Abstract
SummaryObjectiveLoss‐of‐function mutations in IGSF1 result in X‐linked central congenital hypothyroidism (CeCH), occurring in isolation or associated 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.Design, Patients and MeasurementsA 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.ResultsThe 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 seven boys as well as their 75‐year‐old grandfather. Clinical features potentially attributable to hypothyroidism were variable; normal free T3 (FT3) and low/low normal reverse T3 (rT3) concentrations suggested that preferential deiodination of FT4 to FT3 may help maintain tissue euthyroidism in some individuals. However, neonatal jaundice, delayed speech or growth, and obesity were observed in seven subjects in whom diagnosis was delayed.ConclusionsAs observed with other IGSF1 mutations, p.L773P results in variably penetrant IGSF1 deficiency syndrome. Our observations emphasize the need for multi‐generation genetic ascertainment in affected families, especially where TSH‐based CH screening programmes may fail to detect CeCH at birth.
Highlights
Central congenital hypothyroidism (CeCH) is a rare entity affecting up to one in 16 000 individuals,[1] and occurs when hypothalamic and/or pituitary pathology results in inadequate thyrotropin (TSH)-mediated stimulation of the thyroid gland.[2]
Subnormal circulating free thyroxine (FT4) concentrations in CeCH are associated with a failure of compensatory TSH elevation, CeCH evades detection by the TSH- based UK and Irish neonatal congenital hypothyroidism (CH) screening programmes, and delayed diagnosis may result in adverse auxological or neurodevelopmental sequelae.[3]
Underlying genetic aetiologies for CeCH include mutations in pituitary transcription factors, which usually manifest as multiple pituitary hormone deficits
Summary
Central congenital hypothyroidism (CeCH) is a rare entity affecting up to one in 16 000 individuals,[1] and occurs when hypothalamic and/or pituitary pathology results in inadequate thyrotropin (TSH)-mediated stimulation of the thyroid gland.[2]. Since the initial description of IGSF1 mutations in eleven European kindreds, larger studies have substantiated the complex nature of the IGSF1 deficiency syndrome as well as confirming the relatively frequent occurrence of IGSF1 mutations in CeCH cases.[4,7] IGSF1 encodes a transmembrane immunoglobulin superfamily glycoprotein that undergoes co-translational proteolysis such that only its seven carboxy- terminal immunoglobulin loops are expressed extracellularly at the plasma membrane.[8] The majority of previously reported IGSF1 mutations adversely affect trafficking and membrane localization of this carboxy-terminal domain[9] (Figure 1A). IGSF1 is abundantly detected at mRNA level in Rathke’s pouch and adult pituitary gland[4]; a paucity of reliable antibodies has hampered expression studies in humans. Despite clinical and murine data supporting a role for IGSF1 in regulation of TRH action in the pituitary, its molecular function remains undefined.[4,12,13]
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