Deflazacort dose optimization and safety evaluation in Duchenne muscular dystrophy (DOSE): A randomized, double-blind non-inferiority trial.

BACKGROUND: US food and drug administration has recently approved deflazacort for Duchenne muscular dystrophy (DMD) and recommended the dosage of 0.9 mg/kg/d for patients aged ≥5years. However, data assessing the minimal efficacious dose and need of dose-titration based on age or disease severity is limited. OBJECTIVE: To determine whether deflazacort 0.45 mg/kg/d (proposed lower dosage) is non-inferior to 0.9 mg/kg/d among newly diagnosed patients with DMD. METHOD: A double-blinded, non-inferiority, randomized trial, conducted between December 2018 and July 2020. Newly diagnosed patient aged 5-15 years with genetic or muscle biopsy confirmed DMD and baseline 6-min walk distance (6MWD) > 150 m were screened. Patients were randomly assigned (1:1), stratified to prespecified subgroups by age (≤7years and >7years), and baseline 6MWD (≤350 m and >350 m), to receive either 0.45 mg/kg/d or 0.9 mg/kg/d regimens. The primary endpoint was the change in 6MWD, from baseline to week-24 of intervention. The trial was powered with a predefined, non-inferiority margin of 30 m. The analyses were by modified intention-to-treat (mITT). RESULT: A total of 97 patients were enrolled, 40 receiving 0.45 mg/kg/d and 45 receiving 0.9 mg/kg/d deflazacort comprised of mITT population. For primary endpoint analysis the mean (SD) change in 6MWD from baseline to week-24 was 9.7 m (41.5) in deflazacort 0.45 mg/kg/d, and 34.7 m (43.5) for 0.9 mg/kg/d. The mean difference in change in 6MWD across the group was 24.8 m (95% CI 6.7 to 43, p value 0.008). The mean difference in change in 6MWD in the subgroups of boys ≤7 years of age was 21.8 m (95% CI -0.82, 44.5, p = 0.059), with baseline 6MWD of >350 m was 19.9 m (95% CI -2.4, 42.4; p = 0.08). The incidence of combined moderate to severe treatment-related adverse events was significant in the 0.9 mg/kg/d group by week 24 (odds ratio 0.36 [95% CI, 0.14 to 0.89], p = 0.03). DISCUSSION: The efficacy of proposed low dose deflazacort in comparison to the standard dose did not meet the prespecified criteria for non-inferiority. The low dose deflazacort was non-inferior in subgroup of patients with age ≤7 years and baseline 6MWD of >350 m. TRIAL REGISTRATION: Clinical Trial Registry-India Identifier: CTRI/2019/02/017388.

Seven novel genetic variants in a North Indian cohort with classical homocystinuria.

Classical homocystinuria is the most common cause of isolated homocystinuria. The variants of the CBS gene remain unidentified in Indian children with this disorder. Based on the hallmark clinical features, family history, and/or biochemical clues for classical homocystinuria, 16 children below the age of 18 years were evaluated by Sanger sequencing of the coding exons of CBS gene with flanking intronic regions. The common C677T variant of the MTHFR gene was also screened by restriction fragment length polymorphism. Fifteen children were clinically suspected of having classical homocystinuria and one asymptomatic child with positive family history. Only seven children had biochemical features of classical homocystinuria. Sanger sequencing of the CBS gene confirmed 15 different pathogenic or likely pathogenic variants in 14 cases. Of these, seven variants were novel (three frameshift deletions, two nonsense, one missense, one splice site variant) and were predicted to be deleterious by Mutation Taster software. Seven cases were homozygous, another six were compound heterozygous, and one case was single heterozygous in the study. None of the three most frequent mutations reported worldwide viz., I278T, G307S, and IVS 11-2A>C were found in our cohort. No variants were detected in the exons 2, 8, 12, and 14 as compared to reported literature. Eleven out of 15 variants were associated with the conserved catalytic domain of the CBS polypeptide. The MTHFR polymorphism C677T was observed in heterozygous state in six cases. Our study reports the detailed genotype and seven novel variants in the CBS gene, causing classical homocystinuria in Indian children. The genetic analysis will help to offer accurate genetic counseling, prenatal diagnosis, and development of mutation-based novel therapeutic strategies.

Management Strategies of Melkersson-Rosenthal Syndrome: A Review.

Melkerrson-Rosenthal syndrome is a rare disorder of unknown aetiology and characterized by the triad of oro-facial edema, facial nerve palsy, and furrowing of the tongue. Two or more of the above are essential for making a clinical diagnosis. The mainstay of treatment is corticosteroids. Intralesional triamcinolone acetonide may be used for the treatment of oro-facial edema. Another treatment option for oro-facial edema includes intralesional betamethasone, along with oral doxycycline. The review discusses the management strategies in Melkersson-Rosenthal syndrome.

Recurrent Streptococcus pneumoniae meningitis and Mondini dysplasia: Association or causation?

Mondini dysplasia is a developmental disorder of the inner ear structures and it is a rare cause of recurrent bacterial meningitis in children. A 10-year-old boy presented with acute febrile encephalopathy and right ear pain. In the past, he had suffered from two distinct episodes of pyogenic meningitis. On examination, he had signs of meningeal irritation and right ear sensorineural deafness. Magnetic resonance imaging of the brain and computerized tomography of the temporal bone was suggestive of Mondini dysplasia in the right ear. Our case highlights the need for (a) screening of hearing loss at the bedside by Rinne and Weber test in case of recurrent bacterial meningitis (b) searching for an underlying inner ear malformation if there is a hearing loss.

Systemic cryptococcosis in an immune-competent child.

Crytococcus neoformans is an encapsulated yeast that frequently affects immune-compromised patients, although increasingly being detected in the immune-competent host as well. We report a case of disseminated cryptococcosis in a young child in whom no immune deficiency was yet identified. A 4-year-old child presented with high-grade fever, intermittent abdominal pain and generalized skin eruptions for the past two months. He had pallor, firm lymphadenopathy, skin lesions with scarring and firm hepatosplenomegaly. Magnetic resonance imaging of brain and bone-marrow aspiration were normal. Fine-needle-aspiration-cytology of cervical lymph nodes demonstrated Cryptococcus. Serum latex-agglutination test showed a positive titer (1:256). Cryptococcus culture was sterile. The patient received intravenous liposomal amphotericin-B and oral flucytosine for 8 weeks followed by oral fluconazole. Disseminated cryptococcosis with involvement of reticuloendothelial and dermatological systems is rare. Early diagnosis and timely management of associated complications would be life saving.

Racemose neurocysticercosis.

Racemose neurocysticercosis refers to the 'aberrant proliferating cestode larvae" presenting as multiple, non-capsulated cystic membranes that bud exogenously giving a multilocular cystic appearance resembling a 'bunch of grapes'. These are typically located in non-confining areas of brain such as cisterns and lack scolex, contrast-enhancement or edema. We describe a 12-year-old boy with acute-onset headache, vomiting, drowsiness and irrelevant speech, irritability, meningismus, brisk muscle-stretch-reflexes and Babinski's sign. Magnetic resonance imaging brain revealed racemose neurocysticercosis. He received ventriculo-peritoneal shunt, oral corticosteroids and albendazole for 4 weeks. Racemose cysts in neurocysticercosis are a rare presentation in children. Treatment is difficult.Racemose neurocysticercosis refers to the 'aberrant proliferating cestode larvae" presenting as multiple, non-capsulated cystic membranes that bud exogenously giving a multilocular cystic appearance resembling a 'bunch of grapes'. These are typically located in non-confining areas of brain such as cisterns and lack scolex, contrast-enhancement or edema. We describe a 12-year-old boy with acute-onset headache, vomiting, drowsiness and irrelevant speech, irritability, meningismus, brisk muscle-stretch-reflexes and Babinski's sign. Magnetic resonance imaging brain revealed racemose neurocysticercosis. He received ventriculo-peritoneal shunt, oral corticosteroids and albendazole for 4 weeks. Racemose cysts in neurocysticercosis are a rare presentation in children. Treatment is difficult.

CNS vasculitis and stroke in neonatal lupus erythematosus: a case report and review of literature.

Neonatal lupus erythematosus refers to the clinical spectrum of cardiac, cutaneous and other systemic abnormalities in neonates born to mothers with autoantibodies against Ro/SSA and La/SSB antigens. Isolated central nervous system involvement is very rare and has been described as transient vasculopathy only. We describe a 2-months-old girl who presented with acute ischemic stroke secondary to central nervous system vasculitis without any cardiac, cutaneous or hematological manifestations. The mother was pauci-symptomatic with raised anti-Ro autoantibody titers; the baby was positive for autoantibodies against Ro-antigen. Angiography confirmed vasculitis in cerebral vasculature. Our case highlights that neonatal lupus erythematosus can present with isolated nervous system manifestations and the vascular damage can be permanent in the form of vasculitis. Early recognition will help pediatricians identify such possible permanent complications in newborns with neonatal lupus erythematosus. A review of previously reported central nervous system manifestations of neonatal lupus is also presented.

Ependymal brain cyst with posterior cerebral artery infarct.

Primary intracranial ependymal cysts are congenital, benign, ependyma-lined cysts rarely seen in the pediatric age group. The authors report such a case of intracranial fronto-parietal ependymal cyst in a 3 y-old girl. Computed tomography showed a large cystic lesion which was not in communication with the ventricular system and was associated with ipsilateral posterior cerebral artery infarct and raised intracranial pressure causing midline shift. A differential diagnosis of the commoner arachnoid, hydatid or porencephalic cyst was considered. Surgical removal to decompress the brain was done; histopathology revealed an ependymal cyst. Identification of this rare pathology in the pediatric age group is emphasized with a review of the literature.

Pulmonary Alveolar Microlithiasis in Children: Case Series and Review of Literature.

Pulmonary alveolar microlithiasis is rare in children. It presents as a chronic disease with early asymptomatic course and is usually idiopathic. Characteristic radiology and high index of suspicion can lead to early diagnosis by lung biopsy. Treatment with drugs targeting phosphate metabolism may be beneficial. We present a series of 3 pediatric cases confirmed by lung biopsies, along with review of literature.