ESPE Abstracts (2022) 95 P1-590

ESPE2022 Poster Category 1 Thyroid (44 abstracts)

Immunoglobulin Superfamily 1 (IGSF1) Deficiency: A Rare Cause of Isolated Congenital Hypothyroidism in Two Siblings

Helen MacGloin 1 , Ved Bhushan Arya 1 , Nadia Schoenmakers 2 & Charles Buchanan 1

1Kings College Hospital, London, United Kingdom; 2Honorary Consultant Endocrinologist, Addenbrooke's Hospital, Cambridge, United Kingdom

Introduction: The Newborn Screening Programme (NBS) enables earlier diagnosis of congenital hypothyroidism (CH). However, cases of central congenital hypothyroidism (CCH) are missed in countries which use thyroid stimulating hormone (TSH) based screening strategy. Understanding the pathogenic aetiology of CCH is particularly important because many patients have additional pituitary hormone deficiencies. New genes have been implicated in CCH, including the recently discovered loss of function mutations in the IGSF-1 gene (1). We report, two siblings with CCH due to novel nonsense IGSF-1 mutation inherited from their mother.

Case Report: The proband (male infant) was born to non-consanguineous, Eastern European parents with no known medical issues. The postnatal course was uneventful; NBS did not detect any abnormalities. He presented with prolonged jaundice and investigations detected central hypothyroidism (FT4 8pmol/l, TSH 7mU/L). Further investigations including standard synacthen test and pituitary MRI were performed, which were normal. Serum prolactin level was borderline (100mIU/L; (100-410)). He was commenced on Levothyroxine and dose was titrated to keep his free T4 levels in the upper part of the normal range. Anticipating evolving hypopituitarism, he had close monitoring of growth and pituitary functions (repeat standard synacthen test, insulin-like growth factor 1 and prolactin). Prolactin deficiency was diagnosed upon repeat sampling (Prolactin 40mIUL/L). Suspecting a genetic aetiology for CCH with prolactin deficiency, mutational analysis of IGSF1 gene was performed, which confirmed a hemizygous nonsense mutation (c.1829G>A, p.W610). Evaluation of his asymptomatic brother at age 1.4 years showed similar phenotype (TSH 1.76mU/l, FT4 8.2pmol/l, free T3 5.1pmol/l, serum prolactin <40mIU/l, normal standard synacthen test and IGF1) and identical IGSF1 mutation. He was also commenced on Levothyroxine. In addition, both boys have isolated speech delay. Their mother was noted to have a typical heterozygous profile with low normal FT4 and the family are closely monitored as per IGSF1 Care Group Recommendations (2).

Conclusion: IGSF-1 mutations are a rare but important cause for CCH for whom the risk of evolving endocrinopathy has implications for monitoring and surveillance(2). To our knowledge, there are only three such families with IGSF-1 deficiency related hypothyroidism, reported nationwide.


1. Sun, Y., et al 2012 Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nature Genet. 44: 1375-1381, 2012.

2. Joustra et al 2016: IGSF1 deficiency: Lessons from an extensive case series and recommendations for clinical management. J. Clin. Endocr. Metab. 101: 1627-1636, 2016

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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