Steel Syndrome

A number sign (#) is used with this entry because of evidence that Steel syndrome (STLS) is caused by homozygous or compound heterozygous mutation in the COL27A1 gene (608461) on chromosome 9q32.

Description

Steel syndrome is characterized by characteristic facies, dislocated hips and radial heads, carpal coalition (fusion of carpal bones), short stature, scoliosis, and cervical spine anomalies. The dislocated hips are resistant to surgical intervention (summary by Flynn et al., 2010).

Clinical Features

Steel et al. (1993) reported 23 children from Puerto Rico with dislocated hips and radial heads, carpal coalition (fusion of carpal bones), and short stature. Carpal coalition was identified radiographically and did not interfere with hand or wrist function. Eight of 23 patients had bilateral talipes cavus, and 3 patients had anomalies of the cervical spine.

Flynn et al. (2010) reported 32 patients with this condition, including 18 patients previously reported by Steel et al. (1993). Congenital hip dislocations were present in all patients. Nearly all patients (29/32) had radial head dislocation, and carpal coalition was seen in 73% of wrists. Scoliosis was seen in over half (17/32), and cavus was seen in 34% of feet. All patients had short stature. Most patients had a characteristic facies including long and oval-shaped face, prominent forehead, hypertelorism, and broad nasal bridge.

Gonzaga-Jauregui et al. (2015) studied a family of Puerto Rican ancestry in which a brother and sister and their female cousin had Steel syndrome. The proband had bilateral congenital hip dysplasia and coxa vara and had undergone 6 unsuccessful surgical procedures to correct the hip dislocation. Radiography showed dislocated femoral heads, underossification of the capital femoral epiphysis, and coxa vara deformity; in addition, the cervical spine was significant for odontoid hypoplasia. His younger sister also had bilateral hip dysplasia, with similar x-ray findings, including poorly ossified femoral heads and bilateral shallow acetabula. Examination at 14 and 12 years of age, respectively, showed short stature, mild midface hypoplasia with slightly anteverted nares, bilateral fifth finger clinodactyly, decreased adduction of the hips bilaterally, and pes planus. The boy had decreased elbow extension bilaterally and thoracic levoscoliosis, with unilateral radial head dislocation, whereas the girl had lumbar lordosis and mild thoracic scoliosis. Both had bilateral capitate/hamate bone coalitions. Family history revealed a maternal female first cousin, who was born in Puerto Rico, with dislocated hips and leg length discrepancy.

Kotabagi et al. (2017) reported a 5-year-old girl, born to nonconsanguineous Indian parents, with features of Steel syndrome, including dysmorphic facies (broad forehead, broad nasal bridge), short stature, partial syndactyly of fingers and toes, bilateral clubfoot, and genu valgum. Radiographs showed carpal coalition, dislocation of radial heads, bilateral hip dislocation, scoliosis of the thoracolumbar region, and vertical talus. The child also had developmental delay and hearing loss.

Gariballa et al. (2017) reported a child, born to first-cousin parents from the United Arab Emirates, with features of Steel syndrome, including bilateral hip dislocations, short upper limbs, and dysmorphic facial features (flat midface, short upturned nose, and thin lips). She also had mild rhizomelic shortening of upper limbs with contractures at the right elbow, genu valgum, and mild bowing of the femur. Radiographic examination showed right hip dislocation with bilateral irregularity of acetabula and coxa vara and a dislocation of the right elbow. She had delayed speech, and hearing assessment at age 2.5 years revealed severe bilateral sensorineural hearing loss.

Belbin et al. (2017) used genomic data linked to health records of individuals living in New York city and identified a locus shared identical by descent (IBD) underlying extreme short stature in persons of Puerto Rican ancestry. In discovery and replication cohorts of Puerto Rican ancestry (4,397 persons), Belbin et al. (2017) identified 5 homozygotes (age 34 to 74 years) and 105 heterozygotes for the G697R (608461.0001) mutation. The 3 homozygotes from the discovery cohort were more than 2.5 standard deviations (SD) below the population mean for height (height reduction of 6 to 10 inches), and the 2 from the replication cohort were 2 or more standard deviations below. All had short stature and bilateral hip dislocation (4 congenital dislocation and 1 leg length discrepancy). One had radial head dislocation, 2 had carpal coalition, and 2 had scoliosis. Four had cervical spine anomalies which in 3 cases required surgery; 1 underwent lumbar spine surgery, and 2 underwent thoracic spine surgery. Three required hip replacement, and 2, both younger than 50 years of age, required knee replacement. There was no evidence that any of these 5 individuals had received a clinical diagnosis of Steel syndrome. Among the 34 heterozygous individuals below the age of 55 years (mean 41.8 years), none had short stature, and none had hip or radial head dislocations. Five (15%) had carpal coalition, 8 (24%) had scoliosis, 7 (21%) had cervical spine anomalies, and 15 (44%) had other spine anomalies. Thirteen (38%) showed evidence of spinal degeneration ranging from severe (multiple level cord compression and neurologic symptoms necessitating surgery) to moderate (lower back pain managed with physical therapy or medication), compared to 4 (13%) of 31 noncarriers. Scoliosis was present in 24% of carriers; arthritis in 38%; lumbar spine degeneration in 29%; and cervical stenosis in 15%.

Inheritance

No parents were affected in the families reported by Steel et al. (1993), but 3 patients had affected sibs, suggesting autosomal recessive inheritance. However, one pair of affected sibs reportedly had the same mother but a different father. No consanguineous parents were identified.

The pedigrees reported by Flynn et al. (2010) were consistent with autosomal recessive inheritance except for 1 family with an affected parent and child. No consanguinity was seen among parents of affected children.

Population Genetics

Belbin et al. (2017) estimated the carrier rate of the COL27A1 G697R mutation (608461.0001) to be 1 in 51 Puerto Rican-born individuals, 1 in 9 individuals born on the island of St. Thomas, and 1 in 346 individuals from the American Hispanic/Latino population. Haplotype analysis suggested that the G697R mutation arose on a Native American haplotype, and IBD tract length analysis found evidence of a population bottleneck in the Puerto Rican population 9 to 14 generations ago, coincident with European immigration and slave trading on the island.

Clinical Management

In the patients reported by Steel et al. (1993), the hip dislocations were resistant to surgical treatment, with poor results in nearly all patients. Better outcomes were reported in patients without surgical treatment, leading the authors to advise that hip surgery not be performed.

Flynn et al. (2010) also reported that patients whose hips were not treated surgically had fewer complaints and less limitation in daily activities than those who underwent surgery.

Molecular Genetics

In a family of Puerto Rican ancestry in which a brother and sister and their female cousin had bilateral hip dislocations, Gonzaga-Jauregui et al. (2015) performed exome sequencing and identified homozygosity for a missense mutation in the COL27A1 gene (G697R; 608461.0001) that segregated completely with disease in the family. There was no evidence for parental consanguinity, suggesting that the variant arose as a founder mutation event that segregates in the Puerto Rican population.

By exome sequencing in a 5-year-old girl, born to nonconsanguineous Indian parents, with Steel syndrome, Kotabagi et al. (2017) identified compound heterozygosity for a nonsense (R707X; 608461.0002) and a frameshift (608461.0003) mutation in the COL27A1 gene. The mutations segregated with the disorder in the family.

By exome sequencing in a 3-year-old girl with Steel syndrome, who was born to first-cousin parents from the United Arab Emirates, Gariballa et al. (2017) identified a homozygous splice site mutation (608461.0004) in the COL27A1 gene. The mutation segregated with the disorder in the family.