Elsahy-Waters Syndrome

A number sign (#) is used with this entry because of evidence that Elsahy-Waters syndrome (ESWS) is caused by homozygous mutation in the CDH11 gene (600023) on chromosome 16q21.

Description

The core phenotype of Elsahy-Waters syndrome consists of brachycephaly, facial asymmetry, marked hypertelorism, proptosis, blepharochalasis, midface hypoplasia, broad nose with concave nasal ridge, and prognathism; radicular dentin dysplasia with consequent obliterated pulp chambers, apical translucent cysts, recurrent infections, and early loss of teeth; vertebral fusions, particularly at C2-C3; and moderate mental retardation. Skin wrinkling over the glabellar region seems common, and in males, hypospadias has always been present. Inter- and intrafamilial variability has been reported regarding the presence of vertebral fusions, hearing loss,and dentigerous cysts. Midface hypoplasia, facial asymmetry, progressive dental anomalies, and impaired cognitive development become more evident in adulthood (Castori et al., 2010).

Clinical Features

Among the children of a first-cousin couple, el-Sahy and Waters (1971) described 3 boys with an identical syndrome of mental retardation, maxillary hypoplasia, mandibular prognathism (relative or absolute), dental cysts, broad nasal bridge, hypertelorism, bifid uvula or partial cleft plate, pectus excavatum, fused cervical spinous processes, penoscrotal hypospadias, and Schmorl nodes.

Balci et al. (1998) described a seemingly distinct syndrome in 2 offspring of double-first-cousin parents. A 17-year-old male had hypertelorism, saddle nose deformity with a midline nasal cleft, a thick philtrum, and prominent lips. He also exhibited mandibular prognathism and bilateral coloboma of the upper lids and midface hypoplasia, as well as pectus carinatum and hypospadias. Bilateral mixed-type hearing loss was demonstrated. His 11-year-old brother had similar, although milder, clinical features. Harms et al. (2018) stated that these brothers likely had Elsahy-Waters syndrome.

Castori et al. (2010) reported a 44-year-old Italian woman and her 45-year-old brother, born of third-cousin parents, who showed features consistent with Elsahy-Waters syndrome. Craniofacial dysmorphism included brachycephaly with facial asymmetry and midface hypoplasia, high forehead with deep skin furrows over the glabellar area, thick eyebrows with mild synophrys, telecanthus, proptosis, blepharochalasis of the eyelids, broad nose with concave ridge and bulbous tip, shortened philtrum, and thin upper lip. Both had psychomotor delay and marked thoracolumbar scoliosis. The brother also exhibited bifid uvula, submucous cleft soft palate, and small penis with hypospadias; the sister declined gynecologic examination, but both sibs had undergone normal puberty. Skull and cervical x-rays showed increased interorbital distance, underdeveloped maxillary bones, and relative prognathism, with synostosis of the posterior arches and body of C2-C3. Orthopanoramic radiography showed severe alveolar resorption with diffuse to complete loss of maxillary teeth as well as some mandibular teeth; most teeth were shortened and had deformed roots, obliterated pulp chambers, and radiolucent areas around the apices, indicative of radicular dentin dysplasia (see 125400).

From a cohort of 337 patients with intellectual disability (documented IQ of 70 or less), Anazi et al. (2017) identified a 3.5-year-old Saudi boy with features of Elsahy-Waters syndrome and mutation in the CDH11 gene (see MOLECULAR GENETICS). The boy was developmentally delayed in fine motor and cognitive skills, and had a history of delayed dental eruption. Dysmorphic features included synophrys with discontinuation of the central eyebrows, broad nasal bridge, hypertelorism, proptosis, upturned nostrils, malar hypoplasia, thin upper lip, absent upper incisors, prominent crease below the lips, short fingers, widely spaced nipples with central dimple, anteriorly placed and stenotic anus, bifid scrotum, cryptorchidism, and severe hypospadias. Brain MRI, echocardiogram, and abdominal ultrasound were all unremarkable. Harms et al. (2018) restudied this Saudi boy and described additional features including bitemporal narrowing, low-set posteriorly rotated ears, proptosis, downslanting palpebral fissures, and bulbous tip of nose.

Taskiran et al. (2017) reported 2 Turkish sisters, born to first-cousin parents, who presented with facial dysmorphism, intellectual disability, and ocular problems. Both sisters had broad foreheads, thick eyebrows with synophrys, hypertelorism, exophthalmos, megalocornea, flat malar regions, broad and bulbous noses, and mild prognathism. Both had glaucoma, and the younger sister also had cataract and phthisis bulbi. Other findings included bilateral partial cutaneous syndactyly of the second and third fingers and a history of impacted teeth with dentigerous cyst in the older sister. Both exhibited malocclusion due to maxillary retrusion and mandibular protrusion.

Harms et al. (2018) described a 5.5-year-old Indian girl who exhibited striking phenotypic similarity to the Saudi boy reported by Anazi et al. (2017). She had global developmental delay, broad forehead, high-arched and thick eyebrows, severe hypertelorism with proptosis, downslanting palpebral fissures, broad nasal bridge, low-set posteriorly rotated ears, midface retraction, high-arched palate, and extensive caries. In addition, she had a small cleft of the upper eyelid with exposure keratitis due to inability to close the eyelids, and showed megalocornea with large optic cups. Her first-cousin parents were unaffected; 2 brothers died in the neonatal period of unclear causes.

Inheritance

Castori et al. (2010) stated that the presence of parental consanguinity in all reported families with Elsahy-Waters syndrome, as well as affected sibs, an affected female, and absence of vertical transmission indicated an autosomal recessive pattern of inheritance.

Molecular Genetics

In a cohort of 337 patients with intellectual disability (documented IQ of 70 or less), Anazi et al. (2017) performed molecular karyotyping, analysis of a multigene panel, and whole-exome sequencing, and identified a 3.5-year-old Saudi boy with features consistent with Elsahy-Waters syndrome who was homozygous for a splice site mutation in the CDH11 gene (600023.0001).

In 2 Turkish sisters with Elsahy-Waters syndrome, Taskiran et al. (2017) performed exome sequencing and identified homozygosity for a deletion/insertion variant in the CDH11 gene (600023.0002) that was present in heterozygosity in their unaffected parents.

By exome sequencing in a 5.5-year-old Indian girl with Elsahy-Waters syndrome, Harms et al. (2018) identified homozygosity for a nonsense mutation in the CDH11 gene (Y232X; 600023.0003) for which her unaffected parents were heterozygous.

Exclusion Studies

In a 44-year-old Italian woman with Elsahy-Waters syndrome, Castori et al. (2010) excluded mutations in selected exons of the FGFR1 (136350), FGFR2 (176943), and FGFR3 (134934) genes, and CGH analysis did not detect any statistically significant aberrant region.