Even-Plus Syndrome

A number sign (#) is used with this entry because of evidence that the EVEN-plus syndrome, involving the epiphyses, vertebrae, ears, and nose, plus associated findings, is caused by homozygous or compound heterozygous mutation in the HSPA9 gene (600548) on chromosome 5q31.

Description

EVEN-PLUS syndrome is characterized by prenatal-onset short stature, vertebral and epiphyseal changes, microtia, midface hypoplasia with flat nose and triangular nares, cardiac malformations, and other findings including anal atresia, hypodontia, and aplasia cutis. The features overlap those reported in patients with CODAS syndrome (600373; Royer-Bertrand et al., 2015).

Clinical Features

Amiel et al. (1999) reported 2 sisters, born to distantly related Algerian parents, who exhibited epiphyseal, vertebral, and ear dysplasia, but had normal stature and psychomotor development. Their facial features were strikingly similar and included flat face, high forehead, depressed nasal bridge, short nose with anteverted nares, midface hypoplasia, and prominent philtrum. Both had dysplastic ears, with hypoplastic helices and antihelices. Passive joint mobility was normal, although the younger sister could spontaneously dislocate her elbows, and the older sister had been able to but could no longer do so at age 3.75 years. The older sister also had a unilateral patch of skin aplasia above the ear, and both had short, overriding toes. Radiologic findings included delayed bone age, polyepiphyseal dysplasia, mild metaphyseal dysplasia, persistent midcoronal vertebral clefts, and odontoid hypoplasia. Cardiac and renal ultrasound were normal. Amiel et al. (1999) noted shared features with CODAS syndrome, including delayed bone age, epiphyseal dysplasia, and vertebral clefts, as well as midface hypoplasia, anteverted nares, and ear anomalies. However, the sisters did not exhibit other features of CODAS syndrome such as neonatal hypotonia, postnatal growth retardation, mental retardation, and eye and dental anomalies. Amiel et al. (1999) proposed the acronym 'EVE' for this syndrome involving epiphyseal, vertebral, and ear dysplasia.

Royer-Bertrand et al. (2015) reported 2 Chilean sisters, born to consanguineous parents, who were very short at birth with short long bones, in whom x-rays showed dysplasia of the femoral heads, acetabula, and epiphyses at the knees, and bifid distal femurs. The younger sister also had vertebral coronal clefts and agenesis of the coccyx. Dysmorphic features included hypoplasia of the midface and nasal bones, resulting in a flat nose with triangular nares, as well as arched eyebrows with synophrys and severe microtia or anotia. Both sisters had a small area of aplasia cutis on the vertex of the skull, and the older sister also had 2 lateral hair whorls. Other features included atrial septal defect in the older sister and patent foramen ovale and aneurysmal septum in the younger; the younger sister also had hypodontia, vesicoureteral reflux with hypoplastic right kidney, imperforate anus, developmental delay, and agenesis of the corpus callosum on brain MRI. Royer-Bertrand et al. (2015) also described a Korean girl with similar bone findings and facial dysmorphism, including anotia. Other features included an atrial septal defect that closed spontaneously by age 20 months, anal atresia, atopic dermatitis, and sparse hair. Psychomotor development was borderline normal, and brain MRI was normal at age 5 months. The authors noted that the skeletal features in these patients were the same as those seen in patients with CODAS syndrome, but stated that the additional features such as prenatal-onset short stature, the craniofacial phenotype with microtia, flat facial profile with flat nose and triangular nares, cardiac malformations, and other findings such as anal atresia, hypodontia, and aplasia cutis distinguished this disorder. Noting similarities to the sisters described by Amiel et al. (1999), Royer-Bertrand et al. (2015) designated this syndrome 'EVEN-plus,' for epiphyseal, vertebral, ear, and nose involvement, plus associated findings.

Molecular Genetics

In 2 Chilean sisters and a Korean girl with EVEN-plus syndrome, who were negative for mutation in the LONP1 gene (605490), Royer-Bertrand et al. (2015) performed exome sequencing and identified mutations in the HSPA9 gene (600548) in all 3 patients: the 2 sisters were homozygous for a missense mutation (R126W; 600548.0003), whereas the Korean girl was compound heterozygous for a missense (Y128C; 600548.0004) and a nonsense mutation (V296X; 600548.0005).