of epidermis with no loss of dermis; (B) ulcer is a defect in the skin which extends into the dermis or deeper and heals with scarring + + + +Fig. 25.10: Burrow: Serpentine, thread-like, grayish curvilinear lesion, diagnostic of scabies +-------------------------------------S-k-i_n D_i_s_o_r_de_r_s__ + +Seborrheic dermatitis + +•k---- Tinea capitis, pediculosis capitis +Impetigo contagiosa �=:-" Acne, atopic dermatitis, +Salmon patch port wine stain Segmental vitiligo + + + + + + + + + +Fig. 25.11: Comedones: Keratin plugs that form within follicular ostia + +Arrangement and Configuration of Lesions +Arrangement and configuration of skin lesions can help +in diagnosis (Table 25.1). + + + + +Diaper dermatitis + +Psoriasis + +lchthyosis + +Lichen planus + +Scabies + + + + ++-----Vitiligo + + +Table 25.1: Arrangement and configuration of skin lesions Arrangement Example + +Linear Grouped Dermatomal Arcuate + +Verrucous epidermal nevus Herpes simplex +Herpes zoster Granuloma annulare + + +Fig. 25.12: Sites of predilection of common skin disease + +a. Lamellar ichthyosis +b. Nonbullous ichthyosiform erythroderma +iv. Keratinopathic ichthyosis + + + +Sites of Predilection +Sites of predilection are important for dermatological diagnosis (Fig. 25.12). + +GENODERMATOSES + +Genodermatoses are a group of inherited single gene cutaneous disorders that manifest themselves wholly or in part in the skin, mucous membranes, hair and nails. + +lchthyoses +Ichthyoses are a heterogeneous group of disorders characterized by the presence of fish-like scales. The etiology is heterogeneous (Table 25.2). They are classified as follows: +i. Ichthyosis vulgaris ii. X-linked ichthyosis +iii. Autosomal recessive ichthyosis + + +The chief clinical features of icthyosis are listed in Table 25.3 and Figs 25.13 to 25.18. + +Treatment +Hydration (by immersing in water) and immediate lubrication with petroleum jelly or urea containing creams and lotions are useful. +Keratolytic agents (hydroxyacids, propylene glycol and salicylic acid) are used when lesions are moderately severe. Oral retinoids (acitretin) are administered in collodion baby, severe cases of lamellar ichthyosis and in keratinopathic ichthyosis. A short course of topical steroid and antibiotic combination is used in eczematized skin. + +Palmoplantar Keratoderma +This condition may be inherited or acquired. The +hereditary keratodermas are caused by a gene abnormality + + +Table 25.2: Inheritance and etiology of ichthyoses + +Type +Ichthyosis vulgaris X-linked ichthyosis +Autosomal recessive ichthyosis* + +Keratinopathic ichthyosis + +Inheritance +Autosomal dominant X-linked +Autosomal recessive + +Autosomal dominant + +Defect +Reduced or absent filagrin (helps form keratin filaments) Deficiency of steroid sulfatase enzyme +Abnormality of gene encoding transglutaminase; several defects identified +Defect in keratin synthesis or degradation + + +*Heterogeneous group of disorders that includes many clinical phenotypes including lamellar ichthyosis and nonbullous ichthyosiform erythroderma +__ _s_s__en_t_ia_i_P_e_d_i_a t_r_ic_s __________________________________ +E + +Table 25.3: Clinical features of ichthyoses + +Ichthyosis vulgaris + + +Age of onset 3-12 mo + + +X-linked ichthyosis + + +Birth + +Lamellar ichthyosis + + +Birth + + +Nonbullous ichthyosiform erythroderma +Birth + + +Keratinopathic ichthyosis + +Birth + + + +Sex + +Incidence + +Equal in both sexes + +Common + +Only males + +Rare + + +Equal in both sexes + +Very rare + + +Equal in both sexes +Rare + + +Equal in both sexes + +Rare + + + +Clinical features + +Fine white scales on most parts of the body +Large mosaic-like scales, attached (pasted) at center and upturned at the +edges on extensors of lower extremities (Fig. 25.13) + +Large dark brown adherent scales (Fig. 25.14) + +Collodion baby, Collodion baby Generalized ensheathed in shiny at bth; followed erythema with lacquer-like membrane by fine branny blistering at +at birth (Fig. 25.15); scales and birth; followed by diffuse large thick marked brown, warty, brown plate-like erythema broad linear +scales (Fig. 25.16) (Fig. 25.17) plaques (Fig. 25.18); which persist for life; scales may fall off erythema minimal leaving skip areas + + + +Sites of Extensors of limbs; predilection major flexures always +spared; face usually spared + + +Generalized involvement; encroachment of flexures; palms and soles spared + + +Generalized involve-ment; accentuation on lower limbs +and flexures + + +Generalized erythema and scaling + + +Generalized involvements; accentuation in flexures + + + +Associated features + + +Hyperlinear palms and soles; keratosis pilaris; atopic diathesis + + +Corneal opacities; cryptorchidism + + +Ectropion and Palmar and Palmar and plantar eclabium; crumpled plantar kerato- keratoderma in ears; palmar and derma are >60% +plantar keratoderma less frequent + + + + + + + + + + + + + + + + + + + + + +Fig. 25.13: lchthyosis vulgaris: Large scales on extremities that are attached at the center and turned up at the edge + +that results in abnormal keratin. Inheritance is either autosomal dominant or autosomal recessive (Table 25.4). The condition is characterized by thickening of skin of palms and soles (Fig. 25.19), which usually manifests at birth or in the first few months of life. Mutilating variants are characterized by massive thickening and mutilation (Fig. 25.20). Sometimes keratoderma extends onto the +dorsae of hands and feet (keratoderma transgrediens). + +Fig. 25.14: X-linked ichthyosis: Large dark brown adherent scales without sparing of flexure + +Therapy for keratoderma includes the topical use of emollients, keratolytics (salicylic acid 6-12%, urea 30-40%), retinoids and vitamin D (calcitriol). Systemic retinoids (acitretin) are used in mutilating variants. + +Epidermolysis Bullosa +These are a heterogeneous group of disorders defined by a tendency to develop blisters even on trivial trauma. The common clinical features are listed in Table 25.5. EB +___________________________________s_k_in_o_i_so_ _rd_e_rs__ + + + + + + + + + + + + + + + + + +Fig. 25.15: Collodion baby: Baby is ensheathed in a shiny lacquer­ like membrane + + + + + + + + + + + + + + + + +Fig. 25.16: Lamellar ichthyosis: Large pasted scales with continuous rippling around ankle + + + + + + + + + + + + + + + + + + +Fig. 25.17: Nonbullous ichthyotic erythroderma, Diffuse erythema, with fine scales + +Fig. 25.18: Keratinopathic ichthyosis, Brownish, warty, broad linear plaques + +Table 25.4: Classification of hereditary palmar and plantar keratoderma +Type Inheritance +Diffuse Autosomal dominant Focal Autosomal dominant Mutilating Autosomal recessive Transgrediens Autosomal recessive + + + + + + + + + + + + + +Fig. 25.19: Palmoplantar keratoderma, Autosomal dominant variant thickening of skin of soles + + + + + + + + + + + + + + + + + +Fig. 25.20: Palmoplantar keratoderma: Autosomal recessive massive thickening and mutilation +_ E_s_s__n_t_iai_P_ed_iat_r ic_________________________________ +_ +_ +s +_ +e +_ +_ +_ +_ + +Table 25.5: Clinical features of epidermolysis bullosa (EB) + + +Age of onset Skin lesions + + +Sites + + + +Mucosa! lesions Nail involvement Complica hons + +Variants + +l LO + +EB simplex +Early childhood +Nonhemorrhagic bullae which heal without scarring + +Hands and feet + + + +None Absent +Heal without scarring +Herpetiformis or Dowling-Meara Localized or Ogna syndrome + +Junctional EB +At birth +Large flaccid bullae which heal slowly + + +Perioral and perianal areas; sites of trauma (knees, elbows, fingers) +Involved Present +One variant is lethal +Gravis Mitis + + +Dominant dystrophic EB +At birth, infancy +Hemorrhagic blisters which heal with some scarring and milia (Fig. 25.21) +Sites of trauma + + + +Minimal Present +Scarring and milia formation +Cockayne-Touraine Pasini syndrome + + +Recessive dystrophic EB +At birth +Hemorrhagic blisters which heal with scarring +(Fig. 25.22) + +Generalized + + + +Severe Present +Severe scarring; esophageal strictures +Mitis +Hallopeau-Siemens Bart syndrome Kindler syndrome + + + + + + + + + + + + + + +Fig. 25.21: Epidermolysis bullosa dominant dystrophic: Bullae heal with minimal scarring and milia formation + +simplex and dominant dystrophic EB are inherited in an autosomal dominant manner. Junctional EB and recessive dystrophic EB are inherited as autosomal recessive. + +Treatment +General measures include avoiding friction and trauma, wearing soft well ventilated shoes and gentle handling. Prompt and appropriate use of antibiotics for injuries and infected lesions is necessary. The role of vitamin E and phenytoin is doubtful. Surgery may be required for release of fused digits, correction of limb contractures and esophageal strictures. +Ectodermal Dysplasias +Ectodermal dysplasias comprise a large, heterogeneous +group of inherited disorders that are defined by primary + +Fig. 25.22: Recessive dystrophic epidermolysis bullosa: Bullae heal with scarring and there is loss of nails + +defects in the development of 2 or more tissues derived from embryonic ectoderm. The disorders can be classified based on inheritance (autosomal dominant, autosomal recessive, and X-linked) or by structures involved (hair, teeth, nails, sweat glands). + +Anhidrotic Ectoderma/ Hypoplasia +This X-linked disorder presents with intolerance to heat, episodes of high fever due to reduced ability to sweat (hypohidrosis) because of few sweat glands. The facies is districtive with prominent forehead, thick lips and a flat bridge of the nose. Additional features include thin, wrinkled, and dark-colored periorbital skin. The hair are sparse, light-colored, brittle and slow-growing. The teeth +may be absent (hypodontia) or malformed (small, conical) (Fig. 25.23). +-------------------------------------5-ki____s_o_r_de__rs____ +D +i +n + + + + + + + + + + + + + + + + + \ No newline at end of file