Clinical and genetic spectrum of 104 Indian families with central nervous system white matter abnormalities.

Genetic disorders with predominant central nervous system white matter abnormalities (CNS WMAs), also called leukodystrophies, are heterogeneous entities. We ascertained 117 individuals with CNS WMAs from 104 unrelated families. Targeted genetic testing was carried out in 16 families and 13 of them received a diagnosis. Chromosomal microarray (CMA) was performed for three families and one received a diagnosis. Mendeliome sequencing was used for testing 11 families and all received a diagnosis. Whole exome sequencing (WES) was performed in 80 families and was diagnostic in 52 (65%). Singleton WES was diagnostic for 50/75 (66.67%) families. Overall, genetic diagnoses were obtained in 77 families (74.03%). Twenty-two of 47 distinct disorders observed in this cohort have not been reported in Indian individuals previously. Notably, disorders of nuclear mitochondrial pathology were most frequent (9 disorders in 20 families). Thirty-seven of 75 (49.33%) disease-causing variants are novel. To sum up, the present cohort describes the phenotypic and genotypic spectrum of genetic disorders with CNS WMAs in our population. It demonstrates WES, especially singleton WES, as an efficient tool in the diagnosis of these heterogeneous entities. It also highlights possible founder events and recurrent disease-causing variants in our population and their implications on the testing strategy.

Novel mutations of the arylsulphatase B (ARSB) gene in Indian patients with mucopolysaccharidosis type VI.

BACKGROUND & OBJECTIVES: Mucopolysaccharidosis type VI (MPS VI) is a rare, autosomal recessive lysosomal storage disorder caused by deficient enzymatic activity of N-acetyl galactosamine-4-sulphatase resulting from mutations in the arylsulphatase B (ARSB) gene. The ARSB gene is located on chromosome 5q11-q13 and is composed of eight exons. More than hundred ARSB mutations have been reported so far, but the mutation spectrum of MPS VI in India is still unknown. Hence, the aim of the present study was to identify the mutational spectrum in patients with MPS VI in India and to study the genotype-phenotype association and functional outcomes of these mutations. METHODS: Molecular characterization of the ARSB gene by Sanger sequencing was done for 15 patients (aged 15 months to 11 yr) who were enzymatically confirmed to have MPS VI. Age of onset, clinical progression and enzyme activity levels in each patient were studied to look for genotype-phenotype association. Haplotype analysis performed for unrelated patients with the recurring mutation W450C, was suggestive of a founder effect. Sequence and structural analyses of the ARSB protein using standard software were carried out to determine the impact of detected mutations on the function of the ARSB protein. RESULTS: A total of 12 mutations were identified, of which nine were novel mutations namely, p.D53N, p.L98R, p.Y103SfsX9, p.W353X, p.H393R, p.F166fsX18, p.I220fsX5, p.W450L, and p.W450C, and three were known mutations (p.D54N, p.A237D and p.S320R). The nine novel sequence variants were confirmed not to be polymorphic variants by performing sequencing in 50 unaffected individuals from the same ethnic population. INTERPRETATION & CONCLUSIONS: Nine novel mutations were identified in MPS VI cases from India in the present study. The study also provides some insights into the genotype-phenotype association in MPS VI.

Neonatal diabetes mellitus due to a novel ABCC8 gene mutation mimicking an organic acidemia.

Neonatal diabetes mellitus and organic acidemias, may present with similar features like hyperglycemia, ketoacidosis and failure to thrive. A four-mo-old girl presented with diabetic ketoacidosis following a febrile respiratory illness during which high anion gap metabolic acidosis and hyperglycemia were detected. She also had hyperammonemia, which led to diagnostic uncertainty. Euglycemia was achieved with insulin injections. Genotyping revealed a homozygous novel mutation of the ABCC8 gene coding for the SUR1 subunit of the pancreatic beta cell potassium channel. Subsequently, the child was successfully transitioned to oral glibenclamide therapy. Developmental delay was noted on follow-up which raised the possibility of intermediate DEND syndrome. A possible cause for hyperammonemia in neonatal diabetes mellitus has been postulated in the discussion.

Are Indian parents of children with Down syndrome engaged in the blame game?

OBJECTIVES: To study blame ascription among parents of children with Down syndrome and to study its correlation with sociodemographic factors, parental perception of dysmorphisms and parents' knowledge about Down syndrome. This is a prospective, observational, non-interventional case control study. METHODS: Interview of biological parents of children with Down syndrome less than 12 y of age was taken. Dysmorphism and parents' feeling of blame was assessed and graded by Likert's scale. Controls were parents of age and gender matched children with non-genetic chronic disorders. RESULTS: During the study period, 50 mothers and 46 fathers of cases and 50 control parents were interviewed. Parents in the study group were older; the mothers were better educated and had more frequent antenatal visits. There was no significant difference in the proportion of parents counseled but genetic counseling was associated with a significantly higher proportion of parents having knowledge about Down syndrome. A higher proportion of parents perceived their child with Down syndrome being dysmorphic. Blame ascription was not significantly different among the two groups and was seen only in a small proportion of parents of cases. When it did occur, it was directed at health professionals. CONCLUSIONS: Blame ascription is not frequent in a cohort of Indian parents of children with Down syndrome even when dysmorphism is perceived by parents. Genetic counseling was associated with better knowledge about Down syndrome in the parents.

Left ventricular failure due to a rare variant of congenital adrenal hyperplasia.

"Hypertensive" variant of congenital adrenal hyperplasia is rare. The authors describe an interesting case of a 6-y-old boy who presented with an acute respiratory illness and progressive breathlessness since 1 y. Genital hyperpigmentation was noticed since 2 y of age; the onset of pubarche and increasing penile size at 4 y. He was admitted in congestive cardiac failure with a blood pressure of 150/100 mm Hg. Facial acne; slight facial, pubic hair and penile enlargement were additionally noted. Chest radiograph revealed cardiomegaly. Basal ACTH and 17-OHP levels were high. A diagnosis of congenital adrenal hyperplasia (11ß-hydroxylase deficiency) was made due to hypertension with virilized genitalia. Cardiac failure was controlled with fluid restriction and diuretics; he was started on prednisolone, spironolactone and nifedipine. This case is presented for its rarity where hypertension can cause complication of cardiac failure, if diagnosis is delayed despite early features of pseudoprecocious puberty.

Human immunodeficiency virus (HIV) infection in a child presenting as acute disseminated encephalomyelitis.

Acute disseminated encephalomyelitis is an extremely rare occurrence in human immunodeficiency virus (HIV) infection. We describe an 8-year-old male child who presented with weakness of both lower limbs for 10 days and focal convulsions for 2 days. The child had left, upper motor neuron facial palsy, lower limb hypotonia, and exaggerated deep tendon reflexes. Enzyme-linked immunosorbent assay antibodies for HIV tested positive and the CD4 count was 109 cells/µL. The magnetic resonance imaging (MRI, brain) revealed extensive confluent hyperintensities (on T2-weighted images) in left parietal, right temporal, and right occipital regions of the white matter, and similar signals were seen in right lentiform nucleus and right posterior thalami, suggesting acute disseminated encephalomyelitis. There was transient improvement with intravenous methyl prednisolone. The patient succumbed to the illness. Perinatally transmitted pediatric HIV infection presenting with acute disseminated encephalomyelitis has not yet been reported in the medical literature.

Extrapontine myelinolysis in a child with nephrotic syndrome.

Extrapontine myelinolysis is rare in children. We describe a 6-year-old girl with nephrotic syndrome who presented with symptomatic hyponatremia, and who developed acute quadriparesis with pseudobulbar palsy during rapid correction of the hyponatremia. Cranial magnetic resonance imaging demonstrated bilateral, symmetric basal ganglia lesions (extrapontine myelinolysis). The extrapontine myelinolysis was caused by rapid correction of severe and prolonged hyponatremia with intravenous 3% sodium chloride. The child demonstrated complete neurologic recovery. Prevention of this rare condition involves recognizing patients at risk for the disorder, and avoiding rapid correction of severe and prolonged hyponatremia. To the best of our knowledge, this is the first case report of extrapontine myelinolysis in a child with nephrotic syndrome.

Anterior sacral pyocele with meningitis: a rare presentation of occult spinal dysraphism with congenital dermal sinus.

The authors describe an interesting case of a hitherto asymptomatic occult spinal defect with a congenital sacral dermal sinus which proved to be the entry point for bacterial meningitis in an otherwise healthy 9-year-old female child. The patient presented with fever and neck stiffness, and a dermal sinus in the lumbosacral region was identified on examination. Cerebrospinal fluid analysis confirmed bacterial meningitis and a spinal magnetic resonance imaging scan revealed a dermal sinus tract with an anterior spinal meningocele, caudal regression syndrome, and a tethered spinal cord. In addition to administration of intravenous antimicrobial agents, surgical exploration of the sacral dermal sinus tract was performed and an anterior sacral pyocele was drained. The pyocele cavity was disconnected from the thecal sac, and the thickened and fatty filum terminale was sectioned. Although congenital sacral dermal sinus manifesting as bacterial meningitis is known, the occurrence of an anterior sacral pyocele has not yet been described in children.

Candida tropicalis endocarditis: Treatment in a resource-poor setting.

Fungal endocarditis (FE) is rare in children and does not usually occur in structurally normal hearts. The commonest causative agent is Candida albicans. We report a 5-year-old female child presenting with high-grade fever and cardiac failure. Anemia, leukocytosis and high CRP were found, but bacterial blood culture was sterile. There was no response to antimicrobial agents. Two-dimensional echocardiography revealed a large heterogeneous mass attached to the right ventricle and tricuspid valve. Provisional diagnosis of FE was made, which was confirmed by growth of Candida tropicalis in blood culture. Liposomal amphotericin B was started, followed by radical curative surgery including excision of the entire vegetation with total tricuspid valve excision. Histopathology and culture of the resected vegetation confirmed the diagnosis. The patient was given antifungal therapy for a total of 7 weeks, including 2 weeks of post-operative treatment, following which she was afebrile.

Psychological consequences in pediatric intensive care unit survivors: the neglected outcome.

OBJECTIVES: To determine whether Pediatric Intensive Care Unit (PICU) hospitalization results in adverse psychological effects and to identify the contributory factors. SETTING: Level III PICU of a tertiary center. DESIGN: Prospective cohort study. METHODS: Consecutive patients 5 years or older admitted to PICU for at least 48 hours constituted the study population. Controls were age and sex matched children hospitalized in the pediatric wards for at least 48 hours. Severity of illness was assessed by the Pediatric Risk of Mortality (PRISM) score. Level of therapeutic intervention was determined by the Therapeutic Interventions Scoring System (TISS--76 score). Temperament Measurement Schedule was used to assess the premorbid temperament. Psychological assessment was performed using Impact of Event Scale (IES), Birleson Depression Scale and the Self-Esteem Scale. Follow-up evaluation was done one month after discharge. RESULTS: There were 30 children each in the study and control groups. They had comparable pre-morbid temperament as well as scores on the self-esteem and depression scales. Significantly higher proportion of patients in PICU had intrusive thoughts (43%) as compared to controls (6.7%). Development of intrusive thoughts correlated significantly with the degree of intervention. Demographic parameters, nature of the disease, duration of hospitalization and severity of illness did not correlate with the psychological outcome. One month after discharge, scores in both groups were comparable. CONCLUSIONS: Children subjected to therapeutic interventions in the PICU develop transient psychological impairment manifested by experiencing intrusive thoughts that resolve within a month.

Wolman disease: diagnosis by leucocyte acid lipase estimation.

Wolman disease is a rare fatal autosomal recessive disorder caused by absence of acid lipase enzyme leading to accumulation of cholesterol ester. Hepatosplenomegaly is a constant feature and occurs as early as fourth day of life. Progressive mental deterioration may occur after few weeks of onset of symptoms. Adrenal calcification seen on X-ray abdomen, USG or CT scan is the hallmark of Wolman disease. For the first time in Indian literature, the authors report a case of Wolman disease that was confirmed by acid lipase enzyme estimation.

Effect of deferiprone on urinary zinc excretion in multiply transfused children with thalassemia major.

A prospective multi-centric study was conducted to determine if iron-chelating agent deferiprone also chelates zinc. Twenty four-hour urinary zinc levels were compared in multiply transfused children with thalassemia major not receiving any chelation therapy (Group A, n = 28), those receiving deferiprone (Group B, n = 30) and age and sex-matched controls of subjects in Group B (Group C, n = 29) by a colorimetric method. The 24-hour mean urinary excretion of zinc was significantly higher in Group B than in the other two groups indicating that deferiprone chelates zinc.

Rabson-Mendenhall syndrome.

Rabson-Mendenhall syndrome is characterized by growth retardation, dysmorphisms, lack of subcutaneous fat, acanthosis nigricans, enlarged genitalia, hirsutism, premature and dysplastic dentition, coarse facial features, paradoxical fasting hypoglycemia and post-prandial hyperglycemia, extreme hyperinsulinemia and pineal hyperplasia. We describe a six-month-old female child with physical features suggestive of the Rabson-Mendenhall syndrome. The child also had medullary nephrocalcinosis.

Incomplete monosymptomatic leptomeningeal angiomatosis.

Phakomatoses or neurocutaneous syndromes are an important cause of seizures in the pediatric age group. The Sturge-Weber syndrome may affect the eye, skin and brain at different times. The skin lesions need not always manifest. We report a case of isolated affection of the central nervous system in a case of Sturge-Weber syndrome in the absence of ocular or cutaneous manifestations. Our case qualifies to be called incomplete monosymptomatic leptomeningeal angiomatosis.

Anticonvulsant hypersensitivity syndrome: lymphocyte toxicity assay for the confirmation of diagnosis and risk assessment.

OBJECTIVE: To report a case of anticonvulsant hypersensitivity syndrome (AHS) precipitated by exposure to phenobarbital. CASE SUMMARY: An 11-year-old girl receiving phenobarbital developed fever, exfoliative skin rash, mucous membrane lesions, alopecia, and hepatic inflammation. Investigations ruled out an infectious etiology; an adverse event following phenobarbital administration was considered. Applying the Naranjo probability scale for objective causality assessment showed the adverse reaction was probably due to phenobarbital. The diagnosis was confirmed by in vitro lymphocyte toxicity assay, which demonstrated increased cell death following exposure to phenobarbital, as well as other aromatic anticonvulsants and lamotrigine. DISCUSSION: AHS is a rare, potentially fatal event with multisystem manifestations. It is reported following exposure to aromatic antiepileptics. The mechanism proposed for AHS is accumulation of toxic arene oxide metabolites due to a defect in epoxide hydrolase-mediated detoxification. Despite the difference in chemical structure of lamotrigine, in vitro susceptibility to AHS was demonstrated in our patient. CONCLUSIONS: Although AHS is a rare event, it should be suspected in patients who develop unexplained systemic manifestations following exposure to aromatic antiepileptics. The potential of lamotrigine to cause AHS should be remembered when this drug is used in subjects who have developed AHS on exposure to phenobarbital and other first-line antiepileptic agents.

Recurrent acute transverse myelopathy: association with antiphospholipid antibody syndrome.

A seven-year-old boy presented with a second episode of acute transverse myelopathy. The first episode had responded dramatically to methylprednisolone. The manifestations of the second episode did not respond to methylprednisolone or IVIG. He showed persistently raised levels of antiphospholipid antibodies in the serum. Primary conditions like collagen vascular diseases, malignancy, exposure to drugs and HIV infection, which are known to be associated with the raised titers of these antibodies were ruled out clinically and by investigations. Recurrent transverse myelopathy is a rare event in childhood and reports of its association with Antiphospholipid Antibody Syndrome (APLAS) are scanty. The etiological role for these antibodies remains to be established. However, once the diagnosis is established, it may be prudent to treat the condition with agents and procedures to bring about a decrease in their titers. Long-term therapy to prevent thromboembolic complications of APLAS may also be instituted.

Congenital factor VII deficiency.

A 1(1/2)-month-old baby with seizures, lethargy and refusal of feeds was diagnosed to have intracranial hemorrhage due to factor VII deficiency. MRI also demonstrated the unusual presence of a hemorrhagic infarct. The case underscores the importance of carrying out neuroimaging and appropriate hematological studies even in the absence of obvious external bleeding. Hypothesis for increased propensity for intra-cranial hemorrhage is discussed.