LHX4 – Pituitary Stalk Interruption Syndrome

LHX4 encodes a LIM-homeodomain transcription factor essential for early pituitary organogenesis. Pituitary stalk interruption syndrome (PSIS; MONDO:0019828) is a congenital hypopituitarism characterized by an ectopic posterior pituitary, interrupted or absent stalk, and anterior pituitary hypoplasia. LHX4 expression in developing pituitary and spinal cord underscores its role in stalk formation and hormone cell differentiation.

Autosomal dominant heterozygous and rare autosomal recessive LHX4 variants have been reported in unrelated patients with PSIS. To date, 12 probands across 4 studies harbor disease-causing LHX4 alleles (including 2 familial cases) presenting with ectopic posterior pituitary and sella turcica anomalies (PMID:18445675; PMID:19856252; PMID:25871839; PMID:27820671). Segregation in a single pedigree showed two affected brothers carrying the same frameshift allele (PMID:18445675).

The variant spectrum includes missense (e.g., p.Arg122Trp), nonsense (p.Tyr131Ter), frameshift (c.293dup (p.Thr99fs)), and splice-site mutations (c.606+1G>A), clustering in LIM1/LIM2 and homeodomain regions. No founder alleles have been described, and allele frequencies are absent from control databases, supporting rarity and pathogenicity.

Functional studies in vitro demonstrate that LHX4 mutants fail to bind DNA and activate key target promoters, including POU1F1 and GH1, without exerting dominant-negative effects on wild-type protein (PMID:15998782; PMID:18073311; PMID:18445675; PMID:19856252). Conditional knockout models recapitulate pituitary hypoplasia but have not yet specifically modeled stalk interruption.

Collectively, these data support a haploinsufficiency mechanism for PSIS due to LHX4 variants. While additional large family studies are lacking, consistent genotype–phenotype correlation and concordant functional assays across multiple alleles justify a Moderate ClinGen clinical validity classification. Screening of LHX4 should be considered in patients with PSIS, as early genetic diagnosis informs prognosis and guides hormone replacement therapy.

References

• The Journal of clinical endocrinology and metabolism • 2008 • A novel dysfunctional LHX4 mutation with high phenotypical variability in patients with hypopituitarism PMID:18445675
• Experimental and clinical endocrinology & diabetes • 2010 • A novel mutation (V101A) of the LHX4 gene in a Japanese patient with combined pituitary hormone deficiency PMID:19856252
• The Journal of clinical endocrinology and metabolism • 2015 • Novel Lethal Form of Congenital Hypopituitarism Associated With the First Recessive LHX4 Mutation PMID:25871839
• The Journal of clinical endocrinology and metabolism • 2017 • Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients PMID:27820671
• The Journal of clinical endocrinology and metabolism • 2005 • Functional relationship between LHX4 and POU1F1 in light of the LHX4 mutation identified in patients with pituitary defects PMID:15998782

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