HESX1 – Panhypopituitarism

HESX1 (Homeobox expressed in ES cells 1) is a paired-like homeodomain transcriptional repressor critical for forebrain and pituitary organogenesis. Loss-of-function variants disrupt anterior pituitary development, leading to combined pituitary hormone deficiency or panhypopituitarism (PMID:12519827; PMID:27000987).

Multiple unrelated probands harbour recessive or de novo heterozygous HESX1 variants. Six affected individuals from four families have been reported, including de novo frameshift and homozygous missense alleles; segregation of a recessive p.Arg160Cys variant was observed in two siblings ([PMID:12519827; PMID:27000987]).

Inheritance is predominantly autosomal recessive, with occasional dominant-negative effects from heterozygous homeodomain mutations. Reported variant classes include frameshift insertions (e.g., c.305_306dup (p.Leu103fsTer)), splice-site defects, nonsense changes, and missense substitutions within the homeodomain and engrailed homology domain.

In vitro and in vivo functional studies demonstrate that HESX1 pathogenic variants abolish DNA binding or impair corepressor (Groucho/TLE) recruitment, leading to defective repression of PROP1-mediated transcription. Hesx1 knockout mice recapitulate anterior pituitary aplasia and optic defects, supporting a haploinsufficiency/dominant-negative mechanism ([PMID:11748154]; [PMID:14561704]).

No large contradictory studies have been reported; rare HESX1 variants in CPHD cohorts without clear pathogenicity further underscore allelic heterogeneity and possible modifier influences.

Taken together, HESX1 variants confer a moderate level of clinical validity for panhypopituitarism. Genetic testing informs early hormone replacement, MRI surveillance, and family counseling.

Key Take-home: HESX1 loss-of-function alleles reliably cause autosomal recessive panhypopituitarism with variable expressivity; molecular diagnosis enables targeted management.

References

• The Journal of clinical endocrinology and metabolism • 2003 • Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient PMID:12519827
• Clinical endocrinology • 2016 • HESX1 mutations in patients with congenital hypopituitarism: variable phenotypes with the same genotype PMID:27000987
• Development (Cambridge, England) • 2001 • Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders PMID:11748154
• The Journal of clinical investigation • 2003 • A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction PMID:14561704

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