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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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Prevalence of youth-onset type 2 diabetes (T2D) has increased worldwide, paralleling the rise in pediatric obesity. Occurrence and clinical manifestations vary regionally and demographically., Objectives: We assessed the incidence, and clinical and demographic manifestations of youth-onset T2D in Israel., Methods: In a national observational study, demographic, clinical, and laboratory data were collected from the medical records of children and adolescents, aged 10-18 years, diagnosed with T2D between the years 2008 and 2019., Results: The incidence of youth-onset T2D in Israel increased significantly from 0.63/100,000 in 2008 to 3.41/100,000 in 2019. The study cohort comprised 379 individuals (228 girls [59.7%], 221 Jews [58.3%], mean age 14.7 ± 1.9 years); 73.1% had a positive family history of T2D. Mean body mass index (BMI) z-score was 1.96 ± 0.7, higher in Jews than Arabs. High systolic (≥ 130 mmHg) and diastolic blood pressure (≥ 85 mmHg) were observed in 33.7% and 7.8% of patients, respectively; mean glycosylated hemoglobin (A1c) level at diagnosis was 8.8 ± 2.5%. Dyslipidemia, with high triglyceride (>150 mg/dl) and low HDL-c (<40 mg/dl) levels, was found in 45.6% and 56.5%, respectively. Microalbuminuria and retinopathy were documented at diagnosis, 15.2% and 1.9%, respectively) and increased (36.7% and 4.6%, respectively) at follow-up of 2.9 ± 2.1 years. Criteria of metabolic syndrome were met by 224 (62.2%) patients, and fatty liver documented in 65%, mainly Jews. Psychosocial comorbidity was found in 31%. Treatment with metformin (45.6%), insulin (20.6%), and lifestyle modification (18%) improved glycemic control., Conclusion: Youth-onset T2D in Israel has increased significantly and presents a unique profile., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Thyroid peroxidase (TPO) deficiency is the most common enzymatic defect causing congenital hypothyroidism (CH). We aimed to characterize the long-term outcome of patients with TPO deficiency., Methods: Clinical and genetic data were collected retrospectively., Results: Thirty-three patients with primary CH caused by TPO deficiency were enrolled. The follow-up period was up to 43 years. Over time, 20 patients (61%) developed MNG. Eight patients (24%) underwent thyroidectomy: one of them had minimal invasive follicular thyroid carcinoma. No association was found between elevated lifetime TSH levels and the development of goiter over the years., Conclusions: This cohort represents the largest long-term follow up of patients with TPO deficiency. Our results indicate that elevated TSH alone cannot explain the high rate of goiter occurrence in patients with TPO deficiency, suggesting additional factors in goiter development. The high rate of MNG development and the risk for thyroid carcinoma indicate a need for long-term follow up with annual ultrasound scans.

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.

Background: Autoimmune thyroiditis (AIT) is the most common cause of acquired hypothyroidism in children. The natural outcome of AIT in childhood has been reported previously however follow-up duration is generally short and results variable. Objectives: To characterize clinical and biochemical findings at presentation of AIT, evaluate long-term outcomes and assess which factors at presentation predict evolution over time. Study cohort: 201 children under 18 years of age at presentation (82% female) were enrolled. Subjects were divided into five subgroups according to thyroid stimulating hormone (TSH) level at referral. Results: Mean follow-up was 8.1 years (range 0-29 years). At presentation, 34% of patients had overt hypothyroidism, 32% subclinical hypothyroidism (SCH), 16% compensated hypothyroidism, 14% were euthyroid, and 3.7% had Hashitoxicosis. Children with overt hypothyroidism were younger (10.6 vs. 13.2 years) and had higher thyroid peroxidase antibody titers. At the time of the study, levothyroxine (LT 4 ) therapy was required in 26% of children who were euthyroid at presentation, 56% of SCH patients, 83-84% of those with TSH above 10 mIU/L, and 57% of those with Hashitoxicosis. Over the years, 16% of children presenting with overt hypothyroidism stopped therapy. Free T 4 at presentation was the only predictor of outcome over time. Conclusions: Our findings suggest that only 26% children who were euthyroid at presentation developed hypothyroidism, whereas over 50% of those with SCH went on to require treatment. Of those presenting with overt hypothyroidism, 16% recovered with time. The only predictive parameter for LT 4 therapy at the end of the study was free T 4 levels at presentation. Long-term follow-up is required to determine ongoing therapy needs and screen for additional autoimmune diseases., (Copyright © 2020 Admoni, Rath, Almagor, Elias-Assad and Tenenbaum-Rakover.)

Background: Congenital hypothyroidism (CH) is a common endocrine disorder in newborns. The cause of CH is thyroid dysgenesis in 80-85% of patients. Paired box gene 8 (PAX8) is a thyroid transcription factor that plays an important role in thyroid organogenesis and development. To date, 22 different PAX8 gene mutations have been reported., Methods: Four generations of a Hungarian Jewish family were affected, and in the 3 generations studied, 9 males and 4 females were affected and 3 first-degree relatives were unaffected. Six were diagnosed at birth [thyroid-stimulating hormone (TSH) level 59-442 mU/l] and 7 at 2-48 years of age (TSH level 6-223 mU/l). One affected patient had thyroid hemiagenesis on ultrasound., Results: Direct sequencing of the PAX8 gene revealed a novel single nucleotide substitution (c.162 A>T) in exon 2 that resulted in the substitution of the normal serine 54 with a cysteine (S54C), which segregated with elevated serum TSH levels. Other mutations of the same amino acid (S54G and S54R) have also been shown to produce functional impairment., Conclusion: We report a large family with a novel mutation in the PAX8 gene presenting with variable phenotype and with a high proportion of affected family members., Competing Interests: The authors declare that they have no conflict of interest., (© 2016 S. Karger AG, Basel.)

Context: Pseudohypoparathyroidism type Ia (PHP1A) is a rare endocrine disorder characterized by hypocalcemia, hyperphosphatemia, multiple hormonal resistance, and features of Albright hereditary osteodystrophy. When the phenotype is present but not associated with hormonal resistance, it is called psedopseudohypoparathyroidism (PPHP). Both entities have been associated to GNAS haploinsufficiency, and are mostly caused by inherited inactivating mutations at GNAS gene that codes for the stimulatory alpha subunit of G protein, although the cause remains unidentified in approximately 30% of patients., Objectives: The aims of our work were 1) to identify GNAS locus defects in 112 patients with clinical diagnosis of PHP1A/PPHP and no point mutations at GNAS, to improve molecular diagnostic and genetic counseling; 2) to outline the underlying molecular mechanism(s)., Methods: Methylation-specific-multiplex ligation-dependent probe amplification, qPCR, array comparative genomic hybridization, and long-PCR were used to search for genomic rearrangements at chromosome 20q and to identify their boundaries. We used different bioinformatic approaches to assess the involvement of the genomic architecture in the origin of the deletions., Results: We discovered seven novel genomic deletions, ranging from 106-bp to 2.6-Mb. The characterization of five of seven deletion breakpoints and the definition of the putative molecular mechanisms responsible for these rearrangements revealed that Alu sequences play a major role in determining the genetic instability of the region., Conclusion: We observed that deletions at GNAS locus represent a significant cause of PPHP/PHP1A and that such defects are mostly associated with Alu-mediated recombination events. Their investigation revealed to be fundamental as, in some cases, they could be misdiagnosed as imprinting defects.

Background: Loss-of-function mutations in the thyrotropin receptor (TSHR) gene lead to resistance to TSH (RTSH) presenting with either congenital hypothyroidism (CH) or subclinical hypothyroidism (SCH). Despite several reports of patients with TSHR mutations, data on the long-term outcome of this condition are limited, and no consensus exists on the need for hormone replacement therapy. The aim of the present study was to assess the long-term outcome in children and adolescents with RTSH due to TSHR mutations., Methods: The TSHR gene was sequenced in 94 subjects (aged 3 days-21 years) with either nonautoimmune SCH or CH with RTSH., Results: Twenty-seven subjects (29%) carried mutations in TSHR. Fifteen infants were identified by neonatal screening, and the other 79 patients were detected in the process of testing for various other conditions or because of family occurrence of thyroid test abnormalities. Six different mutations were identified: c.484C>G (p.P162A), c.202C>T (p.P68S), c.790C>T (p.P264S), c.269A>C (p.Q90P), c.1957C>G (p.L653V), and c.1347C>T (p.R450C). Twelve subjects were homozygous, three were compound heterozygous, and 12 were heterozygous. Mean serum TSH levels at diagnosis and at last visit were significantly higher in patients with TSHR mutations than in those without mutations (29.04 vs. 14.15, p=0.002; 31.73 vs. 6.19, p<0.0001, respectively). Homozygous patients had a more severe phenotype (TSH 53.6 vs. 9.24, p<0.0001). Mean serum free thyroxine (fT4) levels at the last visit were significantly lower than at the first visit in the homozygous individuals (p=0.05) for a follow-up period of as long as 11 years. Heterozygous subjects had only mild hyperthyrotropinemia with stable TSH levels. However, homozygous subjects showed a trend toward increased TSH and decreased fT4 with time., Conclusion: SCH in heterozygotes with TSHR mutations is a stable compensated condition with an appropriately adjusted set point for pituitary-thyroid feedback that does not require replacement therapy. However, homozygous subjects, with incompletely compensated SCH, show reduced fT4 levels over time and may require levothyroxine treatment. Replacement therapy should be considered on an individual basis, and long-term follow up is recommended.