Clinical profile and thiamine transporter gene (SLC19A2 and SLC19A3) variations in infants with thiamine-responsive pulmonary hypertension and acute respiratory infection.

Maternal thiamine deficiency is prevalent in low- and middle-income countries. Thiamine-responsive pulmonary hypertension (TRPHTN) in exclusively breastfed infants is reported in India. Thiamine transporter gene (ThTR) variations have not been studied. This study compared the presentation of exclusively breastfed infants with respiratory distress diagnosed as TRPHTN or acute respiratory infection (ARI). We investigated pathogenic variations in the SLC19A2 and SLC19A3 ThTr genes in a representative sample. Observational study. Tertiary care pediatric unit of a teaching hospital in southern India. Data collection was prospective. We included exclusively breastfed infants between 1 and 6 months of age with respiratory distress. Infants with PHTN in echocardiography and lactic acidosis (LA) received thiamine. TRPHTN was diagnosed based on response within 72 h. Infants with fever, chest findings, and positive microbiology were managed as ARI. The ThTr genes were sequenced and analyzed. Chi-square and stratified analysis were done to determine TRPHTN risk. Forty infants with TRPHTN and 42 with ARI were included. The median pulmonary arterial pressure in the TRPHTN group was 51.5 mmHg. Mild PHTN was seen in 65%, moderate in 22.5%, and severe in 12.5%. Cardiac failure (P < .001), stridor and aphonia (P < .001), encephalopathy (P = .024), LA (P < .001), and PHTN (P <.001) facilitated the diagnosis. The adjusted risk was 17.3 (95% confidence interval 7.8-38.3; P <.001). The ThTR sequencing showed wild-type genotypes. TRPHTN has a distinct, identifiable presentation. Lactate and pulmonary pressure estimations are useful investigations in thiamine deficiency endemic areas. We could not demonstrate a genetic variation that determines susceptibility.

Trichobezoars in children - A psychological perspective.

Trichobezoars or hairballs in the gastrointestinal tract occur as a complication of trichotillomania or compulsive hair pulling, and trichophagia, or compulsive eating of hair. The DSM-5 classifies trichotillomania as an obsessive-compulsive spectrum disorder. In this case series of four children with trichobezoar, we present the varied psychopathology that led to the same and discuss the current literature on complex issues underlying trichotillomania.

Nuclear Mitochondrial Disorder Due to a Variant in NAXE in Two Unrelated Indian Children.

Progressive encephalopathy with brain edema and/or leukoencephalopathy type 1 (PEBEL1) is a nuclear mitochondrial disorder involving the NAD(P)HX repair mechanism due to a NAXE variation. PEBEL1 is characterized by rapid neurologic deterioration culminating in death following high-grade fever during infancy. Currently, 23 patients from 14 families are described in the literature, with only three survivors. The authors report two living children from unrelated families with PEBEL1. Both children presented in infancy with ptosis, squint, and ataxia with no skin manifestations. Whole-exome sequencing revealed previously reported c.804_807delInsA (p.Lys270del) variation in exon 6 of NAXE. This is the first Indian report of PEBEL1.

Tissue plasminogen activator receptor ANXA2 and its complementary regulator anti-inflammatory ANXA1 as prognostic indicators of inflammatory response in COVID-19 pathogenesis.

COVID-19 patients demonstrating hyperactive immunologic response appear to have a severe illness with a poor prognosis. This study hypothesizes that the pro-inflammatory Annexin A2 (ANXA2) has role in COVID-19 pathogenesis. In thisobservational study, serum levels of ANXA2 along with interleukin 1 beta (IL1ß), IL6, tumour necrosis factor-alpha (TNFα), and anti-inflammatory ANXA1 were determined by sandwich ELISA in 20 each control, mild, moderate, and severe COVID-19 subjects.The ANXA2 levels (130 ng/mL, p < 0.001) were significantly elevated in severe COVID-19 subjects, compared to mild, moderate and controls. Similarly, all the other pro-inflammatory biomarkers levels were also significantly correlated with disease severity (p < 0.0001). However, ANXA1 showed significantly negative correlation with disease severity (p < 0.0001). Furthermore, the pro-inflammatory ANXA2 showed utility in mortality prediction with 86% sensitivity and specificity, and 57% positive predictive value at a serum threshold of 94 ng/mL. Overall,ANXA2 and ANXA1 along with IL1ß, IL6, TNFα, would be beneficial biomarkers in assessing the COVID-19 severity and mortality prediction.

Acute Bacterial Meningitis and Petrous Apicitis in a Child with Aplasia Cutis Congenita: A Case Report.

Petrous apicitis and acute bacterial meningitis are uncommon in the present antibiotic era. The diagnosis of petrous apicitis is seldom considered unless there is cranial nerve palsy. A young child with aplasia cutis congenita presented with acute bacterial meningitis and an incidental opacified left mastoid in brain imaging. During the course, fever persisted, and high-resolution temporal bone imaging showed rapid progression to coalescent mastoiditis, petrous apicitis with erosions of tegmen tympani, and petrous apex. Other findings included bony dehiscences and thinning of left calvaria. Tympanomastoid exploration showed herniated brain and cerebrospinal fluid leak through tegmen tympani, which was closed with temporalis fascia graft. Herein, we report a rare presentation of petrous and tegmen erosion along with aplasia cutis congenita and discuss the challenges in diagnosis and management.

Exome Sequencing in Monogenic Forms of Rickets.

OBJECTIVE: To understand the phenotypic and genotypic spectrum of genetic forms of rickets in 10 families. METHODS: Detailed clinical, radiographic, and biochemical evaluation of 10 families with phenotypes suggestive of a genetic cause of rickets was performed. Molecular testing using exome sequencing aided in the diagnosis of six different forms of known genetic causes. RESULTS: Eleven disease-causing variants including five previously reported variants (CYP27B1:c.1319_1325dup, p.(Phe443Profs*24), VDR:c.1171C>T, p.(Arg391Cys), PHEX: c.1586_1586+1del, PHEX: c.1482+5G>C, PHEX: c.58C>T, p.(Arg20*)) and six novel variants (CYP27B1:c.974C>T, p.(Thr325Met), CYP27B1: c.1376G>A, p.(Arg459His), CYP2R1: c.595C>T, p.(Arg199*), CYP2R1:c.1330G>C, p.(Gly444Arg),SLC34A3:c.1336-11_1336-1del, SLC2A2: c.589G>C, p.(Val197Leu)) in the genes known to cause monogenic rickets were identified. CONCLUSION: The authors hereby report a case series of individuals from India with a molecular diagnosis of rickets and provide the literature review which would help in enhancing the clinical and molecular profile for rapid and differential diagnosis of rickets.

Inborn error of metabolism precipitated by COVID-19: challenges in the absence of an expanded newborn screening as state health programmes.

Inborn errors of metabolism constitute a differential diagnosis in infants presenting with encephalopathy in developing countries where expanded newborn screening is not a state health programme. Acute neurological presentation with encephalopathy is documented in paediatric COVID-19. The pandemic has also altered parents' healthcare-seeking behaviour, leading to delays in emergency care. We illustrate the challenges faced in diagnosing and managing an 18-month-old child who presented with acute metabolic crisis due to methylmalonic acidaemia on the background of the COVID-19 pandemic. We discuss the current global status of expanded newborn screening services for inborn error of metabolism and the impact of the pandemic on the healthcare of children.

Smokeless Tobacco Exposure and Fetal Iron Status: An Analytical Study.

Objectives: To compare the cord serum ferritin and fetal iron status in newborns with and without maternal occupational smokeless tobacco exposure and determine the influencing factors. Methods: This cross-sectional study included mother-infant dyads with occupational tobacco exposure (exposed) and an unexposed group. Umbilical cord serum ferritin was compared in both groups. Fetal nicotine absorption was established by cord cotinine. Results: A total of 140 newborns each were analyzed in each group. There was no significant mean difference (MD) (P = 0.900) between the cord serum ferritin in the tobacco exposed and unexposed group. Fetal nicotine absorption was seen in 43.6% of the exposed group. Cord serum ferritin was 14.1 µg/L (95% confidence interval [(95% CI:-43.1, 14.9); P=0.338] lower in this group compared with the group without fetal nicotine absorption. A higher adjusted MD for ferritin was present for maternal hypertension (12.5 [95% CI: -75.5, 100.5]; P = 0.777) and gestational diabetes mellitus (21.4 [95% CI: -54.0, 96.9]; P = 0.571) in the group with fetal nicotine absorption. Fetal nicotine absorption exaggerated fetal iron depletion in maternal anemia [aOR 4.8 (95%CI: 1.2, 19.0); P=0.025]. Conclusion: Cord serum ferritin and fetal iron status were comparable in tobacco exposed and unexposed groups. In those with fetal nicotine absorption, cord ferritin levels reflect the fetal inflammatory state.

Phenotypic and Molecular Heterogeneity in Mandibulofacial Dysostoses: A Case Series From India.

OBJECTIVE: Facial dysostosis is a group of rare craniofacial congenital disabilities requiring multidisciplinary long-term care. This report presents the phenotypic and genotypic information from South India. DESIGN: The study is a case series. SETTING: This was an international collaborative study involving a tertiary craniofacial clinic and medical genetics unit. PATIENTS, PARTICIPANTS: The participants were 9 families with 17 affected individuals of facial dysostosis. INTERVENTION: Exome analysis focused on known genes associated with acrofacial and mandibulofacial syndromes. MAIN OUTCOME MEASURE: The outcome measure was to report phenotyptic and genetic heterogeneity in affected individuals. RESULTS: A Tessier cleft was seen in 7 (41%), lower eyelid coloboma in 12 (65%), ear anomalies in 10 (59%), uniolateral or bilateral aural atresia in 4 (24%), and deafness in 6 (35%). The facial gestalt of Treacher Collins syndrome (TCS) showed extensive phenotypic variations. Pathogenic variants in TCOF1 (Treacher Collins syndrome) were seen in six families, POLR1A (acrofacial dysostosis, Cincinnati type) and EFTUD2 (mandibulofacial dysostosis with microcephaly) in one each. One family (11.1%) had no detectable variation. Five out of six probands with Treacher Collins syndrome had other affected family members (83.3%), including a non-penetrant mother, identified after sequencing. CONCLUSION: Our report illustrates the molecular heterogeneity of mandibulofacial dysostosis in India.

Clinical and genetic spectrum of 104 Indian families with central nervous system white matter abnormalities.

Genetic disorders with predominant central nervous system white matter abnormalities (CNS WMAs), also called leukodystrophies, are heterogeneous entities. We ascertained 117 individuals with CNS WMAs from 104 unrelated families. Targeted genetic testing was carried out in 16 families and 13 of them received a diagnosis. Chromosomal microarray (CMA) was performed for three families and one received a diagnosis. Mendeliome sequencing was used for testing 11 families and all received a diagnosis. Whole exome sequencing (WES) was performed in 80 families and was diagnostic in 52 (65%). Singleton WES was diagnostic for 50/75 (66.67%) families. Overall, genetic diagnoses were obtained in 77 families (74.03%). Twenty-two of 47 distinct disorders observed in this cohort have not been reported in Indian individuals previously. Notably, disorders of nuclear mitochondrial pathology were most frequent (9 disorders in 20 families). Thirty-seven of 75 (49.33%) disease-causing variants are novel. To sum up, the present cohort describes the phenotypic and genotypic spectrum of genetic disorders with CNS WMAs in our population. It demonstrates WES, especially singleton WES, as an efficient tool in the diagnosis of these heterogeneous entities. It also highlights possible founder events and recurrent disease-causing variants in our population and their implications on the testing strategy.

Solitary median maxillary central incisor with congenital strabismus and autoimmune thyroiditis in a young child.

Single median maxillary central incisor (SMMCI) syndrome is rare. It is commonly associated with other midline defects. About 50% of children with SMMCI have short stature, associated with isolated growth hormone deficiency or panhypopituitarism.A 6-year-old girl presented to us with worsening convergent squint, slowing linear growth and a suspected pituitary macroadenoma on neuroimaging. The key findings on examination included a disproportionate short stature, SMMCI, congenital abduction defect and pseudohypertrophy of calf muscles with myopathy. The evaluation showed autoimmune thyroiditis with pituitary hyperplasia. Bone age corresponded to 3 years.Three months after initiation of thyroxine, her myopathy resolved, and the hormone profile and neuroimaging were normal. Autoimmune thyroiditis in association with SMMCI is not reported previously. This case study emphasises the importance of growth monitoring and the exclusion of common treatable conditions.

Maternal Occupational Tobacco Exposure and Newborn Umbilical Cord Serum Leptin Concentration.

OBJECTIVE: To assess the effect of maternal occupational tobacco handling (bidi rolling) on cord serum leptin levels. METHODS: We enrolled 64 neonates born to women who were bidi-rollers, and 64 small for gestational age (SGA) neonates and 57 term appropriate for gestational age (AGA) neonates born to mothers with no tobacco exposure. Cord blood leptin levels between the groups were compared. Adjusted mean difference in leptin was calculated using regression model. RESULTS: Cord leptin showed moderate correlation with birthweight (r=0.16; P=0.027) across the groups. Mean (SD) cord serum leptin levels (ng/mL) of study group was 19.79 (13.32), in comparison to 21.4 (13.4) of SGA (P=0.497), and 27.70 (13.96) of term AGA (P=0.002). Maternal occupational tobacco exposure contributed to significant decrease in cord leptin (adjusted mean difference (95%CI): -4.5 ng/mL (-8.82, -0.19); P=0.041). CONCLUSIONS: Maternal occupational tobacco exposure causes signifi-cant reduction in fetal leptin levels.

Maternal and neonatal iodine status in Dakshina Kannada district of Karnataka, India.

This study was designed to assess iodine status of mother-fetus dyad by estimation of spot urine iodine concentration (UIC) in the study district. It is a cross-sectional study of 250 pregnant women with euthyroid status and their term neonates residing in Dakshina Kannada district. Neonates with foetal growth restriction or requiring intensive care were excluded. Median UIC was quantified using modified Sandell-Kolthoff reaction by microplate method. World Health Organization (WHO) classification was used to categorise the iodine status of pregnant women. Among 250 pregnant women, the majority were primigravida (38%). Median maternal thyroid stimulating hormone (TSH) was 1.54 mIU/l, and median UIC was 352 mcg/l. Urine iodine levels were insufficient (<150 mcg/l) in 1.2% (n = 3), adequate (150-249 mcg/l) in 9.2% (n = 23) and above requirement (250-499 mcg/l) in 89.6% (n = 224); none had excess (> 500 mcg/l). Median birth weight was 3,000 g and head circumference was 34 cm. Median cord blood TSH was 8.1 mIU/l, and median UIC 344.5 mcg/l. All the newborns had adequate (> 100 mcg/l) iodine status, including those born to mothers with insufficient values. Maternal and newborn median UIC showed positive correlation (r = 0.139; p = 0.028). Iodine statuses were above requirement or adequate in pregnant women from the study district and their neonates, respectively, indicating successful salt iodisation.

Reports of a Conus Cauda Tumor with Holocord Syrinx in an Adolescent Girl.

INTRODUCTION: Spinal cord ependymoma seldom presents with holocord syringomyelia in pediatric age-group. Association of ependymoma with a lipoma is also rare. The child presented critically ill with polymicrobial pneumonia, and the neurologic findings were missed until recovery. We report a case highlighting these findings. CASE REPORT: A 16-year-old adolescent presented critically ill with respiratory failure due to severe pneumonia. Evaluation showed fungal pneumonia with secondary bacterial infection. On recovery, she had nasal regurgitation and required nasogastric tube feeding. Examination showed palatal and left vocal cord palsy. Neuroimaging of brain showed conus cauda tumor with syringobulbia and holocord multiseptate syrinx extending from medulla to filum terminale with lipoma. Histopathology examination showed myxopapillary ependymoma. She improved with excision and postoperative radiotherapy. DISCUSSION: Our case is a rare report of an adolescent girl with conus cauda tumor and holocord syrinx.

Pregnancy Outcome in Occupational Tobacco Exposure: A Cohort Study from South India.

BACKGROUND: Women constitute a significant labor pool in the Indian tobacco industry as bidi (hand-rolled cigarette) rollers. On an average, they roll around 600 bidis/day and are exposed to 120 g of tobacco and 3 g of nicotine. Bidis do not have chemical preservatives or stabilizing agents, and therefore, the rollers are exposed only to nicotine by handling and inhalation. The study objective was to assess pregnancy outcome in these women with occupational tobacco exposure. MATERIALS AND METHODS: A prospective cohort study of bidi-rollers (n = 177) and women with no tobacco exposure (n = 354), followed up for pregnancy outcome, neonatal anthropometry, and nicotine absorption by cotinine assays. Adjusted risk and adjusted mean differences with a 95% confidence interval were derived. RESULTS: Outcomes included increased adjusted risk for gestational hypertension (3.54 [1.21, 10.31]; P = 0.021) and fetal growth restriction (2.71 [1.39, 5.29]; P = 0.004). Risk for prematurity was not statistically significant (1.81 [0.74, 4.45]; P = 0.194). Lower adjusted mean difference of birth weight (-104 g [-177, -31]; P = 0.005), length (-0.4 cm [-0.8, -0.1]; P = 0.006), and head circumference (-0.4 cm [-0.6, -0.1]; P = 0.002) were seen with increased risk for small for gestational age (1.75 [1.12, 2.73]; P = 0.015). Nicotine absorption was evident in one-third of maternal and cord blood estimations. CONCLUSION: Occupational passive tobacco exposure results in adverse pregnancy outcome.

Cystine Urolithiasis in Early Childhood.

Urolithiasis in children is rare with reported incidence of 1.8 per 1000 children. A metabolic cause is identifiable in 40-50% of children with stones and is considered when multiple, recurrent and bilateral. Cystinuria is an important preventable cause of urolithiasis. We present an infant with recurrent gross hematuria due to cystine urolithiasis for its rarity.

Chromosomal Abnormalities in Syndromic Orofacial Clefts: Report of Three Children.

This case series of three children reports clinical features and chromosomal abnormalities seen in a craniofacial clinic. All presented with orofacial cleft, developmental or intellectual disability, and dysmorphism. Emanuel syndrome or supernumerary der (22)t(11; 22), the prototype of complex small supernumerary marker disorders, was seen in one child. Duplication 4q27q35.2 with concomitant deletion 21q22.2q22.3 and duplication 12p13.33p13.32 with concomitant deletion 18q22.3q23 seen in the remaining two children are not reported in literature. Maternal balanced translocation was established in both of these children.

Diagnostic Utility of Cord Blood Thyroid Stimulating Hormone in Congenital Hypothyroidism in the Era of Expanded Newborn Screening.

Even in the era of expanded newborn screening, utility of cord blood thyroid stimulating hormone (cTSH) for diagnosis of congenital hypothyroidism (CH) cannot be marginalised. This study was to assess the diagnostic utility of cTSH > 20 µIU/L for screening CH. Generation of new cTSH value was the main outcome measure, to increase specificity. Designed as a cross-sectional analytic study in the neonatal unit of teaching hospital, 1200 term neonates with birth weight ≥2500 g, with no perinatal complications were included. Newborn cTSH assay was done by chemi-luminescence. All screen positive were followed up on day five, 14 and 28 of life, to rule in or out CH (true or false positive). Positive predictive value and specificity were calculated. Receiver operating characteristic (ROC) was done to assess diagnostic accuracy of cTSH > 20 µIU/L and to ascertain new cut-off to reduce false positivity. Of 1200 newborns screened, 69 (5.8%) were screen positive and followed up. In five, CH was confirmed (true positive); one in 240 newborns required thyroxine therapy. False positivity was noted in 59. Recall and dropouts were 6.25 and 7.2% respectively. Median cTSH of screen, true and false positives were 28.8, 43.5 and 27.2 µIU/L respectively. Comparison of median values of cord blood (U = 59; p = 0.017) and day five serum TSH (U = 0.0; p < 0.001) among true and false positive subjects were statistically significant. Specificity calculated was 94.6% and positive predictive value 7.25%. ROC generated new permissible cTSH cut-off value of 30 µIU/L. In conclusion, an extended cTSH cut-off value of 30 µIU/L improves specificity.

Audit of Organic Acidurias from a Single Centre: Clinical and Metabolic Profile at Presentation with Long Term Outcome.

INTRODUCTION: Organic Acidurias (OA) accounts between 10% and 40% of confirmed Inborn Errors of Metabolism (IEM) in India. With prompt recognition and management, better survival but adverse neurodevelopmental outcome is reported. AIM: To study the clinical and metabolic presentation, management with immediate and long term outcome of symptomatic children with confirmed OA. MATERIALS AND METHODS: Hospital based study of symptomatic children diagnosed to have OA between 2003 and 2009 and the survivors followed up over next five years. Diagnosis was based on clinical and metabolic presentation and confirmed by spectrometry analyses of urine and blood. Management, immediate outcome, compliance to treatment and recurrence of crises were documented. Neurodevelopmental outcome was assessed in follow up. Mean with Standard Error (Mean ± SE) and frequencies with percentages were calculated. RESULTS: Of 72 cases suspected to have IEM, 38 (52.8%) were confirmed of (IEM), and out of which 15 (39.5%) had OA. Methyl malonic acidemia, multiple carboxylase deficiency and Propionic Acidemia (PA) constituted the largest proportion. Neurodevelopmental issues (73.3%) and metabolic crisis (53.3%) were common presenting features. Mean ± SE of ammonia was 639.0±424.1 µg/dl and lactate was 33.6±4.9 mg/dl. Mean pH, bicarbonate, and anion gap was 7.27±0.07, 14.1±2.3 and 17.9±2.3 respectively. Management was protocol based. Death was reported in two cases of PA; other morbidities were seen in five. Recurrent crisis (46.7%) complicated the follow up in survivors. Spasticity, extrapyramidal movement disorder, intellectual subnormality, autism spectrum, attention deficit hyperactivity disorder and sensory neural deafness were seen amongst survivors, in spite of compliance to therapy. CONCLUSION: OA is part of differential diagnosis in sick children and treatment needs to be prompt and specific. Prognosis is guarded even with long term cofactor supplementation in the symptomatic.