Stickler Syndrome – Causes, Symptoms, Treatment

Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Robin sequence); and mild spondyloepiphyseal dysplasia and/or precocious arthritis. Variable phenotypic expression of Stickler syndrome occurs both within and among families; interfamilial variability is in part explained by locus and allelic heterogeneity.

Diagnosis/testing.

The diagnosis of Stickler syndrome is clinically based. At present, no consensus minimal clinical diagnostic criteria exist. Pathogenic variants in one of six genes (COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3) have been associated with Stickler syndrome; because a few families with features of Stickler syndrome are not linked to any of these six loci, pathogenic variants in other genes may also cause the disorder.

Management.

Treatment of manifestations: Management in a comprehensive craniofacial clinic when possible; tracheostomy as needed in infants with Robin sequence; mandibular advancement procedure to correct malocclusion for those with persistent micrognathia; correction of refractive errors with spectacles; standard treatment of retinal detachment and sensorineural and conductive hearing loss; symptomatic treatment for arthropathy.

Prevention of secondary complications: Antibiotic prophylaxis for certain surgical procedures if mitral valve prolapse is present.

Surveillance: Annual examination by a vitreoretinal specialist; audiologic evaluations every six months through age five years, then annually thereafter; screening for mitral valve prolapse (MVP) on routine physical examination.

Agents/circumstances to avoid: Activities such as contact sports that may lead to traumatic retinal detachment.

Evaluation of relatives at risk: It is appropriate to determine which family members at risk have Stickler syndrome and thus warrant ongoing surveillance.

Genetic counseling.

Stickler syndrome caused by pathogenic variants COL2A1, COL11A1, or COL11A2 is inherited in an autosomal dominant manner; Stickler syndrome caused by pathogenic variants in COL9A1, COL9A2, or COL9A3 is inherited in an autosomal recessive manner. In families with autosomal dominant inheritance, affected individuals have a 50% chance of passing on the pathogenic variant to offspring. In families with autosomal recessive inheritance, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal testing is possible in pregnancies at increased risk if the pathogenic variant(s) in the family are known.

Suggestive Findings

Stickler syndrome should be suspected in individuals with a combination of the following findings:

• Cleft palate (open cleft, submucous cleft, or bifid uvula)
• Characteristic facial features including malar hypoplasia, broad or flat nasal bridge, and micro/retrognathia
• Vitreous changes or retinal abnormalities (lattice degeneration, retinal hole, retinal detachment, or retinal tear)
• High-frequency sensorineural hearing loss
• Skeletal findings including:
  • Slipped epiphysis or Legg-Perthes-like disease
  • Scoliosis, spondylolisthesis, or Scheuermann-like kyphotic deformity
  • Osteoarthritis before age 40
• An independently affected first-degree relative

Establishing the Diagnosis

The diagnosis of Stickler syndrome is established in a proband who meets the proposed clinical diagnostic criteria and/or has a heterozygous pathogenic variant in COL2A1, COL11A1, or COL11A2 or biallelic pathogenic variants in COL9A1, COL9A2, or COL9A3.

Clinical Description

Stickler syndrome is a multisystem connective tissue disorder that can affect the craniofacies, eyes, inner ear, skeleton, and joints.

Craniofacial findings include a flat facial profile or an appearance that is often referred to as a “scooped out” face. This profile is caused by underdevelopment of the maxilla and nasal bridge, which can cause telecanthus and epicanthal folds. Midface retrusion is most pronounced in infants and young children; older individuals may have a normal facial profile. Often the nasal tip is small and upturned, making the philtrum appear long.

Micrognathia is common and may be associated with cleft palate as part of the Pierre Robin sequence (micrognathia, cleft palate, glossoptosis). The degree of micrognathia may compromise the upper airway, necessitating tracheostomy.

Cleft palate may be seen in the absence of micrognathia.

Eye findings include high myopia (>−3 diopters) that is non-progressive and detectable in the newborn period [Snead & Yates 1999] and vitreous abnormalities. Two types of vitreous abnormalities are observed:

• Type 1 (“membranous”), which is much more common, is characterized by a persistence of vestigial vitreous gel in the retrolental space that is bordered by a folded membrane.
• Type 2 (“beaded”), much less common, is characterized by sparse and irregularly thickened bundles throughout the vitreous cavity.

The ocular phenotype runs true within families [Snead & Yates 1999].

Posterior chorioretinal atrophy was described by Vu et al [2003] in a family with vitreoretinal dystrophy, a novel pathogenic variant in COL2A1, and systemic features of Stickler syndrome, suggesting that individuals with Stickler syndrome may have posterior pole chorioretinal changes in addition to the vitreous abnormalities.

Note: Previously, families with posterior chorioretinal atrophy were thought to have Wagner syndrome.

Hearing impairment is common. The degree of hearing impairment is variable and may be progressive.

Some degree of sensorineural hearing impairment (typically high-tone, often subtle) is found in 40% of individuals [Snead & Yates 1999]. The exact mechanism is unclear, although it is related to the expression of type II and IX collagen in the inner ear [Admiraal et al 2000]. Overall sensorineural hearing loss in type I Stickler syndrome is typically mild and not significantly progressive; it is less severe than that reported for types II and III Stickler syndrome.

Conductive hearing loss can also be seen. This may be secondary to recurrent ear infections that are often associated with cleft palate and/or may be secondary to a defect of the ossicles of the middle ear.

Skeletal manifestations are early-onset arthritis, short stature relative to unaffected sibs, and radiographic findings consistent with mild spondyloepiphyseal dysplasia. Some individuals have a slender body habitus, but without tall stature.

Joint laxity, sometimes seen in young individuals, becomes less prominent (or resolves completely) with age [Snead & Yates 1999].

Early-onset arthritis is common and may be severe, leading to the need for surgical joint replacement even as early as the third or fourth decade. More commonly, the arthropathy is mild, and affected individuals often do not complain of joint pain unless specifically asked. However, nonspecific complaints of joint stiffness can be elicited even from young children.

Spinal abnormalities commonly observed in Stickler syndrome that result in chronic back pain are scoliosis, endplate abnormalities, kyphosis, and platyspondylia [Rose et al 2001].

Mitral valve prolapse (MVP) has been reported in nearly 50% of individuals with Stickler syndrome in one series [Liberfarb & Goldblatt 1986]; diagnosis of Stickler syndrome was made on clinical features prior to the identification of the involved genes. A later study [Liberfarb et al 2003] reported MVP on echocardiogram in only one of 25 individuals with Stickler syndrome and a COL2A1 pathogenic variant. Ahmad et al [2003] screened a group of 75 individuals with molecularly confirmed Stickler syndrome and found no individuals with clinical or echocardiographic evidence of significant mitral valve or other valve abnormality. It was suggested that among those with Stickler syndrome, the prevalence of MVP may be similar to that in the general population. No additional studies reviewing cardiac findings in Stickler syndrome have been reported.

Genotype-Phenotype Correlations

Although inter- and intrafamilial variation was observed among 25 individuals from six families with the same molecular diagnosis [Liberfarb et al 2003], some generalities can be made regarding genotype–phenotype correlation:

• COL2A1 pathogenic variants. The majority of individuals who have Stickler syndrome as a result of a COL2A1 pathogenic variant – including the kindred originally reported by Stickler et al [1965] – have premature stop (i.e., nonsense, frameshift, or splicing) variants that result in functional haploinsufficiency of the COL2A1 product. Most affected individuals have type 1 congenital vitreous abnormalities and are at high risk for retinal detachment and precocious osteoarthritis. Most have normal hearing or mild sensorineural hearing loss. The craniofacial features are variable, ranging from mild nasal anteversion to Robin sequence [Faber et al 2000]. A large family with a unique p.Leu667Phe pathogenic variant had a novel “afibrillar” vitreous gel devoid of all normal lamella structure [Richards et al 2000].
  A COL2A1 missense variant has been described in some families with characteristic ophthalmologic and craniofacial findings, as well as a mild multiple epiphyseal dysplasia with brachydactyly, suggesting that mild heterozygous pathogenic variants may also cause Stickler syndrome. Pathogenic variants involving exon 2 of COL2A1 are characterized by a predominantly ocular variant phenotype, in which individuals are at high risk for retinal detachment.
  In the nine families with an exon 2 pathogenic variant of COL2A1 reported by Donoso et al [2003], all pathogenic variants resulted in stop codons. The phenotype was characterized by optically empty vitreous, typical perivascular pigmentary changes, and/or early-onset retinal detachment with minimal or absent systemic findings of Stickler syndrome.
• COL11A1 pathogenic variants. Missense and splicing variants and deletions within COL11A1 have been observed in individuals with the typical Stickler syndrome phenotype. Typically these individuals have more severe hearing loss and type 2 congenital vitreous anomaly or “beaded” vitreous phenotype; however, three individuals or families with a “membranous” vitreous (type 1) phenotype have been reported [Parentin et al 2001, Majava et al 2007].
• COL11A2 pathogenic variants. Pathogenic variants in COL11A2 have been shown to cause autosomal dominant non-ocular Stickler syndrome [Vikkula et al 1995, Sirko-Osadsa et al 1998, Vuoristo et al 2004, Acke et al 2014].
• COL9A1 pathogenic variants. Biallelic pathogenic variants in COL9A1 have been shown to cause autosomal recessive Stickler syndrome (Stickler syndrome, type IV). Affected individuals have moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, cataracts, and epiphyseal dysplasia [Van Camp et al 2006, Nikopoulos et al 2011]. Of note, the vitreous abnormality resembled an aged vitreous rather than the typical membranous, beaded, or nonfibrillar type.
• COL9A2 pathogenic variants. Biallelic pathogenic variants in COL9A2 have been shown to cause autosomal recessive Stickler syndrome (Stickler syndrome, type V). In the family of Asian Indian origin described by Baker et al [2011] two children had Stickler syndrome manifest as mild-to-moderate hearing loss, high myopia, and vitreoretinopathy.
• COL9A3 pathogenic variants. Biallelic pathogenic variants in COL9A3 have been shown to cause autosomal recessive Stickler syndrome. Affected individuals have moderate-to-severe sensorineural hearing loss, moderate-to-high myopia, midface retrusion, and intellectual disability [Faletra et al 2014]. In the consanguineous family reported by Faletra et al [2014], the intellectual disability is likely unrelated to pathogenic variants in COL9A3.

Penetrance

Penetrance is complete.

Prevalence

No studies to determine the prevalence of Stickler syndrome have been undertaken. However, an approximate incidence of Stickler syndrome among newborns can be estimated from data regarding the incidence of Robin sequence in newborns (1:10,000-1:14,000) and the percent of these newborns who subsequently develop signs or symptoms of Stickler syndrome (35%). These data suggest that the incidence of Stickler syndrome among neonates is approximately 1:7,500-1:9,000 [Printzlau & Andersen 2004].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Stickler syndrome, the following evaluations are recommended:

• Evaluation of palate by a craniofacial specialist
• Baseline ophthalmologic examination
• Baseline audiogram
• Directed history to elicit complaints suggestive of mitral valve prolapse (MVP), such as episodic tachycardia and chest pain. If symptoms are present, referral to a cardiologist should be made.
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Craniofacial. Infants with Robin sequence need immediate attention from specialists in otolaryngology and pediatric critical care, as they may require tracheostomy to ensure a competent airway. It is recommended that evaluation and management occur in a comprehensive craniofacial clinic that provides all the necessary services, including otolaryngology, plastic surgery, oral and maxillofacial surgery, pediatric dentistry, orthodontics, and medical genetics.

In most individuals, micrognathia tends to become less prominent over time, allowing for removal of the tracheostomy. However, in some individuals, significant micrognathia persists, causing orthodontic problems. In these individuals, a mandibular advancement procedure is often required to correct the malocclusion.

Ophthalmologic. Refractive errors should be corrected with spectacles.

Individuals with Stickler syndrome should be advised of the symptoms associated with retinal detachment and the need for immediate evaluation and treatment when such symptoms occur.

Audiologic. See Hereditary Hearing Loss and Deafness Overview. Otitis media may be a recurrent problem secondary to palatal abnormalities. Myringotomy tubes are often required.

Joints. Treatment of arthropathy is symptomatic and includes using over-the-counter anti-inflammatory medications before and after physical activity.

Prevention of Secondary Complications

Individuals with mitral valve prolapse may need antibiotic prophylaxis for certain surgical procedures.

Surveillance

An annual examination by a vitreoretinal specialist is appropriate.

Follow-up audiological evaluations are appropriate every six months through age five years, and annually thereafter.

While the prevalence of mitral valve prolapse (MVP) among affected individuals is unclear, all individuals with Stickler syndrome should be screened for MVP through routine physical examination. More advanced testing (e.g., echocardiogram) should be reserved for those with suggestive symptoms.

Agents/Circumstances to Avoid

Affected individuals should be advised to avoid activities that may lead to traumatic retinal detachment (e.g., contact sports).

At present, no prophylactic therapies to minimize joint damage in affected individuals exist. Some physicians recommend avoiding physical activities that involve high impact to the joints in an effort to delay the onset of arthropathy. While this recommendation seems logical, there are no data to support it.

Evaluation of Relatives at Risk

Because of the variable expression of Stickler syndrome [Faber et al 2000], it is appropriate to evaluate the older and younger sibs of a proband as well as other at-risk relatives in order to identify those who warrant ongoing evaluation. Evaluation can be done in one of two ways:

• By documenting medical history and performing physical examination and ophthalmologic, audiologic, and radiographic assessments. The examination of childhood photographs may be helpful in the assessment of craniofacial findings of adults, since the craniofacial findings characteristic of Stickler syndrome may become less distinctive with age.
• By molecular genetic testing if the pathogenic variant(s) in the family are known

It is recommended that relatives at risk in whom the diagnosis of Stickler syndrome cannot be excluded with certainty be followed for potential complications.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Stickler syndrome caused by heterozygous pathogenic variants in COL2A1, COL11A1, or COL11A2 is inherited in an autosomal dominant manner.

Stickler syndrome caused by biallelic pathogenic variants in COL9A1, COL9A2, or COL9A3 is inherited in an autosomal recessive manner.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• The majority of individuals with autosomal dominant Stickler syndrome inherited a COL2A1, COL11A1, or COL11A2 pathogenic variant from a parent.
• A proband with Stickler syndrome may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is not known.
• It is appropriate to evaluate both parents of a proband for manifestations of Stickler syndrome (see Management) and, if a pathogenic variant has been identified in the proband, offer molecular genetic testing.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.

Sibs of a proband. The risk to sibs depends on the genetic status of the parents:

• If a parent has Stickler syndrome, the risk to each sib of a proband is 50%.
• When the parents are clinically unaffected and/or the pathogenic variant identified in the proband has not been identified in the leukocyte DNA of either parent, it is presumed that the variant occurred de novo and risk to sibs is low. No instances of germline mosaicism have been reported, although it remains a theoretic possibility.

Offspring of a proband. Each child of an individual with Stickler syndrome has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband’s parents: if a parent is affected, his or her family members are at risk.

Autosomal Recessive Inheritance

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

High-risk pregnancies

• Molecular genetic testing. Once the pathogenic variant(s) in a family with Stickler syndrome have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
• Ultrasound evaluation. Alternatively, or in conjunction with molecular genetic testing, ultrasound examination can be performed at 19 to 20 weeks’ gestation to detect cleft palate. Absence of a cleft palate, however, does not exclude the diagnosis of Stickler syndrome.

Low-risk pregnancies. For fetuses with no known family history of Stickler syndrome, but in which cleft palate is detected prenatally, it is appropriate to obtain a three-generation pedigree and to evaluate relatives who have findings suggestive of Stickler syndrome. Molecular genetic testing of the fetus is usually not offered in the absence of a known pathogenic variant in a parent.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.