CDON – Pituitary stalk interruption syndrome

CDON, a coreceptor in the Sonic Hedgehog signaling pathway, has limited clinical evidence linking it to pituitary stalk interruption syndrome (PSIS). One sporadic case was reported with a heterozygous nonsense variant, c.2764T>C (p.Glu922Ter), absent from 1000 Genomes, ExAC and 400 ancestry-matched controls in an individual presenting neonatal hypoglycemia, cholestasis, and combined GH, TSH, and ACTH deficiencies (PMID:26529631). The variant was maternally inherited from a parent with isolated strabismus, indicating incomplete penetrance and no additional affected relatives. No further CDON variants have been identified in PSIS cohorts, and replication in larger patient series is lacking.

Functional data from holoprosencephaly studies demonstrate that CDON must associate with PTCH1 and GAS1 to mediate SHH-dependent transcription. Loss-of-function mutations disrupt these receptor interactions and impair pathway activation in cell-based assays, supporting a haploinsufficiency mechanism (PMID:21802063). While these mechanistic findings lend biological plausibility, direct functional studies in PSIS models are not yet available.

Key Take-home: CDON haploinsufficiency may underlie PSIS in rare cases and should be considered in genetic testing panels for sporadic or familial PSIS.

References

• The Journal of clinical endocrinology and metabolism • 2016 • A Nonsense Mutation in the Hedgehog Receptor CDON Associated With Pituitary Stalk Interruption Syndrome. PMID:26529631
• American journal of human genetics • 2011 • Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors. PMID:21802063

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