ESPEYB20 1. Thyroid Genetics (3 abstracts)
1.9. IGSF1 mutations are the most frequent genetic aetiology of thyrotropin deficiency
Fourneaux R , Reynaud R , Mougel G , Castets S , Bretones P , Dauriat B , Edouard T , Raverot G , Barlier A , Brue T , Castinetti F & Saveanu A
Eur J Endocrinol. 2022 Nov 3;187(6):787–795. doi: 10.1530/EJE-22-0520. Print 2022 Dec 1. PMID: 36201163
Brief summary: Congenital central hypothyroidism is caused by thyrotropin deficiency, either isolated or in combination with other pituitary deficiencies. So far, mutations in five genes have been identified in patients with isolated thyrotropin deficiency: thyroid stimulating hormone subunit β (TSHβ), thyrotropin-releasing hormone receptor (TRHR), immunoglobulin superfamily member 1 (IGSF1), transducin-like protein 1 (TBLX1), and insulin receptor substrate 4 (IRS4). The phenotype of patients with mutations in IGSF1 is more complex, as transient growth hormone deficiency can occur during childhood. This study aimed at systematically investigate the genetic cause of non-syndromic isolated thyrotropin deficiency (ITSHD) or thyrotropin deficiency combined with growth hormone deficiency (TSHD-GHD) in a large cohort.
In the context of the GENHYPOPIT network, the authors identified n=22 index cases with ITSHD and n=42 index cases with TSHD-GHD. All n=64 patients were analyzed by a next generation sequencing panel for mutations in genes associated with ITSHD as well as all known genes associated with combined pituitary deficiencies. In n=22 ITSHD cases mutations in IGSF1, and TSHβ were found in n=6 patients, and n=2 patients, respectively. In n=42 patients with TSHD-GHD, n=2 patients suffered from IGSF1 mutations, while n=7 patients showed mutations in POUF, PROP1, GH1, THRH. A genetic cause of TSHD was identified in 36.3% of ITSHD patients and in 21.4% of TSHD-GHD patients.
Data on genetic causes of central hypothyroidism are scarce. This is the so far largest cohort study of ITSHD and TSHD-GHD. The authors confirm earlier results from a smaller cohort that IGSF1 mutations are the most frequent cause of ITSHD. IGSF1 mutations need also be considered in TSHD-GHD patients because of the specific phenotype with transient GHD in childhood.
Reference: 1. Clinical and genetic characteristics of Dutch children with central congenital hypothyroidism, early detected by neonatal screening. Naafs JC, Verkerk PH, Fliers E, van Trotsenburg ASP, Zwaveling-Soonawala N. Clinical and genetic characteristics of Dutch children with central congenital hypothyroidism, early detected by neonatal screening\. Eur J Endocrinol. 2020 Dec;183(6):627–636. doi: 10.1530/EJE-20-0833. PMID: 33107432.
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ESPE Yearbook of Paediatric Endocrinology
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