Diastrophic Dysplasia

Clinical characteristics.

Diastrophic dysplasia (DTD) is characterized by limb shortening, normal-sized skull, hitchhiker thumbs, spinal deformities (scoliosis, exaggerated lumbar lordosis, cervical kyphosis), and contractures of the large joints with deformities and early-onset osteoarthritis. Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. On occasion the disease can be lethal at birth, but most affected individuals survive the neonatal period and develop physical limitations with normal intelligence.

Diagnosis/testing.

The diagnosis of DTD rests on a combination of clinical, radiologic, and histopathologic features. The diagnosis is confirmed by molecular genetic testing of SLC26A2, the only gene in which pathogenic variants are known to cause DTD. Biochemical studies of fibroblasts and/or chondrocytes may be used in the rare instances in which molecular genetic testing fails to identify SLC26A2 pathogenic variants.

Management.

Treatment of manifestations: In children, physiotherapy and casting to maintain joint positioning and mobility as much as possible; surgical correction of clubfoot when ambulation becomes impossible; cervical spine surgery restricted to individuals with clinical or neurophysiologic evidence of spinal cord impingement; surgical correction of scoliosis in those at risk for rapid increase in curvature; total arthroplasty of hips and knees in relatively young adults to decrease pain and increase mobility; treatment of cystic ear swelling is conservative.

Prevention of Primary Manifestations: Physical therapy may prevent early joint contractures.

Surveillance: Annual monitoring of spinal curvature and joint contractures.

Agents/circumstances to avoid: Obesity, which places an excessive load on the large, weight-bearing joints.

Other: Undertake orthopedic surgery with caution as deformities tend to recur.

Genetic counseling.

DTD is inherited in an autosomal recessive manner. At conception, each sib of a proband with DTD has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. The unaffected sibs of a proband have a 2/3 chance of being heterozygotes. Prenatal diagnosis for pregnancies at increased risk is possible if both disease-causing alleles of an affected family member have been identified. Ultrasound examination early in pregnancy is a reasonable complement or alternative to prenatal diagnosis by molecular genetic testing.

Clinical Diagnosis

Diastrophic dysplasia (DTD) encompasses a range of disease that varies from severe (atelosteogenesis type 2) to mild (formerly called "diastrophic variant," recessive multiple epiphyseal dysplasia [rMED, EDM4]).

Clinical features [Superti-Furga 2001, Superti-Furga 2002]

• Limb shortening
• Normal-sized skull
• Slight trunk shortening
• Hitchhiker thumbs (Figure 1)
• Small chest
• Protuberant abdomen
• Contractures of large joints
• Dislocation of the radius
• Cleft palate (in ~1/3 of individuals)
• Cystic ear swelling in the neonatal period (in ~2/3 of infants with classic findings)
• Other usual findings: ulnar deviation of the fingers, gap between the first and second toes, clubfoot, and flat hemangiomas of the forehead

Figure 1.

Hand of a newborn with diastrophic dysplasia, showing brachydactyly (short fingers), absence of flexion creases of the fingers, and proximally placed, abducted "hitchhiker thumb." The thumb deformity results in difficulty with thumb opposition, affecting (more...)

Radiographic findings

• The skull appears of normal size with disproportionate short skeleton.
• Cervical kyphosis is seen in most newborns and children with DTD.
• Ossification of the upper thoracic vertebrae may be incomplete with broadening of cervical spinal canal ("cobra-like" appearance).
• Coronal clefts may be present in the lumbar and lower thoracic vertebrae.
• Narrowing of the interpedicular distance from L1 to L5 is a constant finding.
• The more cephalad ribs are short and the chest can be bell shaped.
• The sternum may present duplication of the ossification centers.
• The ilia are hypoplastic with flat acetabula.
• The long bones appear moderately shortened with some metaphyseal flaring.
• The distal humerus is sometimes bifid or V-shaped, sometimes pointed and hypoplastic.
• The femur is distally rounded.
• The patella may appear fragmented or multilayered.
• Radius and tibia may be bowed.
• Proximal radial dislocation may be present at birth.
• Hands may exhibit typical features (Figure 2):
  • Hitchhiker thumb with ulnar deviation of the fingers
  • Shortness of the first metacarpal
  • Delta-shaped proximal and middle phalanges
  • In some severe cases, ossification of two to three carpal bones in the newborn, simulating advanced skeletal age

Figure 2.

Radiograph of the hand of a three-year-old child with diastrophic dysplasia. The phalanges are short; some show a "delta"-shape deformity. Ossification of the carpal bones is advanced for age, a phenomenon known as "pseudo-acceleration" of the bone age, (more...)

Testing

Histologic and biochemical testing provide important information.

Histopathology testing. The histopathology of cartilage is similar to that seen in atelosteogenesis type 2 (AO2) and achondrogenesis type 1B (ACG1B), as it reflects the paucity of sulfated proteoglycans in cartilage matrix. It shows an abnormal extracellular matrix with threads of fibrillar material between cystic acellular areas and areas of normal cellularity. Some chondrocytes appear surrounded by lamellar material forming concentric rings; in some cases, these are indistinguishable from the collagen rings typical of ACG1B. The growth plate shows disruption of column formation and hypertrophic zones with irregular invasion of the metaphyseal capillaries and fibrosis. These cartilage matrix abnormalities are present in long bones as well as in tracheal, laryngeal, and peribronchial cartilage, whereas intramembranous bone shows no ossification abnormalities [Superti-Furga 2001, Superti-Furga 2002].

Biochemical testing. The incorporation of sulfate into macromolecules can be studied in cultured chondrocytes and/or skin fibroblasts through double labeling with 3H-glycine and 35S-sodium sulfate. After incubation with these compounds and purification, the electrophoretic analysis of medium proteoglycans reveals a lack of sulfate incorporation, which can be observed even in total macromolecules.

Note: (1) The determination of sulfate uptake is cumbersome and not used for diagnostic purposes. (2) The sulfate incorporation assay in cultured skin fibroblasts (or chondrocytes) is recommended only in the rare instance in which the diagnosis of DTD is strongly suspected but molecular genetic testing fails to detect SLC26A2 pathogenic variants [Rossi et al 1996, Superti-Furga et al 1996a, Rossi et al 1997, Rossi et al 1998, Rossi et al 2003].

Testing Strategy

To confirm/establish the diagnosis in a proband

• Clinical and radiologic features can strongly suggest the diagnosis of DTD.
• Molecular genetic testing, the diagnostic test of choice in probands with clinical and radiologic findings compatible with DTD, allows for precise diagnosis in the great majority of cases.
• Single gene testing of SLC26A2:
  • Targeted analysis for the four most common pathogenic variants is likely to identify one or both alleles in a significant proportion of probands (one allele in >1/2 of cases and both alleles in 1/3 of cases).
  • Sequence analysis of the entire coding region may be performed initially, or when only one or neither allele has been identified by targeted analysis for pathogenic variants.
• Histologic and biochemical tests provide confirmatory information but are usually not required to establish the clinical diagnosis. Note: These tests are particularly helpful in aborted fetuses, when the radiographic material is of poor quality.
• The sulfate incorporation assay in cultured skin fibroblasts (or chondrocytes) is possible in the rare cases in which the diagnosis of DTD is strongly suspected but variant analysis fails to detect SLC26A2 pathogenic variants.

Clinical Description

Neonates with diastrophic dysplasia (DTD) may experience respiratory insufficiency because of the small rib cage and tracheal instability and collapsibility. Mechanical ventilation is required in a significant proportion of infants. Mortality in the first months of life is increased, mainly because of respiratory complications such as pneumonia, sometimes aspiration pneumonia.

From the newborn period throughout life, the disorder appears to involve the skeleton as well as the tendons, ligaments, and joint capsules, which are tighter and shorter than normal, causing restricted joint mobility. Growth of the tendons and joint capsules may be impaired; Peltonen et al [2003] reported a high prevalence of congenital aplasia of menisci and cruciate ligaments within the knee joints. Pretibial dimples may be present, possibly a consequence of reduced intrauterine movement.

Joint contractures and spine deformity tend to worsen with age. Painful degenerative arthrosis of the hip is common in young adults. Anterior tilting of the pelvis may occur as a consequence and contribute to exaggerate the lumbar lordosis. The spine frequently develops excessive lumbar lordosis, thoracolumbar kyphosis, and scoliosis. In anteroposterior radiographs of the lumbar spine, a decrease of the vertebral interpedicular distance is almost invariably observed; however, related neurologic symptoms are only rarely observed [Remes et al 2004].

The knee may be unstable in childhood, but flexion contractures develop with progressive valgus deformity and lateral positioning of the patella. The development and position of the patella may determine whether contraction of the quadriceps muscle results in extension of the knee or paradoxical flexion of the knee. If paradoxical flexion occurs, severe difficulty with walking results [Remes et al 2004].

Because of foot deformities and shortened tendons, many adults with DTD are unable to place their heels on the ground. Thus, they stand solely on their metatarsals and toes. Typically, the adult with classic DTD stands on his toes because of severe clubfoot and has marked lumbar lordosis and thoracic kyphoscoliosis; this appearance originally prompted use of the term "diastrophic" (twisted).

Brachydactyly, ulnar deviation, phalangeal synostosis, and ankylosis of the fingers with significant disability may be observed. Phalangeal synostosis, usually between proximal and middle phalanges, develops in those fingers that have an abnormal phalangeal patterning at birth, including so-called delta-shaped phalanges that usually lack a proper joint space. Often, newborns with DTD lack phalangeal flexion creases (Figure 1), a sign of marked reduction of joint motion already present at early developmental stages. The thumb may be placed more proximally than usual and may also be hypotonic and thus weak (probably because of ligamentous dysplasia). As a consequence, some individuals may have difficulty opposing the thumb and the index finger to accomplish a pincer grasp. In older children and adults, ulnar deviation of the second finger frequently occurs together with radial deviation of the fifth finger (clinodactyly), giving a characteristic "brackets" appearance.

The facial appearance of children and young adults with DTD is remarkably different from the "standard" chondrodysplasia face with a depressed nasal bridge and anteverted nares. The forehead is broad with a high anterior hairline; the palpebral fissures may be downslanting; the nose is not shortened or stubby as in other chondrodysplasias but rather long and thin because of hypoplastic alae nasi; the nares are not anteverted; the facial tissues are tight; the mouth is small, and the mandible normally developed. Cystic ear swelling is frequent in individuals with DTD, a feature not reported in individuals with milder findings consistent with the recessive multiple epiphyseal dysplasia (rMED) phenotype. Ear swelling can be associated with inflammation and pain [Cushing et al 2011].

Adult stature ranged between 100 and 140 cm in an early review of Americans and Europeans with DTD. A 1982 study reported a mean adult height of 118 cm [Horton et al 1982], while a study of Finnish individuals with DTD (who are genetically homogeneous at the SLC26A2 locus) revealed a mean adult height of 136 cm for males and 129 cm for females [Mäkitie & Kaitila 1997]. The discrepancy in mean height between the older studies and the later Finnish study may be the result of variant heterogeneity or may reflect bias of ascertainment of more severely affected individuals in the older studies. It must be noted that the usefulness of such growth curves in predicting adult height is limited by the occurrence of many different allelic combinations [Superti-Furga 2001, Superti-Furga 2002]

In addition to the skeletal abnormalities, a mild degree of muscular hypoplasia of the thighs and legs is common.

Neurologic complications may occur, particularly in the cervical region. Cervical kyphosis is seen in lateral radiographs in most newborns; in most cases, it lessens over the first three to five years of life but in some cases, severe cervical kyphosis may lead to spinal cord compression, either spontaneously or during the procedure of endotracheal intubation, which requires hyperextension of the neck. A newborn with DTD and severe cervical kyphosis died immediately after birth of respiratory insufficiency; autopsy revealed neuronal degeneration and gliosis of the cervical spinal cord that had developed before birth.

Newer MRI findings have confirmed that in DTD, the foramen magnum is of normal size but the cervical spinal canal is narrowed. Individual cervical vertebral bodies (usually C3 to C5) may be hypoplastic, but the frequently observed kyphosis is not explained by changes of the vertebral bodies and may thus be the consequence of abnormal intervertebral disks. The rate of spontaneous correction of cervical kyphosis is rather high.

Cervical spina bifida occulta has been frequently reported in individuals with DTD.

Hearing loss is unusual in individuals with DTD, although it may be overestimated if studies are based on small cohorts [Tunkel et al 2012]. Vision defects are seldom observed, although a tendency towards myopia has been reported.

Mental development and intelligence are usually normal; numerous individuals affected by DTD attain high academic and social recognition or success in the arts.

MRI studies have shown a peculiar signal anomaly of intervertebral disks, suggesting reduced water content. This anomaly may be the consequence of reduced proteoglycan sulfation.

Genotype-Phenotype Correlations

Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype in this spectrum of disorders that extends from lethal achondrogenesis type 1B (ACG1B) to mild recessive multiple epiphyseal dysplasia (EDM4/rMED). Homozygosity or compound heterozygosity for pathogenic variants predicting stop codons or structural pathogenic variants in transmembrane domains of the sulfate transporter are associated with ACG1B, while pathogenic variants located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5'-flanking region of the gene result in less severe phenotypes [Superti-Furga et al 1996b, Karniski 2001, Maeda et al 2006].

The pathogenic variant p.Arg279Trp is the most common SLC26A2 variant found outside of Finland (45% of alleles); it results in the mild EDM4 phenotype when homozygous and mostly in the diastrophic dysplasia (DTD) and atelosteogenesis type 2 (AO2) phenotypes when found in the compound heterozygous state [Barbosa et al 2011].

Pathogenic variant p.Arg178Ter is the second most common variant (9% of alleles) and is associated with a more severe DTD phenotype or even the perinatal-lethal AO2 phenotype, particularly when combined in trans with the p.Arg279Trp variant.

Pathogenic variants p.Cys653Ser and c.-26+2T>C are the third most common variants (8% of alleles).

Pathogenic variant p.Cys653Ser results in EDM4/rMED when homozygous and in EDM4/rMED or DTD when present in trans with other pathogenic variants [Czarny-Ratajczak et al 2010].

Pathogenic variant c.-26+2T>C is sometimes referred to as the "Finnish" variant, because it is much more frequent in Finland than in the remainder of the world population. It produces low levels of correctly spliced mRNA and results in DTD when homozygous. It is the only variant that has been identified in all four SLC26A2-related dysplasias, in compound heterozygosity with mild (rMED and DTD) or severe (AO2 and ACG1B) alleles [Dwyer et al 2010].

The same pathogenic variants found in the ACG1B phenotype can also be found in the milder phenotypes (AO2 and DTD) if the second allele is a relatively mild variant. Indeed, missense variants located outside of the transmembrane domain of the sulfate transporter are often associated with a residual activity that can "rescue" the effect of a null allele [Rossi & Superti-Furga 2001].

Penetrance

For pathogenic variants in SLC26A2, penetrance is complete.

Nomenclature

Diastrophic dysplasia (DTD) was recognized as a distinct entity by Lamy & Maroteaux [1960]. At that time, they described a disorder that "resembled achondroplasia in the newborn period but had a quite distinct evolution." The name was chosen to indicate the "twisted" appearance of the spine and limbs in severely affected individuals. The clinical and radiographic features of diastrophic dysplasia are so characteristic that no other name has been associated with the condition.

The existence of clinical variability was recognized early; instances of "severe" or "lethal" DTD are now classified as atelosteogenesis type 2 (AO2), while milder cases, once termed "diastrophic variant," are now classified as recessive multiple epiphyseal dysplasia (rMED, EDM4).

DTD is classified in the "sulfation disorder" group of the current Nosology and Classification of Genetic Skeletal Disorders [Superti-Furga & Unger 2007].

Prevalence

No reliable data exist regarding the prevalence of DTD. In the experience of several genetic and metabolic centers that can compare its incidence with that of other genetic diseases, DTD disorders are generally believed to be in the range of approximately 1:100,000.

Treatment of Manifestations

In children, the principle is to maintain joint positioning and mobility as much as possible by physical means (physiotherapy and casting, e.g., for clubfeet); however, tightness of joint capsules and ligaments in diastrophic dysplasia makes correction by casting or other physical means difficult.

Surgical correction of clubfoot is indicated when the foot deformity makes ambulation impossible; however, surgery needs to be undertaken with caution as deformities tend to recur. Simple tenotomy does not suffice, and more extensive plasty of tarsal bones may be needed [Weiner et al 2008].

The rate of spontaneous correction of cervical kyphosis is rather high, and cervical spine surgery in infancy may be restricted to individuals with clinical or neurophysiologic evidence of spinal cord impingement.

Indications for surgical correction of scoliosis have not been established nor have criteria to define a successful surgical outcome [Matsuyama et al 1999, Remes et al 2001]. It should be noted that surgical series are inevitably biased toward more severely affected individuals. Although surgery before puberty may be helpful for those who have developed severe spinal deformity with respiratory compromise or neurologic signs, surgical correction of scoliosis is best postponed until after puberty in the majority of individuals with diastrophic dysplasia [Jalanko et al 2009]. The key issue seems to be the early identification of those individuals at risk for rapid increase in scoliotic curvature.

Total arthroplasty of hips and knees decreased pain and increased mobility in a group of adult Finnish individuals with premature degenerative arthrosis [Helenius et al 2003a, Helenius et al 2003b]. The authors concluded that arthroplasty is indicated in "relatively young adults" with DTD.

A conservative approach to the treatment of cystic ear swelling is recommended [Cushing et al 2011].

Prevention of Primary Manifestations

Physical therapy may prevent early joint contractures.

Surveillance

Annual monitoring of spinal curvature to prevent neurologic complications and joint contractures is appropriate.

Agents/Circumstances to Avoid

Obesity places an excessive load on the large weight-bearing joints and thus should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although not specific to DTD, women with severe kyphoscoliosis may experience complications related to thoracic compression in later stages of pregnancy and need to be monitored closely. Kyphoscoliosis can also complicate the use of spinal anaesthetics and consultation with an anaesthesiologist prior to delivery would be advisable.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu 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.