Spondylometaphyseal dysplasia

Recommended panel testing at Breda Genetics for this condition:

Spondylometaphyseal dysplasias and its differential diagnosis (ACP5, BMP2, BMPR1B, C21orf2, COL11A1, COL11A2, COL2A1, GALNS, GDF5, GLB1, GPX4, HSPG2, IHH, NEK1, NOG, PAM16, PAPSS2, PCYT1A, PITX1, ROR2, TRAPPC2, TRPV4)

Summary

Spondylometaphyseal dysplasias are a heterogeneous group of disorders characterized by platyspondyly (flattened vertebrae) and marked hip and knee metaphyseal lesions leading to walking and growth disturbances that become evident during the second year of life. Prevalence is estimated at around 1 on 100,000.

Detailed clinical description

The disorders are characterized by platyspondyly (flattened vertebrae) and marked hip and knee metaphyseal lesions. The different forms of spondylometaphyseal dysplasia are distinguished by the localization and severity of involvement of the affected metaphyses. The most common form is the Kozlowski type of spondylometaphyseal dysplasia.

The form of spondylometaphyseal dysplasia referred to as Sutcliffe type (or “corner fracture”) results in very severe coxa vara. A rarer form (Algerian or Schmidt type) appears to have more predominant knee involvement. Lastly, some moderate forms are at present not well classified and other forms have also been identified, including type A4, and an axial type associated with retinitis pigmentosa and optic atrophy. Spondylometaphyseal dysplasia may also occur in association with other clinical manifestations such as facial dysmorphism and dentinogenesis imperfecta.

Molecular genetics

Inheritance is variable. The most common form, Kozlowski type spondylometaphyseal dysplasia, is inherited in an autosomal dominant fashion. Spondylometaphyseal dysplasia type A4 and axial spondylometaphyseal dysplasia associated with retinitis pigmentosa and optic atrophy are autosomal recessively inherited.

Mutations have been so far identified in the following genes: TRPV4 (spondylometaphyseal dysplasia Kozlowski type – SMDK, autosomal dominant), GPX4 (spondylometaphyseal dysplasia, Sedaghatian type – SMDS, autosomal recessive), ACP5 (spondyloenchondrodysplasia with immune dysregulation – SPENCDI, autosomal recessive), PCYT1A (spondylometaphyseal dysplasia with cone-rod dystrophy – SMDCRD, autosomal recessive), NEK1 and C21orf2 (axial spondylometaphyseal dysplasia, autosomal recessive), COL2A1 (spondyloepimetaphyseal dysplasia, Strudwick type – SEMDSTWK, autosomal dominant), PAM16 (spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type – SMDMDM, autosomal recessive).

Some forms of spondylometaphyseal dysplasia are caused in as-yet unknown genes at known/unknown chromosomal loci (e.g. spondylometaphyseal dysplasia Algerian type, Sutcliffe type, type A4, Richmond type)

Differential diagnosis

Dysspondyloenchondromatosis is a rare skeletal dysplasia characterized by enchondroma-like lesions and anisospondyly.  Radiographic features of dysspondyloenchondromatosis with overlap into the type II collagenopathy spondyloepimetaphyseal dysplasia, Strudwick type, has been reported. TRPV4-associated skeletal dysplasias have a broad phenotypic spectrum and, thus, many skeletal dysplasias to consider in the differential diagnosis, including: forms of brachydactyly (IHH, GDF5, BMPR1B, BMP2, ROR2, NOG, PITX1), brachyolmia (PAPSS2 mutations), X-linked spondyloepiphyseal dysplasia tarda (TRAPPC2 mutations), Morquio syndrome type A (GALNS mutations) and type B (GLB1 mutations), Weissenbacher-Zweymuller syndrome (COL11A2 mutations), Fibrochondrogenesis 1 (COL11A1 mutations), Fibrochondrogenesis 2 (COL11A2 mutations), Kniest dysplasia (COL2A1), dyssegmental dysplasia (HSPG2 mutations).

Genetic testing strategy

Given the genetic heterogeneity and the proportion of cases attributable to mutations in as yet unknown genes, a large multi-gene panel based on exome sequencing or genome sequencing is recommended.

Recommended panel testing at Breda Genetics for this condition:

Spondylometaphyseal dysplasias and its differential diagnosis (ACP5, BMP2, BMPR1B, C21orf2, COL11A1, COL11A2, COL2A1, GALNS, GDF5, GLB1, GPX4, HSPG2, IHH, NEK1, NOG, PAM16, PAPSS2, PCYT1A, PITX1, ROR2, TRAPPC2, TRPV4)

References

Orphanet: ORPHA254

Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations. Wang Z, Horemuzova E, Iida A, Guo L, Liu Y, Matsumoto N, Nishimura G, Nordgren A, Miyake N, Tham E, Grigelioniene G, Ikegawa S. J Hum Genet. 2017 Apr;62(4):503-506. PMID: 28123176

Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations. Wang Z, Iida A, Miyake N, Nishiguchi KM, Fujita K, Nakazawa T, Alswaid A, Albalwi MA, Kim OH, Cho TJ, Lim GY, Isidor B, David A, Rustad CF, Merckoll E, Westvik J, Stattin EL, Grigelioniene G, Kou I, Nakajima M, Ohashi H, Smithson S, Matsumoto N, Nishimura G, Ikegawa S. PLoS One. 2016 Mar 14;11(3):e0150555. PMID: 26974433

Dysspondyloenchondromatosis (DSC) associated with COL2A1 mutation: Clinical and radiological overlap with spondyloepimetaphyseal dysplasia-Strudwick type (SEMD-S). Merrick B, Calder A, Wakeling E. Am J Med Genet A. 2015 Dec;167A(12):3103-7. PMID: 26250472

TRPV4-Associated Disorders. Schindler A, Sumner C, Hoover-Fong JE. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2014 May 15. PMID: 24830047

Clinical and radiographic features of the autosomal recessive form of brachyolmia caused by PAPSS2 mutations. Iida A, Simsek-Kiper PÖ, Mizumoto S, Hoshino T, Elcioglu N, Horemuzova E, Geiberger S, Yesil G, Kayserili H, Utine GE, Boduroglu K, Watanabe S, Ohashi H, Alanay Y, Sugahara K, Nishimura G, Ikegawa S. Hum Mutat. 2013 Oct;34(10):1381-6. PMID: 23824674.