Metatropic Dysplasia, Jeune (Asphyxiating Thoracic) & Ellis-van Creveld

Jeune asphyxiating thoracic dysplasia, Ellis-van Creveld syndrome and metatropic dysplasia are rare skeletal dysplasias that share a small thorax and limb shortening. A handful of hallmarks tells them apart, and each carries its own systemic association.

The two threats. The life- and function-threatening problems converge on the respiratory system. Thoracic insufficiency, the small thorax restricting respiration, is prominent in Jeune and contributory in metatropic dysplasia and Ellis-van Creveld. Progressive spinal deformity, especially the severe kyphoscoliosis of metatropic dysplasia, with a risk of atlantoaxial or cervical instability in some, can compromise the airway and respiration as well.

Diagnosis. The diagnosis rests on the clinical and radiographic phenotype with genetic confirmation. It is completed by looking for the systemic associations: renal and hepatic disease in Jeune, the heart in Ellis-van Creveld, the spine and airway in metatropic dysplasia.

The phenotype. Jeune syndrome, the asphyxiating thoracic dysplasia, is now classified within the short-rib thoracic dysplasias (SRTD), which are often ciliopathies. The thorax is narrow and bell-shaped with short ribs, the long bones are shortened, and there is sometimes polydactyly.

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Thoracic insufficiency. The small rib cage restricts lung growth and ventilation. The result is a restrictive lung disease that can be fatal in infancy and may require thoracic-expansion surgery.

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Beyond the skeleton. Progressive renal (and hepatic) disease accompanies the thoracic dysplasia and must be monitored.

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Variable severity. The phenotype is highly variable, from mild to lethal. Earlier antenatal presentation and greater femoral shortening and bowing predict a poorer prognosis.

How few patients sit behind the proportions. Pattani's series is just 9 individuals from 8 families across three English centres, all with DYNC2H1-related disease, so its proportions are indicative only.

• Severity was mild in 4, moderate requiring respiratory support in 2, and severe or lethal in 3: roughly a third severe or lethal, fewer than half mild
• All nine had a narrow thorax and 8 had shortened long bones
• Polydactyly was present in only 4 of 9, a minority feature rather than a defining one
• Eight of the nine presented antenatally, between 14 and 36 weeks
• No clear genotype-phenotype correlation was found, a finding made within DYNC2H1 rather than across the whole SRTD spectrum

The phenotype. Ellis-van Creveld syndrome, the chondroectodermal dysplasia, is autosomal recessive and combines:

• Postaxial polydactyly, extra ulnar or fibular digits
• Short, acromesomelic limbs
• Ectodermal defects: dysplastic nails and teeth, sparse hair
• Congenital heart disease, classically a single atrium (atrial septal defect)

The heart. The cardiac lesion is the dominant systemic risk and an important cause of morbidity. It must be assessed and treated alongside the polydactyly and ectodermal features.

Overlap with Jeune. A narrow thorax also occurs, placing Ellis-van Creveld alongside the short-rib dysplasias. The pelvis shows the characteristic trident acetabular roof with spurring and dysplastic iliac wings.

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The changing pattern. The name comes from the Greek metatropos, changing. The child is short-limbed in infancy and becomes short-trunked with growth.

The hallmarks. Look for a coccygeal 'tail-like' appendage, platyspondyly (flat vertebrae), and 'dumbbell'-shaped long bones with large joints and contractures.

The spine. The threat is a severe, progressive kyphoscoliosis. Together with the platyspondyly and the small thorax it compromises respiration and the cord, and there is a risk of cervical or atlantoaxial instability.

• Jeune (SRTD). Autosomal-recessive ciliopathies of retrograde intraflagellar transport and the dynein-2 motor. The commonest gene is DYNC2H1 (the dynein-2 heavy chain), with IFT80, WDR19, IFT140, TTC21B and others; all disrupt the primary cilium.
• Ellis-van Creveld. Autosomal recessive, EVC or EVC2, adjacent head-to-head genes on 4p16 encoding basal-cilium proteins that regulate Hedgehog signalling. Classically seen in the Old Order Amish, a founder effect.
• Metatropic dysplasia. Autosomal dominant, usually de novo, TRPV4 (a calcium-permeable cation channel). It is allelic with a family of TRPV4 skeletal dysplasias (spondylometaphyseal dysplasia Kozlowski, brachyolmia) and, separately, the TRPV4 neuropathies.

Why 'ciliopathy'. The primary cilium is an antenna-like organelle on growth-plate chondrocytes, built and maintained by intraflagellar transport: anterograde transport (kinesin-2) assembles it and retrograde transport (dynein-2) recycles it. It is the signalling hub for Hedgehog. A defective cilium cannot transduce Hedgehog properly, so chondrocyte proliferation and digit patterning fail, producing short ribs, short limbs and polydactyly. That is why these are skeletal ciliopathies.

The short-rib spectrum. These disorders form a phenotypic continuum, from the lethal neonatal short-rib polydactyly syndromes (historically Saldino-Noonan, Majewski, Verma-Naumoff) through the viable Jeune to Ellis-van Creveld. They are now unified genetically as the short-rib thoracic dysplasias with overlapping IFT and dynein genes, which is why genotype predicts phenotype poorly and the entities overlap.

Care is multidisciplinary and complication-directed, delivered within a skeletal-dysplasia team, with genetic diagnosis and counselling for every family.

• Jeune. Respiratory support and thoracic-expansion surgery (expansion thoracoplasty or VEPTR-type devices) for thoracic insufficiency, with renal and hepatic monitoring.
• Ellis-van Creveld. Cardiac assessment and repair of the single atrium or ASD, polydactyly surgery, and dental and limb care.
• Metatropic. Vigilant spinal surveillance and timely management of the kyphoscoliosis, by bracing, growth-friendly or definitive spinal surgery; watching for cervical instability; and respiratory care.

Jeune has a neck and a spine too. The largest surgical series reports that C1 stenosis and scoliosis are both common in Jeune syndrome, and essentially every child develops scoliosis during treatment whether or not it was present at the outset. The cervical spine therefore needs assessing, rather than attention going only to the chest; neither problem is a metatropic-only concern.

The wider context sits on neighbouring pages. The framework for classifying a short child is skeletal dysplasias; the spinal deformity of metatropic dysplasia, and the scoliosis that emerges during thoracic expansion, are managed on the principles of early-onset scoliosis and congenital scoliosis, with cervical narrowing assessed as in cervical instability. The extra digits of Ellis-van Creveld are addressed under polydactyly and, in the foot, polydactyly of the foot.

The series. O'Brien and colleagues treated 24 children with Jeune syndrome by VEPTR dynamic posterolateral expansion thoracoplasty, at a mean age at first implant of 23 months and with a mean follow-up of 8.4 years. Survival was 68 percent, set against a reported 70 to 80 percent mortality without treatment. That is a real and substantial gain, and the strongest argument for offering the operation.

What to promise. The thorax enlarges, CT lung volumes rose and survival improves, but forced vital capacity fell from 34 to 27 percent predicted across follow-up. The operation buys survival and reduced ventilator dependence rather than normal lung function, and complications are frequent: migration in half the patients and an infection rate of 4.6 percent per procedure, across many procedures.

How far the numbers travel. This is a retrospective single-institution series of 24 patients using one device. The figures describe that programme rather than a general standard.