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.

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.

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.

Down syndrome: clinical profile from India.

BACKGROUND: Our objective was to study demographic features, clinical features, and karyotype analyses of patients with Down syndrome (DS). Our study design was a retrospective analysis, while the study was conducted in the Genetic Clinic of a tertiary-care teaching hospital. METHODS: Retrospective analysis of cases referred to the Genetic Clinic was performed. Case proformas of the patients presenting with phenotypic features of DS were analyzed. The following information was recorded from the proformas: age at presentation; sex; maternal age; craniofacial and other physical features; presence and type of congenital heart disease; gastrointestinal abnormalities, and results of cytogenetic evaluation. Clinical features in neonates with DS were separately analyzed. RESULTS: Analysis included cases of DS presenting over a period of 7.5 years; a total of 524 patients were studied (303 males and 221 females; M:F ratio 1.37:1). Average age at presentation was 19.4 months (range: 1 day-26 years). Average maternal age at birth of the affected child was 26.8 years (range: 16-45 years). Craniofacial features noted in >50% of the cases included mongoloid slant (83.9%), ear abnormalities (66.9%), epicanthic folds (56.9%), and flat facial profile (50.9%). A total of 76.3% cases had hypotonia. Characteristic limb and dermatoglyphic anomalies were seen in less than one half of cases. These included sandle sign (46.2%), unilateral or bilateral simian crease (33.2%), clinodactyly (36.1%), and brachydactyly (11.1%). Ophthalmologic abnormalities included hypertelorism (33.9%), nystagmus (3.2%), Brushfield spots (3.2%), squint (2.7%), and cataracts (1.9%). Congenital heart disease was clinically diagnosed in 96 cases (18.3%). The nature of the cardiac defect was ascertained by color Doppler examination and/or 2D-echocardiography in 58 cases. The most common cardiac anomalies were ventricular septal defect (25.8%), tetralogy of Fallot (15.5%), and atrial septal defect (12.1%). Gastrointestinal anomalies were noted in seven cases and included three cases with imperforate anus, two with Hirschsprung disease, and one each with duodenal atresia and Morgagni hernia. Results of cytogenetic abnormalities were available in 42.2%. Free trisomy (non-dysjunction) was present in 95%, 3.2% had translocation, and 1.8% were mosaics. In neonates, common features noted were mongoloid slant, ear abnormalities, flat facial profile, hypotonia, sandle sign, and clinodactyly+/-brachydactyly. CONCLUSIONS: All characteristic craniofacial and physical features of DS need not be present in every case. Major features noted in the present study were mongoloid slant, ear abnormalities, epicanthic folds, flat facies, and hypotonia. Congenital heart disease was present in 18.3% of cases, with ventricular septal defect being the most common type of defect. Non-dysjunction was the most common cause of the chromosomal anomaly.

Trisomy 21 with XYY.

A case of double aneuploidy involving chromosome 21 and Y is reported in an eight-month-old infant with developmental delay and failure to thrive. Patient had all classical phenotypical features of trisomy 21 except, absence of epicanthal folds. The diagnosis was confirmed by cytogenetic study performed on peripheral blood leucocyte culture using G-banding. Literature review revealed only 17 cases of XYY and trisomy 21 reported so far. No such case is reported in Indian literature. Relevant literature is reviewed and possible effects of trisomy 21 on XYY and that of XYY on trisomy 21 has been discussed. A routine chromosomal study even in patient with classical features of Down syndrome has been advocated. Interestingly, our patient also had left to right shunts at atrial and ductal level and tricuspid regurgitation. Given the rarity of the disorder and scanty published data the incidence, phenotype and recurrence risk are difficult to establish.

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.

Mycotic aneurysm: an uncommon cause for intra-cranial hemorrhage.

Intra-cranial mycotic aneurysms due to an infective process elsewhere in the body constitute an uncommon cause of intra-cranial hemorrhage. The condition carries a grave prognosis. Mycotic aneurysms secondary to infective endocarditis (IE) rarely occur in children. This communication describes a seven-year-old girl who presented with fever and neurological abnormalities. She was diagnosed to have a mycotic aneurysm secondary to IE. Digital subtraction angiography (DSA) confirmed the diagnosis, delineated anatomical details and later detected the complete resolution of the aneurysm following conservative management with intravenous antimicrobial agents.

Kocher-Debre-Semelaigne syndrome: hypothyroidism with muscle pseudohypertrophy.

Kocher-Debre-Semelaigne syndrome is a rare association of muscular pseudohypertrophy and hypothyroidism in children. We report two cases of this syndrome in this communication. The first case was a seven-years-old female who presented with features of hypothyroidism and muscle pseudohypertrophy. The second child had similar manifestations but was only fifteen months of age at diagnosis. This is one of the youngest patients reported to have the Kocher-Debre-Semelaigne syndrome. A short review of the literature is also presented.

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.

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.

Neonatal Bartter syndrome.

A case of neonatal Bartter syndrome is reported. The baby born pre-term following a pregnancy complicated by polyhydramnios, presented at 7 months of age with failure to thrive, gastroenteritis and facial dysmorphisms. An unusual feature was the absence of the classical biochemical abnormality of hypochloremic alkalosis early in the course of the disease. Metabolic acidosis was the initial manifestation at 5 weeks of age. Awareness of this presentation is important to avoid delay in diagnosis and treatment.

Congenital and inherited ophthalmologic abnormalities.

OBJECTIVE: To identify genetic disorders associated with ophthalmologic abnormalities; type and frequency of various ophthalmologic abnormalities associated with selected genetic and inherited disorders; and devise a suitable classification for ophthalmologic abnormalities. METHODS: Pediatric cases referred with mental retardation, congenital malformations and suspected genetic and metabolic disorders were enrolled prospectively. Relevant clinical details (including an ophthalmologic examination) and investigations were recorded. RESULT: Of the 1308 patients enrolled, 679 (51.9%) had ophthalmologic abnormalities. 458 cases (67.45%) out of these 679 had mental retardation and 20 (2.94%) had neuroregression. Environmental (12.22%) and chromosomal anomalies (10.9%) were the largest etiological groups. Down syndrome was the commonest of the chromosomal anomalies and mongoloid slant and epicanthic folds were its commonest ophthalmologic features. Mucopolysaccharidoses (21.4%), Wilson disease (19.64%), oculocutaneous albinism (16.07%) and lipid storage disorders (14.29%) were the most common inborn errors of metabolism associated with ophthalmologic abnormalities. Of the 39 cases with Mendelian inheritance of disorders, autosomal dominant disorders (56.41%) were the commonest associated with ocular abnormalities. A simple anatomical classification has been devised for various ophthalmologic abnormalities encountered (wherein, positional and adnexal abnormalities were the commonest). CONCLUSION: Up to 50% of cases referred to the genetic services have ophthalmologic abnormalities. Conditions including chromosomal abnormalities, metabolic disorders, Mendelian syndromes and environmental factors are associated with ocular abnormalities. Anatomically, positional and adnexal abnormalities are the commonest.

Neurological complications of rabies vaccines.

The rabies vaccines containing neural elements are used in some countries including India. We report three cases that presented with various neurological complications following the use of these vaccines. The presenting manifestations included those of encephalitis, radiculitis and acute inflammatory demyelinating polyradiculoneuropathy. These neurological complications are highlighted so that scientific evidence compels the community to discontinue the use of the neural tissue rabies vaccines. Newer generation cell culture rabies vaccines should be preferred over the neural tissue rabies vaccines for post-exposure prophylaxis.

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.