Whole-exome sequencing and variant spectrum in children with suspected inherited renal tubular disorder: the East India Tubulopathy Gene Study.

BACKGROUND: Inherited tubulopathies are a heterogeneous group of genetic disorders making whole-exome sequencing (WES) the preferred diagnostic methodology. METHODS: This was a multicenter descriptive study wherein children (< 18 years) with clinically suspected tubular disorders were recruited for molecular testing through WES. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were done when required. Variants were classified as per American College of Medical Genetics 2015 guidelines and pathogenic (P)/likely pathogenic (LP) variants were considered causative. RESULTS: There were 77 index cases (male =73%). Median age at diagnosis was 48 months (IQR 18.5 to 108 months). At recruitment, the number of children in each clinical group was as follows: distal renal tubular acidosis (dRTA) = 25; Bartter syndrome = 18; isolated hypophosphatemic rickets (HP) = 6; proximal tubular dysfunction (pTD) = 12; nephrogenic diabetes insipidus (NDI) = 6; kidney stone/nephrocalcinosis (NC) = 6; others = 4. We detected 55 (24 novel) P/LP variants, providing genetic diagnoses in 54 children (70%). The diagnostic yield of WES was highest for NDI (100%), followed by HP (83%; all X-linked HP), Bartter syndrome (78%), pTD (75%), dRTA (64%), and NC (33%). Molecular testing had a definite impact on clinical management in 24 (31%) children. This included revising clinical diagnosis among 14 children (26% of those with a confirmed genetic diagnosis and 18% of the overall cohort), detection of previously unrecognized co-morbidities among 8 children (sensorineural deafness n = 5, hemolytic anemia n = 2, and dental changes n = 1) and facilitating specific medical treatment for 7 children (primary hyperoxaluria n = 1, cystinosis n = 4, tyrosinemia n = 2). CONCLUSION: WES is a powerful tool in the diagnosis and management of children with inherited tubulopathies in the Indian population. A higher resolution version of the Graphical abstract is available as Supplementary information.

A comparative study of IL-6, CRP and NT-proBNP levels in post-COVID multisystem inflammatory syndrome in children (MISC) and Kawasaki disease patients.

BACKGROUND: Post-COVID multisystem hyperinflammatory syndrome in children (MISC) has clinical and laboratory similarities with Kawasaki disease (KD). Inflammatory markers like C-reactive protein (CRP), interleukin 6 (IL6) as well as N-terminal probrain natriuretic peptide (NT-proBNP) are elevated in both. This study attempts a comparative analysis of the 3 markers in an attempt at early differentiation for planning appropriate management. METHODOLOGY: This analytical study conducted at the Institute of Child Health, Kolkata, India compared the levels of the above 3 markers at admission between 72 patients with KD, 30% of whom had coronary artery lesions (CALs) collected over a period of 18 months (Jan 2017-June 2018), with 71 MISC patients over a period of 6 months (July 2020-December 2020). The non-parametric Mann-Whitney U test was used to test for similarity in distributions of the samples of CRP, NT-proBNP and IL6 in KD and MISC patients using correction factor for similar ranks. The 3 parameters were compared using receiver operating characteristic (ROC) curve analysis. RESULTS: Mean IL6 value in KD was 83.22 pg/mL and in MISC 199.91 pg/mL, which was not found to be statistically significant (P = .322 > .05).However mean NT-proBNP (914.91 pg/mL) with CRP level (96.32 mg/L) in KD was significantly lower (P < .05 for both cases) than that in MISC (9141.16 pg/mL and 145.66 mg/L respectively). ROC analysis showed NT-proBNP has the best sensitivity and specificity in predicting MISC. CONCLUSION: NT-proBNP and CRP are significantly higher among MISC patients; ROC analysis shows levels >935.7 pg/mL and >99.55 mg/L respectively might act as a guide to differentiate between them.

Langerhans cell histiocytosis in children: A retrospective case series of 126 cases.

BACKGROUND/OBJECTIVES: Langerhans cell histiocytosis (LCH), a rare neoplasm of hematopoietic myeloid precursor cells, is clinically characterized by spontaneously resolving lesions to a progressive life-threatening multisystem disorder. Diagnosing LCH in children is challenging as it mimics other skin disorders. This study describes the varied clinical presentation and disease course in children less than 18 years diagnosed with LCH. METHODS: We performed a retrospective observational study of all cases diagnosed with LCH presenting to a children's hospital in the last 26 years. Data on history, cutaneous and systemic examination, and laboratory evaluation performed, were recorded. RESULTS: A total of 126 children diagnosed with LCH were included in the study. There were 68% cases limited only to skin, and 32% children with multisystem involvement at the initial presentation. Scaly papules were the most common morphologic finding in skin. The skeletal system was the second most common organ system to be affected. Failure to thrive was a common symptom. Progression of skin to systemic involvement was seen in 27.9%. In 76.7%, skin lesions cleared over a period of 2 to 4 years. Complete remission was seen in 56.9% of children over a period of 3 to 7 years, while 8.1% children died of complicationsand 31.8% were lost to follow-up. CONCLUSIONS: Long-term follow-up in this study has shown cutaneous LCH without systemic involvement has a good prognosis. Skin involvement,along with failure to thrive, was the most common clinical presentation in our study. The skeletal system was the second most common organ system involved.

A comparison of serum IL6 and CRP levels with respect to coronary changes and treatment response in Kawasaki disease patients: a prospective study.

To evaluate serum levels of IL6 in patients with Kawasaki disease and compare it with CRP, and to assess the role of these biomarkers in predicting coronary changes and resistance to the first-line therapy of this disease in a subset of Indian population. A single centre prospective observational study was conducted amongst all Kawasaki disease patients for a period of 18 months from January 2017 at Institute of Child Health, Kolkata. Serum IL6 and CRP were compared at diagnosis and after 48 h of administering IVIG in patients who developed coronary changes with those who did not and also among the responders and non-responders to IVIG, the first-line therapy given to these patients. Out of total 72 patients of KD [mean age of presentation: 24 months, M:F = 1.22:1], 30% (n = 22) had coronary artery involvement (CALs), and 15% (n = 11) were IVIG non-responders. Mean IL6 prior to IVIG in those with CALs was 143.60 pg/ml, which was about three times higher than in those without CALs (mean = 52.90 pg/ml), the difference being significant (p < 0.01). Mean CRP values also were significantly raised in patients with CALs (p < 0.01) whereas post-IVIG levels of mean serum IL6 was found to be 108.15 pg/ml in non-responders which was about 17 times raised than that in the responders (mean IL6 = 6.22),the difference again was statistically significant (p < 0.001).Also, ROC analysis revealed a sensitivity and specificity of 81.0% and 82.0%, respectively, for IL6; 72% and 74%, respectively, for CRP for predicting CALs. This study also shows a sensitivity of 72% and specificity of 68% for IL6 in predicting IVIG resistance whereas that of CRP being 90% sensitive and 36% specific. These results suggest that higher levels of IL-6 and CRP at diagnosis are associated with occurrence of CALs and IVIG resistance in KD patients. Using the cutoff for IL6 and CRP from our study, chances of developing CALs and IVIG resistance can be predicted, which might prevent the development of future complications like aneurysms in such patients.

Recognizing missed opportunities to diagnose and treat iron deficiency anemia: A study based on prevalence of anemia among children in a teaching hospital.

BACKGROUND: In developing world, anemia is a significant cause of mortality and morbidity in children under 5 years of age. Iron deficiency anemia (IDA) is a very important causative factor for childhood anemia. The aim of this study was to find the prevalence of anemia in different age group, sex, and its pattern of severity in hospitalized children. MATERIALS AND METHODS: A cross-sectional study was carried out in a teaching hospital in Kolkata between April 2016 and September 2016. Children 1-168 months of age were included in the study. RESULTS: Of 697 children, 296 (42.5%) had anemia as per the World Health Organization criteria. Males outnumbered the females with a ratio of 1.6:1. The median age of presentation was 29.6 months. The majority were from 1-5 years of age. About 73.3% of children had moderate anemia, whereas 21.3% had severe anemia and only 5% had mild anemia. The mean hemoglobin, mean mean corpuscular volume, mean mean corpuscular hemoglobin concentration, and mean red cell distribution width were 9.3 ± 1.4 g/dL, 73.6 ± 8.8 (fL), 32.2 ± 2.6, and 16.3 ± 3.4 (%), respectively. Microcytic hypochromic anemia (71.3%) was the most common morphological type in all age groups, whereas macrocytic anemia was the least common among them. Prevalence of IDA was 69%. IDA was documented in close to 80% of children with microcytic hypochromic anemia. Interestingly, IDA was also documented in almost half of the children with normocytic normochromic anemia. CONCLUSION: The high prevalence of IDA among these hospitalized children indicates the role of early screening for IDA in all children with anemia. This early diagnosis and prompt management can prevent the mortality and morbidity related to IDA.

Hyperferritinemia in Hemophagocytic Lymphohistiocytosis: A Single Institution Experience in Pediatric Patients.

Hemophagocytic lymphohistiocytosis (HLH) is an inflammatory condition that may run a rapid fatal course and calls for prompt diagnosis. Early intervention with steroids and other immunosuppressive drugs can contain the disease process and favours positive outcome. Ferritin ≥500 ng/ml is a HLH diagnostic criterion. We evaluated the diagnostic potential of admission ferritin, in children with HLH. Pediatric patients of a referral teaching hospital from Feb 2010-Oct 2013 having been investigated for ferritin on admission were included. HLH was confirmed when patients had clinical features and met 5/8 diagnostic criteria of the revised 2004 HLH guidelines. Ferritin was estimated on Cobas e411 by electrochemiluminiscence, with a measuring range of 0.5-2000 ng/ml. Dilutions were made when linearity exceeded and absolute values were reported. 905 on-admission ferritin investigations were reviewed out of which 346 values ≥500 ng/ml. Hyperferritinemia was seen in HLH/MAS (macrophage activation syndrome) [HLH group, median age 4 year 4 month, 59% male] and in systemic lupus erythematosus, sepsis, juvenile idiopathic arthritis, impending HLH, haemolytic anemias and malignancy [non-HLH group, median age 4 year 6 month, 60% male]. Of 346, 72 cases of hyperferritinemia were diagnosed with secondary HLH while one patient had primary HLH. 13/73 patients expired. The median ferritin level of the HLH group was significantly higher [6556 (2402-11,734) ng/ml] compared to non-HLH group [median 1175 (943-2000) ng/ml] (p < 0.0001). Receiver operator characteristics curve analysis revealed optimal admission ferritin of 3120 ng/ml as the cut-off with sensitivity of 70% and specificity of 88.9% for HLH diagnosis, exceeding the currently prescribed cut-off of 500 ng/ml. Hyperferritinemia below 3120 ng/ml has higher negative predictive value to rule out secondary HLH on admission in the study population of children predominantly diagnosed with infection associated HLH than the prescribed cut-off as per the 2004 guidelines. This may prove to be beneficial to alert physicians for prompt intervention which considerably decreases mortality in this often fatal condition.

Evaluation of sweat production by pilocarpine iontophoresis: a noninvasive screening tool for hypohidrosis in ectodermal dysplasia.

Ectodermal dysplasia (ED) is a genetic disorder affecting the skin, hair, nails, teeth and sweat glands. The clinical presentation is heterogenous; however, hypohidrotic (reduced sweat) ectodermal dysplasia (HED) being the commonest. Also known as anhidrotic ED, sweat glands are sparse or rudimentary, leading to dysregulation of body temperature and episodes of uncontrolled hyperthermia due to reduced sweating. Of the many aids to document hypohidrosis in HED, we present here the technique of pilocarpine iontophoresis to induce, collect and measure sweat. Evaluation of sweat generated (against normally obtained values) is a non-invasive alternative to establish hypohidrosis in disorders such as HED. This augments clinical decision levels to plan skin biopsy for confirmation of diagnosis and facilitates patient management and early discharge. We present two cases of HED that were primarily diagnosed with sweat gland dysplasia using pilocarpine iontophoresis, and later confirmed with skin biopsy findings.