Spondylometaphyseal Dysplasia, Corner Fracture Type

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