Consensus Statement of the Neurodevelopmental Pediatrics Chapter of Indian Academy of Pediatrics (IAP) on the Management of Children With Down Syndrome

Justification: The diagnosis of Down syndrome (DS) is easily made clinically but the management is multi-disciplinary and life-long. There is no standard protocol available for its management in India. Process: A committee was formed under the Indian Academy of Pediatrics (IAP) chapter of Neuro developmental pediatrics consisting of 20 experts working in the related field. The various aspects of the condition were discussed and allotted to the concerned experts related for preparing the guidelines. The material received was collated to form a set of guidelines, which were reviewed by the committee, and a consensus statement made. The guidelines were then approved by the chapter, and by the IAP. Objectives: To define the condition and to look into the various aspects of antenatal and postnatal diagnosis. To explain briefly about the involvement of the various systems that are involved and formulate recommendations for management. To recommend early and sustained interventional therapies to enable children with DS lead an independent life. Recommendations: The stress on bio-psycho-social strategy for the management of children with DS is reiterated, and the need for a medical, social and rights model is recommended after each section. The age-wise recommendations are also highlighted in addition to the recommendations under each system.

Mevalonate Kinase Deficiency as Cause of Periodic Fever in Two Siblings

Mevalonate kinase deficiency (MKD) is a rare autosomalrecessive autoinflammatory disease caused by mutations inMVK. We report two siblings with MKD, presenting withrecurrent febrile illnesses, detected to have compoundheterozygous variants in MVK. MKD mimics common pediatricconditions and should be considered as a differential diagnosis.

Management of Infants with Congenital Adrenal Hyperplasia

Treatment of congenital adrenal hyperplasia (CAH) requires lifelong replacement of glucocorticoids with regular follow up to manageassociated morbidities. The current review focuses on follow-up and management of infants diagnosed with classical CAH pertinent toIndian context. Early initiation of oral hydrocortisone in divided doses is recommended after diagnosis in newborn period, infancy andchildhood. Fludrocortisone is recommended for all infants with classical CAH. All infants should be monitored as per protocol fordisease and treatment related complications. The role of prenatal steroids to pregnant women with previous history of CAH affectedinfant for prevention of virilization of female fetus is controversial.

Newborn Screening and Diagnosis of Infants with Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is an autosomal recessive endocrine disorder which can manifest after birth with ambiguousgenitalia and salt-wasting crisis. However, genital ambiguity is not seen in male babies and may be mild in female babies, leading to amissed diagnosis of classical CAH at birth. In this review, we provide a standard operating protocol for routine newborn screening forCAH in Indian settings. A standardization of first tier screening tests with a single consistent set of cut-off values stratified by gestationalage is also suggested. The protocol also recommends a two-tier protocol of initial immunoassay/time resolved fluoroimmunoassayfollowed by liquid chromatography tandem mass spectrometry for confirmation of screen positive babies, wherever feasible. Routinemolecular and genetic testing is not essential for establishing the diagnosis in all screen positive babies, but has significant utility inprenatal diagnosis and genetic counseling for future pregnancy.

Molecular Testing of MECP2 Gene in Rett Syndrome Phenotypes in Indian Girls

Objective: To assess yield of MECP2 gene sequence variationsanalysis and large deletions in suspected cases of Rettsyndrome.Design: Descriptive study.Setting: Tertiary-care medical genetics center.Patients: Girls with neuroregression, postnatal microcephaly andsigns and symptoms suggestive of classical and atypical Rettsyndrome were classified into two groups. Group I consisted ofgirls with Classical and atypical Rett syndrome on basis on theRevised Rett Syndrome diagnostic criteria, 2010. Group II includedgirls with neuroregression and postnatal microcephaly and otherRett like features but not fulfilling the above criteria.Procedure: Sanger sequencing of coding regions and largedeletional analysis of MECP2 gene.Outcome measure: Identification of mutation in MECP2 gene.Result: Mutation in MECP2 gene was identified in 74% (14/19) ingroup I and none (0/17) in group II. The mutation detection ratewas 93% (13/14) in group I classical Rett syndrome girls (2 withlarge deletions identified with Multiplex ligation dependent probeamplification) and 20% (1/5) in group I atypical Rett syndromegirls. One novel MECP2 sequence variation was identified ingroup I classical Rett syndrome.Conclusion: The yield of the mutation detection in MECP2 ishigher in classical Rett syndrome. In girls with some Rett likefeatures, but not fulfilling revised Rett syndrome diagnosticcriteria, mutation testing for MECP2 gene has a low yield

Diagnostic Accuracy of MRI in Breast Cancer-A Study of 156 Cases

Background: Background- MRI helps in detection of multicentric and multifocal disease in the same breast as well as in identification of synchronous lesions in contralateral breast. MRI imaging done with dedicated breast coil and thin section imaging of the axilla is an effective tool in determining the axillary lymph node metastasis in newly diagnosed cases of breast cancer. Aims-To study those interpretation criteria of MRI that serve to increase the sensitivity and specificity of identifying non-mass like enhancement, multi centricity and nodal characteristics in breast cancer patients undergoing breast conservation surgery. Methods: Retrospective analysis of 156 patients was conducted in the Department of Radio diagnosis; Max Hospital, New Delhi, from September 2011 to June 2014. Both were correlated for tumor size, multifocality, multicentricity, extension of DCIS, nodal characteristics, extension to nipple and contralateral breast lesions. Results: In our study, detection of NMLE on MRI had a sensitivity of 89% and specificity of 78%. Lymph nodes with cortical thickening had a higher sensitivity (86% vs 65%) but lower specificity (69 % vs 89 %) than fatty hilum. Sensitivity was high for post lumpectomy with positive surgical margins and post NACT patients (100%). Conclusion: MRI has a high sensitivity in detection of breast cancer lesions. The detection of multicentric/ multifocal lesions in the same as well as contralateral breast and non-mass like enhancements is critical in deciding breast conservation surgery.

SVC Obstruction Secondary To Indwelling Central Venous Catheter – A Case Report

SVC obstruction is attributed to intraluminal and extraluminal causes. A 55 year lady, known diabetic was diagnosed with carcinoma left breast. The preoperative PET scan showed FDG avid index lesion with enlarged axillary nodes but none in neck or thorax. In this case, carcinoma breast -associated hyper coaguable state and infection may have promoted thrombus formation rather than the CVAD.

Angiosarcoma – A Case Report

Angiosarcoma is an aggressive malignant tumor of vascular origin. We present a case of secondary angiosarcoma in a 66 year old female patient, who presented with a history of left breast wide local excision with intraoperative brachytherapy.The only chance of curative treatment for secondary angiosarcoma is extensive surgery, preferably with resection of all irradiated tissue.

Diagnosis and Management of Gaucher Disease in India – Consensus Guidelines of the Gaucher Disease Task Force of the Society for Indian Academy of Medical Genetics and the Indian Academy of Pediatrics

Justification: Gaucher disease (GD) is amongst the most frequently occurring lysosomal storage disorder in all ethnicities. The clinicalmanifestations and natural history of GD is highly heterogeneous with extreme geographic and ethnic variations. The literature on GD haspaucity of information and optimal management guidelines for Indian patients.Process: Gaucher Disease Task Force was formed under the auspices of the Society for Indian Academy of Medical Genetics. Invitedexperts from various specialties formulated guidelines for the management of patients with GD. A writing committee was formed andthe draft guidelines were circulated by email to all members for comments and inputs. The guidelines were finalized in December 2016at the annual meeting of the Indian Academy of Medical Genetics.Objectives: These guidelines are intended to serve as a standard framework for treating physicians and the health care systems foroptimal management of Gaucher disease in India and to define unique needs of this patient population.Recommendations: Manifestations of GD are protean and a high index of suspicion is essential for timely diagnosis. Patients frequentlyexperience diagnostic delays during which severe irreversible complications occur. Leucocyte acid ?-glucosidase activity ismandatory for establishing the diagnosis of Gaucher disease; molecular testing can help identify patients at risk of neuronopathicdisease. Enzyme replacement therapy for type 1 and type 3 Gaucher disease is the standard of care. Best outcomes are achieved byearly initiation of therapy before onset of irreversible complications. However, in setting of progressive neurological symptoms such asseizures and or/ neuroregression, ERT is not recommended, as it cannot cross the blood brain barrier. The recommendations herein arefor diagnosis, for initiation of therapy, therapeutic goals, monitoring and follow up of patients. We highlight that prevention of recurrenceof the disease through genetic counseling and prenatal diagnosis is essential in India, due to uniformly severe phenotypes encounteredin our population

Ghosal Type Hematodiaphyseal Dysplasia.

Background: Ghosal Type Hematodiaphyseal Dysplasia is an autosomal recessive disorder characterized by refractory anemia and diaphyseal bone dysplasia. Case characteristics: A 3 y 9 mo-old male child presented with progressive anemia and bowing of thighs. Child was found to have a previously reported homozygous point mutation c.1238G>A, (p.Arg413Glu) in Exon 16 of TBXAS1 gene. Outcome: Low dose steroid therapy resulted in normalization of hemoglobin and prevented further progression of bony changes. Message: Refractory anemia in association with bony deformities should prompt pediatricians to investigate for inherited bony dysplasia.

Biologicals in Juvenile Idiopathic Arthritis.

We share our experience with biological agents in children with juvenile idiopathic arthritis with an aim to highlight the adverse events and response to treatment. Out of a total of 10 children treated with biological agents, one patient had serious infection, all showed good response and none had tuberculosis. High cost was limiting factor for their use.

ADRB2 Polymorphism and Salbutamol Responsiveness in Northern Indian Children with Mild to Moderate Exacerbation of Asthma.

Objectives: The primary objective was to determine the association between beta-2 adrenergic receptor (ADRB2) gene polymorphism (rs1042713, c.46A>G, p.Arg16Gly) and the response to inhaled salbutamol in North Indian children aged 5 to 15 years, with mild to moderate exacerbation of asthma. Methods: This cross-sectional study was done at a tertiary-care hospital in Northern India from June 2011 to May 2013. 120 children with asthma with mild to moderate exacerbation underwent spirometry at baseline and after administration of three doses of salbutamol. An increase in FEV1 ³15% was considered as positive response. Blood samples from these children were analysed for ADRB2 polymorphism (p.Arg16Gly). 94 non-asthmatic adult controls were also studied to determine the prevalence of ADRB2 polymorphism. Results: In asthmatic children, the frequency of AA, GG, AG genotypes were 24.2%, 24.2% and 51.7% compared to 20.2%, 20.2 % and 59.6%, respectively in the non-asthmatic adults. Salbutamol responsiveness showed no correlation with the studied ADRB2 polymorphism (p= 0.55). A trend towards greater bronchodilator responsiveness amongst AA genotype, compared to GG genotype was observed (Median change in percent predicted FEV1 14.5% and 7.5%, respectively). Conclusions: No correlation was found between salbutamol responsiveness and ADRB2 genotype in Northern Indian children with asthma with mild-to moderate exacerbation.

Clinical profile and mutation analysis of xeroderma pigmentosum in Indian patients.

Background: Xeroderma pigmentosum (XP) is an autosomal recessive genetic disorder characterized by cutaneous and ocular photosensitivity and an increased risk of developing cutaneous neoplasms. Progressive neurological abnormalities develop in a quarter of XP patients. Aim: To study the clinical profile and perform a mutation analysis in Indian patients with xeroderma pigmentosum. Methods: Ten families with 13 patients with XP were referred to our clinic over 2 years. The genes XPA, XPB and XPC were sequentially analyzed till a pathogenic mutation was identified. Results: Homozygous mutations in the XPA gene were seen in patients with moderate to severe mental retardation (6/10 families) but not in those without neurological features. Two unrelated families with a common family name and belonging to the same community from Maharashtra were found to have an identical mutation in the XPA gene, namely c.335_338delTTATinsCATAAGAAA (p.F112SfsX2). Testing of the XPC gene in two families with four affected children led to the identification of the novel mutations c.1243C>T or p.R415X and c.1677C>A or p.Y559X. In two families, mutations could not be identified in XPA, XPB and XPC genes. Limitation: The sample size is small. Conclusion: Indian patients who have neurological abnormalities associated with XP should be screened for mutations in the XPA gene.

Establishing National Neonatal Perinatal Database and Birth Defects Registry Network – Need of the Hour.

Early detection and prevention of birth defects is necessary to further reduce neonatal morbidity and mortality. A birth defect registry or surveillance system is necessary to assess the exact magnitude, profile and modifiable risk factors for birth defects. We review the existing efforts and suggest possible options for addressing this important issue. Connecting birth defects registry with the pre-existing programs such as National Neonatal Perinatal Database could be one of the option.

Fluorescence in situ hybridization (FISH) using non-commercial probes in the diagnosis of clinically suspected microdeletion syndromes.

Background & objectives: Microdeletion syndromes are characterized by small (<5 Mb) chromosomal deletions in which one or more genes are involved. These are frequently associated with multiple congenital anomalies. The phenotype is the result of haploinsufficiency of genes in the critical interval. Fluorescence in situ hybridization (FISH) technique is commonly used for precise genetic diagnosis of microdeletion syndromes. This study was conducted to assess the role of FISH in the diagnosis of suspected microdeletion syndrome. Methods: FISH was carried out on 301 clinically suspected microdeletion syndrome cases for the confirmation of clinical diagnosis using non-commercial probes. Of these, 177 cases were referred for 22q11.2 microdeletion, 42 cases were referred for William syndrome, 38 cases were referred for Prader Willi/Angelman and 44 cases were referred for other suspected microdeletion syndromes. Results: FISH was confirmatory in 23 cases only (7.6%). There were 17 cases of 22q11.2 microdeletion, four cases of Prader Willi syndrome and two cases of William syndrome. Interpretation & conclusion: We conclude that FISH should not be the method of choice for clinically suspected microdeletion syndromes. We propose to follow strict clinical criteria for FISH testing or preferably to follow better methods (genotype first approach). Whole genome screening may be used as first line of test and FISH may be used for confirmation of screening result, screening of family members and prenatal diagnosis.

Mutation Analysis of Indian Patients with Urea Cycle Defects.

Molecular testing for a specific metabolic disorder remains the gold standard due to its high specificity and sensitivity and possibility of accurate prenatal diagnosis. We report four cases of urea cycle defect where mutational analysis of the involved genes was performed and subsequently, prenatal diagnosis could be offered to one of the family.