Diastrophic Dysplasia

Clinical characteristics.

Diastrophic dysplasia (DTD) is characterized by limb shortening, normal-sized head, 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 is established in a proband with characteristic clinical and radiographic features and/or biallelic pathogenic variants in SLC26A2 identified by molecular genetic testing. 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: Cervical spine surgery in infancy restricted to individuals with clinical or neurophysiologic evidence of spinal cord impingement; physical therapy may prevent early joint contractures; in children, physiotherapy and casting to maintain joint positioning and mobility as much as possible; surgical correction of clubfoot when ambulation becomes impossible; undertake orthopedic surgery with caution as deformities tend to recur; postpubertal surgical correction of scoliosis is recommended unless severe spinal deformity is causing respiratory compromise or neurologic signs; total arthroplasty of hips and knees in relatively young adults to decrease pain and increase mobility; treatment of cystic ear swelling is conservative.

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.

Genetic counseling.

DTD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC26A2 pathogenic variant, each sib of an affected individual has at conception 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. Once the SLC26A2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

DTD should be suspected in individuals with the following clinical and radiographic features.

Clinical findings

• Limb shortening
• Normal-sized head
• Slight trunk shortening
• Hitchhiker thumbs (Figure 1)
• Symphalangism with missing interphalangeal creases
• 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)
• Other common findings: ulnar deviation of the fingers, gap between the first and second toes, clubfoot, and flat hemangiomas of the forehead

Radiographic findings

• The skull is of normal size with disproportionate short skeleton.
• Cervical kyphosis is seen in most newborns and children.
• 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.
• Sternum may show duplication of the ossification centers.
• Ilia are hypoplastic with flat acetabula.
• Long bones appear moderately shortened with some metaphyseal flaring.
• Distal humerus is sometimes bifid or V-shaped, sometimes pointed and hypoplastic.
• Femur is distally rounded.
• 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
  • Symphalangism
  • In some severe cases, ossification of two to three carpal bones in the newborn, simulating advanced skeletal age

Establishing the Diagnosis

The diagnosis of DTD is established in a proband with the characteristic clinical and radiographic features described in suggestive findings and/or biallelic pathogenic (or likely pathogenic) variants in SLC26A2 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic SLC26A2 variants of uncertain significance (or of one known SLC26A2 pathogenic variant and one SLC26A2 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype and/or clinical context.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other skeletal dysplasias are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Neonatal respiratory compromise. 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, including aspiration pneumonia.

Musculoskeletal manifestations. The tendons, ligaments, and joint capsules are tighter and shorter than normal, causing restricted joint mobility. 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 exacerbate 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, Shafi et al 2023].

The knee may be unstable in childhood; 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 paradoxic flexion of the knee. If paradoxic flexion occurs, severe difficulty with walking results [Remes et al 2004].

Because of foot deformities (clubfoot) and shortened tendons, many adults with DTD are unable to place their heels on the ground, and thus stand solely on their metatarsals and toes.

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 (see 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 be hypotonic and thus weak. 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.

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

Facial features. The forehead is broad with a high anterior hairline; the palpebral fissures may be downslanting; the nose is long and thin with hypoplastic alae nasi; the facial tissues are tight; the mouth is small, and the mandible normally developed. Cystic ear swelling is frequent and 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.

Neurologic complications may occur, particularly in the cervical region. Cervical kyphosis is seen in lateral radiographs in most newborns; in most children, the kyphosis becomes less severe over the first three to five years of life, but in some instances severe cervical kyphosis may lead to spinal cord compression, either spontaneously or during 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.

MRI findings have confirmed that in individuals with 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. 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.

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

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

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 toward myopia has been reported.

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, which extends from lethal achondrogenesis type 1B (ACG1B) to SLC26A2-related multiple epiphyseal dysplasia (SLC26A2-MED). 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 1996, 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 SLC26A2-MED phenotype when homozygous and mostly in the DTD and SLC26A2-related atelosteogenesis 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 SLC26A2-related atelosteogenesis 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 SLC26A2-MED when homozygous and in SLC26A2-MED 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 (SLC26A2-MED and DTD) or severe (SLC26A2-related atelosteogenesis and ACG1B) alleles [Dwyer et al 2010].

The same pathogenic variants found in the ACG1B phenotype can also be found in the milder phenotypes (SLC26A2-related atelosteogenesis 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].

Nomenclature

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 SLC26A2-related atelosteogenesis, while milder cases ‒ once termed "diastrophic variant" ‒ are now classified as SLC26A2-MED.

In the 2023 revised Nosology of Genetic Skeletal Disorders [Unger et al 2023], DTD is referred to as SLC26A2-related diastrophic dysplasia and is included in the sulfation disorders group.

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.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with diastrophic dysplasia (DTD), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

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 anesthetics; thus, consultation with an anesthesiologist prior to delivery is advisable.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register 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.

Mode of Inheritance

Diastrophic dysplasia (DTD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one SLC26A2 pathogenic variant based on family history).
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SLC26A2 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are usually asymptomatic and have normal stature. There is no evidence that they are at increased risk for degenerative joint disease.

Sibs of a proband

• If both parents are known to be heterozygous for an SLC26A2 pathogenic variant, each sib of an affected individual has at conception 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.
• Heterozygotes (carriers) are usually asymptomatic and have normal stature.

Offspring of a proband. The offspring of an individual with DTD are obligate heterozygotes (carriers) for a pathogenic variant in SLC26A2.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC26A2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SLC26A2 pathogenic variants in the family.

Carrier detection in reproductive partners of a heterozygous individual is possible.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Molecular Pathogenesis

SLC26A2 pathogenic variants are responsible for the family of chondrodysplasias including achondrogenesis 1B (ACG1B), SLC26A2-related atelosteogenesis, diastrophic dysplasia (DTD), and SLC26A2-related multiple epiphyseal dysplasia (SLC26A2-MED). Impaired activity of the sulfate transporter in chondrocytes and fibroblasts results in the synthesis of proteoglycans that are not sulfated or are insufficiently sulfated [Rossi et al 1998, Satoh et al 1998], most likely because of intracellular sulfate depletion [Rossi et al 1996, Gualeni et al 2010]. Undersulfation of proteoglycans affects the composition of the extracellular matrix and leads to impairment of proteoglycan deposition, which is necessary for proper enchondral bone formation [Corsi et al 2001, Forlino et al 2005, Dawson 2011]. The clinical severity can be correlated with the residual activities of the sulfate transporter resulting from different pathogenic variants [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.Arg178Ter pathogenic variant was shown to abolish sulfate transporter activity, and the p.Val341del pathogenic variant showed detectable but very low activity (17% of the wild type) of sulfate transporter [Karniski 2001]. The same variants associated in some individuals with the ACG1B phenotype can be found in individuals with a milder phenotype (SLC26A2-related atelosteogenesis and DTD) if the second allele is a relatively mild variant. Indeed, missense variants 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 1996, 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 ACG1B-causing variants are associated with no residual transport activity, while the milder phenotypes result from either different combinations of "null" variants with other alleles that allow for some residual activity or from two variants with residual activity. Original observations were: (1) intracellular retention of the sulfate transporter protein with the variant p.Gly678Val and (2) abnormal molecular weight of sulfate transporter with p.Gln454Pro, possibly indicating protease sensitivity or aberrant glycosylation.

Mechanism of disease causation. Loss of function

Author History

Diana Ballhausen, MD; Lausanne University Hospital (2013-2021)
Luisa Bonafé, MD, PhD; Lausanne University Hospital (2004-2021)
Lauréane Mittaz-Crettol, PhD; Lausanne University Hospital (2013-2021)
Andrea Superti-Furga, MD (2004-present)
Sheila Unger, MD (2021-present)

Revision History

• 16 March 2023 (sw) Revision: "SLC26A2-Related Diastrophic Dysplasia" added as synonym; Nomenclature updated
• 23 December 2021 (sw) Comprehensive update posted live
• 18 July 2013 (me) Comprehensive update posted live
• 12 June 2007 (me) Update posted live
• 15 November 2004 (me) Review posted live
• 17 February 2004 (asf) Original submission

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