Schmid Metaphyseal Chondrodysplasia

Clinical characteristics.

Schmid metaphyseal chondrodysplasia (SMCD) is characterized by progressive short stature that develops by age two years. The clinical and radiographic features are usually not present at birth, but manifest in early childhood with short limbs, genu varum, and waddling gait. Facial features and head size are normal. Radiographs show metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping); shortening of the tubular bones; widened growth plates; coxa vara; and anterior cupping, sclerosis, and splaying of the ribs. Mild hand involvement often includes shortening of the tubular bones and metaphyseal cupping of the metacarpals and proximal phalanges. Platyspondyly and vertebral end plate irregularities are less common. Hand and vertebral involvement can resolve with age. Early motor milestones may be delayed due to orthopedic complications. Intelligence is normal. Joint pain in the knees and hips is common and may limit physical activity. Adult height is typically more than 3.5 standard deviations below the mean, although a wide spectrum that overlaps normal height has been reported. There are no extraskeletal manifestations.

Diagnosis/testing.

The diagnosis of SMCD is established in a proband with characteristic clinical and radiographic features and/or identification of a heterozygous pathogenic variant in COL10A1 by molecular genetic testing.

Management.

Treatment of manifestations: Management of orthopedic complications by an orthopedist, physiotherapist, occupational therapist, and pain specialist as indicated; joint-friendly exercise, weight management; mobility device as needed; corrective osteotomy by guided growth surgery or valgus osteotomy may be considered in late childhood / adolescence in those with progressive or symptomatic varus deformity, significant coxa vara, triangular fragment in the interior femoral neck, or poor or deteriorating function; exercise and support from nutritionist to maintain healthy weight; psychosocial support; environmental or occupational modifications as needed for short stature with recommendations from occupational therapist as needed.

Surveillance: Annual growth assessment; clinical evaluation for orthopedic manifestations; psychosocial evaluation.

Agents/circumstances to avoid: Obesity; physical activities that cause excessive joint strain.

Genetic counseling.

SMCD is inherited in an autosomal dominant manner. Approximately half of individuals diagnosed with SMCD have an affected parent (the heterozygous parent almost always exhibits features of the condition; however, considerable intrafamilial phenotypic variability is observed). Approximately half of individuals diagnosed with SMCD have the disorder as the result of a de novo COL10A1 pathogenic variant. Each child of an individual with SMCD has a 50% chance of inheriting the COL10A1 pathogenic variant. If the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, genetic counseling becomes more complicated because of the risk of inheriting two dominantly inherited bone growth disorders. Once the COL10A1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for SMCD and preimplantation genetic testing are possible.

Suggestive Findings

SMCD should be suspected in individuals with the following clinical, laboratory, radiographic, and family history findings.

Clinical findings

• Short-limbed short stature by age two years (in >60%)
• Genu varum (bowed legs) (>60%)
• Waddling gait (>80%)
• Lumbar lordosis by age three to five years
• Normal craniofacies and absence of extraskeletal manifestations

Laboratory findings. Normal serum calcium, phosphate, vitamin D, and alkaline phosphatase

Radiographic findings (See Figure 1.)

• Shortening of the tubular bones (>60%)
• Metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping), especially the proximal and distal femora (~100%)
• Widening of the growth plates
• Coxa vara (>80%)
• Anterior cupping, sclerosis, and splaying of the ribs (>90%)
• Mild hand involvement including shortening of the tubular bones and metaphyseal cupping of the metacarpals and proximal phalanges (~50%). Radiographic phalangeal and metacarpal findings may resolve with age.
• Vertebral involvement including platyspondyly and end plate irregularities (~10%)

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis, as approximately half of individuals have a de novo pathogenic variant, and in those with an inherited pathogenic variant, considerable intrafamilial variability can be present.

Establishing the Diagnosis

The diagnosis of SMCD is established in a proband with characteristic clinical and radiographic features (see Suggestive Findings) and/or a heterozygous pathogenic (or likely pathogenic) variant in COL10A1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous COL10A1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Schmid metaphyseal chondrodysplasia (SMCD) is typically diagnosed in early childhood and is the most common and least severe metaphyseal chondrodysplasia [Al Kaissi et al 2018]. It results from disrupted calcification of metaphyseal cartilage and consequent restricted longitudinal growth of bones with preservation of the epiphyses. The clinical and radiographic features are usually not present at birth, but manifest in early childhood with limb shortening, genu varum, and a waddling gait [Bateman et al 2005]. The pattern of radiographic features is generally similar across individuals with SMCD, but clinical severity varies considerably [Mäkitie et al 2005]. There are no extraskeletal manifestations.

A comprehensive review of the published reports and clinical databases identified at least 150 published unrelated individuals with SMCD and a confirmed pathogenic variant in COL10A1. The following description of the phenotypic features associated with this condition is based on these reports and author observations in a multidisciplinary skeletal dysplasia clinic.

Growth. Most neonates with SMCD have normal growth parameters. Progressive growth failure typically begins in the second year of life, with individuals coming to medical attention after age two years with short-limbed short stature and bowed legs [Mäkitie et al 2005]. Adult height is typically more than 3.5 standard deviations (SD) below the mean, although a wide spectrum that overlaps normal height has been reported [Mäkitie et al 2005]. No standardized growth curves for SMCD are available.

Musculoskeletal. Most individuals with SMCD have genu varum (outward bowing at the knees), although valgus deformity has been reported. Waddling gait due to coxa vara is common by age two years and may require surgical correction. Joint pain in the knees and hips is common in children and adults with SMCD and may limit physical activity. Chronic joint pain may develop and limit mobility for some individuals. Lumbar lordosis is common, with typical onset by age three to five years. Scoliosis is less commonly reported [Park et al 2015, Cammarata-Scalisi et al 2019].

Radiographic findings. The metaphyses of the long bones become flared or widened. The proximal and distal femoral and proximal tibial metaphyses are consistently affected (ragged, cupped, sclerotic, or splayed) with widening of the growth plates. Enlarged capital femoral epiphyses are commonly reported and typically resolve between age 11 and 14 years [Tüysüz et al 2023]. Coxa vara (reduced angle to <120 degrees between the head and the shaft of the femur) is seen in a majority of individuals and is more prominent after age five years [Tüysüz et al 2023]. Coxa vara distinguishes SMCD from other forms of metaphyseal chondrodysplasia. Tibial and femoral bowing is typical. Metaphyseal irregularities of the distal ulnae and radii, and proximal and distal humeral metaphyses are less commonly reported [Lachman et al 1988, Al Kaissi et al 2018, de França et al 2020]. The anterior rib ends are often cupped or sclerotic [Bateman et al 2005].

Hand involvement is present in fewer than half of individuals and is usually mild. Metaphyseal cupping of the distal metacarpals and proximal phalanges and shortening of the phalanges may be seen and are more pronounced in the fifth ray. Hand features may become less apparent with age [Elliott et al 2005].

Vertebral involvement is less common and, when present, is usually mild. Reported findings include platyspondyly and vertebral end plate anomalies (e.g., rounding of the anterior aspects of the vertebral bodies, superior and inferior indentations of the vertebral bodies, posterior wedging of the vertebrae) [Hasegawa et al 1994, Savarirayan et al 2000]. Vertebral changes may become less apparent with age.

Obesity. Limited mobility due to chronic joint pain may contribute to the development of obesity and associated comorbidities.

Craniofacial. The craniofacial bones and facial appearance are normal [Bateman et al 2005].

Neurodevelopment. Intelligence is normal. Attainment of early motor milestones is usually preserved in infancy; however, mild gross and fine motor delays may accompany orthopedic complications in early childhood.

Other. Hypothyroidism, growth hormone deficiency, celiac disease, hypospadias, and mild microcephaly have been rarely reported [de França et al 2020, Chreitah et al 2023]; however, these may represent coincidental occurrences and may be unrelated to SMCD.

Homozygotes. Biallelic pathogenic variants in COL10A1 have been associated with a more severe phenotype [Ain et al 2018, Tüysüz et al 2023] and in some instances embryonic lethality [Zhang et al 2018].

Genotype-Phenotype Correlations

A more severe phenotype has been observed in individuals with missense pathogenic variants in the signal peptide domain at the N-terminal end of the protein and in the NC1 domain compared to truncating pathogenic variants [Tüysüz et al 2023]; however, no established genotype-phenotype correlations have been identified.

Penetrance

Penetrance approaches 100%; however, there is wide inter- and intrafamilial phenotypic variation [Kong et al 2019]. Males and females are equally represented in published reports. Normal stature has been reported, but radiographic features are usually still present. Age-dependent phenotypic manifestations are suggested by apparent reduction in hand and spine features [Savarirayan et al 2000, Elliott et al 2005] and resolution of enlarged capital femoral epiphyses with age [Tüysüz et al 2023].

Nomenclature

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], SMCD is referred to as metaphyseal dysplasia Schmid (MCS), COL10A1-related.

Spondylometaphyseal dysplasia (SMD) Japanese type. Affected individuals from one reported family had bowed legs, short stature, coxa vara, metaphyseal changes, and mild platyspondyly [Hasegawa et al 1994]. A heterozygous COL10A1 pathogenic variant was identified in affected individuals [Ikegawa et al 1998]. Expansion of the clinical phenotype of SMCD to include spinal changes led to the conclusion that SMD Japanese type and SMCD are the same disorder [Savarirayan et al 2000].

Prevalence

The exact prevalence of SMCD is unknown. Incidence has historically been estimated at between three and six individuals per million [Gokhale & Mehta 2005]; however, these figures may be an underestimate [Al Kaissi et al 2018]. More than 150 unrelated individuals with SMCD and a confirmed pathogenic variant in COL10A1 have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SMCD, the evaluations summarized in Table 5 (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 6).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Agents/Circumstances to Avoid

Individuals with SMCD should maintain an appropriate weight for height, as obesity increases stress on the joints and may exacerbate joint pain and worsen the impact of genu varum and waddling gait on mobility. Education should include advice regarding weight loss (when appropriate), maintenance of a healthy diet, and regular low-impact exercise.

High-impact exercise or exercise that causes repetitive strain on affected joints should be avoided in favor of joint-friendly low-impact activities, including swimming and biking.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Carbamazepine is an FDA-approved medication for use in epilepsy and bipolar affective disorder. Its additional action as a stimulator of autophagy and proteasomal degradation pathways have led to its repurposing as a candidate therapy for conditions caused by retention of misfolded mutated structural proteins, such as SMCD [Hidvegi et al 2010]. In preclinical studies, carbamazepine alleviates endoplasmic reticulum stress (unfolded protein response) caused by the presence of structurally abnormal and misfolded type X collagen in prehypertrophic chondrocytes, restoring growth and improving coxa vara in a validated mouse model of SMCD [Hidvegi et al 2010]. Carbamazepine received orphan drug designation by the European Commission for the treatment of SMCD in September 2016 (EMA/OD/148/16 and EMA/COMP/513538/2016).

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.

Mode of Inheritance

Schmid metaphyseal chondrodysplasia (SMCD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately half (45%-57%) of individuals diagnosed with SMCD inherited the condition from a parent. The heterozygous parent almost always exhibits features of the condition; however, considerable intrafamilial phenotypic variability is observed in SMCD, and the heterozygous parent may only have mild features [Wu et al 2021, Tüysüz et al 2023].
• Approximately half (43%-55%) of individuals diagnosed with SMCD represent simplex cases (i.e., a single occurrence in a family) and have the disorder as the result of a de novo COL10A1 pathogenic variant.
• If the proband appears to be the only affected family member, recommendations for the parents of the proband include physical examination and measurement of proportions. Recommendations may also include radiographs (as isolated asymptomatic individuals have been reported with radiographic changes only) and, if a molecular diagnosis has been established in the proband, molecular genetic testing.
• If a molecular diagnosis has been established in the proband, 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 germline (or somatic and germline) mosaicism. 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.
• The family history of some individuals diagnosed with SMCD may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance (reported in rare, isolated cases), or mild radiographic features in an affected parent that have not previously come to medical attention. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has established that neither parent is heterozygous for the pathogenic variant identified in the proband.

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 COL10A1 pathogenic variant identified in the proband, the risk to the sibs is 50%. Because considerable intrafamilial phenotypic variability is observed in SMCD, a heterozygous sib may have milder or more severe manifestations of SMCD.
• If the proband has a known SMCD-causing variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [Rahbari et al 2016]. (Note: Recurrence of SMCD in sibs of a proband with an apparently de novo COL10A1 pathogenic variant has not been reported to date.)
• If the parents are clinically unaffected (based on physical examination, measurement of proportions, and radiographs) but their genetic status is unknown, 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 SMCD because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.

Offspring of a proband

• Each child of an individual with SMCD has a 50% chance of inheriting the COL10A1 pathogenic variant.
• Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with SMCD 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 have serious sequelae and poor outcomes [Flynn & Pauli 2003].
• If the proband and the proband's reproductive partner are both affected with SMCD, each child has a 25% likelihood of average stature (unaffected), a 50% likelihood of having SMCD due to a heterozygous pathogenic variant, and a 25% likelihood of having a more severe SMCD phenotype due to inheritance of biallelic pathogenic variants.
  • Two individuals with biallelic SMCD-causing pathogenic variants and more severe presentations have been reported [Ain et al 2018, Tüysüz et al 2023].
  • Multiple miscarriages have been reported in a large consanguineous family segregating SMCD, suggesting that some homozygous COL10A1 pathogenic variants may result in early fetal demise [Zhang et al 2018].
• If the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child has at conception a 25% likelihood of average stature, a 25% likelihood of having the same skeletal dysplasia as the father, a 25% likelihood of having the same skeletal dysplasia as the mother, and a 25% likelihood of inheriting a pathogenic variant from both parents and being at risk for a more severe blended skeletal phenotype, including fetal demise.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the COL10A1 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

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 COL10A1 pathogenic variant has 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.

Molecular Pathogenesis

Type X collagen, encoded by COL10A1, is a homotrimer non-fibrillar collagen protein consisting of three α-1(X) chains. Type X collagen is present in the extracellular matrix and expressed exclusively by hypertrophic chondrocytes in the cartilage growth plates of growing bones undergoing endochondral ossification.

Pathogenic variants in COL10A1 are clustered in the C-terminal non-collagenous (NC1) domain, which contains motifs required for normal assembly of the collagen trimer. Both missense and truncating (frameshift and nonsense) variants in COL10A1 cause collagen X protein misfolding during protein synthesis, resulting in a failure of trimerization and aggregation within the endoplasmic reticulum (ER) of hypertrophic chondrocytes. Resultant ER stress, activation of the unfolded protein response, and reduced levels of functional type X collagen in the growth plate cause chondrodysplasia and development of the SMCD phenotype [Rajpar et al 2009].

Mechanism of disease causation. Both haploinsufficiency [Bateman et al 2003] and dominant-negative [Chan et al 1998, Wilson et al 2005] mechanisms have been proposed. Recognition of the central role of the unfolded protein response in molecular pathogenesis suggests a neomorphic, dominant-negative model in which the misfolding and accumulation of mutated type X collagen is responsible for the SMCD phenotype.

Author Notes

Dr Richmond and Prof Savarirayan are actively involved in clinical research regarding individuals with SMCD. They would be happy to communicate with persons who have any questions regarding diagnosis of SMCD or other considerations.

Acknowledgments

The authors wish to acknowledge the patients, their families, and the clinicians of the multidisciplinary bone dysplasia clinics at the Victorian Clinical Genetics Services, Royal Children's Hospital, Genetic Health Queensland, and Queensland Children's Hospital.

Revision History

• 9 May 2024 (sw) Comprehensive updated posted live
• 21 October 2019 (sw) Review posted live
• 5 July 2019 (rs) Original submission

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