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Purpose: The coronavirus disease 2019 (COVID-19) pandemic has led to an association between COVID-19 and pediatric diabetes. Studies have indicated the increased likelihood of children with COVID-19 infection developing diabetes. Our objective was to assess not only the increase in pediatric diabetes at our hospital and identify possible risk factors, but also to correlate the psychosocial changes resulting from the pandemic with new-onset diabetes., Methods: We analyzed data from 58 children aged 1 to 18 years admitted to our hospital with new-onset diabetes between March 2020 and December 2021. The data included inflammatory biomarkers and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies (Abs), as well as the results of a lifestyle questionnaire., Results: The average number of hospital admissions per month for new-onset diabetes increased from 10 to 18 with the start of the pandemic. Of the 58 children in our analysis, 33% had positive SARS-CoV-2 IgG Ab, 31% had type 1 diabetes mellitus, and 62% had type 2 diabetes mellitus (T2DM). More than half (54%) were experiencing diabetic ketoacidosis. Those with T2DM were older, majority African American, had higher median body mass index (BMI) percentiles, and lower vitamin D levels. There were no significant correlations between any psychosocial risk factors and either diabetes type or SARS-CoV2 Ab status., Conclusion: Despite the increased incidence of new-onset diabetes among children in Mississippi during the pandemic, this study was unable to demonstrate a significant correlation between COVID-19 infection and new-onset diabetes. The findings of this study highlighted the correlation between increased BMI and type 2 diabetes, underscoring the significant problems of obesity and diabetes in our study region. Further research is warranted.

Kallmann syndrome (KS) is a rare genetic disease characterized by pubertal failure and olfactory defects. Although many genes associated with KS have been reported, most are rare. Recently, heterozygous inactivating mutations in the neuron-derived neurotrophic factor gene (NDNF) were reported to cause KS. Here, we present a 14-year-old Kurdish boy with KS who has a novel homozygous nonsense c.1251C>A (p.Tyr417Ter) variant in NDNF. The variant was not observed in reference population databases and was predicted to be deleterious. Segregation analysis performed with Sanger sequencing indicated the autosomal recessive inheritance of the clinical phenotype. His heterozygous parents have experienced timely pubertal development and normal reproductive features. This study reported the first homozygous truncating NDNF variant, enabling the direct observation of the clinical consequences of predictively absent NDNF function. These results support the contention that the inactivating mutations in NDNF cause KS, and provide additional evidence for the complex inheritance of KS., (© 2022 Wiley Periodicals LLC.)

Context: Primary ovarian insufficiency (POI) is a genetically heterogeneous condition associated with infertility and an increased risk of comorbidities. An increased number of genes implicated in DNA damage response pathways has been associated with POI as well as predisposition to cancers., Objective: We sought to identify and characterize patients affected by POI caused by pathogenic variants in genes involved in DNA damage response during meiosis., Setting: Study subjects were recruited at academic centers., Patients or Other Participants: Individuals with a diagnosis of POI and their family members were enrolled for genetic analysis. Clinical findings, family history, and peripheral blood samples were collected., Research Design: Exome sequencing was performed on the study participants and their family members (when available). Protein conservation analysis and in silico modeling were used to obtain the structural model of the detected variants in the ZSWIM7 gene., Main Outcome Measure(s): Rare deleterious variants in known and candidate genes associated with POI., Results: Homozygous deleterious variants in the ZSWIM7 gene were identified in 2 unrelated patients with amenorrhea, an absence of puberty, and prepubertal ovaries and uterus. Observed variants were shown to alter the ZSWIM7 DNA-binding region, possibly affecting its function., Conclusions: Our study highlights the pivotal role of the ZSWIM7 gene involved in DNA damage response during meiosis on ovarian development and function. Characterization of patients with defects in DNA repair genes has important diagnostic and prognostic consequences for clinical management and reproductive decisions., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Hereditary Hypophosphatemic Rickets (HHR) is a heterogeneous group of disorders characterized by hypophosphatemia. Although the X-linked dominant HHR is the most common form, the genetic etiology of HHR is variable. Recently, developed next-generation sequencing techniques may provide opportunities for making HHR diagnosis in a timely and efficient way., Methods: We investigated clinical and genetic features for 18 consecutive probands and their 17 affected family members with HHR. All patient's clinical and biochemical data were collected. We first analyzed a single gene with Next-generation sequencing if the patients have a strong clue for an individual gene. For the remaining cases, a Hypophosphatemic Rickets gene panel, including all known HHR genes by Next-generation sequencing, was employed., Results: We were able to diagnosis all of the consecutive 35 patients in our tertiary care center. We detected nine novel and 10 previously described variants in PHEX (9; 50%), SLC34A3 (3; 17%), ENPP1 (3; 17%), SLC34A1 (1; 5%), CLCN5 (1; 5%), and DMP1 (1; 5%)., Conclusions: To delineate the etiology of HHR cases in a cost and time-efficient manner, we propose single gene analysis by next-generation sequencing if findings of patients indicate a strong clue for an individual gene. If that analysis is negative or for all other cases, a Next-generation Sequence gene panel, which includes all known HHR genes, should be employed., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Introduction: Idiopathic hypogonadotropic hypogonadism (IHH) is caused by dysfunction of the hypothalamic-pituitary-gonadal axis. DLG2 was recently implicated as a gene associated with delayed puberty and which may also contribute to IHH. The confirmation of the candidate puberty genes in independent IHH cohorts has become crucial due to the lack of proper genotype-phenotype segregations in reported pedigrees. Therefore, we aimed to screen DLG2 in patient variants in a large cohort of IHH patients., Methods: The present study included a total of 336 IHH patients from 290 independent families. The coding and flanking regions of DLG2 were screened for potentially important variants in the WES data. Candidate variants were evaluated in the -gnomAD and GME databases according to their allele frequencies, and only those with a frequency <0.0001 were considered rare. Detected variants were classified according to the ACMG/AMP criteria., Results: We found 1 homozygous and 2 heterozygous missense variants in 3 independent pedigrees. Identified variants were found extremely rare or not reported in gnomAD. Two variants were categorized as "uncertain significance," and the other one was "likely pathogenic" according to the ACMG criteria. All patients were normosmic, and in 2 of the 3 families, there were no causal variants in other IHH-related genes., Conclusion: We detected 3 rare sequencing variants in DLG2 in 5 patients with IHH or delayed puberty in a large IHH cohort. Our results support the contention that the DLG2 mutations are associated with IHH in human puberty., (© 2021 S. Karger AG, Basel.)

Background and Aim: Hypoaldosteronism is associated with either insufficient aldosterone production or aldosterone resistance (pseudohypoaldosteronism). Patients with aldosterone defects typically present with similar symptoms and findings, which include failure to thrive, vomiting, hyponatremia, hyperkalemia and metabolic acidosis. Accurate diagnosis of these clinical conditions therefore can be challenging. Molecular genetic analyses can help to greatly clarify this complexity. The aim of this study was to obtain an overview of the clinical and genetic characteristics of patients with aldosterone defects due to biosynthesis defects or aldosterone resistance., Design and Patients: We investigated the clinical and molecular genetic features of 8 consecutive patients with a clinical picture of aldosterone defects seen in our clinics during the period of May 2015 through October 2017. We screened CYP11B2 for aldosterone synthesis defects and NR3C2 and the three EnaC subunits (SCNN1A, SCNN1B and SCNN1G) for aldosterone resistance., Results: We found 4 novel and 2 previously reported mutations in the genes CYP11B2, NR3C2, SCNN1A and SCNN1G in 9 affected individuals from 7 unrelated families., Conclusion: Molecular genetic investigations can help confidently diagnose these conditions and clarify the pathogenicity of aldosterone defects. This study may expand the clinical and genetic correlations of defects in aldosterone synthesis or resistance., (© 2018 John Wiley & Sons Ltd.)

Roberts syndrome is a very rare autosomal recessive inheritance pattern genetic disorder characterised by symmetric bilateral extremity deformities, midfacial defect, and severe intellectual deficit. These patients also grow slowly prenatal and postnatal. RBS is caused by mutation in the ESCO2 gene. With these clinical and radiological findings, the case was diagnosed as Roberts syndrome. Full gene sequencing of the ESCO2 gene for the patient was done. In this patient, a novel frameshift mutation was identified in the ESCO2 gene.

The Sertoli cell only syndrome (SCOS) is a rare genetic disorder with a variable phenotype ranging from a severe ambiguous genitalia to a normal male phenotype with infertility. SCOS is diagnosed on testicular histopathology as germ cells are absent without histological impairment of Sertoli or Leydig cells. The SRY positive XX male syndrome is usually diagnosed in adulthood during infertility investigations. Here, we report a rare case of 46,XX maleness with ambiguous genitalia due to Sertoli cell only syndrome (SCOS).

The purpose of this study was to determine the levels of leptin, ghrelin, and nesfatin-1 to elucidate the causes of poor appetite and growth retardation in patients receiving methylphenidate therapy for attention deficit hyperactivity disorder. The study was performed on 89 male subjects; 48 patients and 41 healthy controls, aged 7-14 years. Following treatment, patients' leptin levels increased and ghrelin levels decreased while no significant change was found in nesfatin-1 levels. Of the 48 patients, 34 developed lack of appetite. In patients who developed lack of appetite, body weight SDS, body mass index (BMI), and BMI SDS were statistically significantly reduced; moreover, height SDS was reduced, though not to a statistically significant extent. This study attempted to elucidate the mechanisms that mediate the association between methylphenidate and appetite and growth, for which no studies have yet to be published.

Objective: To evaluate etiology of the patients with micropenis presenting to a tertiary health care center., Methods: In this prospective study all patients who were referred with a diagnosis of micropenis from October 2009 through October 2010, underwent a complete evaluation including measurement of stretched penile length., Results: In 20 (31 %) among a total of 65 patients, measured stretched penile length was not consistent with the description of micropenis. True presence of micropenis was confirmed in the remaining 45 of total 65 cases (69 %). Etiological cause was determined in 29 patients (44 %) with the most common cause being hypogonadotropic hypogonadism. No etiological cause could be found in 16 patients (25 %)., Conclusions: In approximately one third of patients the presence of micropenis was not confirmed. The most common causes of misdiagnosis were buried penis due to obesity, erroneous measurement of stretched penile length, and/or lack of knowledge on population standards for penile length. Etiological basis of micropenis is rather heterogeneous. Despite extensive investigations, no causal link was found in around one fourth of cases. Accurate measurement and utilization of internationally accepted standards is utmost important for diagnosis and management of micropenis.

Background: The aim of this study was to compare the chromium levels of plasma (PCL), erythrocyte (ECL) and urine (UCL) in type 1 diabetics and healthy subjects and to review the relation between metabolic parameters., Methods: We evaluated 165 subjects who were: newly diagnosed type 1 diabetics (group 1 [n= 29]); previously diagnosed type 1 diabetics (group 2 [n= 18]); non-diabetic control subjects who were admitted and treated for any reason in hospital (group 3 [n= 21]); and two other groups of control subjects from two schools that have different socioeconomic levels (group 4 [n= 48] and group 5 [n= 49])., Results: PCL in group 1 and group 2 subjects (7.21 ± 4.78 and 10.94 ± 3.04 mcg/L, respectively) was significantly lower than in all control groups (21.84 ± 7.87, 16.11 ± 7.44, 17.25 ± 8.58 mcg/L, respectively) (P < 0.05). A significant difference in PCL between the group 1 and group 2 subjects was present (7.21 ± 4.78 and 10.94 ± 3.04, respectively) (P= 0.021). ECL (as tissue chromium) in group 1 and group 2 subjects (13.99 ± 11.37 and 19.64 ± 12.58, respectively) was significantly lower than in all control groups (28.20 ± 7.34.25, 49 ± 12.47, 26.37 ± 9.77 mcg/L, respectively) (P= 0.05). UCL in group 1 and group 2 subjects (11.44 ± 6.88 and 15.68 ± 6.75 mcg/L, respectively) was significantly lower than in group 3 subjects (28.83 ± 9.37 mcg/L) (P < 0.05). There were significant correlations between length, bodyweight and PCL in the group 1 subjects (r = 0.42, P= 0.22 and r = 0.53, P= 0.03, respectively). There was a negative correlation between plasma glucose and UCL, which was not statistically significant in group 2 subjects (r =-0.4, P= 0.061)., Conclusion: There was a negative chromium balance in type 1 diabetics. This negative balance may affect the insulin function badly. If this negative balance should be confirmed by recent studies we suggest that chromium supplementation with insulin is necessary for type 1 diabetes., (© 2012 The Authors. Pediatrics International © 2012 Japan Pediatric Society.)

Objective: The aim of this study was to elucidate the role of adiponectin, leptin, TNF-α and IL-6 on the early detection of the microvascular complications of type I diabetes., Materials and Methods: A total of 88 children were included in the study. There were 60 type I diabetic patients and 28 healthy control children., Results: The gender, age, weight, height, BMI and puberty status characteristics were similar in the patient and control groups (p>0.05). The serum leptin, TNF-α and IL-6 levels were similar between the patient and control groups (p>0.05) and the only difference was in the serum adiponectin level which was higher in the patient group (p:0.042). We also found no association between the adiponectin, leptin, TNF-α and IL-6 levels and diabetes duration (p>0.05). Leptin was high in the pubertal period (p:0.016), while adiponectin TNF-α and IL-6 levels were similar in the prepubertal and pubertal periods (p>0.05). The serum leptin level was high in microalbuminuria patients (p<0.041). The serum adiponectin, TNF-α, and IL-6 levels were not different in patients with and without microalbuminuria (p>0.05). The serum adiponectin level was lower in diabetic retinopathy patients (p:0.003), while the serum leptin level was higher (p:0.003). The TNF-α and IL-6 levels were similar in patients with and without retinopathy (p>0.05)., Conclusion: We found increased serum adinopectin levels in children and adolescents with type I diabetes mellitus and low levels in diabetic retinopathy patients. Patients with low serum adiponectin levels and high leptin levels should be more closely monitored for chronic complication development and better metabolic control should be aimed for.

WISP3 is a member of the CCN (for CTGF, CYR61, and NOV) gene family, which encodes cysteine-rich secreted proteins with roles in cell growth and differentiation. Mutations in the WISP3 gene are associated with the autosomal recessive skeletal disorder, also known as progressive pseudorheumatoid arthropathy of childhood (PPAC). We diagnosed three siblings from a non-consanguineous family with PPAC. The patients were asymptomatic in early childhood. Signs and symptoms of disease that include progressive joint stiffness, swelling of the finger joints, and osteopenia, and slow linear growth developed between 2 and 8 years of age. PCR amplification and direct sequencing of the WISP3 gene revealed a homozygous mutation at nucleotide 156 of the WISP3 gene, resulting in a Cys52-to-ter substitution. This mutation has previously been reported in French, Italian, and Arab families. Interestingly, the C52X mutation was found to be associated with a c.248G-->A (G83E) variation, suggesting the existence of a founder effect. By contrast, the presence of the same aberration in three different ethnic groups could imply that this particular site is prone to mutation. Basal fasting concentrations of growth hormone, insulin-like growth factor-1, and insulin-like growth factor binding protein-3, as well as glucose and insulin levels revealed no aberrations. In conclusion, consideration of this rare disease that causes significant morbidity with short stature, osteopenia and arthritic complaints would prevent unnecessary examinations and treatment attempts. Testing for this specific mutation in suspected cases could provide a rapid and definitive diagnosis.

Purpose of Review: What controls puberty remains largely unknown and current gene mutations account for only about one-third of the apparently genetic cases of idiopathic hypogonadotropic hypogonadism. Lately important developments have occurred in this field., Recent Findings: Substantial variation in clinical expression, from complete anosmia and hypogonadotropic hypogonadism to delayed puberty and normosmia, of the same Kallmann syndrome gene defects including in newer ones (FGF8 and CHD7) continues to be repeatedly observed. Digenic or oligogenic inheritance becomes another feature of Kallmann syndrome. Recent reports of mutations in TAC3 or TACR3 [encoding neurokinin B (NKB) and its receptor, NK3R, respectively] provided compelling evidence for the involvement of NKB signaling in puberty. This energized the field to understand the exact mechanism through which NKB signaling exerts its effects. With the important findings from these recent studies in association with the substantial data from kisspeptin studies in the last 6 years a sketch of GnRH pulse generator has emerged in which NKB signaling appears to play a key role., Summary: Autozygosity mapping may continue helping identify the other genes including those upstream to the GnRH pulse generator in this complex and elusive developmental process.

Growth Hormone (GH) is a 22 kDa protein that has effects on growth and glucose and fat metabolisms. These effects are initiated by binding of growth hormone (GH) to growth hormone receptors (GHR) expressed in target cells. Mutations or deletions in the growth hormone receptor cause an autosomal disorder called Laron-type dwarfism (LS) characterized by high circulating levels of serum GH and low levels of insulin like growth factor-1 (IGF-1). We analyzed the GHR gene for genetic defect in seven patients identified as Laron type dwarfism. We identified two missense mutations (S40L and W104R), and four polymorphisms (S473S, L526I, G168G and exon 3 deletion). We are reporting a mutation (W104R) at exon 5 of GHR gene that is not previously reported, and it is a novel mutation.

In Turkey congenital hypothyroidism (CH) occurs with a prevalence of one in 2,736 newborns while the worldwide incidence is one in 3,000-4,000 newborns. 85-90% of these cases are due to dysgenesis of the thyroid gland, whereas defects in thyroid hormone synthesis account for 10-15%. The majority of patients with dyshormonogenesis have a defect in thyroid peroxidase (TPO). To date, more than 60 different mutations have been described in the TPO gene, mostly single nucleotide substitutions. Five children from three consanguineous families were diagnosed with CH on the basis of clinical symptoms and signs--goiter, macroglossia and prolonged jaundice at newborn age. Two different mutations in the TPO gene were identified. Affected children in families I and II had a nonsense mutation in exon 10 (R540X). Genotyping of polymorphic markers within the TPO gene revealed that these families shared a common haplotype, suggesting a founder effect. In the third family, a novel mutation (G319R) in exon 8 was identified.

Diabetic ketoacidosis (DKA) is a widely known acute metabolic complication of diabetes mellitus (DM), which can be potentially fatal. It is not difficult to diagnose when a patient with DM comes with symptoms such as coma, fruity breath, hyperglycemia, acidosis, and tachypnea. If the patient has not been diagnosed with DM before, then other sicknesses characterized by an increased anion gap should be considered. A 12-year-old boy with type 1 DM and repeated earlier admissions for DKA was admitted to the emergency department in another apparent case of DKA with coma, hyperglycemia, and profound metabolic acidosis. When his condition did not improve with initial treatment, intoxication was suspected as an alternate cause of his condition. Further laboratory tests detected methanol and amitriptyline. The patient underwent hemodialysis and recovered completely. This case illustrates that a seemingly obvious medical condition can mask serious intoxication. This report is the only publication on two different entities characterized by an increased anion gap and at the end the patient has been cured completely without any complications.

Type 1 diabetes mellitus (DM) develops as a result of autoimmune destruction of the pancreatic beta-cells. The aim of this study was to explore possible associations between serum levels of cytokines, IL-1, IL-2, TNFalpha and INFgamma and metabolic parameters in children with type 1 DM and their non-diabetic siblings to determine whether these cytokines could be indicators of disordered immune regulation. The study population consisted of 41 children with type 1 DM, 32 non-diabetic siblings, and 28 healthy controls. Children with DM were divided into three subgroups: 1) newly diagnosed patients with diabetic ketoacidosis (ND + DKA), 2) newly diagnosed patients without DKA (ND - DKA), and 3) previously diagnosed patients (PD). The highest serum IL-1alpha level was found in the ND - DKA group, which was significant compared to both the ND + DKA (p < 0.05) and the siblings (S) (p < 0.005). IL-2 levels were similar among all groups. The highest TNFalpha level was observed in the ND + DKA group, which was significant against the ND - DKA (p < 0.05), PD (p < 0.001), S (p < 0.05), and control (C) (p < 0.005) groups. TNFalpha concentration in the PD group was significantly lower than those of S (p< 0.005) and C (p < 0.001) groups. The ND - DKA group had the highest INFgamma and this was statistically significant when compared with the S (p < 0.005) and C (p < 0.05) groups. Both the newly diabetics and all diabetics as a group had statistically significantly higher INFgamma levels than both the S (p < 0.01 for both) and C (p < 0.05 for both) groups. In the diabetics as a whole group, TNFalpha showed correlations with INFgamma (r = 0.370, p < 0.05). IL-1 showed correlation with TNFalpha (r = 0.368, p < 0.05) INFgamma (r = 0.796, p < 0.001) and IL-2 (r = 0.862, p < 0.001) in the all diabetics group. IL-2 was correlated with TNFalpha (r = 0.320, p < 0.05) and INFgamma (r = 0.754, p < 0.01) in the all diabetics group. In conclusion, our results suggest that proinflammatory cytokines TNFalpha, INFgamma, IL-1alpha and IL-2 may play important roles alone or in combination in the pathogenesis of type 1 diabetes mellitus.