DCHS1 – Van Maldergem syndrome

Van Maldergem syndrome is a rare autosomal recessive disorder characterized by intellectual disability, craniofacial dysmorphism and auditory malformations. Pathogenic DCHS1 variants were identified in a single female proband with compound heterozygous missense changes, expanding the cohort to 13 reported patients (PMID:29046692). No additional affected relatives were noted, and segregation beyond the index case is lacking. A representative missense variant affecting a highly conserved residue is c.7385G>A (p.Arg2462Gln), illustrating the spectrum of deleterious DCHS1 alleles.

Functional modelling in mouse demonstrates that loss of Dchs1–Fat4 signalling recapitulates human craniofacial anomalies through increased osteoprogenitor proliferation and delayed osteoblast differentiation (PMID:31358536). These data support a loss-of-function mechanism. Although endocrine features such as hypogonadotropic hypogonadism (HP:0000044) and amazia were observed in the index case, the molecular basis for these anomalies remains unexplained. Key mouse and cellular assays confirm the pathogenic role of DCHS1 disruption in Van Maldergem syndrome.

Key take-home: Biallelic DCHS1 variants cause Van Maldergem syndrome via loss of protocadherin signalling, justifying clinical genetic testing in affected individuals.

References

• International journal of pediatric endocrinology • 2017 • A patient with van Maldergem syndrome with endocrine abnormalities, hypogonadotropic hypogonadism, and breast aplasia/hypoplasia. PMID:29046692
• Development (Cambridge, England) • 2019 • Dchs1-Fat4 regulation of osteogenic differentiation in mouse. PMID:31358536

Evidence Based Scoring (AI generated)