IGSF1 – X-linked Central Congenital Hypothyroidism with Late-Onset Testicular Enlargement

X-linked central congenital hypothyroidism with late-onset testicular enlargement is caused by hemizygous loss-of-function variants in the immunoglobulin superfamily member 1 gene (IGSF1). Affected males present with central hypothyroidism, variable prolactin and growth hormone deficiencies, and adult macroorchidism. Female carriers may exhibit mild pituitary dysfunction. This X-linked recessive disorder requires early recognition to prevent developmental sequelae.

Genetic evidence includes a five-generation kindred with a 42-kb deletion spanning the entire IGSF1 coding sequence, identified in 10 affected males (n = 10) with perfect segregation across 5 generations (PMID:27146357). A separate infant case harbored a hemizygous frameshift duplication, c.2422dup (p.His808ProfsTer14), confirming the diagnosis in a male with central hypothyroidism and hepatic steatosis (PMID:37493943). Additional kindreds include at least 4 unrelated families with nonsense or missense alleles (e.g. p.Leu768Pro) segregating with central hypothyroidism and macroorchidism.

Segregation analysis reveals 9 additional affected male relatives carrying IGSF1 variants beyond probands. The variant spectrum encompasses large deletions, frameshift duplications, nonsense, and missense changes, all predicted to truncate or destabilize the IGSF1 C-terminal domain critical for plasma membrane trafficking.

Functional studies demonstrate that loss-of-function IGSF1 mutants (e.g. R762QfsTer7, Leu768Pro) fail to reach the cell surface, leading to deficient thyrotropin-releasing hormone receptor expression and impaired TSH secretion in CRISPR-generated Igsf1-deficient mice (PMID:27310681; PMID:28324000). Rescue of TRH responsiveness is absent, corroborating haploinsufficiency as the pathogenic mechanism.

Conflicting reports of IGSF1 variants in boys with familial delayed puberty (constitutional delay of growth and puberty) found no cosegregation or functional defects, arguing against a broader role of IGSF1 in isolated pubertal delay and supporting specificity for central hypothyroidism with macroorchidism.

Taken together, >20 hemizygous IGSF1 loss-of-function alleles across >10 independent families, robust segregation, and concordant in vitro and in vivo functional data establish a definitive gene–disease relationship. Early genetic screening for IGSF1 variants is clinically indicated in males with idiopathic central hypothyroidism to guide hormone replacement and monitor testicular development.

References

• Clinical Endocrinology • 2016 • Identification of an IGSF1-specific deletion in a five-generation pedigree with X-linked Central Hypothyroidism without macroorchidism PMID:27146357
• Hormones (Athens, Greece) • 2023 • Hepatomegaly and fatty liver disease secondary to central hypothyroidism in combination with macrosomia as initial presentation of IGSF1 deficiency syndrome PMID:37493943
• The Journal of Clinical Endocrinology and Metabolism • 2013 • Three novel IGSF1 mutations in four Japanese patients with X-linked congenital central hypothyroidism PMID:23966245
• Thyroid : official journal of the American Thyroid Association • 2016 • Familial Central Hypothyroidism Caused by a Novel IGSF1 Gene Mutation PMID:27310681
• Endocrinology • 2017 • TRH Action Is Impaired in Pituitaries of Male IGSF1-Deficient Mice PMID:28324000
• Clinical Endocrinology • 2015 • IGSF1 variants in boys with familial delayed puberty PMID:25354429

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