Elsahy-Waters Syndrome

1. Disease Information

Overview

Elsahy-Waters syndrome (EWS), also known as branchioskeletogenital syndrome (BSGS), is an ultra-rare autosomal recessive multiple congenital anomaly/intellectual disability (MCA/MR) syndrome characterized by distinctive craniofacial features, premature loss of teeth with radicular dentin dysplasia, vertebral and genital anomalies, and intellectual disability (castori2018anovelmutation pages 1-2, castori2010elsahy–waterssyndromeevidence pages 1-2). The condition was first described in 1971 by Elsahy and Waters in three affected brothers (castori2010elsahy–waterssyndromeevidence pages 4-6). CDH11 was identified as the causal gene in 2017–2018 through exome sequencing studies (castori2018anovelmutation pages 1-2, castori2018anovelmutation pages 2-4).

Key Identifiers

The following table summarizes the disease identifiers, nomenclature, and core genetic information:

Table: This table summarizes the core disease identifiers, nomenclature, inheritance, and CDH11-related molecular genetics for Elsahy-Waters syndrome. It is useful as a compact reference for knowledge-base curation and for distinguishing this recessive CDH11 disorder from dominant CDH11-related Teebi hypertelorism syndrome.

Synonyms

• Branchioskeletogenital syndrome (BSGS)
• Branchio-skeleto-genital syndrome
• BSG syndrome

Data Sources

Information for this entry is derived from aggregated disease-level resources including OMIM (211380), OpenTargets (MONDO:0008885), and published case reports in the primary literature rather than individual patient EHR data (OpenTargets Search: Elsahy-Waters syndrome, castori2010elsahy–waterssyndromeevidence pages 1-2).

2. Etiology

Disease Causal Factors

Elsahy-Waters syndrome is a monogenic Mendelian disorder caused by biallelic loss-of-function mutations in the CDH11 gene (OMIM 600023) located on chromosome 16q21 (castori2018anovelmutation pages 1-2, castori2018anovelmutation pages 2-4). Cadherins are Ca²⁺-dependent cell-adhesion molecules that control morphogenesis, cell migration, and cell shape changes during multiple developmental processes (castori2018anovelmutation pages 1-2). The identified pathogenic variants include homozygous nonsense mutations resulting in prematurely truncated forms of the cadherin-11 protein, such as c.127A>T (p.Lys43*) (castori2018anovelmutation pages 2-4). There are no known environmental, infectious, or lifestyle risk factors for this genetic condition.

Risk Factors

• Genetic risk factors: Biallelic pathogenic variants in CDH11 are the sole known cause. All reported families have demonstrated parental consanguinity, which greatly increases the risk of autosomal recessive disease (castori2010elsahy–waterssyndromeevidence pages 4-6, castori2010elsahy–waterssyndromeevidence pages 1-2).
• Environmental risk factors: Not applicable for this Mendelian disorder.
• Gene-environment interactions: None documented.

Protective Factors

No genetic or environmental protective factors have been identified for this condition. The partial redundancy of cadherin-11 with N-cadherin (CDH2) in bone tissue may mitigate the severity of the skeletal phenotype, as evidenced by the relatively mild skeletal phenotype in Cdh11 null mice compared to compound Cdh2 heterozygous/Cdh11 null mice (castori2018anovelmutation pages 4-5).

3. Phenotypes

The clinical phenotype of EWS is distinctive, multisystemic, and shows both intra-familial and inter-familial variability (castori2010elsahy–waterssyndromeevidence pages 4-6). The facial phenotype evolves with age, initially resembling craniosynostosis syndromes but becoming more characteristic in adulthood (castori2010elsahy–waterssyndromeevidence pages 4-6). The following table provides a comprehensive listing of all reported phenotypic features with suggested HPO terms:

Table: This table summarizes the reported clinical phenotype spectrum of Elsahy-Waters syndrome across major organ systems, with suggested HPO mappings and supporting citations from the gathered evidence. It is useful for disease knowledge base curation, phenotype annotation, and differential diagnosis.

Summary of Key Phenotype Characteristics

Age of Onset: Congenital/childhood. The craniofacial gestalt and dental anomalies become more recognizable with age, and cognitive impairment becomes clearer during childhood (castori2010elsahy–waterssyndromeevidence pages 4-6).

Severity: Moderate. Intellectual disability is typically mild to moderate. The dental phenotype, however, is severe and significantly impacts daily functioning, preventing solid food consumption in some patients (castori2018anovelmutation pages 2-4).

Progression: Progressive features include worsening dental pathology (progressive tooth loss, dentigerous cysts), progressive alopecia, and progressive hearing loss in some patients (castori2010elsahy–waterssyndromeevidence pages 2-4, castori2018anovelmutation pages 2-4). The characteristic facial phenotype becomes more pronounced with age (castori2010elsahy–waterssyndromeevidence pages 4-6).

Quality of Life Impact: Severely impacted. Both affected siblings in the study by Castori et al. (2018) were dependent on their parents without occupational activity. The dental complications represent a major clinical burden, impairing mastication and nutritional intake (castori2018anovelmutation pages 2-4).

4. Genetic/Molecular Information

Causal Gene

CDH11 (Cadherin-11; HGNC:1750; OMIM: 600023; Ensembl: ENSG00000140937) on chromosome 16q21 is the sole gene known to cause EWS when mutated in a biallelic fashion (OpenTargets Search: Elsahy-Waters syndrome, castori2018anovelmutation pages 1-2).

Pathogenic Variants

• Variant type: Homozygous nonsense and other truncating variants (castori2018anovelmutation pages 1-2, li2021pathogenicvariantsin pages 9-11).
• Classification: Pathogenic (per ClinGen Syndromic Disorders Gene Curation Expert Panel evaluation) (OpenTargets Search: Elsahy-Waters syndrome).
• Example variant: c.127A>T (p.Lys43*) — a nonsense variant in exon 1 creating a premature stop codon that severely truncates the cadherin-11 protein (castori2018anovelmutation pages 2-4).
• Functional consequence: Loss of function. The variants truncate the transmembrane and intracellular domains, abolishing cell-adhesion capability (li2021pathogenicvariantsin pages 9-11, li2021pathogenicvariantsin pages 1-3).
• Origin: Germline.
• Allele frequency: Not reported in population databases given the ultra-rare nature of the condition. All reported families have demonstrated consanguinity (castori2010elsahy–waterssyndromeevidence pages 4-6).

Allelic Disorder: Teebi Hypertelorism Syndrome

Notably, heterozygous missense variants in CDH11 cause a distinct allelic disorder — Teebi hypertelorism syndrome (THS; OMIM 145420) — which presents with hypertelorism but generally normal or only mildly delayed development and minimal skeletal findings, contrasting with the biallelic loss-of-function mechanism in EWS (li2021pathogenicvariantsin pages 9-11, li2021pathogenicvariantsin pages 1-3). This genotype-phenotype correlation distinguishes dominant (haploinsufficiency or dominant-negative) from recessive (complete loss-of-function) CDH11-related conditions.

Modifier Genes

No specific modifier genes have been identified. However, partial redundancy between CDH11 and CDH2 (N-cadherin) in bone tissue has been demonstrated in mouse models, where compound Cdh2 heterozygous/Cdh11 null mice display more pronounced bone phenotypes than single Cdh11 null mice, suggesting CDH2 may modify disease expression (castori2018anovelmutation pages 4-5).

Epigenetic Information

CDH11 is known to undergo promoter methylation inactivation in certain cancer contexts (Chen et al. 2021, J Cancer 12:1190-1199), but no specific epigenetic findings have been reported in EWS.

5. Environmental Information

No environmental factors, lifestyle factors, or infectious agents have been implicated in the etiology or modification of Elsahy-Waters syndrome. This is consistent with its classification as a Mendelian genetic disorder.

6. Mechanism / Pathophysiology

Molecular Pathways

CDH11 encodes cadherin-11 (also termed OB-cadherin or osteoblast-cadherin), a type II classical cadherin that mediates Ca²⁺-dependent homophilic cell-cell adhesion (castori2018anovelmutation pages 1-2, li2021pathogenicvariantsin pages 1-3). Key pathways and molecular mechanisms include:

1. Cell adhesion and migration: CDH11 localizes to focal adhesions and promotes cell-substrate adhesion. Pathogenic variants reduce cell-to-substrate transadhesion activity and alter fibroblast morphology, with delayed lamellipodia formation and abnormal membrane dynamics observed in patient-derived fibroblasts (li2021pathogenicvariantsin pages 14-16, li2021pathogenicvariantsin pages 17-24, li2021pathogenicvariantsin pages 8-9). CDH11 regulates protrusive activity in cranial neural crest cells through interactions with Trio and small GTPases (GO:0007155 cell adhesion; GO:0016477 cell migration) (li2021pathogenicvariantsin pages 14-16).

2. TGFβ1/Smad signaling: Cadherin-11 regulates extracellular matrix (ECM) production via the TGFβ1 pathway. Cells lacking cadherin-11 show increased TGFβ1 expression and subsequent translocation of phosphorylated SMAD2/3 into the nucleus, with changes in ECM composition including decreased type VI collagen and increased fibronectin (Passanha et al. 2022, Stem Cells 40:669-677).

3. RhoA/ROCK signaling: CDH11 modulates RhoA/ROCK pathway activity, which is involved in cytoskeletal organization and fibrosis (Franzè et al. 2020, J Crohn's Colitis 14:406-417).

4. Smad2/3, ERK1/2, and JNK pathways: RNA-seq of CDH11-null atrial fibroblasts showed significant decreases in transcripts associated with Smad2/3, ERK1/2, and JNK pathways (Cao et al. 2021, J Inflamm Res 14:2897-2911).

Cellular Processes

• Osteoblast differentiation: CDH11 shows prevalent expression in osteoblastic cell lines with upregulation during differentiation, suggesting a specific function in bone formation and development (castori2018anovelmutation pages 1-2). Loss-of-function CDH11 mutations delay osteogenic differentiation, which may underlie craniofacial defects in EWS patients (pan2023theodontoblasticdifferentiation pages 15-16).
• Mesenchymal stem cell differentiation: CDH11 is required for mesenchymal stem cell commitment to multiple lineages, regulating the balance between osteogenic and adipogenic differentiation (Passanha et al. 2022, Stem Cells 40:669-677).
• Cranial neural crest cell migration: CDH11 is expressed in cranial neural crest cells and plays critical roles in their migration and morphogenetic processes during craniofacial development (li2021pathogenicvariantsin pages 14-16, li2021pathogenicvariantsin pages 17-24).

Causal Chain

The pathophysiological sequence from molecular defect to clinical manifestation proceeds as follows: 1. Initial trigger: Biallelic loss-of-function CDH11 mutations → absence/severe truncation of functional cadherin-11 protein 2. Upstream mechanism: Loss of Ca²⁺-dependent cell-cell adhesion and impaired cell-substrate interactions in mesenchymal tissues 3. Intermediate processes: Disrupted cranial neural crest cell migration, impaired osteoblast differentiation, altered ECM production, and dysregulated TGFβ1/Smad signaling 4. Downstream effects: Abnormal craniofacial morphogenesis, defective bone formation (vertebral fusions, calvarial abnormalities), defective dentin formation (radicular dentin dysplasia), and impaired neurodevelopment 5. Clinical manifestation: The distinctive craniofacial gestalt, dental anomalies, skeletal malformations, genital anomalies, and intellectual disability characteristic of EWS

Cell Types Involved

• Cranial neural crest cells (CL:0000008)
• Osteoblasts (CL:0000062)
• Dental mesenchymal stem cells / odontoblasts (CL:0000060)
• Mesenchymal stem cells (CL:0000134)
• Fibroblasts (CL:0000057)

Protein Dysfunction

Cadherin-11 normally contains five extracellular cadherin (EC) repeat domains, a transmembrane domain, and an intracellular domain. The truncating variants identified in EWS eliminate the transmembrane and intracellular domains entirely, preventing membrane anchoring and intracellular signaling (li2021pathogenicvariantsin pages 9-11, li2021pathogenicvariantsin pages 1-3). The Ca²⁺-binding regions between EC domains are critical for cadherin stability, and disruption of these regions impairs the protein's adhesive function (li2021pathogenicvariantsin pages 1-3).

7. Anatomical Structures Affected

Organ Level

• Primary: Craniofacial skeleton (UBERON:0003128), teeth/dentin (UBERON:0001751), vertebral column (UBERON:0001130)
• Secondary: External genitalia (UBERON:0004176), brain (UBERON:0000955), ear/auditory system (UBERON:0002105), skin (UBERON:0002097)
• Body systems: Skeletal, nervous, genitourinary, integumentary, special senses

Tissue and Cell Level

• Bone tissue — osteoblasts (CL:0000062) — defective bone formation
• Dental tissues — odontoblasts (CL:0000060) — radicular dentin dysplasia
• Neural tissue — neurons — intellectual disability, seizures
• Mesenchyme — mesenchymal stem cells (CL:0000134) — impaired differentiation
• Skin — dermal fibroblasts — pachydermia, alopecia

Localization

• Craniofacial: bilateral involvement with facial asymmetry
• Vertebral: cervical (particularly C2-C3) and lumbar spine (castori2010elsahy–waterssyndromeevidence pages 2-4, castori2018anovelmutation pages 2-4)
• Genital: ventral penile (hypospadias)
• Auditory: bilateral hearing loss (castori2010elsahy–waterssyndromeevidence pages 2-4)

8. Temporal Development

Onset

• Typical age of onset: Congenital. Craniofacial dysmorphism is present at birth, though it becomes more recognizable with age (castori2010elsahy–waterssyndromeevidence pages 4-6).
• Onset pattern: Congenital with progressive features.

Progression

• The dental phenotype is progressive, with early tooth loss and recurrent dentigerous cysts (castori2010elsahy–waterssyndromeevidence pages 2-4, castori2018anovelmutation pages 2-4).
• Hearing loss may be progressive and bilateral (castori2010elsahy–waterssyndromeevidence pages 2-4).
• Alopecia is progressive (castori2018anovelmutation pages 2-4).
• The facial gestalt evolves with age, becoming more characteristic in adulthood (castori2010elsahy–waterssyndromeevidence pages 4-6).
• Disease course: Chronic lifelong condition.

Critical Periods

Early dental intervention could potentially improve quality of life, though dental implants have not been feasible in reported cases due to alveolar bone resorption (castori2018anovelmutation pages 2-4).

9. Inheritance and Population

Epidemiology

• Prevalence: Unknown; estimated fewer than 1 in 1,000,000 given the ultra-rare nature. As of 2018, only approximately 6 patients from 4 families had been documented in the medical literature (castori2018anovelmutation pages 2-4).
• Incidence: Not calculable from available data.

Inheritance Pattern

• Autosomal recessive (castori2010elsahy–waterssyndromeevidence pages 1-2, castori2010elsahy–waterssyndromeevidence pages 4-6).
• Parental consanguinity has been documented in all reported families, consistent with a rare autosomal recessive condition (castori2010elsahy–waterssyndromeevidence pages 4-6).
• Both sexes are affected; an affected female was first reported by Castori et al. in 2010, refuting earlier hypotheses of X-linked inheritance based on the original report of three affected brothers (castori2010elsahy–waterssyndromeevidence pages 1-2, castori2010elsahy–waterssyndromeevidence pages 4-6).

Penetrance and Expressivity

• Penetrance: Appears to be complete in individuals with biallelic loss-of-function CDH11 variants.
• Expressivity: Variable. Intra-familial and inter-familial variability has been noted, particularly in vertebral fusions, hearing loss, and dentigerous cysts (castori2010elsahy–waterssyndromeevidence pages 4-6).

Population Demographics

• Geographic distribution: Cases have been reported from the Middle East, Italy, Turkey, and East Asia (first East Asian patient reported in 2021) (castori2018anovelmutation pages 2-4).
• Sex ratio: Both males and females affected, approximately equal (castori2010elsahy–waterssyndromeevidence pages 1-2).

10. Diagnostics

Clinical Diagnosis

Diagnosis of EWS is based on recognition of the characteristic clinical phenotype: distinctive craniofacial features (hypertelorism, brachycephaly, midface hypoplasia, facial asymmetry), radicular dentin dysplasia with premature tooth loss, vertebral fusions, hypospadias in males, and intellectual disability (castori2018anovelmutation pages 1-2, castori2010elsahy–waterssyndromeevidence pages 1-2).

Diagnostic Imaging

• Craniofacial imaging: Radiography or CT demonstrating brachycephaly, increased interorbital distance, thick calvaria (castori2010elsahy–waterssyndromeevidence pages 1-2).
• Dental imaging: Panoramic radiographs revealing radicular dentin dysplasia with shortened roots, obliterated pulp chambers, and dentigerous cysts (castori2010elsahy–waterssyndromeevidence pages 2-4, castori2010elsahy–waterssyndromeevidence pages 1-2).
• Spinal imaging: Radiography or MRI of the spine demonstrating vertebral fusions (particularly C2-C3) and scoliosis (castori2010elsahy–waterssyndromeevidence pages 2-4, castori2018anovelmutation pages 2-4).

Genetic Testing

• Whole exome sequencing (WES): The primary modality through which CDH11 mutations were identified as the cause of EWS. WES is the recommended first-tier genetic testing approach (castori2018anovelmutation pages 1-2, castori2018anovelmutation pages 2-4).
• Whole genome sequencing (WGS): May also identify CDH11 variants.
• Single gene testing: Targeted sequencing of CDH11 can confirm a clinical diagnosis.
• Gene panels: CDH11 should be included in panels for syndromic intellectual disability, craniofacial disorders, and skeletal dysplasias.

Differential Diagnosis

• Teebi hypertelorism syndrome (OMIM 145420): Caused by heterozygous CDH11 missense variants; distinguished by generally normal development and minimal skeletal findings (li2021pathogenicvariantsin pages 9-11).
• Craniosynostosis syndromes: The facial phenotype in childhood may resemble craniosynostosis (castori2010elsahy–waterssyndromeevidence pages 4-6).
• Other conditions with hypertelorism and intellectual disability.

11. Outcome/Prognosis

Life Expectancy and Survival

No specific mortality data are available for EWS. The condition is not known to be life-limiting, but longitudinal data are extremely limited given the ultra-rarity of the disorder.

Morbidity and Function

• Affected individuals may have significant morbidity from dental complications, which can prevent solid food consumption (castori2018anovelmutation pages 2-4).
• Both siblings followed long-term by Castori et al. (2018) were dependent on their parents without occupational activity, indicating significant functional impairment in adulthood (castori2018anovelmutation pages 2-4).
• Mild-to-moderate intellectual disability limits academic and vocational achievement (li2021pathogenicvariantsin pages 9-11, castori2018anovelmutation pages 2-4).

Complications

• Recurrent dentigerous cysts (castori2010elsahy–waterssyndromeevidence pages 4-6, castori2018anovelmutation pages 2-4)
• Progressive tooth loss and alveolar bone resorption (castori2010elsahy–waterssyndromeevidence pages 2-4)
• Progressive hearing loss (castori2010elsahy–waterssyndromeevidence pages 2-4)

12. Treatment

Pharmacotherapy

No disease-specific pharmacotherapy exists for EWS. Management is entirely symptomatic and supportive (MAXO:0000009 — supportive care).

Surgical and Interventional

• Dental management: Dental complications represent the major clinical challenge. Surgical evaluation for dental implants was performed in reported cases but determined not to be feasible due to severe alveolar bone resorption (castori2018anovelmutation pages 2-4). Dentigerous cyst excision may be required (MAXO:0000004 — surgical procedure).
• Craniofacial surgery: May be considered for specific features, though no reports detail craniofacial surgical outcomes in EWS.
• Hypospadias repair: Standard urological surgical approaches may be applied in affected males (MAXO:0000004).

Supportive and Rehabilitative

• Nutritional support for patients unable to consume solid foods (castori2018anovelmutation pages 2-4)
• Speech therapy and hearing aids for hearing loss (MAXO:0000930 — hearing aid fitting)
• Special education and developmental support for intellectual disability (MAXO:0000950 — educational intervention)
• Occupational therapy
• Genetic counseling for affected families (MAXO:0000079 — genetic counseling)

Experimental Treatments

No clinical trials are registered for EWS on ClinicalTrials.gov. No gene therapy, cell therapy, or targeted therapeutic approaches have been reported or are in development for this condition.

13. Prevention

Primary Prevention

Not applicable as a Mendelian genetic disorder.

Genetic Screening and Counseling

• Carrier screening: CDH11 sequencing in consanguineous couples from families with known EWS may identify carriers (MAXO:0000079).
• Prenatal diagnosis: Possible through targeted genetic testing (chorionic villus sampling or amniocentesis) if the familial variant is known.
• Preimplantation genetic diagnosis (PGD): Theoretically available for families with identified CDH11 pathogenic variants.
• Cascade screening: Recommended in families with affected members, particularly in consanguineous populations (castori2010elsahy–waterssyndromeevidence pages 4-6).

14. Other Species / Natural Disease

No naturally occurring animal model of Elsahy-Waters syndrome has been reported. The disease has not been documented in companion animals or livestock.

15. Model Organisms

Mouse Models

• Cdh11 knockout (Cdh11⁻/⁻) mice: Global Cdh11 null mice have been generated and studied extensively. These mice exhibit phenotypic features relevant to EWS, though the skeletal phenotype is milder than expected due to partial redundancy with N-cadherin (Cdh2) (castori2018anovelmutation pages 4-5). Key findings include:
• Altered behavioral responses, consistent with the neurodevelopmental aspect of EWS, linked to high CDH11 expression in developing mouse brains with differential expression in hippocampal synaptic junctions (castori2018anovelmutation pages 4-5).
• Reduced bone phenotype compared to compound Cdh2 heterozygous/Cdh11 null mice, demonstrating functional redundancy (castori2018anovelmutation pages 4-5).
• Decreased collagen and elastin synthesis, reduced tissue contractile function (Row et al. 2016, J Cell Sci 129:2950-2961).
• Protection from fibrosis in various organ models including cardiac (Schroer et al. 2019, JCI Insight 4), intestinal (Franzè et al. 2020, J Crohn's Colitis 14:406-417), and hepatic (Wu et al. 2022, Pediatr Invest 6:100-110) fibrosis models.

Model Characteristics

• Phenotype recapitulation: Partial. Cdh11 null mice recapitulate the skeletal and behavioral aspects of EWS but with milder severity. Dental phenotypes have not been well characterized in mouse models.
• Limitations: The partial redundancy of CDH11 with CDH2 in mouse bone tissue limits the severity of the skeletal phenotype relative to the human disease (castori2018anovelmutation pages 4-5). Mouse dental biology also differs substantially from human dental development.

Zebrafish Models

CDH11 expression has been documented during zebrafish skull development, and zebrafish models may be useful for studying craniofacial aspects of the syndrome, though no specific EWS zebrafish model has been reported.

16. Open Targets Disease-Target Associations

OpenTargets (MONDO:0008885) identifies CDH11 (ENSG00000140937) as the sole molecular target associated with Elsahy-Waters syndrome, with an association score of 0.71 based on 5 evidence items from multiple curation sources including ClinGen and the Developmental Disorders Gene Curation Expert Panel (OpenTargets Search: Elsahy-Waters syndrome). Key supporting PMIDs include 28988429, 33811546, 29271567, 27431290, 30194892, and 34278706 (OpenTargets Search: Elsahy-Waters syndrome).

17. Ontology Term Summary

Disease Ontology: - MONDO:0008885 (Elsahy-Waters syndrome) - OMIM:211380

Gene Ontology (Biological Process): - GO:0007155 (cell adhesion) - GO:0016477 (cell migration) - GO:0001649 (osteoblast differentiation) - GO:0060349 (bone morphogenesis) - GO:0007275 (multicellular organism development)

Gene Ontology (Cellular Component): - GO:0005913 (cell-cell adherens junction) - GO:0005925 (focal adhesion) - GO:0016020 (membrane)

Gene Ontology (Molecular Function): - GO:0005509 (calcium ion binding) - GO:0045296 (cadherin binding)

Cell Ontology: - CL:0000062 (osteoblast) - CL:0000060 (odontoblast) - CL:0000134 (mesenchymal stem cell) - CL:0000008 (cranial neural crest cell)

UBERON: - UBERON:0003128 (craniofacial skeleton) - UBERON:0001751 (dentin) - UBERON:0001130 (vertebral column) - UBERON:0000955 (brain)

CHEBI: - CHEBI:29108 (calcium(2+)) — required for CDH11 function

Summary

Elsahy-Waters syndrome is an ultra-rare autosomal recessive Mendelian disorder caused by biallelic loss-of-function mutations in CDH11, the gene encoding cadherin-11 (OB-cadherin). As of 2018, approximately 6 patients from 4 families had been reported worldwide, with all families demonstrating consanguinity (castori2018anovelmutation pages 2-4, castori2010elsahy–waterssyndromeevidence pages 4-6). The clinical phenotype encompasses distinctive craniofacial dysmorphism (hypertelorism, brachycephaly, midface hypoplasia), severe dental anomalies (radicular dentin dysplasia, dentigerous cysts, premature tooth loss), skeletal malformations (vertebral fusions), genital anomalies (hypospadias in males), and mild-to-moderate intellectual disability (castori2018anovelmutation pages 1-2, castori2010elsahy–waterssyndromeevidence pages 2-4, castori2018anovelmutation pages 2-4). The molecular pathophysiology involves impaired Ca²⁺-dependent cell adhesion, disrupted cranial neural crest cell migration, and delayed osteogenic differentiation (li2021pathogenicvariantsin pages 14-16, castori2018anovelmutation pages 1-2, pan2023theodontoblasticdifferentiation pages 15-16). No disease-specific therapies exist; management is supportive with particular challenges in dental rehabilitation (castori2018anovelmutation pages 2-4). CDH11 heterozygous variants cause the allelic but phenotypically distinct Teebi hypertelorism syndrome (li2021pathogenicvariantsin pages 9-11). Cdh11 knockout mice provide a partial animal model but exhibit a milder phenotype due to functional redundancy with N-cadherin (castori2018anovelmutation pages 4-5).

References

1. (castori2018anovelmutation pages 1-2): Marco Castori, Claus‐Eric Ott, Luigi Bisceglia, Maria Pia Leone, Tommaso Mazza, Stefano Castellana, Jurgen Tomassi, Silvia Lanciotti, Stefan Mundlos, Raoul C. Hennekam, Uwe Kornak, and Francesco Brancati. A novel mutation in cdh11, encoding cadherin‐11, cause branchioskeletogenital (elsahy‐waters) syndrome. American Journal of Medical Genetics Part A, 176:2028-2033, Sep 2018. URL: https://doi.org/10.1002/ajmg.a.40379, doi:10.1002/ajmg.a.40379. This article has 8 citations.

2. (castori2010elsahy–waterssyndromeevidence pages 1-2): Marco Castori, Piero Cascone, Michele Valiante, Luigi Laino, Giorgio Iannetti, Raoul C.M. Hennekam, and Paola Grammatico. Elsahy–waters syndrome: evidence for autosomal recessive inheritance. American Journal of Medical Genetics Part A, 152A:2810-2815, Nov 2010. URL: https://doi.org/10.1002/ajmg.a.33634, doi:10.1002/ajmg.a.33634. This article has 16 citations.

3. (castori2010elsahy–waterssyndromeevidence pages 4-6): Marco Castori, Piero Cascone, Michele Valiante, Luigi Laino, Giorgio Iannetti, Raoul C.M. Hennekam, and Paola Grammatico. Elsahy–waters syndrome: evidence for autosomal recessive inheritance. American Journal of Medical Genetics Part A, 152A:2810-2815, Nov 2010. URL: https://doi.org/10.1002/ajmg.a.33634, doi:10.1002/ajmg.a.33634. This article has 16 citations.

4. (castori2018anovelmutation pages 2-4): Marco Castori, Claus‐Eric Ott, Luigi Bisceglia, Maria Pia Leone, Tommaso Mazza, Stefano Castellana, Jurgen Tomassi, Silvia Lanciotti, Stefan Mundlos, Raoul C. Hennekam, Uwe Kornak, and Francesco Brancati. A novel mutation in cdh11, encoding cadherin‐11, cause branchioskeletogenital (elsahy‐waters) syndrome. American Journal of Medical Genetics Part A, 176:2028-2033, Sep 2018. URL: https://doi.org/10.1002/ajmg.a.40379, doi:10.1002/ajmg.a.40379. This article has 8 citations.

5. (li2021pathogenicvariantsin pages 9-11): Dong Li, Michael E. March, Paola Fortugno, Liza L. Cox, Leticia S. Matsuoka, Rosanna Monetta, Christoph Seiler, Louise C. Pyle, Emma C. Bedoukian, María José Sánchez-Soler, Oana Caluseriu, Katheryn Grand, Allison Tam, Alicia R. P. Aycinena, Letizia Camerota, Yiran Guo, Patrick Sleiman, Bert Callewaert, Candy Kumps, Annelies Dheedene, Michael Buckley, Edwin P. Kirk, Anne Turner, Benjamin Kamien, Chirag Patel, Meredith Wilson, Tony Roscioli, John Christodoulou, Timothy C. Cox, Elaine H. Zackai, Francesco Brancati, Hakon Hakonarson, and Elizabeth J. Bhoj. Pathogenic variants in cdh11 impair cell adhesion and cause teebi hypertelorism syndrome. Human Genetics, 140:1061-1076, Apr 2021. URL: https://doi.org/10.1007/s00439-021-02274-3, doi:10.1007/s00439-021-02274-3. This article has 12 citations and is from a peer-reviewed journal.

6. (OpenTargets Search: Elsahy-Waters syndrome): Open Targets Query (Elsahy-Waters syndrome, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

7. (li2021pathogenicvariantsin pages 14-16): Dong Li, Michael E. March, Paola Fortugno, Liza L. Cox, Leticia S. Matsuoka, Rosanna Monetta, Christoph Seiler, Louise C. Pyle, Emma C. Bedoukian, María José Sánchez-Soler, Oana Caluseriu, Katheryn Grand, Allison Tam, Alicia R. P. Aycinena, Letizia Camerota, Yiran Guo, Patrick Sleiman, Bert Callewaert, Candy Kumps, Annelies Dheedene, Michael Buckley, Edwin P. Kirk, Anne Turner, Benjamin Kamien, Chirag Patel, Meredith Wilson, Tony Roscioli, John Christodoulou, Timothy C. Cox, Elaine H. Zackai, Francesco Brancati, Hakon Hakonarson, and Elizabeth J. Bhoj. Pathogenic variants in cdh11 impair cell adhesion and cause teebi hypertelorism syndrome. Human Genetics, 140:1061-1076, Apr 2021. URL: https://doi.org/10.1007/s00439-021-02274-3, doi:10.1007/s00439-021-02274-3. This article has 12 citations and is from a peer-reviewed journal.

8. (castori2018anovelmutation pages 4-5): Marco Castori, Claus‐Eric Ott, Luigi Bisceglia, Maria Pia Leone, Tommaso Mazza, Stefano Castellana, Jurgen Tomassi, Silvia Lanciotti, Stefan Mundlos, Raoul C. Hennekam, Uwe Kornak, and Francesco Brancati. A novel mutation in cdh11, encoding cadherin‐11, cause branchioskeletogenital (elsahy‐waters) syndrome. American Journal of Medical Genetics Part A, 176:2028-2033, Sep 2018. URL: https://doi.org/10.1002/ajmg.a.40379, doi:10.1002/ajmg.a.40379. This article has 8 citations.

9. (li2021pathogenicvariantsin pages 1-3): Dong Li, Michael E. March, Paola Fortugno, Liza L. Cox, Leticia S. Matsuoka, Rosanna Monetta, Christoph Seiler, Louise C. Pyle, Emma C. Bedoukian, María José Sánchez-Soler, Oana Caluseriu, Katheryn Grand, Allison Tam, Alicia R. P. Aycinena, Letizia Camerota, Yiran Guo, Patrick Sleiman, Bert Callewaert, Candy Kumps, Annelies Dheedene, Michael Buckley, Edwin P. Kirk, Anne Turner, Benjamin Kamien, Chirag Patel, Meredith Wilson, Tony Roscioli, John Christodoulou, Timothy C. Cox, Elaine H. Zackai, Francesco Brancati, Hakon Hakonarson, and Elizabeth J. Bhoj. Pathogenic variants in cdh11 impair cell adhesion and cause teebi hypertelorism syndrome. Human Genetics, 140:1061-1076, Apr 2021. URL: https://doi.org/10.1007/s00439-021-02274-3, doi:10.1007/s00439-021-02274-3. This article has 12 citations and is from a peer-reviewed journal.

10. (pan2023theodontoblasticdifferentiation pages 15-16): Houwen Pan, Yiling Yang, Hongyuan Xu, Anting Jin, Xiangru Huang, Xin Gao, Siyuan Sun, Yuanqi Liu, Jingyi Liu, Tingwei Lu, Xinyu Wang, Yanfei Zhu, and Lingyong Jiang. The odontoblastic differentiation of dental mesenchymal stem cells: molecular regulation mechanism and related genetic syndromes. Frontiers in Cell and Developmental Biology, Sep 2023. URL: https://doi.org/10.3389/fcell.2023.1174579, doi:10.3389/fcell.2023.1174579. This article has 35 citations.

11. (castori2010elsahy–waterssyndromeevidence pages 2-4): Marco Castori, Piero Cascone, Michele Valiante, Luigi Laino, Giorgio Iannetti, Raoul C.M. Hennekam, and Paola Grammatico. Elsahy–waters syndrome: evidence for autosomal recessive inheritance. American Journal of Medical Genetics Part A, 152A:2810-2815, Nov 2010. URL: https://doi.org/10.1002/ajmg.a.33634, doi:10.1002/ajmg.a.33634. This article has 16 citations.

12. (li2021pathogenicvariantsin pages 17-24): Dong Li, Michael E. March, Paola Fortugno, Liza L. Cox, Leticia S. Matsuoka, Rosanna Monetta, Christoph Seiler, Louise C. Pyle, Emma C. Bedoukian, María José Sánchez-Soler, Oana Caluseriu, Katheryn Grand, Allison Tam, Alicia R. P. Aycinena, Letizia Camerota, Yiran Guo, Patrick Sleiman, Bert Callewaert, Candy Kumps, Annelies Dheedene, Michael Buckley, Edwin P. Kirk, Anne Turner, Benjamin Kamien, Chirag Patel, Meredith Wilson, Tony Roscioli, John Christodoulou, Timothy C. Cox, Elaine H. Zackai, Francesco Brancati, Hakon Hakonarson, and Elizabeth J. Bhoj. Pathogenic variants in cdh11 impair cell adhesion and cause teebi hypertelorism syndrome. Human Genetics, 140:1061-1076, Apr 2021. URL: https://doi.org/10.1007/s00439-021-02274-3, doi:10.1007/s00439-021-02274-3. This article has 12 citations and is from a peer-reviewed journal.

13. (li2021pathogenicvariantsin pages 8-9): Dong Li, Michael E. March, Paola Fortugno, Liza L. Cox, Leticia S. Matsuoka, Rosanna Monetta, Christoph Seiler, Louise C. Pyle, Emma C. Bedoukian, María José Sánchez-Soler, Oana Caluseriu, Katheryn Grand, Allison Tam, Alicia R. P. Aycinena, Letizia Camerota, Yiran Guo, Patrick Sleiman, Bert Callewaert, Candy Kumps, Annelies Dheedene, Michael Buckley, Edwin P. Kirk, Anne Turner, Benjamin Kamien, Chirag Patel, Meredith Wilson, Tony Roscioli, John Christodoulou, Timothy C. Cox, Elaine H. Zackai, Francesco Brancati, Hakon Hakonarson, and Elizabeth J. Bhoj. Pathogenic variants in cdh11 impair cell adhesion and cause teebi hypertelorism syndrome. Human Genetics, 140:1061-1076, Apr 2021. URL: https://doi.org/10.1007/s00439-021-02274-3, doi:10.1007/s00439-021-02274-3. This article has 12 citations and is from a peer-reviewed journal.

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