Stickler syndrome

Stickler syndrome is a group of hereditary conditions characterized by a distinctive facial appearance, eye abnormalities, hearing loss, and joint problems. These signs and symptoms vary widely among affected individuals.

A characteristic feature of Stickler syndrome is a somewhat flattened facial appearance. This is caused by underdeveloped bones in the middle of the face, including the cheekbones and the bridge of the nose. A particular group of physical features, called Robin sequence, is also common in people with Stickler syndrome. Robin sequence includes an opening in the roof of the mouth (a cleft palate), a large tongue (macroglossia), and a small lower jaw (micrognathia). This combination of features can lead to feeding problems and difficulty breathing.

Many people with Stickler syndrome have severe nearsightedness (high myopia). In some types of Stickler syndrome, the clear gel that fills the eyeball (the vitreous) has an abnormal appearance, which is visible upon eye examination. Other eye problems are also common, including increased pressure within the eye (glaucoma), clouding of the lens of the eyes (cataracts), and tearing of the lining of the eye (retinal detachment). These eye abnormalities can cause impaired vision or blindness in some cases.

Another feature of Stickler syndrome is hearing loss. The degree of hearing loss varies among affected individuals and may become more severe over time.

Most people with Stickler syndrome have skeletal abnormalities that affect the joints. The joints of affected children and young adults may be loose and very flexible (hypermobile), though joints become less flexible with age. Arthritis often appears early in life and may cause joint pain or stiffness. Problems with the bones of the spine (vertebrae) may also occur, including abnormal curvature of the spine (scoliosis or kyphosis) and flattened vertebrae (platyspondyly). These spinal abnormalities may cause back pain.

Researchers have described four types of Stickler syndrome, which are distinguished by their genetic cause and their characteristic signs and symptoms. In particular, the eye abnormalities and severity of hearing loss differ among the four types. One type, often called non-ocular Stickler syndrome, does not affect the eyes.

A similar condition called Marshall syndrome is characterized by a distinctive facial appearance, eye abnormalities, hearing loss, and early-onset arthritis. Marshall syndrome can also include short stature, which is typically not seen in people with Stickler syndrome. Whether Marshall syndrome represents a variant form of Stickler syndrome or a separate disorder is controversial.

Stickler syndrome affects an estimated 1 in 7,500 to 9,000 newborns.

Mutations in the COL2A1, COL9A1, COL11A1, and COL11A2 genes cause Stickler syndrome. These genes are involved in the production of three types of collagen: type II, type IX, and type XI. Collagens are complex molecules that provide structure and strength to connective tissues that support the body's joints and organs. Type II, type IX, and type XI collagen are components of vitreous, cartilage, and other connective tissues.

Mutations in any one of these genes impair the production, processing, or assembly of type II, type IX, or type XI collagen. Defective collagen molecules or reduced amounts of collagen disrupt the development of connective tissues, leading to the characteristic features of Stickler syndrome.

Not all individuals with Stickler syndrome have mutations in one of the four known genes. Researchers believe that mutations in other genes may also cause this condition, but those genes have not been identified.

Marshall syndrome, which may be a variant of Stickler syndrome, results from mutations in the COL11A1 gene.

Stickler syndrome caused by mutations in COL2A1, COL11A1, or COL11A2 is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits a gene mutation from one affected parent. Other cases may result from new mutations. These cases occur in people with no history of Stickler syndrome in their family.

Marshall syndrome also has an autosomal dominant pattern of inheritance.

When Stickler syndrome is caused by mutations in the COL9A1 gene, it is inherited in an autosomal recessive pattern. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.