Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 58561002; ICD10CM: Q77.5; ORPHA: 628; DO: 14687;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q32 | Diastrophic dysplasia, broad bone-platyspondylic variant | 222600 | Autosomal recessive | 3 | SLC26A2 | 606718 |
| 5q32 | Diastrophic dysplasia | 222600 | Autosomal recessive | 3 | SLC26A2 | 606718 |
A number sign (#) is used with this entry because diastrophic dysplasia (DTD) is caused by homozygous or compound heterozygous mutation in the DTDST gene (SLC26A2; 606718) on chromosome 5q32.
Patients with diastrophic dysplasia show scoliosis, a form of clubbed foot bilaterally, malformed pinnae with calcification of the cartilage, premature calcification of the costal cartilages, and cleft palate in some cases. Particularly characteristic is the 'hitchhiker' thumb due to deformity of the first metacarpal. The term 'diastrophic' was borrowed by Lamy and Maroteaux (1960) from geology: diastrophism is the process of bending of the earth's crust by which mountains, continents, ocean basins, etc., are formed. Cases have been described under many different designations in the past. See the case described by Mau (1958) in his section on 'multiple congenital malformations and contractures.' These cases have frequently been placed in the wastebasket of arthrogryposis multiplex congenita in hospital diagnostic files. Many cases of so-called achondroplasia with clubfoot are examples of diastrophic dwarfism (e.g., Kite, 1964). The foot deformity is relatively refractory to surgical treatment. Langer (1967) referred to an entity that phenotypically is a mild form of diastrophic dwarfism as 'diastrophic variant.' Bony changes are qualitatively similar but less severe. Soft tissue changes are absent or mild and the clubfoot is not as resistant to treatment as in regular diastrophic dwarfism. Consanguinity was noted in the reports of Taybi (1963) and Jager and Refior (1969). Friedman et al. (1974) described death from collapsed airway resulting from abnormality of tracheal, laryngeal, and bronchial cartilage. Holmgren et al. (1984) observed a brother and sister with diastrophic dysplasia and E trisomy (probably trisomy 18) mosaicism. Gustavson et al. (1985) studied 14 cases of DTD, including 3 pairs of sibs. Six died shortly after birth of respiratory and circulatory insufficiency. The authors suggested that these cases, which included 2 pairs of sibs, had a lethal variety of DTD. All were of lower birth weight than the nonlethal cases and they had radiographic differences; overlapping joints and dislocation of the cervical spine were present in all 6. A congenital heart defect was found in 4 of the 6 lethal cases but in none of the nonlethal cases.
Hall (1996) described extreme variability within a sibship in which 3 sibs were diagnosed with diastrophic dysplasia. He commented that the phenotype may be sufficiently mild in some instances as to render the diagnosis uncertain.
Makitie and Kaitila (1997) collected growth data on 121 Finnish patients with DTD. They reported that the median adult height was 135.7 cm for males and 129 cm for females. Growth failure was progressive, partly because of absent or weak pubertal growth spurt. Severity of the growth failure varied greatly, even among sibs. The final height did not correlate with midparental height but correlated well with height at age 1 year and 5 years. The relative weight was normal in childhood but increased after puberty; head circumferences were normal. Makitie and Kaitila (1997) developed standard growth curves for use in following patients with DTD. They noted that these charts would be useful in predicting adult height and in evaluating growth-promoting therapies.
Ayoubi et al. (2001) described a successful pregnancy in a woman with diastrophic dwarfism and height of less than 100 cm. Respiratory complications of severe restrictive pulmonary disease required close attention.
Prenatal Diagnosis
Gollop and Eigier (1987) diagnosed this disorder at 16 weeks of gestation from the abnormally short limbs and lateral projection of the thumbs on ultrasound examination. Studies were prompted by the previous birth of an affected child. Normal values for bone length were taken from Hobbins et al. (1982). Butler et al. (1987) concluded that the metacarpophalangeal pattern profile (MCPP) may be a useful diagnostic tool. Gembruch et al. (1988) made the sonographic diagnosis of diastrophic dysplasia at 31 weeks of gestation in a woman not known to be at increased risk for this disorder.
Hastbacka et al. (1993) used DNA markers to predict the status of 5 fetuses in families with a previous history of DTD. The results predicted that 3 were unaffected and 2 affected. These results were concordant with those obtained by ultrasonography, and the phenotype of the fetus was correctly predicted in all cases. Thus, DNA analysis is a reliable means of prenatal diagnosis in the first trimester of pregnancy; ultrasonography permits prenatal detection in the second trimester.
By routine prenatal ultrasound, Jung et al. (1998) made the prenatal diagnosis of diastrophic dysplasia in a massively obese mother at 21 weeks of gestation. The proportionate shortening of tubular bones by about 50% of the normal length, the absence of thoracic dysplasia, and a normal head circumference narrowed the diagnosis down to a severe but nonlethal skeletal dysplasia. Ulnar deviation of the hands and talipes made diastrophic dysplasia the most likely diagnosis. The pregnancy was terminated at the request of the parents. The diagnosis was confirmed at postmortem clinical examination where the highly specific 'hitchhiker thumbs,' similarly luxated big toes, facial dysmorphism, and cleft palate were found. Retrospective reevaluation of the prenatal ultrasound videos revealed the misplaced thumbs, which together with the ulnar deviation of the wrist and suspected talipes, made the diagnosis possible. Deviation of the thumb into the third dimension made demonstration in the 2-dimensional ultrasound difficult.
Hastbacka et al. (1990) stated that 160 patients affected with DTD were known in Finland.
In a study of 13 Finnish families with 2 or 3 sibs with diastrophic dysplasia, Hastbacka et al. (1990) demonstrated linkage to markers on chromosome 5. The highest pairwise lod score estimate was 7.37 at zero recombination with locus D5S72. There was no evidence of heterogeneity. The findings placed the DTD locus distal to the gene for adenomatous polyposis coli (APC; 611731). From the relationship of the DTD locus to 16 polymorphic markers on distal 5q, Hastbacka et al. (1991) concluded that the locus is probably situated in the 5q31-q34 area. Hastbacka et al. (1992) used linkage disequilibrium mapping to estimate the recombination fraction between the disease locus and markers, to establish allelic homogeneity in the Finnish population, and to estimate a mutation rate for the marker loci.
Hastbacka et al. (1992) demonstrated striking linkage disequilibrium for diastrophic dysplasia indicating that the DTD gene should lie within 0.06 cM (or about 60 kb) of the CSF1R gene (164770).
In the process of positional cloning of the gene involved in Treacher Collins syndrome (154500), the Treacher Collins Syndrome Collaborative Group (1996) showed that the DTDST gene is within approximately 900 kb proximal to the TCOF1 gene (606847) on 5q32-q33.1.
Hastbacka et al. (1992) confirmed a high mutation rate of CCTT repeats in their DTD families; in 3 instances a nonparental allele was present in children. In each instance, the new allele differed by a single repeat unit. Since the DTD families provided a total of 234 meioses, these data suggested a mutation rate of about 1.3% (range 0.3-2.7%). They estimated that about 5 to 6% of DTD-causing alleles did not descend from the common ancestral mutation.
Hastbacka et al. (1994) identified mutations in the DTDST gene in non-Finnish patients with diastrophic dysplasia.
Hastbacka et al. (1999) reported identification of the Finnish founder mutation as a GT-to-GC transition in the splice donor site of the previously undescribed 5-prime untranslated exon of the DTDST gene (606718.0010). The mutation acts by severely reducing mRNA levels. Among 84 DTD families in Finland, patients carried 2 copies of the mutation in 69 families, 1 copy in 14 families, and no copies in 1 family. Thus, roughly 90% of the Finnish DTD chromosomes carried the splice site mutation, which Hastbacka et al. (1999) designated DTDST(Fin). Unexpectedly, they found that 9 of the DTD chromosomes having the apparently ancestral haplotype did not carry the Finnish mutation but rather 2 other mutations. Eight of these chromosomes had an R279W mutation (606718.0002) and 1 had a V340 deletion (606718.0008). One possible explanation was that the 3 DTD mutations arose in a population in which this 'rare' haplotype was in fact common and conferred a heterozygote advantage in this population, resulting in an excess of DTD mutations on this haplotype which were then admixed with a larger population in which the haplotype was rare. There was, however, no evidence to support the existence of such an ancestral population or of a heterozygote advantage conferred by DTD chromosomes. A second possibility was that the chromosomes with the rare haplotype are more prone to mutation, although again there was no evidence to support such a hypothesis. A third possibility was that the presence of multiple mutations on a rare haplotype is simply a matter of chance.
Megarbane et al. (1999) reported a 1-year-old Lebanese girl, the first child of second-cousin parents, who had clinical features suggesting diastrophic dysplasia but with unusual radiographic features including severe platyspondyly, wide metaphyses, and fibular overgrowth, which were partially reminiscent of metatropic dysplasia (see 156550). Analysis of the SLC26A gene revealed homozygosity for a missense mutation (606718.0009). Megarbane et al. (2002) reported an aborted female fetus, the third child in this family, with almost the same clinical features as observed in the girl described by Megarbane et al. (1999). Megarbane et al. (2002) suggested that this represents a distinctive form of the DTDST chondrodysplasias, a clinical variant between a mild form of atelosteogenesis type II (256050) and a severe form of diastrophic dysplasia.
In 7 Finnish individuals with diastrophic dysplasia, Bonafe et al. (2008) identified compound heterozygosity for 2 mutations in the SLC26A2 gene: the common Finnish mutation (IVS1+2T-C; 606718.0010) and the T512K mutation (606718.0013).
In a girl with features suggesting diastrophic dysplasia as well as features that are usually observed in Desbuquois dysplasia (see 251450) such as neonatal scoliosis, flat acetabular roof, and proximal femur monkey wrench configuration (which was present in early but not later radiographs), Panzer et al. (2008) identified compound heterozygosity for mutations in the SLC26A2 gene: the common R178X mutation (606718.0005) and a novel A133V (606718.0014) mutation.
In a Mexican girl with diastrophic dysplasia presenting some unusual clinical and radiographic features that are usually observed in atelosteogenesis type II, Macias-Gomez et al. (2004) identified compound heterozygosity for the R279W (606718.0002) and R178X (606718.0005) mutations in the SLC26A2 gene. The patient had cystic swelling of the external ears, cervical kyphosis, rhizomelia, 'hitchhiker' thumbs, bilateral talipes equinovarus, and short toes, features highly suggestive of diastrophic dysplasia. However, she also displayed severe and progressive cervical kyphosis, V-shaped distal humerus, bowed radii, horizontal sacrum, and gap between the first and second toes, features typical of atelosteogenesis type II. Macias-Gomez et al. (2004) concluded that the combination of a mild and a severe mutation led to an intermediate clinical picture, representing an apparent genotype-phenotype correlation.
Forlino et al. (2005) generated Slc26a2-knockin mice with a partial loss of function of the sulfate transporter resulting from abnormal splicing. Homozygous mutant mice were characterized by growth retardation, skeletal dysplasia and joint contractures, recapitulating essential aspects of the human DTD phenotype. The skeletal phenotype included reduced toluidine blue staining of cartilage, chondrocytes of irregular size, delay in the formation of the secondary ossification center, and osteoporosis of long bones. Impaired sulfate uptake was demonstrated in chondrocytes, osteoblasts, and fibroblasts. In spite of the generalized nature of the sulfate uptake defect, significant proteoglycan undersulfation was detected only in cartilage. Chondrocyte proliferation and apoptosis studies suggested that reduced proliferation and/or lack of terminal chondrocyte differentiation might contribute to reduced bone growth.
In patients with diastrophic dysplasia in the Finnish population, Elima et al. (1989) excluded the COL2A1 gene (120140) as the site of mutation by 2 methods: Southern analysis of the patients' DNA, which showed no disease-related differences in any of the restriction fragments covering the 30-kb COL2A1 gene; and multipoint linkage analysis using RFLP markers, which gave a lod score of -2.95.
Diab et al. (1994) reported that type IX collagen (120210) appeared abnormal on sodium dodecylsulfate polyacrylamide gel electrophoresis. That the primary defect is not in type IX collagen is indicated by the fact that, whereas diastrophic dysplasia maps to chromosome 5, COL9A1 maps to chromosome 6.
Ayoubi, J.-M., Jouk, P.-S., Pons, J.-C. Diastrophic dwarfism and pregnancy. Lancet 358: 1778 only, 2001. [PubMed: 11734236] [Full Text: https://doi.org/10.1016/S0140-6736(01)06806-4]
Bonafe, L., Hastbacka, J., de la Chapelle, A., Campos-Xavier, A. B., Chiesa, C., Forlino, A., Superti-Furga, A., Rossi, A. A novel mutation in the sulfate transporter gene SLC26A2 (DTDST) specific to the Finnish population causes de la Chapelle dysplasia. (Letter) J. Med. Genet. 45: 827-831, 2008. [PubMed: 18708426] [Full Text: https://doi.org/10.1136/jmg.2007.057158]
Butler, M. G., Gale, D. D., Meaney, F. J. Metacarpophalangeal pattern profile analysis in diastrophic dysplasia. Am. J. Med. Genet. 28: 685-689, 1987. [PubMed: 3425635] [Full Text: https://doi.org/10.1002/ajmg.1320280316]
Diab, M., Wu, J.-J., Shapiro, F., Eyre, D. Abnormality of type IX collagen in a patient with diastrophic dysplasia. Am. J. Med. Genet. 49: 402-409, 1994. [PubMed: 8160734] [Full Text: https://doi.org/10.1002/ajmg.1320490411]
Elima, K., Kaitila, I., Mikonoja, L., Elonsalo, U., Peltonen, L., Vuorio, E. Exclusion of the COL2A1 gene as the mutation site in diastrophic dysplasia. J. Med. Genet. 26: 314-319, 1989. [PubMed: 2732992] [Full Text: https://doi.org/10.1136/jmg.26.5.314]
Forlino, A., Piazza, R., Tiveron, C., Della Torre, S., Tatangelo, L., Bonafe, L., Gualeni, B., Romano, A., Pecora, F., Superti-Furga, A., Cetta, G., Rossi, A. A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype. Hum. Molec. Genet. 14: 859-871, 2005. [PubMed: 15703192] [Full Text: https://doi.org/10.1093/hmg/ddi079]
Friedman, S. I., Taber, P., Hollister, D. W., Rimoin, D. L. A lethal form of diastrophic dwarfism.In: Bergsma, D. : Skeletal Dysplasias. Amsterdam: Excerpta Medica (pub.) 1974. Pp. 43-49.
Gembruch, U., Niesen, M., Kehrberg, H., Hansmann, M. Diastrophic dysplasia: a specific prenatal diagnosis by ultrasound. Prenatal Diag. 8: 539-545, 1988. [PubMed: 3065771] [Full Text: https://doi.org/10.1002/pd.1970080709]
Gollop, T. R., Eigier, A. Prenatal ultrasound diagnosis of diastrophic dysplasia at 16 weeks. Am. J. Med. Genet. 27: 321-324, 1987. [PubMed: 3300333] [Full Text: https://doi.org/10.1002/ajmg.1320270210]
Gustavson, K.-H., Holmgren, G., Jagell, S., Jorulf, H. Lethal and non-lethal diastrophic dysplasia: a study of 14 Swedish cases. Clin. Genet. 28: 321-334, 1985. [PubMed: 4064368] [Full Text: https://doi.org/10.1111/j.1399-0004.1985.tb00406.x]
Hall, B. D. Diastrophic dysplasia: extreme variability within a sibship. Am. J. Med. Genet. 63: 28-33, 1996. [PubMed: 8723083] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960503)63:1<28::AID-AJMG8>3.0.CO;2-O]
Hastbacka, J., de la Chapelle, A., Kaitila, I., Sistonen, P., Weaver, A., Lander, E. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nature Genet. 2: 204-211, 1992. Note: Erratum: Nature Genet. 2: 343 only, 1992. [PubMed: 1345170] [Full Text: https://doi.org/10.1038/ng1192-204]
Hastbacka, J., de la Chapelle, A., Mahtani, M. M., Clines, G., Reeve-Daly, M. P., Daly, M., Hamilton, B. A., Kusumi, K., Trivedi, B., Weaver, A., Coloma, A., Lovett, M., Buckler, A., Kaitila, I., Lander, E. S. The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell 78: 1073-1087, 1994. [PubMed: 7923357] [Full Text: https://doi.org/10.1016/0092-8674(94)90281-x]
Hastbacka, J., Kaitila, I., Sistonen, P., de la Chapelle, A. Diastrophic dysplasia gene maps to the distal long arm of chromosome 5. Proc. Nat. Acad. Sci. 87: 8056-8059, 1990. [PubMed: 1978318] [Full Text: https://doi.org/10.1073/pnas.87.20.8056]
Hastbacka, J., Kerrebrock, A., Mokkala, K., Clines, G., Lovett, M., Kaitila, I., de la Chapelle, A., Lander, E. S. Identification of the Finnish founder mutation for diastrophic dysplasia (DTD). Europ. J. Hum. Genet. 7: 664-670, 1999. [PubMed: 10482955] [Full Text: https://doi.org/10.1038/sj.ejhg.5200361]
Hastbacka, J., Salonen, R., Laurila, P., de la Chapelle, A., Kaitila, I. Prenatal diagnosis of diastrophic dysplasia with polymorphic DNA markers. J. Med. Genet. 30: 265-268, 1993. [PubMed: 8487268] [Full Text: https://doi.org/10.1136/jmg.30.4.265]
Hastbacka, J., Sistonen, P., Kaitila, I., Weiffenbach, B., Kidd, K. K., de la Chapelle, A. A linkage map spanning the locus for diastrophic dysplasia (DTD). Genomics 11: 968-973, 1991. [PubMed: 1783404] [Full Text: https://doi.org/10.1016/0888-7543(91)90021-6]
Hobbins, J. C., Bracken, M. B., Mahoney, M. J. Diagnosis of fetal skeletal dysplasia with ultrasound. Am. J. Obstet. Gynec. 142: 306-312, 1982. [PubMed: 7065020] [Full Text: https://doi.org/10.1016/0002-9378(82)90735-9]
Holmgren, G., Jagell, S., Lagerkvist, B., Nordenson, I. A pair of siblings with diastrophic dysplasia and E trisomy mosaicism. Hum. Hered. 34: 266-268, 1984. [PubMed: 6479995] [Full Text: https://doi.org/10.1159/000153477]
Jager, M., Refior, H. J. Diastrophischer Zwergwuchs. Z. Orthop. 106: 830-840, 1969. [PubMed: 4242538]
Jung, C., Sohn, C., Sergi, C. Prenatal diagnosis of diastrophic dysplasia by ultrasound at 21 weeks of gestation in a mother with massive obesity. Prenatal Diag. 18: 378-383, 1998. [PubMed: 9602486]
Kite, J. H. The Clubfoot. New York: Grune and Stratton (pub.) 1964. Pp. 210-218.
Lamy, M., Maroteaux, P. Le nanisme diastrophique. Presse Med. 68: 1977-1980, 1960. [PubMed: 13758600]
Langer, L. O., Jr. Personal Communication. Minneapolis, Minn. 1967.
Macias-Gomez, N. M., Megarbane, A., Leal-Ugarte, E., Rodriguez-Rojas, L. X., Barros-Nunez, P. Diastrophic dysplasia and atelosteogenesis type II as expression of compound heterozygosis: first report of a Mexican patient and genotype-phenotype correlation. Am. J. Med. Genet. 129A: 190-192, 2004. [PubMed: 15316973] [Full Text: https://doi.org/10.1002/ajmg.a.30149]
Makitie, O., Kaitila, I. Growth in diastrophic dysplasia. J. Pediat. 130: 641-646, 1997. [PubMed: 9108864] [Full Text: https://doi.org/10.1016/s0022-3476(97)70250-6]
Mau, H. Wesen und Bedeutung der enchondralen Dysostosen. Stuttgart: Georg Thieme Verlag (pub.) 1958. P. 108ff.
Megarbane, A., Farkh, I., Haddad-Zebouni, S. How many phenotypes in the DTDST family chondrodysplasias? (Letter) Clin. Genet. 62: 189-190, 2002. [PubMed: 12220459] [Full Text: https://doi.org/10.1034/j.1399-0004.2002.620214.x]
Megarbane, A., Haddad, F. A., Haddad-Zebouni, S., Achram, M., Eich, G., Le Merrer, M., Superti-Furga, A. Homozygosity for a novel DTDST mutation in a child with a 'broad bone-platyspondylic' variant of diastrophic dysplasia. Clin. Genet. 56: 71-76, 1999. [PubMed: 10466420] [Full Text: https://doi.org/10.1034/j.1399-0004.1999.560110.x]
Panzer, K. M., Lachman, R., Modaff, P., Pauli, R. M. A phenotype intermediate between Desbuquois dysplasia and diastrophic dysplasia secondary to mutations in DTDST. Am. J. Med. Genet. 146A: 2920-2924, 2008. [PubMed: 18925670] [Full Text: https://doi.org/10.1002/ajmg.a.32543]
Taybi, H. Diastrophic dwarfism. Radiology 80: 1-10, 1963. [PubMed: 13993535] [Full Text: https://doi.org/10.1148/80.1.1]
Treacher Collins Syndrome Collaborative Group. Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. Nature Genet. 12: 130-136, 1996. [PubMed: 8563749] [Full Text: https://doi.org/10.1038/ng0296-130]