ROBO1 – Pituitary Stalk Interruption Syndrome

Inherited heterozygous loss-of-function variants in ROBO1 have been implicated in Pituitary Stalk Interruption Syndrome, a developmental disorder characterized by interrupted pituitary stalk, ectopic posterior pituitary, and anterior pituitary hypoplasia. Based on three independent reports describing a familial gene deletion, a novel missense variant, and a frameshift mutation, the clinical validity of this association is classified as Moderate. The cumulative evidence comprises three unrelated probands (PMID:30530901, PMID:31448886, PMID:38444307) and segregation of the deletion and missense variants in two families (PMID:30530901, PMID:31448886). This level of evidence aligns with haploinsufficiency as the likely mechanism. Further multicenter sequencing studies suggest that ROBO1 contributes to PSIS in a subset of patients but explains <5% of cases.

The inheritance pattern for ROBO1-associated PSIS is autosomal dominant. The first report described a 343.7 kb deletion at 3p12.3 encompassing ROBO1 in a father–daughter pair, both with anterior pituitary hypoplasia and pituitary stalk anomalies (PMID:30530901). A second kindred harbored a missense variant c.1690C>T (p.Pro564Ser) in a boy and his mother, both showing the triad of PSIS features (PMID:31448886). A third case involved a de novo heterozygous frameshift mutation in a 2.9-year-old boy with combined pituitary hormone deficiency and central diabetes insipidus (PMID:38444307). Altogether, these reports document segregation and de novo occurrence consistent with dominant haploinsufficiency.

The variant spectrum includes whole-gene deletion, missense, and frameshift alleles. ROBO1 deletions abrogate protein production, and the c.1690C>T (p.Pro564Ser) variant affects a conserved immunoglobulin-like domain. The frameshift mutation predicted truncates the protein and abolishes SLIT binding. No recurrent or founder alleles have been identified to date, and no genotype–phenotype correlations have been established.

Functional studies demonstrate that ROBO1, a receptor for SLIT ligands, is crucial for axonal guidance and hypothalamic–pituitary tract formation. Although no pituitary-specific in vivo models exist, ROBO1-deficient mice exhibit CNS axon guidance defects. Expression studies confirm ROBO1 presence in developing hypothalamic neurons. These data support a haploinsufficiency mechanism underlying the pituitary phenotype.

No conflicting evidence has been reported. PSIS is genetically heterogeneous, with ROBO1 variants accounting for a minority of cases (<5%). The identification of ROBO1 mutations in isolated and familial cases confirms its role within the broader context of midline developmental genes.

In summary, heterozygous loss-of-function variants in ROBO1 cause autosomal dominant PSIS through haploinsufficiency. Genetic testing for ROBO1 variants is clinically useful for diagnosis and familial counseling. Future studies should explore targeted functional assays and broader patient cohorts to refine penetrance estimates.

References

• Journal of pediatric endocrinology & metabolism : JPEM | 2019 | Familial ROBO1 deletion associated with ectopic posterior pituitary, duplication of the pituitary stalk and anterior pituitary hypoplasia. PMID:30530901
• Journal of clinical research in pediatric endocrinology | 2020 | A Novel Missense Mutation in Human Receptor Roundabout-1 (ROBO1) Gene Associated with Pituitary Stalk Interruption Syndrome PMID:31448886
• Journal of pediatric endocrinology & metabolism : JPEM | 2024 | Pituitary stalk interruption syndrome due to novel ROBO1 mutation presenting as combined pituitary hormone deficiency and central diabetes insipidus. PMID:38444307

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