Practice Essentials
Skeletal dysplasias are a heterogeneous group of dysplasias that include more than 200 recognized conditions. They are disorders of growth and remodeling of bone and cartilage. Most disorders result in short stature, which is defined as height more than two standard deviations below the mean for the population at a given age. (When one discusses height in patients with short stature, one may say "smaller than average" rather than "dwarf.")
Lamy and Maroteaux first delineated this syndrome in 1960 and coined the term diastrophic dwarfism. [1] The term diastrophic is derived from the Greek word diastrophe ("distortion, twisting"); it is a geologic term used to describe the bending and twisting of the earth's crust during geomorphogenesis. In 1977, at the Second International Conference for Nomenclature for Constitutional Diseases of Bone, the name was changed from diastrophic dwarfism to diastrophic dysplasia. [2, 3] The term pseudodiastrophic dwarfism is used for a disorder that is clinically, radiologically, and histologically distinct from true diastrophic dysplasia, and it should not be used inadvertently.
Conditions that cause dwarfing are frequently referred to as short-limb or short-trunk types, depending on whether the trunk or limbs are more extensively involved. Diastrophic dysplasia is considered a short-limb dwarfing condition. Additional terms used to describe the segment of the limb with the greatest involvement are rhizomelic (proximal), mesomelic (middle), and acromelic (distal). In diastrophic dysplasia, the extremity involvement is rhizomelic in 40% of cases and mesomelic in 29% of cases.
Diastrophic dysplasia [4] is a recessively inherited chondrodysplasia, one that is particularly common in Finland. This term describes dwarfism with perhaps the most numerous and severe skeletal abnormalities from cervical spine to the feet. In the past, this condition was referred to as achondroplasia with clubfeet or arthrogryposis multiplex congenita.
A distinct group of patients who have many features of diastrophic dysplasia are referred to as having diastrophic variants; these individuals are taller and less severely affected than persons with classic diastrophic dwarfism. Classic diastrophic dysplasia and diastrophic variants are different expressions of a single genetic disorder (with variable penetrance) rather than separate entities. Individuals identified as having a diastrophic variant should be referred to as having mild diastrophic dysplasia.
Impairment of physeal, epiphyseal, and articular cartilage throughout the body is responsible for characteristic findings. Unlike those with achondroplasia or hypochondroplasia, patients with diastrophic dysplasia have epiphyseal involvement and are at risk for degenerative joint disease. Although the development and growth of cartilaginous structures are disturbed, the intramembranous ossification and appositional growth pattern are not primarily affected.
The diagnosis can be made at birth with the observation of pathognomic features or within the first few months of life, when the cystic swelling of the ears becomes apparent. The expression and severity of diastrophic dysplasia vary greatly. Patients may present with complaints pertaining to the head and neck, spine, major joints, and hands and feet.
One half to one third of patients develop cervical kyphosis. Generally, external signs of cervical abnormalities are absent; however, 80% of patients present with some degree of spinal curvature. Scoliosis is not present at birth, but it tends to develop within the first year of life; it becomes progressively severe with weightbearing. Lumbar lordosis is usually significant. Spinal stenosis is less common.
The hips maintain a persistent flexion contracture. Patients may present with hip subluxation. Hip dysplasia is usually progressive and may result in a significant decrease in the range of motion. The knees, too, have flexion contractures. Excessive valgus with lateral dislocation of the patella may occur. Genu valgum with patellar dislocation may occur in patients with diastrophic dysplasia. Genu varum is uncommon.
The hands are short, broad, and ulnarly deviated due to shortening of the ulna. The fingers appear widely spaced. The first metacarpal is characteristically short, leading to the clinical appearance of proximal insertion of the thumb. Flexion is absent at multiple proximal interphalangeal (PIP) joints of the fingers. Foot deformities are stiff and involve bony malformations, contracture, and malalignment, and they are difficult to correct passively. Deformities may range from equinovarus to pure equinus or valgus.
Pathophysiology
Proteoglycans are considered to be among the chief constituents of cartilage. Undersulfation of proteoglycan in the cartilaginous matrix is responsible for the impairment of performance and load-bearing ability of physeal, epiphyseal, and articular cartilage throughout the body.
The DTDST (SLC26A2) protein acts as a sodium-independent sulfate/chloride transporter and belongs to the SLC26 anion transporter family. The Finnish founder mutation in DTDST (SLC26A2) has been identified. [5] Approximately 95% of affected Finnish patients have a rare ancestral haplotype that was found in only 4% of a Finnish control population. The founder mutation is a guanine-thymine (GT) to guanine-cytosine (GC) transition in the splice donor site of a 5'-untranslated exon of the DTDST gene. The mutation acts by severely reducing levels of mRNA of the DTDST transcript. [6]
Mutations in DTDST are responsible for a family of chondrodysplasias that include four recessively inherited conditions: diastrophic dysplasia, multiple epiphyseal dysplasia, atelosteogenesis type 2, and achondrogenesis type 1B. In addition to the intrinsic sulfate transport properties of the DTDST protein, other factors influence the phenotype in individuals with these mutated alleles. [7]
Etiology
In 1994, Hastbacka et al identified the gene DTDST (SLC26A2). This gene, which codes for a sulfate transporter protein, has been mapped to distal end of chromosome bands 5q31-q34. [5] DTDST is inherited in an autosomal recessive manner. [8] Diastrophic dysplasia and McKusick-type metaphyseal chondrodysplasia are the only skeletal dysplasias with autosomal recessive transmission.
About 5% of cases may involve sporadic new mutations. Both parents of an affected individual are carriers of the abnormal gene but are clinically healthy. For a carrier couple, each pregnancy entails a 25% risk of producing an affected child. Each unaffected full sibling of an affected individual has a 67% likelihood of being a carrier. The offspring of an affected individual is a carrier and therefore unaffected unless the other parent is a carrier or affected with the same condition.
Diastrophic dysplasia is a disorder with a wide range of clinical manifestations; this variation has important implications. Parents of a child with mild diastrophic dysplasia, which would previously have been called a diastrophic variant, must be informed that they are at 25% risk of having other children with disproportionate dwarfism. In addition, they should be made aware that the expression of the disorder may be more severe in subsequent children.
Epidemiology
Although diastrophic dysplasia is extremely rare, the percentage of carriers in certain groups is high. A 2003 review reported a prevalence of 1 in 22,000 for Finland, [9] compared with an estimated prevalence of 1 in 100,000 elsewhere in the world. [4] However, a 2021 registry-based study found that the frequency of this condition in Finland has been decreasing since 1960. [10]
Diastrophic dysplasia has been observed in most white populations. [11]
Diastrophic dysplasia is an autosomal recessive disorder and occurs with equal frequency in males and females.
Prognosis
Patients have a minimally (5%) increased rate of perinatal mortality due to cervical myelopathy or respiratory problems such as aspiration pneumonia and laryngotracheomalacia. Patients with severe spinal deformities are also predisposed to the development of respiratory problems. A lethal form of diastrophic dysplasia has been described that can cause death soon after birth as a consequence of cardiorespiratory insufficiency. Overall, life expectancy is not reduced, and patients are able to lead productive lives at work and with their families.
Patient Education
Patients may benefit from the information on the Web site for diastrophic dysplasia, Diastrophic Help.
An important resource for individuals with short stature is the Little People of America (LPA) Organization. The LPA is a national organization that addresses the social, physical, and medical needs of its constituency. It holds annual regional and national conventions. Philosophically, this organization emphasizes the positive aspects of their members' abilities and lives rather than presenting short stature as a disability.
The Dwarf Athletic Association of America (DAAA) is a member of the US Olympic Committee that promotes athletic participation for individuals with short stature.
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Child with diastrophic dysplasia. Note micromelic dwarfing with hitchhiker thumb, flexion contractures of the knee, and clubfeet.
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Ear deformity in a patient with diastrophic dysplasia.
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Characteristic abducted position of the thumb in a patient with diastrophic dysplasia.
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Scoliosis in a patient with diastrophic dysplasia. The curve is a mild, nonprogressive-type curve. Note the degenerative changes associated with the scoliosis.
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Lumbar lordosis in a patient with diastrophic dysplasia. Note the horizontal sacrum and mild degenerative changes in the lumbar spine.
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Radiograph of the cervical spine obtained with the neck in neutral alignment shows severe kyphosis between C2 and C6 in a patient with diastrophic dysplasia.
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Early progressive type of scoliosis in a patient with diastrophic dysplasia. These curves typically have short segments and are sharply curved; they may have associated dysplastic changes in the vertebrae.
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The humerus in a patient with diastrophic dysplasia. Typically, all of the long bones are short and thick. Note the epiphyseal flattening and irregularity of the proximal humeral epiphysis. Metaphyseal flaring of the distal humerus is present.
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Pelvis with both hips in an adult with diastrophic dysplasia. Note the dysplastic shape of the femoral head, along with characteristic degenerative changes.
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Pelvis and both hips in a patient with diastrophic dysplasia. Note the short and broad neck of the femur. The appearance of the femoral epiphyses is delayed. Flattening of the epiphyses is present.
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Image in a patient with diastrophic dysplasia. The acetabulum is shallow and shows a double-hump configuration on the right side. Both the femoral heads are severely dysplastic.
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Image in a patient with diastrophic dysplasia. The patella is subluxed laterally, with mild hypoplasia of the lateral femoral condyle.
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Image in a patient with diastrophic dysplasia. The tubular bones of the hand are short and broad. The first metacarpal is particularly shortened. The ulna is shorter, and the radius shows flaring at its distal end.
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Image in a patient with diastrophic dysplasia. Oblique view of the hand shows a short first ray with marked abduction.
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Image in a patient with diastrophic dysplasia. Radiograph of the hands shows abducted and short first metatarsal, along with affection of the proximal interphalangeal (PIP) joint of all fingers. Ankylosis of the fifth PIP joint is present. The middle phalanges appear extremely short.
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Image in a patient with diastrophic dysplasia. The metatarsus adductus with medial twisting of metatarsals is evident. The first metatarsal is shortened. Also note the lateral subluxation of the navicular over the talus that gives the appearance of a skew foot.
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Deformity of the foot in a patient with diastrophic dysplasia.
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Severe equinus deformity in a patient with diastrophic dysplasia.
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Image in a patient with diastrophic dysplasia. CT scan, A 3-dimensional reconstruction, shows bilateral dysplasia and dislocation of hips.
