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Background: Data on the prevalence and type of endocrine disorders in β-thalassemia intermedia (β-TI) patients are scarce. This multicenter study was designed to determine the prevalence of endocrine complications and the associated risk factors in a large group of β-TI patients. Methods: In this cross-sectional multicenter study, 726 β-TI patients, aged 2.5–80 years, registered at 12 thalassemic centers, from nine countries, were enrolled during 2017. In a subgroup of 522 patients (mean age 30.8 ± 12.1; range: 2.5–80 years) from Qatar, Iran, Oman, Cyprus, and Jordan detailed data were available. Results: Overall, the most prevalent complications were osteopenia/osteoporosis (22.3%), hypogonadism (10.1%), and primary hypothyroidism (5.3%). In the subgroup multivariate analysis, older age was a risk factor for osteoporosis (Odds ratio: 7.870, 95% CI: 4.729–13.099, P< 0.001), hypogonadism (Odds ratio: 6.310, 95% CI: 2.944–13.521, P< 0.001), and non-insulin-dependent diabetes mellitus (NIDDM; Odds ratio: 17.67, 95% CI: 2.217–140.968, P= 0.007). Splenectomy was a risk factor for osteoporosis (Odds ratio: 1.736, 95% CI: 1.012–2.977, P= 0.045). Hydroxyurea was identified as a “protective factor” for NIDDM (Odds ratio: 0.259, 95% CI: 0.074–0.902, P= 0.034). Conclusions: To the best of our knowledge, this is the largest cohort of β-TI patients with endocrine disorders evaluated in extremely heterogenic thalassemic populations for age, clinical, hematological, and molecular composition. The study demonstrates that endocrine complications are less common in patients with β-TI compared with β-TM patients. However, regular monitoring with timely diagnosis and proper management is crucial to prevent endocrine complications in β-TI patients.

Context:Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHRunderlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken.Objective:Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD,and TSHR) in CH cases with GIS.Patients, Design, and Setting:We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.Results:Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG(12), TPO(four), DUOX2(two), and TSHR(one). Ten cases harbored triallelic (digenic) mutations: TGand TPO(one); SLC26A4and TPO(three), and DUOX2and TG(six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases.Conclusions:The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHRor known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TGor TPOmutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.

AbstractBackground:Neonatal severe primary hyperparathyroidism (NSHPT, MIM 239200) is most often an isolated disorder that is due to biallelic inactivating mutations in the CASR, the gene encoding the calcium sensing receptor; NSHPT is inherited from parents with familial hypocalciuric hypercalcemia, each of whom has one mutated CASRallele.Objectives:To report clinical and genetic findings in a brother and sister with NSHPT due to a novel mutation in the CASRtransmitted as an autosomal recessive trait and to examine the functional effect of the mutation.Subjects and methods:A brother and sister with marked hypercalcemia due to NSHPT were identified; the boy also had craniosynostosis requiring surgical repair. The genotyping of the CASRin both children and their parents who were eucalcemic and normophosphatemic was undertaken. In order to examine the significance of the variant CASRidentified, the CASRvariant was expressed in vitro and examined by three computer computational programs [PolyPhen2, MutationTaster, Sorting Intolerant From Tolerant (SIFT)] designed to evaluate the effect of a nucleotide variant on the structure and likely functional consequence upon the protein product.Results:A sequence variant in the CASRwas identified [G>T point mutation at nucleotide c.2303 in exon 7 (c.2303G>T) resulting in the replacement of glycine by valine at codon 768 (p.Gly768Val)]. Two copies of this CASRvariant were present in the genome of the siblings while a single copy of the CASRvariant was present in both of the clinically and biochemically normal parents, a pattern of transmission consistent with autosomal recessive inheritance of NSHPT in this family. When expressed in HEK293 cells in vitro, the novel Gly768Val variant did not interfere with protein generation or migration to the cell membrane in vitro. The analysis of the functional effect of the Gly768Val CASRvariant by the PolyPhen2, MutationTaster, and Sorting Intolerant From Tolerant computer programs revealed that this mutation was very likely to be deleterious.Conclusion:The NSHPT associated with biallelic Gly768Val mutations of the CASRin two siblings with severe hypercalcemia and hyperparathyroidism and their clinically and biochemically normal heterozygous parents was transmitted as an autosomal recessive disorder in this family.

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The diagnosis of beta thalassemia intermedia (BTI) is mainly based on the severity of clinical phenotype. It is associated with a wide range of specific complications including extramedullary hematopoiesis, leg ulcers, gallstones, hypercoagulable state, pulmonary hypertension (PHT), endocrine disorders and osteoporosis. The commonest endocrine complication in beta thalassemia major (TM) patients is hypogonadism followed by hypothyroidism and diabetesbut the data on endocrine disorders in BTI patients are scarce. The aim of this study is to determine the prevalence of endocrine complications in a large series of BTI patients.