Clinical and Molecular Characteristics and Long-term Follow-up of Children With Pseudohypoparathyroidism Type IA.

CONTEXT: Pseudohypoparathyroidism type IA (PHPIA) is a rare genetic disorder characterized by hormone resistance and a typical phenotype named Albright hereditary osteodystrophy. Unawareness of this rare disease leads to delays in diagnosis. OBJECTIVE: The aims of this study were to describe the clinical and molecular characteristics of patients with genetically confirmed GNAS mutations and to evaluate their long-term outcomes. METHODS: A retrospective search for all patients diagnosed with PHPIA in 2 referral centers in Israel was conducted. RESULTS: Nine children (8 females) belonging to 6 families were included in the study. Five patients had GNAS missense mutations, 2 had deletions, and 2 had frameshift mutations. Four mutations were novel. Patients were referred at a mean age of 2.4 years due to congenital hypothyroidism (5 patients), short stature (2 patients), or obesity (2 patients), with a follow-up duration of up to 20 years. Early obesity was observed in the majority of patients. Elevated parathyroid hormone was documented at a mean age of 3 years; however, hypocalcemia became evident at a mean age of 5.9 years, about 3 years later. All subjects were diagnosed with mild to moderate mental retardation. Female adult height was very short (mean -2.5 SD) and 5 females had primary or secondary amenorrhea. CONCLUSION: Long-term follow-up of newborns with a combination of congenital hypothyroidism, early-onset obesity, and minor dysmorphic features associated with PHPIA is warranted and molecular analysis is recommended since the complete clinical phenotype may develop a long time after initial presentation.

Alarming increase in ketoacidosis in children and adolescents with newly diagnosed type 1 diabetes during the first wave of the COVID-19 pandemic in Israel.

OBJECTIVE: To evaluate the incidence and severity of ketoacidosis (DKA) at type 1 diabetes diagnosis during the first wave of the coronavirus disease 2019 (COVID-19) pandemic in Israel. RESEARCH DESIGN AND METHODS: A population-based study the product of a national collaboration of Israeli pediatric diabetes centers investigated the presentation of childhood-onset type 1 diabetes. The frequencies of DKA and severe DKA observed during the COVID-19 period from March 15, 2020 (commencement of the first nationwide lockdown) until June 30, 2020 were compared with the same periods in 2019, 2018, and 2017 using multivariable logistic regression, adjusting for age, sex, and socioeconomic position. RESULTS: During the COVID-19 period, DKA incidence was 58.2%, significantly higher than in 2019 (adjusted OR [aOR] 2.18 [95% CI, 1.31-3.60], P = 0.003); 2018 (aOR 2.05 [95% CI, 1.26-3.34], P = 0.004); and 2017 (aOR, 1.79 [95% CI, 1.09-2.93], P = 0.022). The incidence of severe DKA was 19.9%, significantly higher than in 2018 (aOR, 2.49 [95% CI, 1.20-5.19], P = 0.015) and 2017 (aOR, 2.73 [95% CI, 1.28-5.82], P = 0.009). In 2020, admissions and duration of stay in the intensive care unit were higher than in previous years (P = 0.001). During the COVID-19 pandemic, children aged 6-11 years had higher incidences of DKA (61.3% vs. 34.0%, 40.6%, and 45.1%, respectively, P = 0.012), and severe DKA (29.3% vs. 15.1%, 10.9%, and 5.9%, respectively, P = 0.002). CONCLUSIONS: The dramatic increase in DKA at presentation of childhood-onset type 1 diabetes during the COVID-19 pandemic mandates targeted measures to raise public and physician awareness.

The evolving role of whole-exome sequencing in the management of disorders of sex development.

OBJECTIVE: Disorders of sex development (DSD) are defined as congenital conditions in which the development of chromosomal, gonadal and anatomical sex is atypical. Despite wide laboratory and imaging investigations, the etiology of DSD is unknown in over 50% of patients. METHODS: We evaluated the etiology of DSD by whole-exome sequencing (WES) at a mean age of 10 years in nine patients for whom extensive evaluation, including hormonal, imaging and candidate gene approaches, had not identified an etiology. RESULTS: The eight 46,XY patients presented with micropenis, cryptorchidism and hypospadias at birth and the 46,XX patient presented with labia majora fusion. In seven patients (78%), pathogenic variants were identified for RXFP2, HSD17B3, WT1, BMP4, POR, CHD7 and SIN3A. In two atients, no causative variants were found. Mutations in three genes were reported previously with different phenotypes: an 11-year-old boy with a novel de novo variant in BMP4; such variants are mainly associated with microphthalmia and in few cases with external genitalia anomalies in males, supporting the role of BMP4 in the development of male external genitalia; a 12-year-old boy with a known pathogenic variant in RXFP2, encoding insulin-like 3 hormone receptor, and previously reported in adult men with cryptorchidism; an 8-year-old boy with syndromic DSD had a de novo deletion in SIN3A. CONCLUSIONS: Our findings of molecular etiologies for DSD in 78% of our patients indicate a major role for WES in early DSD diagnosis and management - and highlights the importance of rapid molecular diagnosis in early infancy for sex of rearing decisions.