Abstract
Introduction: Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Loss of function mutations in the immunoglobulin superfamily member 1 (IGSF1) gene cause X-linked central hypothyroidism and represent the most common genetic cause of central hypothyroidism. In addition to central hypothyroidism, some patients with IGSF1 deficiency have hypoprolactinemia, transient and partial growth hormone deficiency, early/normal timing of testicular enlargement but delayed testosterone rise in puberty, and adult macro-orchidism. Here, we describe a case series of 3 patients with central hypothyroidism caused by two novel IGSF1 mutations. Case Presentation: Three males (including two siblings) were diagnosed with central hypothyroidism between 0.06 and 1.5 years of age. Additional features included hypoprolactinemia, normal cortisol and growth hormone – insulin like growth factor 1 axis, high body mass index, birth weight greater than 0 SDS, and isolated speech delay. Genetic testing identified two novel IGSF1 mutations [(c.1829G>A, p.W610* and c.3692G>A, p.(Cys123Tyr)]. Both variants have not been reported in the gnoMAD database (∼90,000 individuals) and are predicted to be deleterious. Conclusions: Loss-of-function mutations in IGSF1 represent the most common genetic cause of central hypothyroidism. Detailed phenotyping of IGSF1 deficiency from extensive case series has led to the formulation of recommendations for clinical management of these patients. We have highlighted the potential adverse consequences of delayed treatment of CCH (speech delay).
