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Introduction: The Alsin Rho Guanine Nucleotide Exchange Factor ( ALS2) gene encodes a protein alsin that functions as a guanine nucleotide exchange factor. The variations in ALS2 gene leads to degeneration of upper motor neurons of the corticospinal tract. The phenotypes resulting from variants in ALS2 gene are infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM # 607225), juvenile primary lateral sclerosis (JPLS, OMIM # 606353), and juvenile amyotrophic lateral sclerosis (JALS, OMIM # 205100). Our study objectives were to describe the clinical phenotype and genotype of children with an established diagnosis of ALS2 gene-related disorder., Methods: The clinical details, laboratory data, and genotype findings of children with an established diagnosis of ALS2 gene-related disorder were collected from the hospital electronic database after obtaining institutional review board approval., Results: One family with three affected siblings, a second family with a proband and an affected fetus, and a third family with two affected siblings with ALS2 gene variants were identified. IAHSP was diagnosed in all of our patients with variants in ALS2 gene. The clinical findings observed in our patients were insidious onset progressive spastic paraparesis, contractures, and dysarthria. Nonsense variants were observed in four patients while frameshift variant was observed in one family. Novel variants in ALS2 gene were identified in two unrelated families., Conclusion: ALS2 mutation results in rare neurodegenerative disorders with the clinical spectrum encompassing IAHSP, JPLS, and JALS disorders. In view of allelic heterogeneity described in the literature, more research studies are needed for establishing genotype-phenotype correlation in patients with ALS2 gene-related disorder., Competing Interests: None declared., (Thieme. All rights reserved.)

Hyperhomocysteinemia is a rare neurometabolic syndrome with diverse manifestations in the pediatric age group, thereby posing a diagnostic challenge. Biochemical testing is imperative to guide plan of evaluation, which may include appropriate genetic testing, in inherited disorders. Through this case-based approach, we demonstrate the heterogeneity of clinical presentation, biochemical and genetic evaluation, and treatment strategies that may reverse this condition among children., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: A neurological assessment before discharge from the NICU would enable early targeted intervention to mitigate the risk and severity of cerebral palsy (CP) and neurodevelop-mental disability., Objective: To assess the accuracy of general movements (GM) in the preterm and fidgety movement periods in predicting neurodevelopmental disability and cerebral palsy in very preterm infants (≤32 weeks gestational age) at 18-24 months corrected gestational age., Study Design: Prospective cohort study., Participants: One hundred and seventy very preterm infants, mean (SD) gestation 29.8 (1.32) weeks, and birthweight 1215 (226) g., Outcomes: Infants underwent GM assessments in the preterm period (31-36 weeks post-conception age) and fidgety movement period (8-18 weeks post term age). Neurodevelop-mental outcomes were assessed in 127 children using the Griffiths Mental Developmental Scales-2., Results: Nine children had neurodevelopmental disability (two infants with cerebral palsy and seven with global developmental delay. The relative risk (95% CI) for neurodevelopmental disability was 1.46 (0.31-6.89) with preterm movements and 6.07 (0.97 - 38.05) with fidgety movements. Sensitivity and specificity values for the prediction of neurodevelopmental disability were 33% and 64% in the preterm period and 25% and 92% in the fidgety movement period, respectively. The sensitivity and specificity values for prediction of CP were 50% and 63% in the preterm period and 100% and 93% in the fidgety movement period, respectively., Conclusion: Preterm movements showed lower sensitivity and specificity than fidgety movements in predicting later CP and neurodevelopmental disability in preterm infants.

We report here two girls from different Indian families identified with novel variants in the AT Hook DNA Binding Motif Containing 1 gene (AHDC1) causing Xia-Gibbs syndrome. The diagnosis was made by clinical exome in both cases. Inconsistent dysmorphic features such as dolichocephaly in the first patient and brachycephaly in the second were observed. Prominent jaw and gelastic seizures were other features of patient 1. Thus, this syndrome, with developmental delay, poor expressive language and overlapping clinical phenotype requires the utility of next generation sequencing for diagnostic confirmation., (© 2022 Wiley Periodicals LLC.)

Justification: Global developmental delay (GDD) is a relatively common neurodevelopmental disorder; however, paucity of published literature and absence of uniform guidelines increases the complexity of clinical management of this condition. Hence, there is a need of practical guidelines for the pediatrician on the diagnosis and management of GDD, summarizing the available evidence, and filling in the gaps in existing knowledge and practices., Process: Seven subcommittees of subject experts comprising of writing and expert group from among members of Indian Academy of Pediatrics (IAP) and its chapters of Neurology, Neurodevelopment Pediatrics and Growth Development and Behavioral Pediatrics were constituted, who reviewed literature, developed key questions and prepared the first draft on guidelines after multiple rounds of discussion. The guidelines were then discussed by the whole group in an online meeting. The points of contention were discussed and a general consensus was arrived at, after which final guidelines were drafted by the writing group and approved by all contributors. The guidelines were then approved by the Executive Board of IAP., Guidelines: GDD is defined as significant delay (at least 2 standard deviations below the mean with standardized developmental tests) in at least two developmental domains in children under 5 years of age; however, children whose delay can be explained primarily by motor issues or severe uncorrected visual/hearing impairment are excluded. Severity of GDD can be classified as mild, moderate, severe and profound on adaptive functioning. For all children, in addition to routine surveillance, developmental screening using standardized tools should be done at 9-12 months,18-24 months, and at school entry; whereas, for high risk infants, it should be done 6-monthly till 24 months and yearly till 5 years of age; in addition to once at school entry. All children, especially those diagnosed with GDD, should be screened for ASD at 18-24 months, and if screen negative, again at 3 years of age. It is recommended that investigations should always follow a careful history and examination to plan targeted testing and, vision and hearing screening should be done in all cases prior to standardized tests of development. Neuro-imaging, preferably magnetic resonance imaging of the brain, should be obtained when specific clinical indicators are present. Biochemical and metabolic investigations should be targeted towards identifying treatable conditions and genetic tests are recommended in presence of clinical suspicion of a genetic syndrome and/or in the absence of a clear etiology. Multidisciplinary intervention should be initiated soon after the delay is recognized even before a formal diagnosis is made, and early intervention for high risk infants should start in the nursery with developmentally supportive care. Detailed structured counselling of family regarding the diagnosis, etiology, comorbidities, investigations, management, prognosis and follow-up is recommended. Regular targeted follow-up should be done, preferably in consultation with a team of experts led by a developmental pediatrician/ pediatric neurologist.

Competing Interests: There are no conflicts of interest.

Competing Interests: There are no conflicts of interest.

Aicardi-Goutieres Syndrome (AGS) is a heterogeneous genetic syndrome, manifesting early as encephalopathy and is associated with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, thrombocytopenia and intracranial calcification. The most severe neonatal type, AGS1, is caused by biallelic disease-causing variants in TREX1. In this study, we describe four patients with TREX1-related AGS1 whose phenotype overlaps with intra-uterine infections and neonatal lupus. Exome sequencing identified a previously reported TREX1 variant, c.223dup (NM_016381.5; p. Glu75GlyfsTer82) in all the four patients belonging to the Indian subcontinent. The functional consequence of the disease-causing variant was predicted by using a new combination of bioinformatics softwares. The recurrence of this pathogenic variant indicates a possible founder effect in TREX1 for AGS1 in this population. The phenotypic variability in those with this founder mutation can mimic intrauterine infections and neonatal lupus, thereby leading to misdiagnosis warranting a targeted genetic testing approach to be a part of the diagnostic workup to obtain a definite, early and cost-effective diagnosis in patients from Indian subcontinent with early onset encephalopathy., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Competing Interests: There are no conflicts of interest.

Background and Aims: Cutaneous lesions are the defining features of several neurocutaneous syndromes like neurofibromatosis1(NF1), tuberous sclerosis complex (TSC), and Sturge Weber syndrome to name a few. With this background, we explored the possibility of identifying congenital and nevoid cutaneous markers that may help in the early recognition of autism spectrum disorders (ASD) in Indian children. The objective of this study was to measure the strength of association between congenital and nevoid cutaneous lesions and ASD among Indian children., Methods: A case-control study was conducted from January 2018 to June 2018. 132 children (18 months-16 years of age) with ASD and equal number of age and sex-matched children without autism were studied. Diagnosis of ASD was based on DSM-5 criteria. All the children were examined for cutaneous lesions with special attention to nevoid and congenital conditions. The strength of association was measured using the diagnostic odds ratio (OR)., Results: The prevalence of congenital and nevoid lesions were higher in ASD group (OR = 3.12, P = 0.0001). Among them, pigmentary mosaicism of hyperpigmented type (OR = 2.76, P = 0.02) and café-au-lait macules (CALMs) (OR = 2.40, P = 0.001) were the most prevalent with hyperpigmented pigmentary mosaicism showing a higher association with autism. Atypical CALMs (OR = 2, P = 0.09) were also more prevalent in the ASD group though not statistically significant., Conclusion: The presence of hyperpigmented pigmentary mosaicism and CALMs warrant closer surveillance by the caregivers and physicians for evolving features of autism. Larger multicentric studies are required to validate these findings., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Indian Dermatology Online Journal.)

Competing Interests: There are no conflicts of interest.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of gamma-aminobutyric acid metabolism. Children with SSADH deficiency usually manifest with developmental delay, behavioral symptoms, language dysfunction, seizures, hypotonia, extrapyramidal symptoms, and ataxia. Diagnosis of SSADH deficiency is established by an abnormal urine organic acid pattern, including increased excretion of 4-hydroxybutyric acid and the identification of biallelic pathogenic variants in aldehyde dehydrogenase 5 family, member A 1 ( ALDH5A1 ) gene. Here, we describe a 15-month-old girl with SSADH deficiency presenting with developmental delay, language deficits, and acute-onset right hemiparesis, following recovery from a diarrheal illness. Brain magnetic resonance imaging revealed hyperintense signal changes involving the left globus pallidus in T2-weighted images with restriction of diffusion in the diffusion-weighted images. Increased excretion of 4-hydroxybutyric acid, threo-4,5-dihydroxyhexanoic acid lactone and erythro-4,5-dihydroxyhexanoic acid lactone was detected by urine organic acid analysis and a diagnosis of SSADH deficiency was confirmed by the identification of homozygous pathogenic variant in ALDH5A1 . Stroke mimic is a novel presentation in our patient with SSADH deficiency. She was initiated on treatment with vigabatrin and has shown developmental gains with the recovery of right hemiparesis. Follow-up neuroimaging shows near complete resolution of signal changes in the left globus pallidus, while there was subtle hyperintensity in the right globus pallidus. The phenotypic spectrum of SSADH deficiency is widely expanding, and this disorder should be considered in the differential diagnosis of children with metabolic stroke., Competing Interests: There are no conflicts of interest., (Copyright: © 2006-2020 Annals of Indian Academy of Neurology.)

Objective: To determine the prevalence and risk factors for poor neurodevelopmental outcome in a cohort of very low birth weight (VLBW) infants., Subjects and Methods: Four hundred and twenty-two infants of a total of 643 VLBW survivors from a teaching hospital in South India were followed up to assess their neurodevelopmental outcomes., Results: Among the 422 children who completed the assessment, results of 359 children whose assessments were done between 18 and 24 months were analysed. Thirty-seven children (10.31%) had poor neurodevelopmental outcome, six children [1.67%] had cerebral palsy, one child had visual impairment and another had hearing impairment. Poor post-natal growth was independently associated with poor neurodevelopmental outcomes in the multivariate analysis (p = 0.045). Neonatal complications were not associated with the developmental outcome., Conclusion: Despite lower rates of neonatal complications compared with Western cohorts, significant proportion of VLBW infants had poor neurodevelopmental outcomes. Poor post-natal growth was an important determinant of the developmental outcome., (© The Author(s) [2019]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a frequent adverse event (AE) associated with mTOR inhibitor therapy and can impact treatment adherence. The objectives are to evaluate two steroid-based mouthrinses for preventing/ameliorating mIAS in patients with metastatic breast cancer (MBC) treated with everolimus., Materials and Methods: This prospective, randomized phase II study enrolled 100 postmenopausal patients with hormone receptor-positive MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor + everolimus (AIE; 10 mg/day). Patients were randomized to prophylactic therapy with one of two oral rinses (Arm 1: Miracle Mouthwash [MMW] 480 mL recipe: 320 mL oral Benadryl [diphenhydramine; Johnson & Johnson, New Brunswick, NJ, USA], 2 g tetracycline, 80 mg hydrocortisone, 40 mL nystatin suspension, water; or Arm 2: prednisolone [P] 15 mg/5 mL oral solution, 1.8% alcohol). Patients were instructed to swish/expectorate 10 mL of the assigned rinse for 1-2 minutes four times daily starting with day 1 of AIE treatment, for the first 12 weeks., Results: A total of 100 patients received treatment (49 MMW; 51 P). The incidence of stomatitis/oral AEs during the first 12 weeks was 35% ( n  = 17/49) and 37% (19/51) in the MMW and P arms, respectively. The incidence of grade 2 oral AEs was 14% (7/49) and 12% (6/51) with MMW or P, respectively. There were two grade 3 oral AEs (MMW arm) and no grade 4 events. There was one everolimus dose reduction (MMW) and six dose delays (four MMW, two P) and one dose reduction + delay (MMW) during the first 12 weeks of treatment. No patients stopped steroid mouthwash therapy because of rinse-related toxicity., Conclusion: Prophylactic use of steroid-containing oral rinses can prevent/ameliorate mIAS in patients with MBC treated with AIE. MMW + hydrocortisone is an affordable option, as is dexamethasone oral rinse., Implications for Practice: This prospective phase-II study showed that two steroid-containing mouthrinses substantially reduced incidences of all-grade and grade ≥2 stomatitis and related oral adverse events (AEs), and the number of everolimus dose-delays and/or dose-reduction in metastatic breast cancer (MBC) patients receiving everolimus treatment plus an aromatase inhibitor. Both oral rinses were well tolerated and demonstrated similar efficacy. Prophylactic use of steroid mouth rinse provides a cost-effective option that substantially decreases the incidence and severity of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis and related oral AEs as well as the need for dose modification in MBC patients undergoing treatment with an mTOR inhibitor., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Nutritional deficiencies related neurological manifestations are not uncommon in infants and children. Here, we describe an infant with Vitamin B12 deficiency due to depleted maternal Vitamin B12 status presenting with progressive encephalopathy and extrapyramidal signs. Diagnosis of infantile tremor syndrome was established in our patient based on the clinical and biochemical parameters. Magnetic resonance imaging had shown frontotemporal atrophy with widened Sylvian fissures and prominent cerebrospinal fluid spaces. Clinical and imaging findings might create a diagnostic dilemma with glutaric aciduria type I. Knowledge and identification of infantile tremor syndrome are essential, as it is a potentially treatable disorder. Our patient had significant developmental gains with Vitamin B12 treatment and infant stimulation program. Vitamin B12 deficiency must be looked for as a cause of neuroregression in children hailing from low socioeconomic status, infants of vegetarian mother, and infants with delayed or improper weaning. Screening for Vitamin B12 deficiency is essential in all infants and children with unexplained neuroregression, as this disorder is potentially treatable. More population-based studies in India are needed to explore the prevalence of Vitamin B12 deficiency in pregnant and lactating women and also to assess the need for Vitamin B12 supplementation during pregnancy and lactation., Competing Interests: There are no conflicts of interest.

Objective: To determine the effect of association of dysembryogenesis (manifested by presence of dysmorphic markers) on the developmental profile of autistic children., Methods: 26 autistic children were classified into complex autism (if they had specific dysmorphic markers) or essential autism (in the absence of dysmorphic markers) using the Miles Autism Dysmorphology Measure (ADM). The developmental abilities (Griffith's Mental Development Scales) and the clinical severity (Childhood Autism Rating Scale) of both groups were compared. The prevalence of dysmorphic markers was also determined in 140 non-autistic controls., Results: Children with complex autism had poorer development (General Quotient 29.4 vs 34.0, P=0.06) and earlier onset of autistic symptoms (18 vs 24 mo, P=0.05). Dysmorphic markers were significantly more in autistic children compared to normal children (27% vs 10%, P=0.002)., Conclusion: Dysembryogenesis may contribute to the clinical heterogeneity of autistic children.

The cri du chat syndrome (CdCS) is a chromosomal deletion syndrome associated with a partial deletion of the short (p) arm of chromosome 5. We describe five children who were diagnosed to have CdCS by conventional cytogenetic analysis. The deletion was at 5p15 in four patients, whereas the fifth had a larger, more proximal deletion at 5p14. Fluorescence in situ hybridization (FISH) analysis confirmed the deletion of the CdCS critical region at 5p15.2. All five children had global developmental delay and dysmorphism with microcephaly. The other clinical features were variable. Since the clinical diagnosis of CdCS may not always be evident because of the phenotypic heterogeneity, cytogenetic analysis is necessary to establish the diagnosis and confirm that the deletion involves the CdCS critical region. This will enable early intervention which plays an important role in improving the outcome.

Pallister-Killian syndrome (PKS; OMIM: # 601803) is a rare sporadic genetic disorder characterized by pigmentary skin changes, distinctive dysmorphology, developmental delay, and mosaicism for tetrasomy of chromosome 12p. The authors report a case of PKS in a 2-y-old boy. He had pigmentary skin changes, characteristic facial features, developmental delay and hearing loss. He had sacral and post-auricular pits in addition, which has not yet been reported. A diagnosis of PKS was suspected on the basis of the patient's clinical features. Skin fibroblast culture was done which showed mosaic tetrasomy of isochromosome 12p consistent with Pallister-Killian syndrome. This case highlights the importance of dysmorphology as a diagnostic tool for recognition and accurate genetic counseling in genetic syndromes.

Malignant hyperthermia (MH) is a rare complication that often leads to adverse outcomes, catastrophic events, or death. Although various risk factors and underlying diseases are associated with this condition, unusual presentations may be missed. Malignant hyperthermia is an uncommon complication encountered during the treatment of patients with diabetic ketoacidosis. We present a case of an MH-like syndrome in a young Hispanic man who was diagnosed with new-onset diabetes mellitus and hyperglycemic hyperosmolar nonketotic state. The patient had no obvious risk or precipitating factors for MH.

Background: Oral rehydration solution (ORS) for treatment of diarrhea relies on enhancement of small intestinal sodium and fluid absorption to correct dehydration. Amylase-resistant starch added to ORS significantly reduced the duration and severity of diarrhea in adults with cholera, presumably by generation of short-chain fatty acids in the colon and enhancement of colonic sodium and fluid absorption. The present study was initiated to determine whether addition of amylase-resistant starch to standard World Health Organization glucose-ORS (G-ORS) would reduce the duration of diarrhea and fecal fluid losses in children with acute diarrhea., Methods: One hundred eighty-three children (6 months to 3 years) with acute watery diarrhea were randomized to receive either standard treatment with G-ORS or G-ORS with additional amylase-resistant starch, HAMS (HAMS-ORS, 50g/L). Stool weight and consistency were monitored serially until development of formed stool or development of treatment failure defined as either the need for unscheduled intravenous fluid therapy or diarrhea longer than 72 hours., Results: Five of the subjects were lost to follow up. In 178 remaining children (87 HAMS-ORS and 91 G-ORS) with evaluable data, time from enrolment to last unformed stool was significantly less in children receiving HAMS-ORS (median, 6.75 hours; 95% confidence interval, 4.27-9.22) than in children treated with G-ORS (12.80 hours, 8.69-16.91) (P = 0.0292). Time to first formed stool was also significantly shorter in children receiving HAMS-ORS (median, 18.25 hours; 95% confidence interval, 13.09-23.41) compared with children receiving G-ORS (median, 21.50 hours; 95% confidence interval, 17.26-25.74) (P = 0.0440). The total amount of ORS consumed was similar in both groups. There was a trend toward lower mean stool weight in first 24 hours (P = 0.0752) as well as total diarrheal stool weight (P = 0.0926) in patients in the HAMS group compared with the G-ORS group., Conclusion: In children with acute diarrhea, the addition of amylase-resistant starch to glucose ORS significantly shortened duration of diarrhea compared with standard treatment.

Acute pancreatitis is a rare but known complication of inflammatory bowel disease in adults. In children, only a few cases with this complication have been reported. We describe a 10-year-old boy with ulcerative colitis who developed acute pancreatitis while on long-term treatment with 5-aminosalicylic acid.