Diagnosis and Management of Global Development Delay: Consensus Guidelines of Growth, Development and Behavioral Pediatrics Chapter, Neurology Chapter and Neurodevelopment Pediatrics Chapter of the Indian Academy of Pediatrics

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. Neuroimaging, 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.

Blood heavy metal levels in children with attention deficit hyperactivity disorder: an unsolved enigma

Background: The role of heavy metals in the etio-pathogenesis of attention deficit hyperactivity disorder (ADHD) is a burning enigma. The available studies with discordant results are from different geographical localities with different monitoring, regulations and sociocultural backgrounds. The differential association of heavy metals with ADHD severity and phenotypes has not been adequately examined. Also, there are concerns about laboratory quality control. Therefore, the present case control study was formulated.Methods: Thirty children with ADHD diagnosed by DSM IV criteria and thirty group age matched controls were enrolled. Detailed perinatal, past, developmental and possible exposure history to various heavy metals was taken. Severity of ADHD was assessed using ConnersTM Parent reporting questionnaire. Blood level of metals was estimated by inductively coupled plasma- atomic emission spectroscopy (ICP-AES).Results: The mean blood lead, mercury, cadmium, arsenic, zinc were comparable in children with ADHD and group age matched controls. The mean blood lead, mercury and cadmium levels in study population was higher than found in studies from developed countries. Elevated arsenic, mercury and cadmium were found in both cases and controls. Blood zinc correlated significantly with inattention T score and blood mercury with hyperactivity-impulsitivity T score of Conners parent rating scale. Blood cadmium was present in greater proportion of predominant hyperactive-impulsive type patients.Conclusions: Zinc deficiency correlates with inattention; cadmium and mercury toxicity correlate with hyperactivity. Mean blood levels of heavy metals is elevated in a substantial proportion of study population. So, there is an urgent need for sensitization and environmental control.

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.

Aquagenic Wrinkling of Skin: A Screening Test for Cystic Fibrosis

Objectives: To study the utility of aquagenic wrinkling asscreening test for children with cystic fibrosis.Design: Evaluation of diagnostic test.Setting: Pediatric Chest Clinic, and Pediatric Wards of a tertiarycare hospital in New Delhi.Participants: Three groups (children with cystic fibrosis,carriers of cystic fibrosis, and controls).Method: Time taken to develop aquagenic wrinkling wasmeasured. The test was performed by asking the enrolled subjectto put their one hand in water and was checked for development ofwrinkling every minute, and a photograph was also taken everyminute.Results: A total of 64 children with cystic fibrosis, 64 controls and64 carriers were enrolled in the study. Median (IQR) time todevelop aquagenic wrinkling in the three groups was 2 (1.5,3)minutes, 4 (3,5) minutes and 8 (5,11) minutes, respectively. Theoptimal cut-off was calculated as 3 minutes by Receiveroperating characteristic curve with a sensitivity and specificityfor identification of children with cystic fibrosis as 81% and 57%,respectively. The area under curve was 76.5%. The 3 minutecut-off for development of aquagenic wrinkling was applied to 54children referred for sweat test. 20 children had sweat chloridevalues of ≥60 mEq/l and diagnosed as cystic fibrosis. 15 of thesedeveloped aquagenic wrinkling at ≤3 minutes, giving a sensitivityof 75%.Conclusion: In places with no facility for sweat test, childrenwith phenotype compatible with cystic fibrosis who developaquagenic wrinkling in 3 minutes may be diagnosed as probablecystic fibrosis and referred for confirmation by sweat tes

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

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.

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.

Prenatal Screening: Perspective for the Pediatrician.

Pediatricians are the first contact of a child with genetic disorders such as Down Syndrome. After diagnosis, parents often express and wish that if it was possible to detect it during pregnancy and could it be avoided in the future pregnancy. This makes it essential that pediatricians should have some idea about the basic screening methods and strategy used during pregnancy.

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.

Disseminated Cryptococcosis.

Background: Fungal infections, especially in immunocompetent children are uncommon causes of fever of unknown origin. Case characteristics: A 5-year-old boy with prolonged fever and no evidence of immunosuppression. Observation: Ultrasound-guided retroperitoneal lymph node biopsy showed granulomas and intracytoplamic fungal yeasts; staining charactristics were suggestive of cryptococci. Clinical and radiological improvement was seen after treatment with amphoterecin-B. Outcome: Disseminated fungal infection should be suspected as a cause of pyrexia of unknown origin after ruling out the commoner causes. Biopsy from enlarged lymph node or organomegaly may yield the diagnosis when non-invasive tests fail.

Intellectual Disability in Indian Children: Experience with a Stratified Approach for Etiological Diagnosis.

Objective: To study the clinico-etiological profile of children with intellectual disability using an algorithmic approach. Design: Cross-sectional study. Setting: Tertiary care centre in Northern India. Participants: Consecutive children aged 3 months to 12 years, presenting with intellectual disability, confirmed by Developmental Assessment Scale for Indian Infants, Binet Kulshreshtha Test and Vineland Social Maturity Scale. Method: All children were assessed on an internally validated structured proforma. A targeted approach included thyroid function tests, Brainstem evoked response audiometry, electroencephalogram, neuroimaging and metabolic screen done as a pre-decided schema. Genetic tests included karyotyping, molecular studies for Fragile X, Multiplex Ligation Dependent Probe Amplification and Array Comparative Genomic Hybridisation. Results: Data of 101 children (median age 22 months) was analyzed. The etiological yield was 82.1% with genetic causes being the most common (61.4%) followed by perinatal acquired (20.4%), CNS malformations (12%), external prenatal (3.6%), and postnatal acquired (2.4%). Mild delay was seen in 11.7%, moderate in 21.7%, severe in 30.6% and profound in 35.6%. Conclusion: It is possible to ascertain the diagnosis in most of the cases of intellectual disability using a judicious and sequential battery of tests.

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.

Incidence of Acute Kidney Injury in Hospitalized Children.

Objective: To determine the incidence and outcome of acute kidney injury (AKI) in hospitalized patients. Design: Prospective, observational. Setting: Tertiary care center in North India. Participants/patients: Inpatients, 1 month to 18-yr-old. Intervention: None. Main Outcome Measures: Incidence of AKI based on the serum creatinine criteria proposed by the AKI Network. Results: During February to September 2008, thirty nine of 108 (36.1%) critically ill patients and 34 of 378 (9.0%) patients who were not critically ill developed AKI (P <0.001); the respective incidence densities were 45.1 and 11.7 cases/1000 patient days, respectively. The maximal stage of AKI was stage 1 in 48 (65.8%) patients, stage 2 in 13 (17.8%) and stage 3 in 12 (16.4%) patients; 11 (15.1%) required dialysis. Patients with AKI had a significantly longer duration of hospital stay (9 days vs 7 days, P<0.02) and higher mortality (37% vs 8.7%; hazard ratio, HR 2.73; 95% CI 1.64, 4.54). Independent risk factors for AKI were young age (HR 0.89; 95% CI 0.83, 0.95), shock (HR 2.65; 95% CI 1.32, 5.31), sepsis (HR 3.64; 95% CI 2.20, 6.01), and need for mechanical ventilation (2.18; 95% CI 1.12, 4.26). Compared to patients without AKI, the mortality was higher for AKI stage 2 (HR 5.18; 95% CI 2.59, 10.38) and stage 3 (HR 4.34; 95% CI 2.06, 9.16). Shock was an independent risk factor for mortality (HR 10.7; 95% CI 4.96, 22.98). Conclusions: AKI is common in critically ill children, especially younger patients with septicemia and shock, and results in increased hospital stay and high mortality.

Alpha 1 Antitrypsin Deficiency in Children with Chronic Liver Disease in North India.

Objective: We attempted to determine the role of alpha-1- antitrypsin (AAT) deficient variants as an etiologic factor for chronic liver disease in North Indian children. Design: This study investigated 1700 children (682 retrospectively and 1018 prospectively) (840 CLD, 410 neonatal cholestasis and 450 without liver disease) for AAT deficiency. Setting: Tertiary referral center, All India Institute of Medical Sciences, New Delhi. Patients: Of 1250 liver disease patients, 98 (7.8%) were suspected to be AAT deficient on the basis of screening tests (low serum AAT levels and/or absent/faint alpha-1- globulin band on serum agarose electrophoresis and/or diastase resistant PAS positive granules on liver biopsy). Main outcome measures: AAT deficient Z or S allele in suspected patients. Results: Z or S allele was not observed on phenotyping (1700 subjects), or with PCR-RFLP, SSCP and sequencing done in 50 of 98 suspected AAT deficient patients. A novel mutation G-to-A at position 333 in exon V was found in two siblings having positive immunohistochemistry for AAT on liver biopsy, both of whom had significant liver disease with portal hypertension. Conclusion: In conclusion, AAT deficiency as an etiologic factor for chronic liver disease in childhood appeared to be uncommon in North India.