Background: Loss-of-function mutations in IGSF1 result in X-linked congenital central hypothyroidism (CeCH), occurring in isolation or in association with additional pituitary hormone deficits. Intrafamilial penetrance is highly variable and a minority of heterozygous females are also affected. We identified and characterized a novel IGSF1 mutation and investigated its associated phenotypes in a large Irish kindred.
Methods: A novel, hemizygous IGSF1 mutation was identified by direct sequencing in two brothers with CeCH and its functional consequences were characterized in vitro. Genotype-phenotype correlations were investigated in the wider kindred.
Results: The mutant IGSF1 protein (c.2318T>C, p.L773P) exhibited decreased plasma membrane expression in vitro due to impaired trafficking from the endoplasmic reticulum. Ten hemizygous males, and 11 heterozygous females, exhibited characteristic endocrine deficits. Ireland operates a TSH-based CH screening programme, which does not detect CeCH; therefore genetic ascertainment preceded biochemical diagnosis of moderate CH in five of eight boys, and their 75 year-old grandfather. Tissue manifestations of hypothyroidism were variable; normal free T3 (FT3) levels and low/low normal reverse T3 (rT3) measurements suggested that preferential deiodination of FT4 to FT3 may help maintain tissue euthyroidism in some individuals. However, growth retardation, speech delay and obesity were associated with delayed diagnosis of endocrinopathy in five cases.
Conclusions: As observed with other loss-of-function IGSF1 mutations, L773P results in variably penetrant IGSF1 deficiency syndrome. Our observations emphasise the need for multi-generation genetic ascertainment in affected families, especially where TSH-based CH screening programmes may fail to detect CeCH at birth.