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Other entities represented in this entry:
SNOMEDCT: 719171005; ORPHA: 1040, 93356; DO: 0080030;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q22.2 | Metaphyseal anadysplasia 1 | 602111 | Autosomal dominant | 3 | MMP13 | 600108 |
| 11q22.2 | ?Spondyloepimetaphyseal dysplasia, Missouri type | 602111 | Autosomal dominant | 3 | MMP13 | 600108 |
A number sign (#) is used with this entry because of evidence that the Missouri type of spondyloepimetaphyseal dysplasia (SEMDM) is caused by heterozygous mutation in the MMP13 gene (600108) on chromosome 11q22. One such family has been described.
A form of metaphyseal anadysplasia (MANDP1) with autosomal dominant inheritance is also caused by mutation in the MMP13 gene.
Also see MANDP2 (613073), an autosomal recessive form of metaphyseal anadysplasia, caused by mutation in the MMP9 gene (120361).
Spondyloepimetaphyseal Dysplasia, Missouri Type
Patel et al. (1993) described a large Missouri kindred with a novel form of SEMD characterized by moderate to severe metaphyseal changes; mild epiphyseal involvement; pear-shaped vertebrae in childhood; rhizomelic shortening, especially of the lower limbs; and genu varum deformities secondary to bowing of the femurs, tibias, or both. The modeling defects improved spontaneously by early adolescence, but the affected individuals remained shorter than their age-matched unaffected sibs. Routine biochemical studies of skeletal homeostasis were normal, but the radiologic and histopathologic studies indicated a primary abnormality in growth plate development.
Metaphyseal Anadysplasia 1
Maroteaux et al. (1991) gave the designation metaphyseal anadysplasia (ana = prefix meaning return) to an early-onset regressive form of metaphyseal dysplasia. Diagnosis was possible in the first months when distal metaphyses of long bones were found to be very irregular. Femoral necks seemed hypoplastic and the edges of the metaphyses were almost vertical. The femoral shaft was bowed. These anomalies disappeared after age 2 years. The main manifestations were a slight shortness and varus deformity of the lower limbs. Stature was not affected. Maroteaux et al. (1991) reported 4 boys with this condition. Wiedemann and Spranger (1970) had reported the case of a boy in whom metaphyseal dysplasia became evident in the first months of life. The early onset and regressive course of the disorder during infancy, evidenced radiologically, and its benign evolution distinguished the case from all previously known forms. The patient attained an adult height of 166 cm. At the time of report in 1970, the patient had been followed from the age of 5 months until 18 years of age. Wiedemann (1992) provided a follow-up into the patient's fifth decade. Amelioration of the metaphyseal irregularities was already evident after 2 to 3 years. Particularly striking was regression of the severe femoral neck anomalies to a normal appearance. Even the patient's initial disproportionate appearance resulting from the rhizomelic micromelia left it less evident by the end of the growth phase after straightening of the limbs. The patient had normal mental development and he was able to take over a physically demanding family bakery from his father. The parents were nonconsanguineous.
Nishimura et al. (1999) reported the cases of 2 unrelated children, a girl and a boy, with regressive metaphyseal dysplasia. Both children had bowed legs and a transient growth decline in early childhood. Metaphyseal modifications of the long bones were most conspicuous at an early age and then subsided by age 2 to 3 years. The father of the boy may have had the same disorder, because he was shorter than his sibs and showed mild modifications of the vertebral end plates with mild narrowing of the interpediculate distance of the lumbar spine. The evolution of the metaphyseal dysplasia in the children closely resembled that of metaphyseal anadysplasia. Molecular studies of type X collagen (COL10A1; 120110), which is mutant in the Schmid type of metaphyseal chondrodysplasia (MCDS; 156500), did not demonstrate a disease-causing mutation.
Song et al. (2019) reported a Chinese boy with metaphyseal anadysplasia-1 who was first referred at age 2.25 years because of a waddling gait. At that age, his height was in the 10th centile. He was developing normally and did not have dysmorphic features. Radiographs at age 2.25 years showed bilateral shortened humeral, ulnar, and radial bones with widened metaphyses, slight 'brush and cup-like' changes, irregular edges, and dense temporary calcification. He also had widened epiphyseal plates, epiphyseal delay, and a physiologic curvature of his spine without lordosis. Vertebrae were flat with pear-shaped changes. Patchy bone defects were seen on the upper and lower edges of the anterior vertebrae. Bilateral coxa vara, shortened iliac stalks, shorted tibia and fibula with widened metaphyses, and slight 'brush and cup-like' changes, irregular edges, and dense temporary calcification were also seen. At age 3.75 years, his height was at the 3rd centile. Follow-up radiographs at age 3.75 years showed improvement of the metaphyseal changes of the proximal humerus, distal ulna and radius, distal femur, and distal tibia and fibula. Epiphyses were developed, although small. The patchy bone effects of the vertebrae could no longer be detected. Bilateral coxa vara was still present. Bone age was also delayed.
Clinical Variability
Lausch et al. (2009) studied 5 families segregating metaphyseal anadysplasia and distinguished 2 types: type 1 (Spranger type), a clinically more severe type with reduced stature and autosomal dominant inheritance over several generations in 3 kindreds; and type 2 (Maroteaux type), a milder type with normal stature and autosomal recessive inheritance. The radiographic presentation of both types was indistinguishable. The proband (patient 11) from one of the autosomal recessive families studied by Lausch et al. (2009) was later determined to have the Spahr type of metaphyseal dysplasia (MDST; 250400) by Bonafe et al. (2014).
The inheritance pattern in the Missouri kindred with SEMD was autosomal dominant (Patel et al., 1993).
The occurrence of an isolated affected girl and possible father-to-son transmission of metaphyseal anadysplasia observed by Nishimura et al. (1999) were consistent with autosomal dominant transmission.
In the Missouri kindred with SEMD originally reported by Patel et al. (1993), in which there were 14 affected members in 4 generations, Gertner et al. (1997) excluded linkage to 12 candidate genes.
Kennedy et al. (2005) mapped the Missouri form of SEMD to a 17-cM region on 11q14.3-q23.2 that contains a cluster of 9 matrix metalloproteinase genes. The matrix metalloproteinases belong to a family of zinc metalloendopeptidases that degrade components of the extracellular matrix (ECM).
Spondyloepimetaphyseal Dysplasia, Missouri Type
Kennedy et al. (2005) considered MMP13 to be the best candidate among the MMP cluster on 11q for causation of Missouri SEMD because the enzyme preferentially degrades collagen type II (120140), abnormalities of which cause skeletal dysplasias that include Strudwick type SEMD (184250). In affected members of the Missouri kindred reported by Patel et al. (1993), they identified heterozygosity for a missense mutation (F56S; 600108.0001) in the prodomain of the MMP13 gene.
Metaphyseal Anadysplasia 1
Lausch et al. (2009) investigated the molecular basis of metaphyseal anadysplasia in 5 families and identified heterozygous mutations in the MMP13 gene (600108.0002 and 600108.0003) in 3. In a fourth family, they identified a homozygous mutation in the MMP9 gene (120361.0001). Lausch et al. (2009) found that recessive metaphyseal anadysplasia (MANDP2; 613073) is caused by homozygous loss of function of MMP9, whereas dominant metaphyseal anadysplasia (MANDP1) is caused by missense mutations in the prodomain of MMP13; these mutations determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency. In the fifth family studied by Lausch et al. (2009), the proband (patient 11) was homozygous for a missense mutation in the MMP13 gene (H213N; 600108.0004). Bonafe et al. (2014) stated that although this Moroccan boy was initially diagnosed as having a recessive form of MANDP1, he could be retrospectively diagnosed with the Spahr type of metaphyseal dysplasia (MDST; 250400).
In a Chinese boy with MANDP1, Song et al. (2019) identified a de novo heterozygous, previously identified missense mutation in the MMP13 gene (M71T; 600108.0003). The variant, which was identified by targeted next-generation sequencing and confirmed by Sanger sequencing, was not present in large population databases, including gnomAD.
Spondyloepimetaphyseal dysplasia (SEMD) is sometimes referred to as spondylometaepiphyseal dysplasia (SMED).
Bonafe, L., Liang, J., Gorna, M. W., Zhang, Q., Ha-Vinh, R., Campos-Xavier, A. B., Unger, S., Beckmann, J. S., Le Bechec, A., Stevenson, B., Giedion, A., Liu, X., Superti-Furga, G., Wang, W., Spahr, A., Superti-Furga, A. MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type. Am. J. Med. Genet. 164A: 1175-1179, 2014. [PubMed: 24648384] [Full Text: https://doi.org/10.1002/ajmg.a.36431]
Gertner, J. M., Whyte, M. P., Dixon, P. H., Pang, J. T., Trump, D., Pearce, S. H. S., Wooding, C., Thakker, R. V. Linkage studies of a Missouri kindred with autosomal dominant spondyloepimetaphyseal dysplasia (SEMD) indicate genetic heterogeneity. J. Bone Miner. Res. 12: 1204-1209, 1997. [PubMed: 9258750] [Full Text: https://doi.org/10.1359/jbmr.1997.12.8.1204]
Kennedy, A. M., Inada, M., Krane, S. M., Christie, P. T., Harding, B., Lopez-Otin, C., Sanchez, L. M., Pannett, A. A. J., Dearlove, A., Hartley, C., Byrne, M. H., Reed, A. A. C., Nesbit, M. A., Whyte, M. P., Thakker, R. V. MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMD(MO)). J. Clin. Invest. 115: 2832-2842, 2005. [PubMed: 16167086] [Full Text: https://doi.org/10.1172/JCI22900]
Lausch, E., Keppler, R., Hilbert, K., Cormier-Daire, V., Nikkel, S., Nishimura, G., Unger, S., Spranger, J., Superti-Furga, A., Zabel, B. Mutations in MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum of metaphyseal anadysplasia. Am. J. Hum. Genet. 85: 168-178, 2009. Erratum: Am. J. Hum. Genet. 85: 420 only, 2009. [PubMed: 19615667] [Full Text: https://doi.org/10.1016/j.ajhg.2009.06.014]
Maroteaux, P., Verloes, A., Stanescu, V., Stanescu, R. Metaphyseal anadysplasia: a metaphyseal dysplasia of early onset with radiological regression and benign course. Am. J. Med. Genet. 39: 4-10, 1991. [PubMed: 1867263] [Full Text: https://doi.org/10.1002/ajmg.1320390103]
Nishimura, G., Ikegawa, S., Saga, T., Nagai, T., Aya, M., Kawano, T. Metaphyseal anadysplasia: evidence of genetic heterogeneity. Am. J. Med. Genet. 82: 43-48, 1999. [PubMed: 9916842] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990101)82:1<43::aid-ajmg9>3.0.co;2-i]
Patel, A. C., McAlister, W. H., Whyte, M. P. Spondyloepimetaphyseal dysplasia: clinical and radiologic investigation of a large kindred manifesting autosomal dominant inheritance, and a review of the literature. Medicine 72: 326-342, 1993. [PubMed: 8412645]
Song, C., Li, N., Hu, X., Shi, Y., Chen, L., Zhou, T., Xu, X., Shen, J., Zhu, M. A de novo variant in MMP13 identified in a patient with dominant metaphyseal anadysplasia. Europ. J. Med. Genet. 62: 103575, 2019. [PubMed: 30439533] [Full Text: https://doi.org/10.1016/j.ejmg.2018.11.009]
Wiedemann, H.-R., Spranger, J. Chondrodysplasia metaphysaria (Dysostosis metaphysaria)-ein neuer Typ? Z. Kinderheilk. 108: 171-186, 1970. [PubMed: 4252978]
Wiedemann, H.-R. Metaphyseal anadysplasia: observation of a patient from infancy to the fifth decade of life. Dysmorph. Clin. Genet. 6: 123-127, 1992.