HESX1 – Pituitary Stalk Interruption Syndrome

In a cohort of 72 patients with pituitary stalk interruption syndrome, three unrelated probands were found to carry HESX1 variants: a homozygous nonsense mutation c.325C>T (p.Arg109Ter), a heterozygous missense mutation c.467T>C (p.Phe156Ser) and a rare variant c.200G>C (p.Ser67Thr) (PMID:22466334). Functional assays demonstrated that p.Arg109Ter and p.Phe156Ser impair HESX1 repressor activity, consistent with a loss-of-function mechanism, whereas p.Ser67Thr had no effect on protein function. These alleles follow autosomal recessive inheritance with occasional dominant-negative potential in heterozygous carriers. No extended segregation data are available, and only three probands have been reported, supporting a Limited gene–disease association. HESX1 variants account for a small fraction of PSIS cases against a background of broad genetic heterogeneity that often includes intellectual disability (HP:0001249) and seizures (HP:0001250) (PMID:33270637). Further studies are needed to confirm penetrance and refine recurrence risks. Key take-home: HESX1 mutational analysis may identify rare truncating or deleterious alleles in PSIS patients to guide diagnosis and genetic counseling.

References

• The Journal of clinical endocrinology and metabolism • 2012 • PROKR2 variants in multiple hypopituitarism with pituitary stalk interruption. PMID:22466334
• PloS one • 2020 • Pituitary stalk interruption syndrome is characterized by genetic heterogeneity. PMID:33270637

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