Clinical characteristics.

Spondylometaphyseal dysplasia, corner fracture type (SMDCF) is a skeletal dysplasia characterized by short stature and a waddling gait in early childhood. Short stature may be present at birth or develop in early infancy. Individuals may present with short limbs and/or short trunk. Radiographic features include enlargement and corner fracture-like lesions of the metaphyses, developmental coxa vara, shortened long bones, scoliosis, and vertebral anomalies. Limited joint mobility and chronic pain are common. Vision impairment and glaucoma have been reported.

Diagnosis/testing.

The diagnosis of SMDCF is established in a proband with characteristic clinical and radiographic features including short stature, corner fracture-like lesions, developmental coxa vara, and vertebral anomalies. Identification of a heterozygous pathogenic variant in COL2A1 or FN1 by molecular genetic testing can confirm the diagnosis if radiographic features are inconclusive.

Management.

Treatment of manifestations: Standard treatment for scoliosis per orthopedist; surgical treatment for coxa vara, genu valgum or varum, bowing of the tibia, leg length discrepancy, atlantoaxial instability per orthopedist; management of mobility issues and chronic joint pain by orthopedist and/or physiatrist and physical therapist; management of vision impairment and glaucoma per ophthalmologist; management of hypertension per internist and/or cardiologist; management of psychosocial issues by a psychotherapist and/or referral to support groups.

Surveillance: Annual evaluation by an orthopedist and/or physiatrist for scoliosis, other orthopedic complications, mobility issues, and chronic pain. Annual evaluation of intraocular pressure and blood pressure in individuals with FN1-related SMDCF. Annual screening for psychosocial issues.

Agents/circumstances to avoid: Contact sports if atlantoaxial instability is present; activities that cause joint strain in those with joint pain.

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 prompt treatment for orthopedic and ophthalmologic complications.

Genetic counseling.

SMDCF is inherited in an autosomal dominant manner. An individual with SMDCF may have an affected parent or, somewhat more frequently, may have the disorder as the result of a de novo pathogenic variant. Each child of an individual with SMDCF has a 50% risk of having SMDCF. If the SMDCF-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

SMDCF should be suspected in individuals with the following clinical and radiographic features and family history.

Clinical features

• Mild-to-moderate short stature noted at birth in some individuals with short lower extremities and/or short trunk
• Mild-to-severe scoliosis
• Genu varum or valgum
• Pectus carinatum
• Limited mobility and/or musculoskeletal pain
• Vision impairment (e.g., myopia, borderline increased intraocular pressure, Brown syndrome [strabismus caused by dysfunction of the superior oblique muscle])
• Normal hearing
• Normal intelligence

Radiographic features

• Irregular metaphyses
  • Corner fracture-like lesions. The lesions can be asymmetric and are most often seen at the proximal and distal tibiae, distal radii, proximal humeri, and distal femora. These are thought to be irregular ossification centers and/or secondary ossification centers. They tend to enlarge in infancy and then disappear once the growth plates fuse at the time of skeletal maturation. Fusion of the growth plates occurs between age 12 and 16 years in females and age 14 and 19 years in males [Crowder & Austin 2005].
  • Enlargement of the metaphyses of the long bones
• Developmental coxa vara (i.e., varus deformity of the proximal femora that develops during early childhood) is typically identified by age six years and was described in one individual at birth [Costantini et al 2019].
• Scoliosis
• Vertebral anomalies (platyspondyly, hypoplasia, ovoid vertebral bodies, biconcave vertebral bodies, anterior wedging, biconvex vertebral bodies, irregular vertebral bodies, hypoplasia, narrow intervertebral spaces, vertebral fusion)
• Shortening of the long bones. This finding can be detected on prenatal ultrasound in some individuals.
• Leg length discrepancy
• Bowing of the tibia
• Epiphyses are usually normal.

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.

Establishing the Diagnosis

The diagnosis of SMDCF is established in a proband with characteristic clinical and radiographic features including short stature, corner fracture-like lesions, developmental coxa vara, and vertebral anomalies. Identification of a heterozygous pathogenic (or likely pathogenic) variant in COL2A1 or FN1 by molecular genetic testing can confirm the diagnosis if radiographic features are inconclusive (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology 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 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (concurrent 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

Spondylometaphyseal dysplasia, corner fracture type (SMDCF) is characterized by short stature and a waddling gait in early childhood. Short stature may be present at birth or develop in early infancy. Individuals may present with short limbs and/or short trunk. Complications include coxa vara, scoliosis, and chronic pain. Some individuals have ocular manifestations. To date, approximately 50 individuals with spondylometaphyseal dysplasia, corner fracture type (SMDCF) have been reported. A heterozygous COL2A1 or FN1 pathogenic variant has been identified in 23 individuals with SMDCF [Walter et al 2007, Lee et al 2017, Machol et al 2017, Cadoff et al 2018, Costantini et al 2019, Sabir et al 2021, Ramos-Mejía et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports. Two affected individuals had no detailed clinical description [Lee et al 2017, Costantini et al 2019].

Presentation. Individuals with SMDCF present at birth or in early childhood with short stature [Lee et al 2017], scoliosis, variable genu varum or valgum, developmental coxa vara, and pectus carinatum. Shortening of the long bones can be detected on prenatal ultrasound in some individuals [Machol et al 2017, Costantini et al 2019] and intrauterine growth restriction was reported in three individuals [Walter et al 2007, Cadoff et al 2018, Sabir et al 2021].

Almost half of the individuals were born premature.

Growth. SMDCF is typically associated with short stature that persists throughout life. Some individuals present with short trunk and others with short limbs. The expected adult height is more than two standard deviations (SD) below the mean, with half of individuals three SD below the mean. In two individuals with COL2A1-related SMDCF, head circumference was above the 90th centile. For most of the other individuals reported, head circumference falls within the normal range for their age.

Scoliosis and other spine manifestations. Scoliosis is common and can be mild to severe. Individuals with FN1-related SMDCF often require scoliosis surgery. In two individuals with COL2A1-related SMDCF, accentuated lumbar lordosis was reported.

Because of the association of SMDCF with scoliosis and short stature, there is a risk for chest deformity; pectus carinatum is reported. One individual with COL2A1-related SMDCF had odontoid hypoplasia [Machol et al 2017]. One individual with FN1-related SMDCF had os odontoideum and C1-C2 instability requiring surgery [Ramos-Mejía et al 2024], and another individual also had C1-C2 instability requiring surgery [Costantini et al 2019].

Hip / lower extremity manifestations. Developmental coxa vara (i.e., varus deformity of the proximal femora that develops during early childhood) is typically identified by age six years and was described in one individual at birth [Costantini et al 2019]. Coxa vara in individuals with SMDCF can cause significant morbidity that can require surgery.

Genu valgum and genu varum are both described and may require surgical treatment [Lee et al 2017, Machol et al 2017]. Leg length discrepancy has been reported [Lee et al 2017, Machol et al 2017, Costantini et al 2019, Sabir et al 2021]. Bowing of the tibia was reported in three individuals [Cadoff et al 2018, Costantini et al 2019, Ramos-Mejía et al 2024].

There have been reports of chronic pain, especially in the legs, in individuals with SMDCF. All individuals described were ambulatory except for one individual who became wheelchair bound in adulthood because of painful joint limitations [Lee et al 2017, Machol et al 2017, Cadoff et al 2018, Costantini et al 2019, Sabir et al 2021, Ramos-Mejía et al 2024]. In one affected individual, pain restricted activity and necessitated physical therapy [Costantini et al 2019]. One individual had acute quadriparesis secondary to spinal cord compression due to odontoid anomalies. This individual required surgical decompression and instrumented occipitocervical stabilization [Ramos-Mejía et al 2024].

Ocular manifestations. Most individuals have normal vision, with the exception of two individuals with myopia [Walter et al 2007, Costantini et al 2019] and one with Brown syndrome (strabismus caused by dysfunction of the superior oblique muscle) [Machol et al 2017]. One child with myopia also had borderline elevated intraocular pressure [Costantini et al 2019].

Hearing impairment has not been reported to date.

Intelligence is normal.

Nonspecific dysmorphic features. The following nonspecific dysmorphic features have been reported in one or more individuals with FN1-related SMDCF: flat facial profile, triangular face, broad and prominent forehead, high anterior hairline, facial asymmetry, prominent eyes, bilateral upslanted palpebral fissures, large almond-shaped eyes, ear anomalies (posteriorly rotated ears, underfolded helix with prominent ears, hypoplastic lobe and antitragus, preauricular tag), high palate, small and/or pointed chin, and micrognathia [Lee et al 2017, Costantini et al 2019, Sabir et al 2021].

Other

• COL2A1-related SMDCF. To date, the following manifestations have been reported in only one affected individual each: short neck, small and round iliac wings, pubic bone hypoplasia, and epiphyses reduced in size [Walter et al 2007, Machol et al 2017].
• FN1-related SMDCF. To date, the following manifestations have been reported in only one affected individual each: hypertension, osteoarthrosis, joint hypermobility, intradural lipoma, megacisterna magna, dental anomalies (missing teeth), bicuspid aortic valve, avascular necrosis of capitulum, short distal phalanges, asymmetry of the feet, low bone mineral density with fractures, elevation of osteocalcin and N-terminal telopeptide, and iron deficiency [Lee et al 2017, Cadoff et al 2018, Costantini et al 2019, Sabir et al 2021].

Phenotype Correlations by Gene

COL2A1. Some distinguishing features reported in individuals with COL2A1-related SMDCF include biconcave vertebral bodies and milder scoliosis [Walter et al 2007, Machol et al 2017].

FN1. Some distinguishing features reported in individuals with FN1-related SMDCF include nonspecific dysmorphic facial features, low bone mineral density with fractures, and chronic musculoskeletal pain. Scoliosis in individuals with FN1-related SMDCF tends to be more severe, and abnormalities of the vertebrae are frequent (e.g., ovoid-shaped vertebral bodies, anterior wedging, narrow intervertebral spaces, vertebral fusion, vertebral hypoplasia) [Lee et al 2017, Cadoff et al 2018, Costantini et al 2019, Sabir et al 2021, Ramos-Mejía et al 2024]. Developmental coxa vara is less frequent in individuals with FN1-related SMDCF.

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations for FN1 and COL2A1 have been identified given the relatively small number of individuals reported to date.

Penetrance

Penetrance is 100%.

Nomenclature

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], COL2A1-related SMDCF is included under COL2A1-related spondyloepimetaphyseal dysplasia and is part of the type 2 collagen disorders group. FN1-related SMDCF is referred to as FN1-related spondylometaphyseal dysplasia Sutcliffe and is included in the spondylometaphyseal dysplasias group.

Prevalence

SMDCF is a rare disorder. Approximately 50 individuals have been described in the literature [Langer et al 1990, Kozlowski et al 1992, Kozlowski et al 1993, Currarino et al 2000, Franceschini et al 2005, Sutton et al 2005, Walter et al 2007, Nair et al 2016, Lee et al 2017, Machol et al 2017, Cadoff et al 2018, Costantini et al 2019, Sabir et al 2021, Ramos-Mejía et al 2024].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SMDCF, 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).

Note: For individuals with COL2A1-related SMDCF, there is no evidence that treatment with human growth hormone supplementation increases final height [Savarirayan et al 2019]; therefore, it is not recommended.

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

Avoid contact sports if atlantoaxial instability is present.

For individuals with joint pain, avoid activities that strain joints; instead, favor joint-friendly activities (e.g., swimming, cycling).

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 prompt treatment for orthopedic and ophthalmologic complications. Evaluations can include:

• Molecular genetic testing if the pathogenic variant in the family is known;
• Measurement of height, physical examination, and radiographs of the spine and limbs 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.

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

Spondylometaphyseal dysplasia, corner fracture type (SMDCF) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• An individual with a clinical and/or molecular diagnosis of SMDCF may have an affected parent.
• Somewhat more frequently, an individual diagnosed with SMDCF represents a simplex case (i.e., the only family member known to be affected). In 15 families in which the parents of a proband with COL2A1- or FN1-related SMDCF underwent molecular genetic testing, the causative pathogenic variant occurred de novo in 11 probands:
  • In ten of 14 evaluated families, the FN1 pathogenic variant occurred de novo in the proband.
  • In a single evaluated family, the COL2A1 pathogenic variant occurred de novo in the proband [Machol et al 2017].
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member, 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 family members due to a milder phenotypic presentation [Machol et al 2017]. Therefore, de novo occurrence of a COL2A1 or FN1 pathogenic variant in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the 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. 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.

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 SMDCF-related pathogenic variant identified in the proband, the risk to the sibs is 50%. Phenotypic variability within families has been reported [Currarino et al 2000, Lee et al 2017, Machol et al 2017].
• If the proband has a known SMDCF-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent and/or the parents are unaffected based on appropriate clinical evaluation but their genetic status is unknown, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].

Offspring of a proband

• Each child of an individual with SMDCF has a 50% risk of having SMDCF.
• Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with SMDCF 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 suffer from serious sequelae and poor outcomes [Krakow 2015].

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

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.

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). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the SMDCF-causing 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

The formation of fibronectin depends on FN1. Fibronectin is a major component of the extracellular matrix and is the foundation of collagen, glycosaminoglycans, and other constituents [Cadoff et al 2018]. By its role in the extracellular matrix, fibronectin is essential for the formation of cartilaginous tissues and bones [Cadoff et al 2018, Costantini et al 2019].

COL2A1 is important for the production of type II collagen. This collagen is synthetized by chondrocytes and is an important component of the extracellular matrix (OMIM 120140). Alterations in this gene can lead to multiple skeletal dysplasias and ocular abnormalities since it is the main constituent of cartilage and vitreous humor [Walter et al 2007].

Mechanism of disease causation. Pathogenic variants in FN1, which occur throughout different domains, often affect cysteine residues that form disulfide bonds in the fibronectin type I domain. Those bonds create the three-dimensional structure of fibronectin, and their perturbation leads to instability and possible risk of degradation by metalloproteinases (MMP9 and MMP13) [Costantini et al 2019, Dinesh et al 2022].

• Pathogenic variants in the N-terminal assembly domain, necessary for fibronectin interaction to form fibrils, affect the assembly of the cell and lower the number of fibrils in the cell matrix [Lee et al 2017, Cadoff et al 2018].
• Pathogenic variants in the III-2 domain, necessary for the assembly of fibronectin, result in similar levels of mutated mRNA and wild type mRNA but greatly reduced secretion of the abnormal protein [Cadoff et al 2018] and accumulation of abnormal fibronectin within the cells [Lee et al 2017].
• Fibronectin is secreted by the liver; levels in the plasma of affected individuals is reduced [Cadoff et al 2018]. Circulating fibronectin in the plasma deposits in the bones. This plays a role in the mineralization, density, and assembly of the collagen fibers [Bentmann et al 2010, Costantini et al 2019].

Mutated fibronectin is exported from rough endoplasmic reticulum into vesicles and accumulates in mutated cells. There is an increase in intracellular fibronectin and a decrease in extracellular fibronectin levels. This impairs stem cell proliferation, mesenchymal condensation, and the differentiation of mesenchymal stem cells into chondrocytes [Dinesh et al 2024].

COL2A1-related diseases generally occur through dominant-negative mechanisms. COL2A1 encodes the alpha-1 chain of type II procollagen. This procollagen contains a triple-helical domain [Zhang et al 2020]. Pathogenic variants in COL2A1, typically resulting in a substitution of a glycine residue [Machol et al 2017], alter the homotrimer assembly and stability of type II collagen. Those residues play an essential role in the collagen helix and assembly into fibrils, and their disruption can lead to manifestation of the disease [Walter et al 2007, Machol et al 2017]. Misfolding can also affect secretion, and the accumulation in chondrocytes could be deleterious to their function.

Author Notes

Philippe Campeau laboratory: pcampeaulab.org

Dr Campeau focuses on studying new skeletal dysplasias, new forms of epilepsy, and chromatin-remodeling disorders. His lab identifies disease-causing genes, studies the pathologic basis of disease in cells and mice, and strives to improve the management of children affected by these conditions, notably through clinical trials.

Author History

Philippe M Campeau, MD (2020-present)
Jade England, MD, MSc (2020-present)
Ashley McFarquhar, BSc; McGill University (2020-2025)

Revision History

• 22 May 2025 (sw) Comprehensive update posted live
• 19 March 2020 (sw) Review posted live
• 3 July 2019 (pmc) Original submission

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