Sweeney-Cox Syndrome

A number sign (#) is used with this entry because of evidence that Sweeney-Cox syndrome (SWCOS) is caused by heterozygous mutation in the TWIST1 gene (601622) on chromosome 7p21.

Description

Sweeney-Cox syndrome is characterized by striking facial dysostosis, including hypertelorism, deficiencies of the eyelids and facial bones, cleft palate/velopharyngeal insufficiency, and low-set cupped ears (Kim et al., 2017).

Clinical Features

Kim et al. (2017) studied a boy who was previously designated as 'family 18' in a cohort of patients with craniosynostosis reported by Miller et al. (2017). Examination revealed severe facial dysmorphism involving marked hypertelorism, prominent metopic ridge, upper eyelid colobomas, deficient bony orbits with pseudoproptosis, hypoplastic alae nasi with short columella and philtrum, high-arched palate, mild micrognathia, and small low-set dysplastic cupped ears with overfolded helices and upturned lobes. He had flattening of the occiput, and x-rays showed a wide anterior fontanel with wide coronal sutures; CT of the head revealed additional findings of very small frontal bones separated by a patent metopic suture, and hypoplastic midface. Other features included broad neck and narrow shoulders, long fingers with fixed flexion of distal phalanges and bilateral 2/3/4 syndactyly, bilateral talipes equinovarus, bilateral undescended testes, imperforate anus, and generalized hirsutism with low hairline. He underwent surgery at age 2 years for noncleft velopharyngeal insufficiency. He also had moderate learning disability with moderate speech delay, associated with bilateral 60-decibel hearing loss caused by narrow external ear canals. Kim et al. (2017) also studied a similarly but more severely affected girl, who had a brachycephalic skull with a widely open metopic suture extending from the anterior fontanel to the nasal bridge, associated with a widow's peak. She exhibited marked hypertelorism, bilateral upper eyelid colobomas with disrupted eyebrows and both globes almost fully exposed. Her nasal bridge was wide, with broad tip and low columella, and she had midline cleft palate and choanal atresia requiring tracheostomy from birth. Her pinnae were small, low-set, fleshy, and crumpled, and fingers were in a flexed position with 2 through 5 cutaneous syndactyly. She had abnormal patches of hair on her back and below her knees. Brain MRI showed widely patent metopic suture, small cerebellum, and small facial nerves, and ultrasould showed absent spleen. She underwent fundoplication and gastrostomy for gastroesophageal reflux. Head CT at age 3 years showed a thickened frontal bone, patency of the basal parts of the coronal and lambdoid sutures, and unilateral fusion of the occipitomastoid suture on the right. The patient exhibited global developmental delay, but had normal hearing. The authors designated the disorder 'Sweeney-Cox syndrome,' based on surnames of the clinicians who first recognized the common features present in their patients.

Molecular Genetics

Kim et al. (2017) restudied a boy with Sweeney-Cox syndrome who had previously been reported by Miller et al. (2017) as 'family 18' and in whom a missense mutation in the TWIST1 gene had been identified (E117V; 601622.0015). Kim et al. (2017) performed trio-based exome sequencing that demonstrated heterozygosity for a de novo E117V TWIST1 mutation that was not found in his unaffected biologically confirmed parents. Analysis of TWIST1 in a similarly affected unrelated girl revealed a different missense mutation involving the same residue, E117G (601622.0016), which also appeared to have arisen de novo.