Diastrophic Dysplasia

Diastrophic dysplasia (DTD) is a form of osteochondrodysplasia typically characterised by abnormalities in the skeletal and cartilaginous systems, which can range from mild to severe. It is often characterised by short limbs, talipes equinovarus, spinal deformities, ‘hitchhiker’ thumbs or toes, early-onset osteoarthritis, and large joint contractures (1, 2).

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The general incidence of DTD is reported to be 1:100,000 births (1). However, an increased incidence has been noted in Finland, where 1-2% of the population carry a mutation in the DTD gene, resulting in an incidence of 1:33,000 births, compared to 1:500,000 births in the United States (2). 

DTD is an autosomal recessive disease, caused by a mutation on the SLC26A2 gene (solute carrier family Homo sapiens 26), found on the long arm of chromosome 5. This causes inactivation of the sulfate-chloride exchanger in the cell membrane, leading to a reduction in intracellular sulfate, and the production of sulfate-deplete proteoglycans in the fibroblasts and chondrocytes. This in turn leads to disruption in cartilage formation, endochondral ossification, thereby affecting skeletal growth and formation (3, 4). This process is outlined in Figure 1.

Histopathological analysis of cartilage in DTD reveals similar findings to atelosteogenesis types 1B and 2. The cartilage matrix displays a reduction in sulfated proteoglycans, which is also present in the long bones. Hypertrophic zones and fibrosis are seen in the growth plates, and the column formation shows signs of disruption (1).  

Aside from the usual associations with talipes equinovarus and hitchhiker’s thumbs or toes, cleft lip and palate are associated with DTD in approximately one quarter to one third of cases. Other structural anomalies may include micrognathia, cervical kyphosis, short ribs and bell-shaped chest, narrowing of the interpedicular distance in the lumbar spine, hypoplastic ilia, and coronal clefts in the lower thoracic and lumbar vertebrae (1, 2, 5). Approximately 85% of babies born with DTD undergo external ear inflammation and subsequent deformity in the neonatal period, but hearing is not affected (2). Figures 2-6 demonstrate the ultrasound appearances of a fetus with DTD at 16 weeks’ gestation.

As DTD is an autosomal recessive condition, there is a 25% chance of having an affected offspring (5).

Prenatal diagnosis can be achieved through sonographic imaging and molecular genetic testing. At the first trimester scan, the presence of hitchhiker’s thumbs, talipes equinovarus, and short long bones can be detected (7). In the second trimester, the appearance of short long bones, talipes equinovarus, normal head shape and size, and hitchhiker thumbs (thumbs in abducted position) should prompt suspicion of this condition (2, 6). The femur may have a distally rounded appearance, the distal humerus may be bifid, and the radius and tibia are sometimes bowed. Single gene testing for the SLC26A2 gene can be performed in the presence of sonographic findings, to allow for accurate diagnosis. Neonatal histological diagnosis can be useful in the rare cases where the genotype does not correlate with the clinical signs of DTD; however, this is not routinely required for diagnosis. This can be done using sulfate incorporation assay in cultured skin fibroblasts or chondrocytes (1). 

Severe forms of DTD can present similarly to atelosteogenesis type 2, and milder forms are often similar to recessive multiple epiphyseal dysplasia (1). Other skeletal dysplasias involving micromelia, such as achondroplasia, should be considered when short long bones are identified on prenatal sonographic assessment. Conditions such as achondrogenesis, thanatophoric dysplasia, and short-rib polydactyly syndrome, are often associated with more severe micromelia, abnormal appearance of the long bones, and other features such as under-ossification of the skull and spine, fractures, and polydactyly (7). 

Detailed sonographic assessment, including a full skeletal survey and examination of the extremities, is important in achieving prenatal diagnosis. Invasive testing to identify a mutation in the SLC26A2 gene is useful to provide information for prenatal counselling, as well as for future pregnancies.

Diagnosis of DTD is often made following the routine anomaly scan. However, if there is a family history of DTD, other similar skeletal dysplasias involving the SLC26A2 gene, or if the parents have a known carrier status, sonographic screening and invasive testing can be offered early in pregnancy.

Neonatal mortality is up to 25% due to respiratory difficulties secondary to the narrow chest and pulmonary hypoplasia (8). Children who survive past the first few months of life often have a good prognosis. Joint contractures and limited mobility are frequently encountered due to impaired growth of the tendons and joint capsules, as well as subluxations and dislocations (9). Cervical kyphosis can lead to neurological sequelae and occasionally spinal cord compression, but often improves in the first few years of life (1). Intelligence, hearing, and sexual function are unaffected.

Patients with a prenatal diagnosis of DTD should referred for counselling to a geneticist and orthopaedic surgeon. Serial casting for talipes equinovarus should begin after birth, followed by soft tissue surgery and prolonged casting for residual disease, as required (9). Cervical spinal surgery can be performed in cases of non-correcting cervical kyphosis leading to spinal cord compression (2). Arthroplasty is usually reserved for young adults with early onset degenerative arthritis (10). General lifestyle advice to avoid excessive weight gain and regular physiotherapy, as well as orthopaedic follow-up should be arranged. 

1. Bonafe L, Mittaz-Crettol L, Ballhausen D, Superti-Furga A. Diastrophic Dysplasia. GeneReviews 2004. Available at https://www.ncbi.nlm.nih.gov/books/NBK1350/. Accessed 12/09/2019
2. Honório JC, Bruns RF, Gründtner LF, Raskin S, Ferrari LP, Júnior EA, Nardozza LMM. Diastrophic Dysplasia: prenatal diagnosis and review of the literature. Sao Paulo Med J. 2013; 131(2):127-32 1
3. Rossi A, Superti-Furga A. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat. 2001;17(3):159-71.
4. Superti-Furga A. Skeletal dysplasias related to defects in sulfate metabolism. In: Royce P, Steinmann B, eds. Connective Tissue and Its Heritable Disorders. 2 ed. New York, NY: Wiley-Liss, Inc; 2002:939-60
5. Babcook CJ, Filly RA. Diastrophic dysplasia.1993-08-17-16 Diastrophic dysplasia © Babcook www.thefetus.net/. Available at https://sonoworld.com/TheFetus/page.aspx?id=345 Accessed 12/09/2019
6. Gonzales CH, Marcondes E. Nanismo diástrofico – estudo clínico e genético em duas meninas afetadas [Diastrophic dwarfism - clinical and genetic studies in two affected girls]. Pediatria (S. Paulo). 1980;2:349-58.
7. Khalil A, Pajkrt E, Chitty LS. Early prenatal diagnosis of skeletal anomalies. Prenat Diagn 2011; 31(1):115-24
8. Castro JLR, Rada AMC, Henao BEM, et al. Displasia diastrófica: Caracterización clínica, radiológica, citogenética y molecular de una paciente [Diastrophic dysplasia: clinical, radiological, cytogenetic and molecular characterization of a patient]. Iatreia. 2005;18(1):40-8.
9. Kaissi AA, Kenis V, Melchenko E, Chehida FB, Ganger R, Klaushofer K, Grill F. Corrections of lower limb deformities in patients with diastrophic dysplasia. Orthopaedic Surgery. 2014;6:274-279
10. Helenius I, Remes V, Lohman M, et al. Total knee arthroplasty in patients with diastrophic dysplasia. J Bone Joint Surg Am. 2003;85-A(11):2097-102. 

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