ESPE Abstracts

Introduction: Mutations in IGSF1 result in X-linked congenital central hypothyroidism, macroorchidism and a variable spectrum of anterior pituitary dysfunction, most commonly including hypoprolactinaemia. We identified a novel hemizygous IGSF1 mutation (c.3191T>C, p.L1064P) in a 17 year-old adolescent, inherited from his heterozygous mother.

Case: A novel hemizygous IGSF1 mutation (c.3191T>C, p.L1064P) was identified by direct sequencing in a 17 year-old male adolescent with central hypothyroidism (fT4 8 pmol/l (8–21 pmol/l), TSH 1.8 mU/l (0.35–3.5 mU/l). This variant was novel, absent from the Exac database and predicted to be probably damaging by Polyphen2. IGSF1 deficiency is almost universally associated with macroorchidism, and he exhibited testicular enlargement (volumes ~35 ml). Additionally, he had hypoprolactinaemia (26 mIU/l (44–479 mIU/l)), consistent with previous reports that basal prolactin is subnormal in ~60% affected males. His mother who was euthyroid was subsequently found to be heterozygous for the same variant. The Proband was also obese (BMI 31.6 kg/m²) and had learning difficulties. Although both are recognized consequences of untreated hypothyroidism, and obesity may be associated with the IGSF1 deficiency syndrome, he also had a paternally-inherited 16p11.2 microdeletion. The relevant section included the SH2B1 gene which has been implicated in a microdeletion syndrome associated with developmental delay, obesity, ADHD, autism and behavioral problems and could explain some of his problems such as developmental delay and obesity.

Conclusion: We described a male with central hypothyroidism, macroorchidism and hypoprolactinaemia due to a maternally-inherited mutation in IGSF1 (c.3191T>C, p.L1064P). Asymptomatic individuals in families with IGSF1 mutations who are detected by family screening need close follow up since their endocrinopathy could progress with time as happened with our patient who was initially euthyroid and progressed to central hypothyroidism.