Goal 1.

Describe the clinical characteristics of type II collagen disorders.

Goal 2.

Provide an evaluation strategy to identify the genetic cause of a type II collagen disorder in a proband.

Goal 3.

Inform genetic counseling of family members of an individual with a type II collagen disorder.

Goal 4.

Review management of type II collagen disorders.

Clinical Description

Type II collagen is an essential component of the cartilage extracellular matrix, and of major importance in endochondral bone formation, growth, and normal joint function. It is also necessary for normal development and function of the eye and the inner ear. Type II collagen disorders encompass a diverse group of clinical phenotypes characterized by skeletal dysplasia, ocular manifestations (e.g., cataract, myopia, subluxation of the lens, vitreous abnormalities, retinal detachment), hearing impairment, and orofacial features [Nishimura et al 2005, Kannu et al 2012, Spranger et al 2012a, Terhal et al 2015, Savarirayan et al 2019].

The spectrum of severity ranges from severe perinatal lethal disorders to milder conditions presenting in adulthood, with premature arthrosis as the primary feature. Included in this overview are the following specific type II collagen phenotypes (disorders included in the Nosology and Classification of Genetic Skeletal Disorders: 2015 Revision) [Bonafe et al 2015], which can be grouped according to severity.

Most severe (often lethal perinatally)

• Achondrogenesis type II
• Hypochondrogenesis
• Platyspondylic dysplasia, Torrance type

Severe/moderately severe (neonatal presentation)

• Kniest dysplasia
• Spondyloepiphyseal dysplasia congenita (SEDC)
• Spondyloepimetaphyseal dysplasia (SEMD), Strudwick type

Intermediate (neonatal/childhood/adolescent presentation)

• Spondyloperipheral dysplasia
• Spondyloepiphyseal dysplasia with metatarsal shortening
• Stickler syndrome type 1

Mild (adolescent/adult presentation). Mild spondyloepiphyseal dysplasia (SED) with premature arthrosis

Genotype-Phenotype Correlations

There is currently no clear genotype-phenotype correlation in type II collagen disorders, and there is significant phenotypic overlap. However, data do support some general rules [Nishimura et al 2005, Hoornaert et al 2006, Terhal et al 2015, Barat-Houari et al 2016b, Barat-Houari et al 2016c, Leiden Open Variation Database (LOVD)]. Most pathogenic COL2A1 variants involve the triple helix domain.

• Missense variants in the Gly position of the Gly-X-Y repeat motif cause substitution of glycine to a bulkier amino acid interfering with triple helix formation. This dominant-negative effect is generally seen in the more severe collagen type II disorders (e.g., achondrogenesis type II; hypochondrogenesis; platyspondyly, Torrance type; SEDC; and SEMD, Strudwick type).
• In Kniest dysplasia exon skipping is more common [Barat-Houari et al 2016b, Barat-Houari et al 2016c], and it appears that splicing variants impose a higher risk for ophthalmologic complications and hearing loss [Terhal et al 2015].
• Arginine-to-cysteine substitutions are most often associated with non-lethal phenotypes [Hoornaert et al 2006]. A p.Arg275Cys substitution in the Y position of the Gly-X-Y repeat motif causes SED with metatarsal shortening [Hoornaert et al 2007].
• In Stickler syndrome type 1, nonsense and frameshift variants dominate, introducing a premature termination codon leading to haploinsufficiency [Richards et al 2006].

Penetrance

Penetrance in type II collagen disorders is high, if not complete; only rare cases of apparently reduced penetrance have been reported [Barat-Houari et al 2016b]. However, the milder disorders have age-dependent phenotypic manifestations, and wide inter- and intrafamilial phenotypic variation has been reported [Liberfarb et al 2003, Nakashima et al 2016]. At present, knowledge of underlying mechanisms is limited, but the phenotypic variation is likely caused by environmental factors and the polymorphisms in disease-modifying genes and/or regulatory elements [Bell et al 1997, Bi et al 1999, Liberfarb et al 2003, Kannu et al 2010, Nakashima et al 2016, Yasuda et al 2017].

Nomenclature

Achondrogenesis type II was formerly known as Langer-Saldino dysplasia.

Spondyloperipheral dysplasia is also referred to as spondyloperipheral dysplasia-short ulna syndrome.

Spondyloepiphyseal dysplasia with metatarsal shortening is also referred to as Czech dysplasia.

Prevalence

The exact prevalence of type II collagen disorders is not known. However, Stickler syndrome type 1 may be the most common type II collagen disorder; the overall incidence of all types of Stickler syndrome is estimated at 1/10,000 [Rose et al 2001].

Differential Diagnosis

The differential diagnosis of type II collagen disorders includes a range of disorders from severe, often lethal skeletal dysplasia with abnormal ossification and major skeletal abnormalities, to milder conditions with limited clinical and radiographic findings. Disorders with a known genetic etiology are listed (from most to least severe) in Table 2a; disorders of unknown or multifactorial etiology are listed in Table 2b.

Mode of Inheritance

Type II collagen disorders are inherited in an autosomal dominant manner. However, rare cases of autosomal recessive inheritance in spondyloepiphyseal dysplasia congenita have been reported [Tham et al 2015, Barat-Houari et al 2016a].

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with a severe form of type II collagen disorder have the disorder as the result of a de novo pathogenic variant. The overall proportion of cases caused by a COL2A1 de novo pathogenic variant is unknown.
• Many individuals diagnosed with the milder form of type II collagen disorder have an affected parent. Clinical variability within a family can be extensive; however, severe and mild forms are not seen in family members with the same pathogenic variant (i.e., the specific type II collagen diagnosis appears to run true in a family, but with variable expressivity).
• Recommendations for the parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing and clinical examination (see Evaluation of Relatives at Risk).
• 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 and somatic and/or germline mosaicism in a parent. The incidence of somatic and germline mosaicism is unknown, but it is likely rare since only a few cases of genetically proven somatic and germline mosaicism have been reported in the literature [Nagendran et al 2012, Okamoto et al 2012, Stevenson et al 2012].
• The family history of some individuals diagnosed with a milder form of type II collagen disorder may appear to be negative because of failure to recognize the disorder in mildly affected family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• Note: If the parent is the individual in whom the COL2A1 pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

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

• If a parent of the proband is affected and/or is known to have the COL2A1 pathogenic variant identified in the proband, the risk to the sibs is 50%. Clinical variability within a family can be extensive; however, severe and mild forms are not seen in family members with the same pathogenic variant (i.e., the specific type II collagen diagnosis appears to run true in a family, but with variable expressivity).
• If the COL2A1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism, with or without somatic mosaicism [Nagendran et al 2012, Okamoto et al 2012, Stevenson et al 2012].
• If the parents have not been tested for the COL2A1 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for a type II collagen disorder because of the possibility of parental somatic and/or germline mosaicism or reduced penetrance in a heterozygous parent.

Offspring of a proband. Each child of an individual with a type II collagen disorder has a 50% chance of inheriting the COL2A1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes for one COL2A1 pathogenic variant.
• To date, autosomal recessive spondyloepiphyseal dysplasia congenita has been reported in two families [Tham et al 2015, Barat-Houari et al 2016a]. In these families: one heterozygous father presented with high myopia, asymmetric lower limbs, and average stature; one heterozygous mother was 154 cm tall; the two other heterozygous parents were of normal stature.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of inheriting two COL2A1 pathogenic variants (one from each heterozygous parent), a 50% chance of inheriting one COL2A1 pathogenic variant, and a 25% chance of inheriting a COL2A1 pathogenic variant from neither parent.
• Heterozygous sibs are predicted to be either unaffected or mildly affected. Homozygous sibs will be affected in a manner similar to the affected individual but, because of variable expressivity, may have a more or less severe clinical outcome.

Offspring of a proband. Unless an individual with biallelic COL2A1 pathogenic variants has children with an individual who also has a type II collagen disorder, the proband's offspring will be obligate heterozygotes for a pathogenic variant in COL2A1.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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 proband may have a de novo pathogenic variant or a parent may have somatic and/or germline mosaicism for the pathogenic variant. 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 and discussion of the availability of prenatal/preimplantation genetic 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.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the COL2A1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with type II collagen disorders, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

In individuals with cervical spine instability, extreme neck extension and neck flexion and contact sports should be avoided.

In case of general anesthesia, the cervical spine should be assessed by imaging prior to the procedure [White et al 2017].

Evaluation of Relatives at Risk

It is appropriate to clarify the clinical/genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from regular surveillance in order to avoid/prevent common complications. Evaluations can include:

• Molecular genetic testing if the pathogenic variant in the family is known;
• Clinical examination, radiographs, eye examination, and hearing evaluation if the pathogenic variant in the family is not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In individuals with a small pelvis, delivery by cesarean section should be considered. However, each individual should be assessed by an obstetrician familiar with skeletal dysplasia [Savarirayan et al 2018].

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.

Acknowledgments

Dr Supriya Raj provided help with the tables, references, and proofreading.

Revision History

• 25 April 2019 (sw) Review posted live
• 22 January 2019 (rs) Original submission

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