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Spondylometaphyseal Dysplasia, Corner Fracture Type

Synonyms: SMD, Corner Fractures Type; SMD, Sutcliffe Type

, MD, MSc, , BSc, and , MD.

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Estimated reading time: 20 minutes

Summary

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.

Diagnosis

Formal diagnostic criteria for spondylometaphyseal dysplasia, corner fracture type (SMDCF) have not been established.

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).

Option 1

When the clinical and radiographic findings suggest the diagnosis of SMDCF, molecular genetic testing approaches can include concurrent gene testing or use of a multigene panel:

  • Concurrent gene testing. Sequence analysis of COL2A1 and FN1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
    Although large deletions and duplications have not been reported, deletion/duplication testing may be considered because of the possibility of single or multiexon in-frame deletion or duplication.
  • A multigene panel that includes COL2A1, FN1, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by spondylometaphyseal dysplasia, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Spondylometaphyseal Dysplasia, Corner Fracture Type

Gene 1, 2Proportion of SMDCF Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 3 Detectable by This Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
COL2A113% 63/3 6Unknown 7
FN157% 813/13 8Unknown 7
Unknown30% 9NA
1.

Genes in alphabetic order

2.
3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.
7.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

8.
9.

There is evidence of locus heterogeneity (i.e., this disorder can be caused by mutation of other as-yet-unidentified genes) [Lee et al 2017].

Clinical Characteristics

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].

Table 2.

Common Physical Findings in Spondylometaphyseal Dysplasia, Corner Fracture Type

Physical Fnding# of Individuals w/Finding/
# of Individuals Examined
Short stature19/19
Short lower extremities5/7
Short upper extremities3/3
Short trunk4/6
Scoliosis15/19
Genu varum8/18
Genu valgum5/17
Pectus carinatum6/14
Limited mobility 18/8
Musculoskeletal pain5/6
Vision impairment3/5
Accentuated lumbar lordosis 22/3
1.

Limited mobility was reported secondary to pain and/or limb deformity.

2.

To date, only reported in individuals with COL2A1-SMDCF

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.

Differential Diagnosis

Table 4.

Genes of Interest in the Differential Diagnosis of Spondylometaphyseal Dysplasia, Corner Fracture Type (SMDCF)

GeneDifferential DisorderMOIClinical Features of Differential DisorderRadiographic Features of Differential Disorder
Like SMDCFUnlike SMDCFLike SMDCFUnlike SMDCF
ATP7AMenkes disease (see ATP7A-Related Copper Transport Disorders)XLShort statureMicrocephaly, kinky sparse hair, skin hypopigmentation, skin/joint laxity, neurologic degeneration, ↓ copper & ceruloplasminCorner fractures, osteoporosisWormian bones
COL10A1Metaphyseal chondrodysplasia, Schmid typeADShort staturePlatyspondyly, corner fracture-like lesions, metaphyseal abnormalities, coxa vara, genu varumEndplate irregularity, metaphyseal abnormalities of phalanges & metacarpals
PTH1RMetaphyseal chondrodysplasia, Jansen type (OMIM 156400)ADShort stature, facial dysmorphismChoanal stenosis, deafness, nephrocalcinosis, hypercalcemia, hypophosphatemiaCorner fracture-like lesions, osteopenia
TRPV4Spondylometaphyseal dysplasia, Kozlowski type (OMIM 184252)ADShort trunk, pectus carinatum, scoliosisOdontoid hypoplasia, irregular metaphyses, coxa varaMarked platyspondyly & kyphoscoliosis, severe involvement of short tubular bones, hand/carpal/foot abnormalities; not assoc w/corner fractures
GALNSMucopolysaccharidosis type IVAARShort stature, scoliosis, short trunk, pectus carinatum, joint pain, normal intelligenceCoarse facial features, corneal opacities, hearing loss, hepatomegaly, hypermobile joints, abnormal glycosaminoglycan excretion in urineOdontoid hypoplasia, platyspondyly, widened metaphyses, genu valgumCervical subluxation, rib abnormalities, compression of spinal cord, epiphyseal involvement, coxa valga, hip dislocation, ulnar deviation of wrists
PCYT1ASpondylometaphyseal dysplasia w/cone-rod dystrophy (OMIM 608940)ARShort stature, scoliosis, short limbsCone-rod dystrophy, macular involvement, nystagmusOvoid vertebral bodies, platyspondyly, coxa vara, metaphyseal involvement, tibial & femoral bowingRib cupping, flat acetabuli, hypoplastic inferior ilia, narrow sacrosciatic notch, brachydactyly, short metacarpals
CFAP410Spondylometaphyseal dysplasia, axial (OMIM 602271)ARShort stature, short limbsRetinal abnormalities, progressive retinal degeneration, optic atrophy, cone-rod dystrophy, nystagmus, splenomegalyPlatyspondyly, coxa vara, metaphyseal dysplasia, short metacarpalsSmall thorax & thoracic deformation, lacy iliac wings, narrow sacrosciatic notch, short femoral neck
SBDS 1Shwachman-Diamond syndromeARShort statureSmall head circumference, failure to thrive, exocrine pancreatic deficiency, bone marrow failure, DD, IDOvoid vertebral bodies, coxa vara, metaphyseal dysplasia of long bones, osteoporosisNarrow thorax & costal abnormalities, narrow sacroiliac notch, delayed skeletal maturation

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.

Mutation of EFL1, DNAJC21, or SRP54 may also be associated with Shwachman-Diamond syndrome (SDS) in rare cases. Note: SDS caused by pathogenic variants in SRP54 is inherited in an autosomal dominant manner.

Disorders of unknown genetic cause

  • Spondyloepimetaphyseal dysplasia Duetting type (SMD, type A4) (OMIM 609052), an autosomal recessive disorder, shares the following features with SMDCF: corner fractures, irregular metaphyses, ovoid vertebral bodies, pectus carinatum, platyspondyly, short limbs, short stature, and small iliac wings.
    Unlike SMDCF, SMD Duetting type is also characterized by bipartite trochlea, brachydactyly, coxa valga, dolichocephaly, irregular patellar margins, osteoporotic tarsals and metatarsals, sclerotic costochondral joints, severe metaphyseal changes of the femoral neck, and tongue-like deformity of the vertebral bodies.
  • Blount disease (OMIM 188700, 259200). Like SMDCF, Blount disease is characterized by corner fracture-like lesions. Unlike SMDCF, Blount disease is also characterized by osteochondritis dissecans (knee), sloping proximal tibial epiphysis, bowleg, and tibia vara.

Other. Corner fractures can also be caused by non-accidental injuries [Leaman et al 2016], congenital contractures, rickets, and scurvy [Lee et al 2017].

Management

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.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with Spondylometaphyseal Dysplasia, Corner Fracture Type

SystemEvaluationComment
MusculoskeletalReferral to orthopedic surgeon, physiatrist, & physiotherapist depending on local practicesTo evaluate for scoliosis, other skeletal manifestations, mobility issues
Flexion-extension radiographs of the cervical spineTo evaluate for cervical instability; 1 if atlantoaxial instability is present, evaluation by anesthesiologist & pulmonary assessment (when indicated) prior to any surgery [White et al 2017]
OphthalmologyReferral to ophthalmologist for vision assessmentIncl evaluation of intraocular pressure in individuals w/FN1-SMDCF 1
CardiovascularEvaluation of blood pressureIn individuals w/FN1-SMDCF 1
OtherConsultation w/clinical geneticist &/or genetic counselor
Psychology or other resources for supportIssues related to short stature, joint pain, limited mobility
Evaluation by pulmonologistRecommended for individuals w/COL2A1-SMDCF 2
1.

Recommendations are based on a single individual reported with this feature.

2.

Recommendations based on the best practice guidelines regarding diagnosis and management of patients with type II collagen disorders [Savarirayan et al 2019]

Treatment of Manifestations

Table 6.

Treatment of Manifestations in Individuals with Spondylometaphyseal Dysplasia, Corner Fracture Type

Manifestation/ConcernTreatmentReferences
ScoliosisTreatment per orthopedist
Coxa varaSurgical treatment per orthopedistCurrarino et al [2000]
Genu valgum or genu varumSurgical treatment per orthopedistLee et al [2017], Machol et al [2017]
Bowing of the tibiaSurgical treatment per orthopedistMachol et al [2017], Cadoff et al [2018], Costantini et al [2019]
Leg-length discrepancySurgical treatment per orthopedistLee et al [2017, Machol et al [2017], Costantini et al [2019]
Atlantoaxial instabilitySurgical treatment per orthopedistCostantini et al [2019]
Joint pain / limited mobilityManagement per physiatrist & physiotherapist; surgical treatment by orthopedist
Vision impairment &/or glaucomaManagement per ophthalmologist
Psychosocial issuesManagement by psychotherapist or referral to support groups

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

Table 7.

Recommended Surveillance for Individuals with Spondylometaphyseal Dysplasia, Corner Fracture Type

System/ConcernEvaluationFrequency
MusculoskeletalEvaluation by orthopedic surgeon & physiatrist depending on local practicesAnnually for scoliosis, other skeletal manifestations, mobility issues, & chronic joint pain
GlaucomaEvaluation of intraocular pressure 1Annual evaluation in individuals w/FN1-SMDCF
HypertensionEvaluation of blood pressure 1Annual evaluation in individuals w/FN1-SMDCF
Psychosocial issuesScreening for psychosocial issuesAnnually
Possible hearing lossRoutine evaluation for hearing lossRecommended in individuals w/a COL2A1 pathogenic variant 2 (not reported to date in SMDCF)
Possible respiratory complicationsRoutine lung capacity assessment & respiratory health statusRecommended in individuals w/a COL2A1 pathogenic variant 2
1.

Recommendations are based on a single individual reported with this feature.

2.

Recommendations based on the best practice guidelines regarding diagnosis and management of patients with type II collagen disorders [Savarirayan et al 2019].

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

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, his or her family members 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 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

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, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Spondylometaphyseal Dysplasia, Corner Fracture Type: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Spondylometaphyseal Dysplasia, Corner Fracture Type (View All in OMIM)

120140COLLAGEN, TYPE II, ALPHA-1; COL2A1
135600FIBRONECTIN 1; FN1
184255SPONDYLOMETAPHYSEAL DYSPLASIA, CORNER FRACTURE TYPE; SMDCF

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.

Table 8.

Spondylometaphyseal Dysplasia, Corner Fracture Type: Notable Pathogenic Variants by Gene

Gene 1Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
COL2A1NM_001844​.5
NP_001835​.3
c.541G>Cp.Gly181ArgGlycine substitutions are implicated in 1/3 of individuals w/type II collagenopathies & are more frequent w/more severe phenotypes [Walter et al 2007, Barat-Houari et al 2016, Machol et al 2017].
c.1034G>Ap.Gly345Asp
c.2833G>Ap.Gly945Ser
FN1NM_212482​.3
NP_997647​.1
c.260G>Tp.Cys87PheImpairs fibronectin secretion [Lee et al 2017]
c.718T>Gp.Tyr240AspImpairs fibronectin secretion [Lee et al 2017]. This tyrosine residue was shown to be important for fibronectin binding to fibroblasts [Sottile et al 1991].
c.2425_2427delp.Thr809delOnly amino acid deletion reported [Lee et al 2017]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Genes in alphabetic order

References

Literature Cited

  • Barat-Houari M, Sarrabay G, Gatinois V, Fabre A, Dumont B, Genevieve D, Touitou I. Mutation update for COL2A1 gene variants associated with type II collagenopathies. Hum Mutat. 2016;37:7–15. [PubMed: 26443184]
  • Bentmann A, Kawelke N, Moss D, Zentgraf H, Bala Y, Berger I, Gasser JA, Nakchbandi IA. Circulating fibronectin affects bone matrix, whereas osteoblast fibronectin modulates osteoblast function. J Bone Miner Res. 2010;25:706–15. [PubMed: 19821765]
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Chapter Notes

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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