Abstract
The main features of immunoglobulin superfamily, member 1 (IGSF1) deficiency are central hypothyroidism and macroorchidism. The phenotype can be variable and may include macrosomia, hypoprolactinemia, growth hormone (GH) secretory abnormalities, delayed puberty, and obesity. We describe a novel de novo nonsense pathogenic variant c.3343C > T, p.(Gln1115*) that localizes to the 12th and last immunoglobulin-like loop in the C-terminal domain of the protein. The patient was born in breech with a birth weight of 3.7 kg. At presentation aged 15 years, he had obesity, central hypothyroidism, reduced attention, macroorchidism with delayed adrenarche and pubertal development. There was evidence of transient biochemical GH deficiency with normoprolactinemia and a small pituitary on magnetic resonance imaging, although interpretation of dynamic GH testing was difficult due to poor adherence with levothyroxine. He continued growing without GH treatment, and after spontaneous puberty, insulin-like growth factor-1 concentration was high. At age 22 years, he was 190 cm (+1.9 SDS), 155.4 kg (body mass index 43.05), with 35 mL testes. The transient GH deficiency and normoprolactinemia support a role for IGSF1 in somatotroph function.