Stickler Dysplasia - Types, Diagnosis, and Treatment.

What Is Stickler Dysplasia?

Also known as hereditary arthro-ophthalmopathy and stickler syndrome, it is a congenital condition characterized by connective tissue disorders. A few examples of connective tissues are cartilage, blood, bone, and adipose (fat) tissue; abnormalities in these will affect the entire body.

Some distinct features of stickler syndrome are a flattened face, severe nearsightedness (myopia), hearing loss, early-onset arthritis, etc. The extent of the symptoms depends on the type of stickler syndrome, and treatment primarily includes the management of the symptoms.

What Are the Various Kinds of Stickler Syndrome?

Stickler syndrome was thought to be a result of mutations in one gene, but soon genetic heterogeneity was recognized, and now at least eight different variations have been identified, all of which cause anomalies in the connective tissue. Some of them are-

• Type 1- It is caused due to mutations (alterations or variations) in the gene COL2A1; some of the distinguishing features of this subtype are-

  • Membranous Or Type 1 Vitreous Anomaly- Vitreous is a clear gel-like fluid between the lens and the retina; individuals with type 1 stickler syndrome will have advanced degeneration of the vitreous.
  • Retinal Detachment- It is the separation of the retinal cells (cells that convert light to electrical signals) from the layer of blood vessels that provide oxygen and nourishment to the eye. The longer the retinal detachment goes untreated, the greater the risk of permanent vision loss.
  • Congenital Megalophthalmos- It is the enlargement in the diameter of the cornea. The cornea is a transparent avascular tissue that acts as a structural barrier and protects the eye from infections.

Patients with type 1 stickler syndrome do not have any systemic manifestations.

• Type 2- This is caused due to mutations in the COL11A1 gene. Symptoms include beaded type 2 vitreous (beaded or fibrous appearance of the vitreous), retinal detachment, congenital megalophthalmos, deafness, arthropathy (joint diseases), and cleft palate (an abnormal gap in the roof of the mouth).

• Type 3- It is caused due to mutations in the COL11A2 gene. The vitreous in these individuals is normal. However, symptoms like deafness, arthropathy, and cleft palate are still present.

• Type 4- This is caused due to mutations in the COL9A1 gene, and symptoms include-

  • Sensorineural Deafness- It is a type of hearing loss that occurs due to damage to the inner ear, auditory nerve, or central nervous system.
  • Myopia- A vision condition in which near objects appear clear, but farther objects appear blurry.
  • Vitreoretinopathy- It is a combination of retinal and vitreous complications, ultimately resulting in the detachment of the retina from the tissue around it. It is a serious condition that, if not attended to immediately, will lead to blindness.
  • Retinal Detachment.
  • Epiphyseal Dysplasia- It is a condition resulting from depositions of oligomeric matrix protein (polypeptide chain) in the cartilage of the long bones, resulting in premature destruction of the defective cartilage leading to early arthritis.

• Type 5- It is caused due to mutations in the COL9A2 gene, and the symptoms are the same as type 4 stickler syndrome.

• Type 6- Mutations in the COL9A3 gene are responsible for this variation, and the manifestations are similar to type 4 stickler syndrome.

• Type 7- It is caused due to mutations in the BMP4 gene leading to symptoms like hypoplastic vitreous (reduced vitreous), retinal detachment, deafness, arthropathy, palate abnormalities, and renal dysplasia (improper development of kidneys).

• Type 8- Caused due to mutations in the LOXL3 gene; symptoms include myopia, hypoplastic vitreous, palate abnormality, and arthropathy with normal face and hearing.

Apart from the symptoms mentioned above, some occasionally seen manifestations are-

• Mid-face facial flatness.

• Small chin.

• Long upper lip (philtrum).

• Scoliosis.

• Chest deformities.

• Hip disorders like Legg-Calve-Perthes disease.

• Mitral valve prolapse.

• Pierre-robin syndrome (combination of the small jaw, retracted tongue, and incomplete closure of the roof of the mouth).

How Is Stickler Syndrome Diagnosed?

There are no standard criteria for the diagnosis of stickler syndrome; it is typically based on patient history, clinical evaluation, and genetic testing. Laboratory investigations like x-rays and eye exams will also be conducted prior, but these are done to evaluate the severity of the condition rather than for diagnosis.

Genetic testing for stickler syndrome can be done in three different ways-

1. Serial Single-Gene Testing- This involves testing one specific gene and is done in the presence of type-specific clinical manifestations with an established family history.

2. A Multigene Panel- This includes multiple genes that might cause the syndrome.

3. Comprehensive Genomic Testing- This includes all the genes that can possibly cause the syndrome and non-related genes that might suggest a diagnosis that was not previously considered.

The different types of genetic testing are done to eliminate other conditions that have similar manifestations of stickler syndrome; a few genetic conditions that mimic stickler syndrome are-

• COL2A1 Disorders - These are a group of disorders caused due to mutations in the COL2A1 gene, out of which type 1 stickler syndrome is also a variant. Other variations of COL2A1 disorders include SEDC (spondyloepiphyseal dysplasia congenital), spondyloepimetaphyseal dysplasia, Kneist dysplasia, etc.

• OSMED (Oto-Spondylo-Meta Epiphyseal-Dysplasia) - This reversible genetic condition causes growth retardation in the initial stages, followed by normal growth later on.

• Marshall Syndrome - It is caused due to mutations in the COA11A1 gene, which is similar to type 2 stickler syndrome, but both of them differ in the location of the mutation.

• Wagner Syndrome - Symptoms of Wagner syndrome are similar to stickler syndrome, but the former is caused due to mutations in chromosome 5.

How Is Stickler Syndrome Treated?

Stickler syndrome is a genetic condition that makes it irreversible, and the only treatment option is to manage the symptoms, which can only be done with a multi-disciplinary approach. Some of the management techniques include-

• Ophthalmic assessment to manage retinal detachment, myopia, and vitreous anomalies.

• Individuals with Pierre-robin syndrome can be managed with the help of orthognathic surgery and orthodontics (to rectify dental malalignment).

• Sensorineural hearing loss seen in type 4, 5, and 6 stickler syndrome can be managed with the help of surgery (myringotomy) or hearing aids depending on the severity.

• Joint abnormalities are addressed with anti-inflammatory medication or surgery.

• Physical therapy is often suggested to relieve joint and other complications.

• Genetic counseling and special education also play a vital role in managing genetic conditions such as stickler syndrome.

Conclusion:

Stickler syndrome primarily affects children and causes serious complications like retinal detachment, skeletal abnormalities, joint problems, etc. It is often underdiagnosed due to its similarities to other genetic disorders, which in turn delays treatment. This can be avoided with prompt molecular genetic analysis, which plays a key role in risk stratification for the prevention of blindness and sensory impairment.