Sheetal Sharda

Intravenous pamidronate therapy in osteogenesis imperfecta: response to treatment and factors influencing outcome.

Pamidronate treatment has been shown to improve outcome in osteogenesis imperfecta (OI); however, factors influencing outcome are unclear. The present study was conducted to evaluate the response to pamidronate therapy with special emphasis on factors influencing outcome. Twenty children with OI treated with pamidronate were evaluated in a prospective, open clinical trial. Pamidronate (9 mg · kg−1 · yr−1) was administered intravenously at the age of 4.5 ± 4.2 years for 2.9 ± 0.7 years (range, 2-3.8 years). Treatment led to increase in bone mineral density (BMD) Z score by 0.7 ± 0.3 every year resulting in significant improvement in BMD Z score (from −4.6 ± 1.1 to −2.5 ± 1.1, P < 0.001). BMD Z score was within the reference range (>−2) in 9 subjects (45%) at the last follow-up as against none at initiation of treatment (P < 0.001). Fracture rate decreased significantly during treatment (3.3 ± 1.4 to 0.8 ± 0.9, P < 0.001) with 8 subjects (40%) having no fracture during the treatment period. Significantly greater proportion (88.2%) of children were able to walk at last follow-up compared with those at initiation of treatment (45.4%). Increase in BMD Z score and final BMD Z score was not influenced by age at initiation of treatment, duration of treatment, or initial BMD Z score. Treatment before infancy (n = 7) was associated with higher final subjective score (6.3 ± 0.5 vs 4.9 ± 1.5, P = 0.03). Our study reiterates the efficacy of pamidronate in OI. The poorer response of our subjects may be related to compromised calcium and vitamin D status.

Recurrent and novel GLB1 mutations in India.

GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in the GLB1 gene, leading to the deficiency of the enzyme β-d-galactosidase. In this study, we report molecular findings in 50 Asian Indian families with GM1 gangliosidosis. We sequenced all the exons and flanking intronic sequences of GLB1 gene. We identified 33 different mutations (20 novel and 13 previously reported). The novel mutations include 12 missense (p.M1?, p.E129Q, p.G134R, p.L236P, p.G262E, p.L297F, p.Y331C, p.G414V, p.K493N, p.L514P, p.P597L, p.T600I), four splicing (c.246-2A>G, c.397-2A>G, c.552+1G>T, c.956-2A>G), three indels (p.R22Qfs*8, p.L24Cfs*47, p.I489Qfs*4) and one nonsense mutation (p.Q452*). Most common mutations identified in this study were c.75+2InsT (14%) and p.L337P (10%). Known mutations accounted for 67% of allele frequency in our cohort of patients, suggesting that these mutations in GLB1 are recurrent across different populations. Twenty three mutations were localized in the TIM barrel domain, β-domain 1 and β-domain 2. In silico sequence and structure analysis of GLB1 reveal that all the novel mutations affect the function and structure of the protein. We hereby report on the largest series of patients with GM1 gangliosidosis and the first from India.

Spontaneous hematomyelia in a child with hemophilia A: a case report.

Hemorrhagic complications in patients with hemophilia have been occasionally reported in the spinal column and the spinal cord. Treatment is based on prompt replacement therapy as the occurrence and development of neurologic dysfunction are related to the length of time between the onset of symptoms and the factor replacement. We report case of a 7-year-old hemophilic boy who presented with flaccid paraparesis resulting from thoracic hematomyelia. The patient showed gradual improvement on medical management with cryoprecipitate infusions. This case calls attention to the need for prompt diagnosis of rarely reported spinal hematomyelia based on clinical manifestations and radiologic features and highlights its management options in patients with hemophilia.

Defect of Cobalamin Intracellular Metabolism Presenting as Diabetic Ketoacidosis: A Rare Manifestation

Hypoglycemia is the usual feature of commonly occurring organic acidemias. Organic acidemias manifesting as hyperglycemia or diabetic ketoacidosis are rare and only a few cases have been reported. We report a 13-month-old boy who presented with vomiting, dehydration, coma, hyperglycemia, high anion gap metabolic acidosis and ketosis, mimicking diabetic ketoacidosis (DKA). Treatment with parenteral fluid, electrolytes, and insulin infusion resulted in an improvement in hyperglycemia, but persistence of metabolic acidosis and lack of improvement of neurologic status led us to suspect an organic acidemia. Urinary organic acid analysis revealed increased methylmalonic acid levels. In addition, hyperhomocysteinemia and homocystinuria were also noted in presence of normal vitamin B12 levels. This confirmed the diagnosis of cobalamin metabolism defect leading to combined methylmalonic aciduria and homocystinuria. There was some improvement in neurologic status and metabolic parameters after treatment with low-protein diet, vitamin B12, folic acid, and L-carnitine, but he ultimately succumbed to polymicrobial nosocomial sepsis. The entire MMACHC gene of the patient was sequenced and no mutations were identified. This is probably the first case report of cobalamin intracellular metabolism defect (CblC/CblD/CblF/CblJ or ABCD4) presenting as diabetic ketoacidosis.

Report of two brothers with short stature, microcephaly, mental retardation, and retinoschisis—A new mental retardation syndrome?†

Involvement of genes on the X‐chromosome as a cause of mental retardation has been recognized for a long time. X‐linked phenotypes of mental retardation have been divided into non‐syndromic and syndromic based on associated manifestations. At present, more than 140 syndromic X‐linked mental retardation (XLMR) conditions have been reported and a causative gene mutation has been identified in almost half of these. Here, we report on two brothers with short stature, microcephaly, severe mental retardation, and retinoschisis. Results of karyotype analysis, fragile‐X and neuroimaging studies were normal. Fundus examination showed bilateral retinoschisis at variable stages in both sibs. X‐linked retinoschisis is a retinal dystrophy caused by mutations in the RS1 gene at Xp22.1, which lead to splitting of the neural retina and reduced visual acuity in affected men. However, as yet there have been no reports of mental retardation in X‐linked retinoschisis although genetic loci for XLMR and short stature have been mapped to Xp22.1. Sequencing and microarray analysis failed to find any alteration of RS1 gene or copy number alteration in the region. In addition, genotype analysis of Xp22.1 provided evidence against linkage to this region. The associated findings of retinoschisis and mental retardation in two brothers suggest a new mental retardation syndrome likely to be an X linked trait.

Zellweger syndrome: prenatal and postnatal growth failure with epiphyseal stippling.

Abstract We present a 2-month-old male affected by Zellweger syndrome, a rare peroxisomal disorder. The diagnosis was supported by clinical and radiological findings and established by biochemical tests. The characteristic radiological features included anomalous ossification (epiphyseal stippling). We also discuss main differential diagnoses of epiphyseal stippling and a brief literature review.

Shwachman-Diamond syndrome in India.

To the Editor: A 4-year-old male presented with fever and pallor for 2 months. There was history of bulky and greasy stool, starting from infancy. This complaint had resolved spontaneously over time. The child was born to a non-consanguineous couple. A brother, aged 7 years, was healthy. The patient was wasted and stunted. Besides pallor, widespread skin petechiae and gingivitis were observed. Blood counts revealed pancytopenia: Hb 6.4 g/dl, WBC 1.4 10/L, ANC 112 10/L, and platelet count 2 10/L. Bone marrow was hypocellular with no excess of blasts. Stool microscopy showed fat globules (>100/high power field). CT-scan demonstrated the pancreas to be replaced by fatty tissue. Biochemical tests for liver and renal function, sweat chloride test, serum immunoglobulins, skeletal survey, and echocardiography were normal. Direct sequence analysis of exon 2 region of Shwachman–Bodian–Diamond Syndrome (SBDS) gene revealed the patient to be homozygous for c.258 þ 2T > C and

Concentrations of leptin, adiponectin and other metabolic parameters in non-obese children with Down syndrome

Abstract Background: Recent data indicates that adults with Down syndrome (DS) are at increased risk for cardiovascular disease (CVD) that significantly contributes to their morbidity and mortality. Although identification of cardiometabolic risk factors during childhood is desirable to design preventive interventions, the data on such risk factors in children with DS is scarce. The aim of this study was to study the cardiometabolic risk factors such as insulin resistance (IR), leptin and adiponectin concentrations, lipid abnormalities and leptin resistance in non-obese children with DS. Methods: This cross-sectional case control study included karyotype confirmed trisomy-21 DS children aged 2–12 years and their matched healthy controls. After detailed anthropometry, weight, height and body mass index (BMI) standard deviation scores (SDSs) were calculated with reference data. Laboratory evaluation included determination of fasting lipid parameters, insulin, glucose, leptin and adiponectin concentrations. The homeostasis model assessment method (HOMA-IR) was used to assess IR and the ratio of leptin to BMI was used as an index of leptin resistance. Results: Seventy-seven children (39 with DS and 38 controls) comprised the study cohort. The anthropometric parameters were similar in the two groups. Children with DS showed significantly higher mean leptin concentrations (2.098±1.68 ng/mL vs. 1.44±0.52 ng/mL, p-value: 0.00) and higher indices of leptin resistance (0.127±0.085 vs. 0.09±0.03, p-value: 0.001) as compared to controls. Fasting adiponectin concentrations were lower (20.64±19.87 ng/mL vs. 32.58±34.25 ng/mL, p-value: 0.21) and fasting glucose higher (89.25±8.12 mg/dL vs. 85.71±5.52 mg/dL, p-value: 0.06) in the DS group as compared to the controls but the differences did not reach statistical significance. The concentrations of insulin, various lipid parameters and calculated HOMA-IR values were similar in the two groups. In the DS group, five children were identified to have high (>75th centile) leptin levels and four as impaired fasting glucose as compared to none in the controls. Conclusions: Alterations of several cardiometabolic risk factors, in particular, leptin concentrations and leptin resistance are present in children with DS. The presence of hyperleptinemia without hyperinsulinemia suggests a probable inherent genetic basis for increased leptin resistance in patients with DS. There is a need for larger studies to further understand increased leptin resistance in DS that may contribute to increased CVD related morbidity and mortality in these patients.

An Indian girl with Fanconi-Bickel syndrome without SLC2A2 gene mutation

Fanconi-Bickel syndrome is a rare autosomal-recessive disorder caused by defects in the facilitative glucose transporter 2 (GLUT2) gene. It is characterized by hepatorenal glycogen accumulation, tubular nephropathy and impaired utilization of glucose and galactose. In this communication, we present the case of a 5-year-old girl who presented with deforming rickets and massive hepatomegaly. Liver biopsy confirmed the diagnosis of glycogen storage disorder. However, the mutation of the SLC2A2 (GLUT2) gene was not found. Mutation negative patients with characteristic Fanconi-Bickel syndrome phenotype suggest additional underlying mechanisms that need exploration.

Hypophosphatemic rickets caused by a novel PHEX gene mutation in an Indian girl.

Abstract We report a girl who presented with clinical and biochemical features of hypophosphatemic rickets. Mutational analysis detected a heterozygous nonsynonymous sequence variation in exon 11 of the PHEX gene (NM_000444.4:c.1216T>C, NP_000435.3:p.Cys406Arg). This previously undescribed PHEX mutation is probably the cause of renal phosphate wasting in our patient that resulted in rickets.