Primary bone dysplasia with micromelia
-Rare bone disease
-Rare developmental defect during embryogenesis
-Rare genetic disease
Sulfation-related bone disorder
-Rare genetic disease
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 ... - 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.
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 ... 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.
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 ... 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.
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. ... 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 (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.
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)]....
DiagnosisClinical DiagnosisDiastrophic 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 FigureFigure 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, (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 FigureFigure 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 (more...)TestingHistologic and biochemical testing provide important information. Histopathologic 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 mutations [Rossi et al 1996, Superti-Furga et al 1996a, Rossi et al 1997, Rossi et al 1998, Rossi et al 2003].Molecular Genetic TestingGene. SLC26A2 is the only gene currently known to be associated with diastrophic dysplasia (DTD) [Hästbacka et al 1994, Superti-Furga et al 1996a, Rossi & Superti-Furga 2001, Superti-Furga 2001, Superti-Furga 2002]. Clinical testing Targeted mutation analysis. The five most common SLC26A2 mutations (p.Arg279Trp, IVS1+2T>C, p.Val340del, p.Arg178X, and p.Cys653Ser) account for approximately 65% of disease alleles. Sequence analysis of the SLC26A2 coding region may detect rare mutations in individuals for whom targeted mutation analysis detects none or only one of the more common alleles. Mutations in SLC26A2 are found in more than 90% of alleles in individuals with radiologic and histologic features compatible with the diagnosis of DTD [Rossi & Superti-Furga 2001]. Table 1. Summary of Molecular Genetic Testing Used in Diastrophic DysplasiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1 Test AvailabilitySLC26A2Targeted mutation analysisPanel of five mutations 2 ~65% ClinicalSequence analysis Sequence variants 3>90% 1. % of disease alleles detected in individuals with typical clinical, radiologic, and histologic features of DTD2. IVS1+2T>C, p.Arg178*, p.Arg279Trp, p.Val340del, p.Cys653Ser. Mutation panel may vary by laboratory.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm 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. Targeted mutation analysis for the five most common mutations is likely to identify one or both alleles in a significant proportion of probands (one allele in 1/3 of cases and both alleles in 1/4 of cases). Sequence analysis of the entire coding region is performed when only one or neither allele has been identified by targeted mutation analysis. Parental DNA analysis for the mutations found in the proband is recommended as most cases are compound heterozygous. 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 mutation analysis fails to detect SLC26A2 mutations. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersThree other phenotypes (all with an autosomal recessive mode of inheritance) are associated with mutations in SLC26A2: Achondrogenesis type 1B (ACG1B), among the most severe skeletal disorders in humans, is characterized by severe hypodysplasia of the spine, rib cage, and extremities, with a relatively preserved cranium. ACG1B is invariably lethal in the perinatal period. Atelosteogenesis type 2 (AO2) is a neonatally lethal chondrodysplasia with clinical and histologic characteristics that resemble those of DTD but are more pronounced. Recessive multiple epiphyseal dysplasia (rMED, EDM4) is characterized by joint pain (usually in the hips and knees), deformities of the hands, feet, and knees, and scoliosis. About 50% of individuals have an abnormal finding at birth (e.g., clubfoot, cleft palate, or cystic ear swelling). Median height in adulthood is at the tenth centile.
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. ...
Natural HistoryNeonates 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; a recent report indicated a high prevalence of congenital aplasia of menisci and cruciate ligaments within the knee joints [Peltonen et al 2003]. 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 high and broad; the palpebral fissures are relatively small and 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.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 recent Finnish study may be the result of mutation 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, and 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.
Diastrophic dysplasia (DTD) is part of a disease spectrum. At the severe end, it borders a condition defined as atelosteogenesis type 2 that is commonly lethal in the perinatal period. Affected individuals present around birth or before. At the mild end, DTD can present as what was formerly called "diastrophic variant" and borders recessive multiple epiphyseal dysplasia; this differential diagnosis is usually considered in toddlers or school-age children....
Differential DiagnosisDiastrophic dysplasia (DTD) is part of a disease spectrum. At the severe end, it borders a condition defined as atelosteogenesis type 2 that is commonly lethal in the perinatal period. Affected individuals present around birth or before. At the mild end, DTD can present as what was formerly called "diastrophic variant" and borders recessive multiple epiphyseal dysplasia; this differential diagnosis is usually considered in toddlers or school-age children.Premature carpal ossification and digital malformations can be seen in newborns and infants with otopalatodigital syndrome (caused by mutations in FLNA; see Otopalatodigital Spectrum Disorders), in the Larsen syndrome/atelosteogenesis 1 spectrum (filamin B mutations), and in Desbuquois dysplasia. Contractures and mesomelic limb shortening reminiscent of diastrophic dysplasia can be seen in omodysplasia. Congenital contractures with mild skeletal anomalies can be seen in various forms of congenital arthrogryposis. Differential diagnosis in the prenatal period must include skeletal dysplasias as well as other conditions with reduced length and/or contractures. Even the demonstration of a hitchhiker thumb deformity is not pathognomic.
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with diastrophic dysplasia (DTD), the following evaluations are recommended:Cervical films Complete skeletal survey Orthopedic referral Physical therapy consultation Treatment of ManifestationsIn 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. 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. 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. SurveillanceAnnual monitoring of spinal curvature and joint contractures is appropriate.Agents/Circumstances to AvoidObesity places an excessive load on the large weight-bearing joints and thus should be avoided.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Diastrophic Dysplasia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSLC26A25q32Sulfate transporterFinnish Disease DatabaseSLC26A2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Diastrophic Dysplasia (View All in OMIM) View in own window 222600DIASTROPHIC DYSPLASIA 606718SOLUTE CARRIER FAMILY 26 (SULFATE TRANSPORTER), MEMBER 2; SLC26A2Molecular Genetic PathogenesisMutations in SLC26A2 are responsible for the family of chondrodysplasias including ACG1B, AO2, DTD, and rMED/EDM4. Impaired activity of the sulfate transporter in chondrocytes and fibroblasts results in the synthesis of proteoglycans that are not sulfated or are insufficiently sulfated [Satoh et al 1998, Rossi et al 1998], most probably because of intracellular sulfate depletion [Rossi et al 1996]. Undersulfation of proteoglycans affects the composition of the extracellular matrix and leads to impaired proteoglycan deposition, which is necessary for proper enchondral bone formation [Corsi et al 2001, Forlino et al 2005]. The predicted severity of the mutations can be correlated with the residual activities of the sulfate transporter and the severity of the phenotypes [Rossi et al 1996, Rossi et al 1997, Corsi et al 2001, Rossi & Superti-Furga 2001, Rossi et al 2003, Karniski 2004, Maeda et al 2006]. In a Xenopus oocyte model, the p.Arg178* mutation was shown to abolish sulfate transporter activity, and the p.Val340del mutation showed detectable but very low activity (17% of the wild type) of sulfate transporter [Karniski 2001]. The same mutations associated in some individuals with the ACG1B phenotype can be found in individuals with a milder phenotype (AO2 and DTD) if the second allele is a relatively mild mutation. Indeed, missense mutations located outside the transmembrane domain of the sulfate transporter are often associated with residual activity that can "rescue" the effect of a null allele. Other conclusions from the Xenopus study are at odds with consistent clinical observations, the discrepancy probably being the result of temperature and cellular processing differences between Xenopus oocytes and the human (20° C vs. 37° C) [Superti-Furga et al 1996b, Rossi & Superti-Furga 2001, Superti-Furga 2001, Superti-Furga 2002]. Similar studies conducted in mammalian cells [Karniski 2004] have produced results that are much more consistent with clinical genotype-phenotype correlations. These studies have essentially confirmed predictions that achondrogenesis 1B mutations are associated with no residual transport activity, while the milder phenotypes result from either different combinations of "null" mutations with others that allow for some residual activity or from two mutations with residual activity. Original observations were: (1) intracellular retention of the sulfate transporter protein with mutation p.Gly678Val and (2) abnormal molecular weight of sulfate transporter with mutation p.Gln454Pro, possibly indicating protease sensitivity or aberrant glycosylation. Normal allelic variants. The coding sequence of SLC26A2 is organized in two exons separated by an intron of approximately 1.8 kb. A further untranslated exon is located 5' relative to the two coding exons; it has probable regulatory functions. The p.Thr689Ser allele has been frequently observed in the heterozygous or homozygous state in several controls of different ethnicities, and it is very likely to be a polymorphism. There is evidence that p.Arg492Trp is a rare polymorphism found in seven of 200 Finnish controls and in five non-Finnish controls [Authors, unpublished data]. This allele was erroneously considered pathogenic in previous reports [Rossi & Superti-Furga 2001].Pathologic allelic variants. Five pathogenic alleles of SLC26A2 appear to be recurrent: p.Arg279Trp, IVS1+2T>C, p.Val340del, p.Arg178*, p.Cys653Ser. The mutation IVS1+2T>C (the "Finnish" allele), located 5' relative to the two coding exons, leads to reduced mRNA transcription. These five alleles represent approximately two thirds of the pathogenic mutations in SLC26A2. The phenotype associated with each pathogenic allele depends, in compound heterozygotes, on the combination with the second mutation. Distinct phenotypes known to be allelic to DTD are ACG1B, AO2, and recessive EDM4. Normal gene product. The protein consists of 739 amino acids and is predicted to have 12 transmembrane domains and a carboxy-terminal, cytoplasmic, moderately hydrophobic domain. This transmembrane protein transports sulfate into chondrocytes to maintain adequate sulfation of proteoglycans. The sulfate transporter protein belongs to the family of anion exchangers known as SLC26 [Mount & Romero 2004], which to date comprises ten members, including PDS (OMIM 274600), a chloride-iodide transporter involved in Pendred syndrome, and CLD, which is responsible for congenital chloride diarrhea. The function of the carboxy-terminal hydrophobic domain of SLC26A2 is not yet known. SLC26A2 is expressed in developing cartilage in human fetuses but also in a wide variety of other tissues. The size of the predominant mRNA species is greater than 8 kb, indicating that there are significant untranslated sequences. Abnormal gene product. Most of the SLC26A2 mutations either predict a truncated polypeptide chain or affect amino acids that are located in transmembrane domains or are conserved in man, mouse, and rat. Individuals homozygous for the "Finnish" mutation IVS1+2>C have reduced levels of mRNA with intact coding sequence. Thus, the mutation presumably interferes with splicing and/or further mRNA processing and transport.