Short Stature, Auditory Canal Atresia, Mandibular Hypoplasia, And Skeletal Abnormalities

A number sign (#) is used with this entry because short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS) is caused by homozygous mutation in the GSC gene (138890) on chromosome 14q32.

Description

Short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS) is an autosomal recessive multiple congenital anomaly syndrome with features of a first and second branchial arch syndrome. Craniofacial abnormalities can lead to conductive hearing loss, respiratory insufficiency, and feeding difficulties. Additional features include rhizomelic skeletal anomalies as well as abnormalities of the shoulder and pelvic joints. Affected individuals may also have some features of a neurocristopathy or abnormal mesoderm development, such as urogenital anomalies, that are distinct from other branchial arch syndromes (summary by Parry et al., 2013).

Clinical Features

Lemire et al. (1998) described a 9-year-old girl, the daughter of consanguineous Mennonite parents, who had a seemingly unique multiple congenital anomaly syndrome consisting of short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities. The skeletal defects consisted of bilateral humeral hypoplasia, delayed ossification of the pubic rami, and previously unreported humeroscapular synostosis. Either autosomal recessive inheritance or new autosomal dominant mutation was considered plausible. The child was the youngest of 6 children. The face was round with somewhat broad forehead, deep-set eyes, downslanting palpebral fissures, micrognathia, and small mouth with prominent incisors. The ears showed a simple, dysplastic pinnae with atretic ear canals.

Ter Heide et al. (2002) described a child with auditory canal atresia and scapulohumeral synostosis who had previously been reported by Schrander-Stumpel et al. (1998). The girl was the fifth child of first-cousin Afghan parents and was noted to have simply formed external ears with bilateral auditory canal atresia, short humeri, and clubfeet. Her external genitalia were hypoplastic and ventrally displaced with the urethra ending within the vagina. She also had severe mandibular hypoplasia, proximally implanted thumbs, delayed ossification of the pubic rami, and dysplastic hips. Chromosomal studies and mental development were normal.

Parry et al. (2013) reported 2 unrelated patients with SAMS. A 6-year-old boy, born of consanguineous Pakistani parents, presented at birth with respiratory insufficiency and poor feeding resulting from craniofacial abnormalities, including high-arched palate, malar hypoplasia, and severe micrognathia. He had rhizomelic shortening of the upper limbs with reduced elbow mobility, proximally placed thumbs, talipes equinovarus, cryptorchidism, and bilateral external auditory canal atresia causing hearing loss. Dysmorphic facial features included scaphocephaly with prominent forehead, slightly downslanting palpebral fissures, short upturned nose, preauricular pits, simple pinnae, and small mouth. Radiographic studies showed left humeroscapular synostosis, dislocated hips, and delayed ossification of the pelvis. The second child was born of consanguineous Bangladeshi parents. At birth, he was noted to have contractures of all limbs, rhizomelic skeletal abnormalities, talipes equinovarus, microphthalmia, micrognathia, external auditory canal atresia with conductive hearing loss, and no testes or scrotal sac. He also had feeding difficulties. Radiographic studies showed scapulohumeral synostosis, mild scapula hypoplasia, and markedly abnormal pelvic ossification, including small iliac bones, narrow sacrosciatic notches, dislocated hips, an absence of the ischial bodies, deficient medial acetabular walls, and an absence of pubic bones.

Inheritance

Consanguinity in the family reported by ter Heide et al. (2002) suggested autosomal recessive inheritance.

Molecular Genetics

In 3 unrelated patients with SAMS, including the patient previously reported by Lemire et al. (1998), Parry et al. (2013) identified homozygous truncating mutations in the GSC gene (138890.0001-138890.0003). The first mutation was found by whole-exome sequencing. A fourth patient with SAMS, previously reported by ter Heide et al. (2002), was found to carry a homozygous 306-kb deletion of chromosome 14q32.13 encompassing the entire GSC gene. The mutations segregated with the disorder in family members available for study.