Stickler syndrome Health Article

Definition

Stickler syndrome is a disorder caused by a genetic malfunction in the tissue that connects bones, heart, eyes, and ears.

Description

Stickler syndrome, also known as hereditary arthroophthalmopathy, is a multisystem disorder that can affect the eyes and ears, skeleton and joints, and craniofacies. Symptoms may include myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate; and mild spondyloepiphyseal dysplasia and/or arthritis. The collection of specific symptoms that make up the syndrome were first documented by Stickler et al., in a 1965 paper published in Mayo Clinic Proceedings titled "Hereditary Progressive Arthro-Opthalmopathy." The paper associated the syndrome's sight deterioration and joint changes. Subsequent research has redefined Stickler syndrome to include other symptoms.

Genetic profile

Stickler syndrome is associated with mutations in three genes: COL2A1 (chromosomal locus 12q13), COL11A1 (chromosomal locus 1p21), and COL11A2 (chromosomal locus 6p21). It is inherited in an autosomal dominant manner. The majority of individuals with Stickler syndrome inherited the abnormal allele from a parent, and the prevalence of new gene mutations is unknown. Individuals with Stickler syndrome have a 50% chance of passing on the abnormal gene to each offspring.

The syndrome can manifest itself differently within families. If the molecular genetic basis of Stickler syndrome has been established, molecular genetic testing can be used for clarification of each family member's genetic status and for prenatal testing.

A majority of cases are attributed to COL2A1 mutations. All COL2A1 mutations known to cause Stickler syndrome result in the formation of a premature termination codon within the type-II collagen gene. Mutations in COL11A1 have only recently been described, and COL11A2 mutations have been identified only in patients lacking ocular findings.

Although the syndrome is associated with mutations in the COL2A1, COL11A1, and COL11A2 genes, no linkage to any of these three known loci can be established in some rare cases with clinical findings consistent with Stickler syndrome. It is presumed that other, as yet unidentified, genes mutations also account for Stickler syndrome.

Genetically related disorders

There are a number of other phenotypes associated with mutations in COL2A1. Achondrogenesis type I is a fatal disorder characterized by absence of bone formation in the vertebral column, sacrum, and pubic bones, by the shortening of the limbs and trunk, and by prominent abdomen. Hypochondrogenesis is a milder variant of achondrogenesis. Spondyloepiphyseal dysplasia congenita, a disorder with skeletal changes more severe than in Stickler syndrome, manifests in significant short stature, flat facial profile, myopia, and vitreoretinal degeneration. Spondyloepimetaphyseal dysplasia Strudwick type is another skeletal disorder that manifests in severe short stature with severe protrusion of the sternum and scoliosis, cleft palate, and retinal detachment. A distinctive radiographic finding is irregular sclerotic changes, described as dappled, which are created by alternating zones of osteosclerosis and ostopenia in the metaphyses (ends) of the long bones. Spondyloperipheral dysplasia is a rare condition characterized by short stature and radiographic changes consistent with a spondyloepiphyseal dysplasia and brachydactyly. Kneist dysplasia is a disorder that manifests in disproportionate short stature, flat facial profile, myopia and vitreoretinal degeneration, cleft palate, backward and lateral curvature of the spine, and a variety of radiographic changes.

Other phenotypes associated with mutations in COL11A1 include Marshall syndrome, which manifests in ocular hypertelorism, hypoplasia of the maxilla and nasal bones, flat nasal bridge, and small upturned nasal tip. The flat facial profile of Marshall syndrome is usually evident into adulthood, unlike Stickler syndrome. Manifestations include radiographs demonstrating hypoplasia of the nasal sinuses and a thickened calvarium. Ocular manifestations include high myopia, fluid vitreous humor, and early onset cataracts. Sensorineural hearing loss is common and sometimes progressive. Cleft palate is seen both as isolated occurrence and as part of the Pierre-Robin sequence (micrognathia, cleft palate, and glossoptosis). Other manifestations include short stature and early onset arthritis, and skin manifestations that may include mild hypotrichosis and hypohidrosis.

Other phenotypes associated with mutations in COL11A2 include autosomal recessive oto-spondylometa-epiphyseal dysplasia, a disorder characterized by flat facial profile, cleft palate, and severe hearing loss. Anocular Stickler syndrome caused by COL11A2 mutations is close in similarity to this disorder. Weissenbach-Zweymuller syndrome has been characterized as neonatal Stickler syndrome but it is a separate entity from Stickler syndrome. Symptoms include midface hypoplasia with a flat nasal bridge, small upturned nasal tip, micrognathia, sensorineural hearing loss, and rhizomelic limb shortening. Radiographic findings include vertebral coronal clefts and dumbbell-shaped femora and humeri. Catch-up growth after age two or three is common and the skeletal findings become less apparent in later years.