IGSF1 – Central Congenital Hypothyroidism

IGSF1, encoding the immunoglobulin superfamily member 1, is X-linked and loss-of-function mutations cause central congenital hypothyroidism. Affected males present with isolated central hypothyroidism, often accompanied by hypoprolactinemia, delayed pubertal testosterone rise, and adult macroorchidism. Female carriers may exhibit variable biochemical abnormalities. Early recognition and treatment with levothyroxine are critical to avoid neurodevelopmental and growth delays.

Genetic evidence for IGSF1 involvement is robust. Exome and candidate gene sequencing in 11 unrelated families identified eight distinct IGSF1 mutations and two gene deletions in males with central hypothyroidism and testicular enlargement ([PMID:23143598]). Subsequent series of 42 male patients from 10 additional families confirmed the phenotype and variant segregation in hemizygous males and heterozygous females ([PMID:24108313]).

The inheritance is X-linked recessive, with segregation of pathogenic alleles through obligate female carriers. At least 7 affected male relatives with concordant IGSF1 variants have been documented across these pedigrees.

Variant spectrum comprises predominantly hemizygous truncating changes and frameshift insertions or deletions, alongside rare missense alleles. A representative pathogenic variant is c.2916G>A (p.Trp972Ter) ([PMID:23143598]).

Functional studies demonstrate that pathogenic IGSF1 mutations impair trafficking of the C-terminal domain to the plasma membrane and reduce TRH receptor expression, leading to blunted TSH secretion. Igsf1-deficient mice recapitulate diminished pituitary Trhr expression, decreased TSH stores, and attenuated TSH release upon TRH challenge, supporting a loss-of-function mechanism ([PMID:28324000]).

Conflicting evidence is limited. Variants of unknown significance identified in boys with isolated constitutional delay of growth and puberty did not cosegregate or impair membrane expression, arguing against a role in that phenotype ([PMID:25354429]).

Integration of abundant genetic and experimental data supports a Definitive gene–disease relationship. IGSF1 sequencing should be considered in males with unexplained central hypothyroidism, hypoprolactinemia, or macroorchidism. Early diagnosis facilitates timely hormone replacement and monitoring of associated endocrine features.

Key take-home: X-linked loss-of-function IGSF1 mutations are a definitive cause of central congenital hypothyroidism, with consistent genetic and functional evidence guiding diagnosis and management.

References

• Nature Genetics | 2012 | Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement PMID:23143598
• The Journal of Clinical Endocrinology & Metabolism | 2013 | The IGSF1 deficiency syndrome: characteristics of male and female patients PMID:24108313
• Endocrinology | 2017 | TRH action is impaired in pituitaries of male IGSF1-deficient mice PMID:28324000

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