CDH11 – Elsahy-Waters syndrome

Elsahy-Waters syndrome is a rare autosomal recessive disorder characterized by craniofacial dysmorphism, cutaneous syndactyly, genitourinary anomalies, and intellectual disability. CDH11 (cadherin-11) has been implicated as the causative gene, with biallelic loss-of-function variants leading to the multisystem phenotype. The gene encodes a cell adhesion protein crucial for cell–cell contacts, osteogenic differentiation, and craniofacial development. This summary reviews genetic and functional evidence supporting CDH11 involvement in Elsahy-Waters syndrome.

Initial case reports described two sisters from a consanguineous family harboring a homozygous indel variant c.1116_1117delinsGATCATCAG (p.Ile372MetfsTer9) segregating with EWS features including hypertelorism, glaucoma, and intellectual disability ([PMID:28988429]). Subsequent studies identified additional homozygous truncating alleles (c.696C>G (p.Tyr232Ter) and c.999+1G>T) in three patients from two independent families, confirming recessive inheritance and a consistent facial-skeletal-genital phenotype ([PMID:29271567]).

A Japanese cohort report expanded the spectrum by describing a novel homozygous splice-site CDH11 variant in a patient with classical EWS and newly recognized cervical vertebral fusions and thoracic anomalies, bringing the total to six molecularly confirmed individuals across four families ([PMID:34278706]). The recurrent observation of biallelic loss-of-function variants underlines the loss-of-function mechanism and phenotypic consistency.

Functional studies in patient-derived fibroblasts demonstrate markedly reduced CDH11 mRNA and absent cadherin-11 protein by immunostaining. Affected cells exhibit decreased proliferation and delayed osteogenic differentiation, mirroring the skeletal and craniofacial defects seen in patients. These assays corroborate a loss-of-function mechanism for CDH11 variants in EWS ([PMID:28988429]).

No conflicting reports have emerged, and all variants described lead to protein truncation or aberrant splicing. The cumulative genetic and experimental evidence supports a mechanistic model in which biallelic CDH11 loss disrupts cell adhesion and osteogenic pathways during development, giving rise to the EWS phenotype.

Key Take-home: Autosomal recessive loss-of-function variants in CDH11 cause Elsahy-Waters syndrome, and diagnostic sequencing of CDH11 is recommended in patients with characteristic craniofacial, skeletal, and genitourinary anomalies.

References

• American journal of medical genetics. Part A • 2017 • Homozygous indel mutation in CDH11 as the probable cause of Elsahy-Waters syndrome. PMID:28988429
• American journal of medical genetics. Part A • 2018 • Elsahy-Waters syndrome is caused by biallelic mutations in CDH11. PMID:29271567
• American journal of medical genetics. Part A • 2021 • Detailed clinical and radiological features of the first patient with Elsahy-Waters syndrome in East Asia. PMID:34278706

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