Diastrophic Dysplasia

Diastrophic dysplasia is an autosomal recessive short-limbed skeletal dysplasia caused by biallelic loss-of-function mutations in SLC26A2, the sulphate transporter gene. It is the prototype of the SLC26A2 spectrum, four allelic disorders that run from perinatally lethal achondrogenesis 1B to recessive multiple epiphyseal dysplasia in an adult of near-normal height. The child is of normal intelligence with a normal life expectancy, and the orthopaedic work is a multi-stage plan that takes the cervical spine, the scoliosis, the hip, the knee, the clubfoot and the thumb in sequence.

Why diagnosis at birth matters. It allows genetic counselling, anticipation of the airway and spinal complications, and the staged plan above. What the condition costs the patient, by system:

• Disability: short stature, restricted joint mobility, pain
• Airway: cervical instability, micrognathia, cleft palate (30 percent), obstructive sleep apnoea
• Spine: cervical kyphosis, progressive scoliosis, cord compression
• Limbs: hip dysplasia, knee flexion contractures, rigid clubfeet
• Hearing: recurrent otitis media, mixed hearing loss

Life expectancy is normal when the cervical and respiratory problems are managed.

How common. About 1 in 100,000 live births worldwide, with no sex predilection. In Finland the figure is 1 in 33,000: the founder mutation c.862C-to-T (p.Arg279Trp) accounts for 90 percent of Finnish diastrophic dysplasia chromosomes, whereas other populations carry private mutations. Carrier frequency is also higher in French-Canadians and African Americans, so counselling must be informed by population of origin, and partners from high-prevalence groups should be offered carrier screening.

Prenatal diagnosis. The second-trimester ultrasound can suggest the diagnosis: micromelia (short, bowed long bones) below the expected centile, and, characteristically, the abducted hitchhiker thumb and great toe can sometimes be seen held away from the hand or foot. Polyhydramnios, from impaired fetal swallowing caused by micrognathia, is a soft marker, and in the severe allelic forms a narrow thorax signals possible lethality. Diastrophic dysplasia is often first suspected at the routine anomaly scan, in an at-risk or even a previously unsuspected pregnancy.

Molecular testing is definitive when the family's two SLC26A2 mutations are already known:

• Chorionic villus sampling at around eleven to thirteen weeks, for targeted mutation analysis
• Amniocentesis from about fifteen weeks
• Preimplantation genetic testing (PGT-M) for known-carrier couples wishing to avoid an affected pregnancy

A couple with one affected child are obligate carriers with a one-in-four recurrence risk in each pregnancy. The prenatal pathway, and the option of declining testing, should be discussed pre-conceptually.

The gene and the transporter. SLC26A2 (solute carrier 26, family A, member 2), originally called DTDST, the diastrophic dysplasia sulfate transporter, sits on chromosome 5q32-q33.1 and encodes a transmembrane sulphate-chloride antiporter that mediates sulphate uptake by chondrocytes in the growth plate. Loss of function depletes intracellular sulphate: the chondrocytes cannot incorporate sulphate, so the chondroitin sulphate chains of the cartilage proteoglycans, aggrecan especially, are undersulphated, leading to an abnormal collagen matrix and a disorganised growth plate.

What undersulphated cartilage does. The matrix is mechanically weak, the chondrocytes are disorganised, and the growth plate loses its ordered columnar arrangement and becomes disorganised and cystic. The long bones come out short and broad, the joints develop multiple contractures and subluxations that stiffen the hip, knee and elbow, and the same weak cartilage produces the cauliflower ear and the hitchhiker thumb.

Why the ears swell. The cartilage of the pinna depends on sulphated proteoglycans for its firm elastic scaffold. With SLC26A2 defective the pinna cartilage is structurally weak, the matrix cannot retain water, and the ear develops cystic swellings, often bilateral, in the first weeks of life; the cysts then fibrose and calcify, leaving the classic cauliflower appearance. This is a sulphate-transporter sign rather than a diastrophic-dysplasia sign: cystic ears occur in atelosteogenesis type II and achondrogenesis 1B too, which is unsurprising once you know they are caused by mutations in the same gene.

Why the thumb hitches. The first metacarpal is short, broad and proximally placed, with a hypermobile metacarpophalangeal joint, so the thumb rests in radial abduction like a hitchhiker's. Function is poor, because the thumb cannot oppose, but it is present, which separates this from thrombocytopenia-absent radius.

Why the cervical kyphosis resolves. In most infants the kyphosis is mechanical and postural. With the neck positioned in extension and with growth of the vertebral bodies, it corrects.

One gene, four phenotypes. The SLC26A2 disorders form a phenotypic series ordered by how much residual sulphate-transport activity the mutations leave. The least function gives lethal achondrogenesis 1B, more gives atelosteogenesis type II, more again gives diastrophic dysplasia, and the mildest alleles give recessive multiple epiphyseal dysplasia. Within the family the discriminator is severity, not phenotype: achondrogenesis 1B and atelosteogenesis type II share the abducted thumbs and cystic ears, which is why the hitchhiker thumb is highly characteristic of the gene family but not specific to diastrophic dysplasia itself.

History. The pregnancy may have been complicated by polyhydramnios or a breech presentation. Ask about consanguinity, a prior affected sibling and ethnic background (Finnish, French-Canadian). At birth there is low birthweight and micromelia noted at delivery, with cystic swelling of the ears in the first weeks. Motor milestones are delayed by joint stiffness; social and language milestones are normal.

Examination. Work through the regions:

• Limbs: micromelia (rhizomelic and mesomelic), limited elbow extension, knee flexion contracture
• Hands: hitchhiker thumb, brachydactyly, ulnar deviation, limited MCP motion
• Spine: cervicothoracic kyphosis, scoliosis, lumbar hyperlordosis
• Feet: rigid equinovarus adductus, hitchhiker great toe
• Face: micrognathia, cleft palate (30 percent), otherwise normal facies
• Ears: cystic pinnae postnatally, then a firm calcified cauliflower ear

The tetrad. Hitchhiker thumb, cauliflower ear, micromelia and rigid clubfoot. The cystic swelling of the pinnae appears within the first weeks of life and, with the hitchhiker thumb, is effectively diagnostic in an infant who survives, because the allelic disorders that share both signs are lethal neonatally.

Not achondroplasia. Both produce short-limbed dwarfism and the two are easily separated clinically. Achondroplasia has rhizomelic shortening of the limbs only, a trident hand, frontal bossing, normal ears, no hitchhiker thumb, V-shaped epiphyses and foramen magnum stenosis. Diastrophic dysplasia has micromelia with a birth length markedly reduced to 35-45 cm, short broad long bones with flared metaphyses, the hitchhiker thumb, the cauliflower ear, rigid clubfeet and a cervical kyphosis at C3-C5. Genetic testing (FGFR3 against SLC26A2) confirms.

The skeletal survey at birth. Request a babygram (whole-body AP), a lateral skull, a lateral cervical spine, an AP chest, an AP pelvis, AP long bones, and AP hands and feet. Look for a short first metacarpal, broad metaphyses, medial deviation of the talus, cervical kyphosis and scoliosis. The first metacarpal is short and ovoid, the radiographic equivalent of the hitchhiker thumb; combined with the cauliflower ear, plain films alone are highly suggestive, and genetic testing confirms the diagnosis and provides the recurrence-risk information.

Genetic confirmation. SLC26A2 sequencing, Sanger or panel, at 3-6 months, with 95 percent sensitivity. The diagnosis needs biallelic pathogenic variants, homozygous or compound heterozygous; if only one variant is found, look for a large deletion with MLPA.

Surveillance and planning imaging. The cervical spine is imaged at the first visit as set out above. Thereafter:

The differential. Short-limbed dysplasias are told apart on the hand, the ear and the spine:

Larsen syndrome is the closest trap, because it shares the cervical kyphosis that dominates early management here. Separate them on everything else: Larsen has multiple large-joint dislocations from birth (the knees especially, often hyperextended), a flat face with a depressed nasal bridge, spatulate thumbs rather than abducted ones, and neither the cauliflower ear nor the combination of cleft palate with rigid clubfoot. Larsen is usually autosomal dominant (FLNB), so the family history and the recurrence counselling differ completely.

Priorities by age. Address the spine, the pinnae, the hip, the knee and the foot in that order to maximise function. Spine surveillance is by serial radiographs, for the cervical kyphosis at 0-2 years and for scoliosis at 4-10 years; the hip dysplasia and the flexion contractures are taken on at 1-4 years, and night splints maintain the correction after surgery. The pinnae are drained of their cysts and reconstructed by otoplasty at school age, and the child is screened for refractive errors and for otitis media.

The airway. A cervical kyphosis plus a small mouth and a short stiff neck is a difficult intubation over an unstable neck, and atlantoaxial instability is present in some. Micrognathia and cleft palate are common (about 30 percent), laryngotracheomalacia adds airway collapse in infancy, and restrictive lung disease from a severe scoliosis compounds the respiratory risk. This applies to every anaesthetic, the casts, the ear cartilage and the dental work included, not just to spine surgery.

What shifts the prognosis. The best outcomes follow early multi-disciplinary care, compliant orthotic use, well-timed scoliosis surgery, and hip and knee surgery before age 4-5. The poor outcomes follow severe scoliosis with cardiopulmonary compromise, an untreated hip dislocation, a fixed knee contracture and a recurrent untreated clubfoot. Adult height is reached along a progressively failing growth curve with little or no pubertal spurt.

The adult. Premature osteoarthritis of the hips and knees is near-universal in adulthood, driven by the dysplastic, incongruent joints, the residual contractures and the altered mechanics. Disabling hip and knee pain in early-to-middle adult life is common and is often the reason an adult with diastrophic dysplasia presents to an arthroplasty surgeon. The same cervical-spine and difficult-airway considerations from childhood apply to that adult, so obtain cervical imaging and plan the airway before any adult arthroplasty.

Arthroplasty is technically demanding in this short-limbed, dysplastic skeleton. The bones are small and deformed, frequently needing small, custom or paediatric implants and sometimes custom femoral stems; there is often retained osteotomy hardware and altered proximal-femoral or condylar geometry from childhood surgery; fixed flexion contractures and soft-tissue tightness complicate balancing; and acetabular dysplasia or protrusio may require augmentation. Meticulous templating, the availability of small or custom implant sets and planned soft-tissue releases are essential, and the outcomes, while worthwhile for pain, are less predictable than in routine arthroplasty.