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.

Review the differential diagnosis of type II collagen disorders with a focus on genetic conditions.

Goal 4.

Review management of type II collagen disorders.

Goal 5.

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

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. Considerable phenotypic overlap notwithstanding, discriminating features can aid in the specific diagnosis (see Table 1). The following individual phenotypes are recognized in the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], and can be grouped according to severity.

Most severe (often lethal perinatally)

• Achondrogenesis, COL2A1-related (formerly type II, type Langer-Saldino)
• Hypochondrogenesis, COL2A1-related
• Platyspondylic dysplasia, type Torrance, COL2A1-related

Severe / moderately severe (neonatal presentation)

• Kniest dysplasia, COL2A1-related
• Spondyloepiphyseal dysplasia congenita (SEDC), COL2A1-related
• Spondyloepimetaphyseal dysplasia (SEMD), COL2A1-related

Intermediate (neonatal/childhood/adolescent presentation)

• Spondyloperipheral dysplasia, COL2A1-related
• Spondyloepiphyseal dysplasia (SED) with metatarsal shortening, COL2A1-related
• Stickler syndrome, COL2A1-related

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] (see also 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 COL2A1-related disorders (e.g., achondrogenesis; platyspondylic dysplasia, type Torrance; SEDC; and SEMD).
• In Kniest dysplasia, COL2A1-related, 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, COL2A1-related [Hoornaert et al 2007].
• In Stickler syndrome, COL2A1-related, 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 instances 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 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, COL2A1-related, was formerly known as achondrogenesis type II or achondrogenesis, type Langer-Saldino.

SED with metatarsal shortening, COL2A1-related, was formerly known as Czech dysplasia.

Prevalence

The exact prevalence of type II collagen disorders is not known. However, Stickler syndrome, COL2A1-related, 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].

Evaluations Following Initial Diagnosis

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

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

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 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 recommended surveillance in order to avoid/prevent common complications.

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.

Mode of Inheritance

Type II collagen disorders are typically inherited in an autosomal dominant manner.

Autosomal recessive inheritance of type II collagen disorders has been reported in several families to date [Tham et al 2015, Barat-Houari et al 2016a, Al-Sannaa et al 2020, Girisha et al 2020, Zhang et al 2021, Tüysüz et al 2023].

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with a severe type II collagen disorder have the disorder as the result of a de novo pathogenic variant. The overall proportion of individuals with a type II collagen disorder caused by a de novo COL2A1 pathogenic variant is unknown.
• Many individuals diagnosed with a milder 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).
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in mildly affected family members. Therefore, de novo occurrence of a COL2A1 pathogenic variant in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the COL2A1 pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * [Nagendran et al 2012, Okamoto et al 2012, Stevenson et al 2012, Yamamoto et al 2020, Morrison et al 2020]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for a COL2A1 pathogenic variant 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 of inheriting the pathogenic variant is 50%.
• Penetrance in type II collagen disorders is high; however, intrafamilial variability among heterozygous family members can be extensive. Note: 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 gonadal mosaicism [Nagendran et al 2012, Okamoto et al 2012, Stevenson et al 2012, Morrison et al 2020, Yamamoto et al 2020].
• 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 reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

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.
• Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with a type II collagen disorder may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals may have serious sequelae and poor outcomes [Unger et al 2001, Flynn & Pauli 2003].

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 presumed to be heterozygous for a COL2A1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a COL2A1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• In the families described by Tham et al [2015] and Barat-Houari et al [2016a], one heterozygous father presented with high myopia, asymmetric lower limbs, and average stature; one heterozygous mother was 154 cm tall; and the two other heterozygous parents were of normal stature.

Sibs of a proband

• If both parents are known to be heterozygous for a COL2A1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• 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 affected individual's reproductive partner also has COL2A1 pathogenic variant(s), 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.

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.

Prenatal Testing and Preimplantation Genetic Testing

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

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

Acknowledgments

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

Revision History

• 24 October 2024 (sw) Comprehensive update posted live
• 25 April 2019 (sw) Review posted live
• 22 January 2019 (rs) Original submission

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