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 physiotherapist; management of vision impairment and glaucoma per ophthalmologist; management of psychosocial issues by a psychotherapist or referral to support groups.

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

Genetic counseling.

SMDCF is inherited in an autosomal dominant manner. An individual with SMDCF may have the disorder as the result of a de novo pathogenic variant. Each child of an individual with SMDCF has a 50% chance of inheriting the COL2A1 or FN1 pathogenic variant. If the SMDCF-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for SMDCF and preimplantation genetic testing are possible.

Suggestive Findings

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

Clinical features

• Mild-to-moderate short stature (in 19/19 individuals examined) noted at birth in some individuals [Sutton et al 2005, Walter et al 2007, Lee et al 2017] with short lower extremities (5/7) and/or short trunk (4/6)
• Mild-to-severe scoliosis (15/19)
• Genu varum or valgum (12/18)
• Pectus carinatum (6/14)
• Vision impairment (3/5) (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 (16/17). 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 women and age 14 and 19 years in men [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) (10/18). Coxa vara was typically identified by age six years and described in one individual at birth [Costantini et al 2019].
• Scoliosis (15/19)
• Vertebral anomalies (14/18; e.g., platyspondyly, hypoplasia, ovoid vertebral bodies, biconcave vertebral bodies, anterior wedging, biconvex vertebral bodies, narrow intervertebral spaces, vertebral fusion)
• Shortening of the long bones. This finding can be detected on prenatal ultrasound in some individuals [Machol et al 2017, Costantini et al 2019].
• Leg length discrepancy (3/8) [Lee et al 2017, Machol et al 2017, Costantini et al 2019]
• Bowing of the tibia (2/8) [Cadoff et al 2018, Costantini et al 2019]
• Epiphyses. Usually normal

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 variant in COL2A1 or FN1 by molecular genetic testing can confirm the diagnosis if radiographic features are inconclusive (see Table 1).

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) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SMDCF is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with spondylometaphyseal dysplasia are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, approximately 45 individuals with spondylometaphyseal dysplasia, corner fracture type (SMDCF) have been reported. A heterozygous COL2A1 or FN1 pathogenic variant has been identified in 21 individuals with SMDCF [Walter et al 2007, Lee et al 2017, Machol et al 2017, Cadoff et al 2018, Costantini et al 2019]. 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.

Growth. SMDCF is typically associated with short stature which 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 3 SD below the mean. In two individuals with COL2A1-SMDCF head circumference was above the 90th percentile.

Progression. Coxa vara (a smaller angle between the head and the shaft of the femur) in individuals with SMDCF can cause significant morbidity that can require surgery. The involvement of the long bones, knees, and spine can also lead to significant morbidity. Leg length discrepancy and bowing of the tibia were reported in some individuals [Lee et al 2017, Machol et al 2017, Cadoff et al 2018, Costantini et al 2019]. There is a report 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]. In one affected individual, pain restricted activity and necessitated physiotherapy [Costantini et al 2019].

Individuals with FN1-SMDCF often require scoliosis surgery. Because of the association of SMDCF with scoliosis and short stature, there is a risk for chest deformity.

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.

Intelligence is normal.

Nonspecific dysmorphic features. The following nonspecific dysmorphic features have been reported in one or more individuals with FN1-SMDCF: flat facial profile, facial asymmetry, prominent eyes, ear anomalies (posteriorly rotated ears, underfolded helix with prominent ears, hypoplastic lobe and antitragus, preauricular tag), high palate, pointed chin, and micrognathia [Lee et al 2017, Costantini et al 2019].

Other

• COL2A1-SMDCF. To date, the following manifestations have been reported in only one affected individual: short neck, odontoid hypoplasia, clinodactyly, small and round iliac wings, epiphyses reduced in size, Brown syndrome, and left myopia [Walter et al 2007, Machol et al 2017]. In two individuals with COL2A1-SMDCF accentuated lumbar lordosis was reported.
• FN1-SMDCF. To date, the following manifestations have been reported in only one affected individual: hypertension, osteoarthrosis, atlantoaxial instability, intradural lipoma, megacisterna magna, dental anomalies (missing teeth), bicuspid aortic valve, avascular necrosis of capitulum, short distal phalanges, glaucoma, 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].

Phenotype Correlations by Gene

COL2A1. Some distinguishing features reported in individuals with COL2A1-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-SMDCF include nonspecific dysmorphic facial features, and low bone mineral density with fractures. Scoliosis in individuals with FN1-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]. Developmental coxa vara is less frequent in individuals with FN1-SMDCF.

Genotype-Phenotype Correlations

No 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

See Bonafe et al [2015] for a complete nosology of constitutional bone disorders.

SMDCF has also been called spondylometaphyseal dysplasia, Sutcliffe-type.

Prevalence

SMDCF is a rare disorder. Approximately 45 individuals have been described in the literature [Langer et al 1990, Kozlowski et al 1992, Kozlowski et al 1993, Currarino et al 2000, 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].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spondylometaphyseal dysplasia, corner fracture type (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

For individuals with COL2A1-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

Agents/Circumstances to Avoid

Avoid contact sports if atlantoaxial instability is present.

For individuals with joint pain, avoid activities that strain joints and 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 x-ray examination 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 diagnosed with COL2A1- or FN1-SMDCF may have the disorder as the result of a de novo pathogenic variant [Machol et al 2017]. In fourteen families in which the parents of the proband underwent molecular genetic testing, the causative pathogenic variant occurred de novo in ten probands:
  • FN1-SMDCF. In nine of thirteen evaluated families, the FN1 pathogenic variant occurred de novo in the proband.
  • COL2A1-SMDCF. In a single evaluated family, the COL2A1 pathogenic variant occurred de novo in the proband [Machol et al 2017].
• Somewhat less frequently, an individual with a clinical and/or genetic diagnosis of SMDCF has an affected parent. Intrafamilial clinical variability is observed in SMDCF [Currarino et al 2000, Lee et al 2017, Costantini et al 2019].
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• 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.
• The family history of some individuals diagnosed with SMDCF may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation [Machol et al 2017]. 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.

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 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-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent and/or the parents have not been tested for the causative pathogenic variant but are unaffected based on appropriate clinical evaluation, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband

• Each child of an individual with SMDCF has a 50% chance of inheriting the causative pathogenic variant.
• 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.

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 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 SMDCF-causing pathogenic variant has 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 hlepful.

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 encodes 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 dysplasia and ocular abnormalities since it is the main constituent of cartilage and vitreous humor [Walter et al 2007]. The most recent nosology includes a group of disorders related to COL2A1 and referred to as the type 2 collagen group [Bonafe et al 2015].

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].

• Pathogenic variants in the N-terminal assembly domain, necessary for fibronectin interaction to form fibrils, affect the assembly on 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. It has a role in the mineralization, density, and assembly of the collagen fibers [Bentmann et al 2010, Costantini et al 2019].

Since mutated fibronectin is not secreted, its accumulation in chondrocytes could be deleterious to their function. This remains to be tested.

COL2A1-related diseases generally occur through dominant-negative mechanisms. Pathogenic variants in COL2A1, typically resulting in a substitution of a glycine residue [Machol et al 2017], alter the homotrimer assembly and stability of the collagen type II. Those residues play an essential role in the collagen helix and assembly into fibrils, their disruption can lead to manifestation of the disease [Walter et al 2007, Machol et al 2017]. However, misfolding could 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.

Revision History

• 19 March 2020 (sw) Review posted live
• 3 July 2019 (pmc) Original submission

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