Kniest Dysplasia

One collagen, many tissues. Kniest dysplasia results from an autosomal dominant mutation in COL2A1, the gene for type II collagen. Type II collagen is the dominant collagen of cartilage, the vitreous of the eye, the nucleus pulposus and the inner ear, and that single shared collagen explains why the disorder combines a skeletal phenotype with eye and ear disease.

The skeleton. Kniest produces a disproportionate short-trunk dwarfism with enlarged, stiff joints, especially the knees, and contractures. Lordosis or kyphoscoliosis develops in childhood, and the kyphoscoliosis is progressive. A flat midface with a depressed nasal bridge and often a cleft palate complete the picture. Histologically the cartilage has a 'Swiss-cheese' appearance from its large chondrocyte lacunae.

The radiographs. The long bones are 'dumbbell'-shaped, with broad metaphyses, and the spine shows platyspondyly with coronal vertebral clefts.

View larger

The eyes and ears. High myopia with vitreoretinal degeneration carries a significant risk of retinal detachment, and there is sensorineural and/or conductive hearing loss. Eye and ear assessment is therefore an essential part of care.

The spectrum. Kniest dysplasia is one of the type II collagenopathies, which run in decreasing severity:

1. Achondrogenesis type II and hypochondrogenesis, often lethal
2. Spondyloepiphyseal dysplasia congenita (SEDC)
3. Kniest dysplasia
4. Stickler syndrome, the mildest

Radiologically Kniest belongs to the 'Kniest-Stickler' group, characterised by dumbbell tubular-bone deformities.

Abnormal type II collagen, autosomal dominant inheritance and 'Swiss-cheese' cartilage are linked by one mechanism, the dominant-negative effect, and it is worth being able to explain it.

The mutations. Kniest-causing variants cluster in the part of COL2A1 that encodes the triple-helical domain of pro-alpha-1(II) collagen. They are characteristically in-frame: small deletions, or splice-site mutations that cause exon skipping. The result is a shortened alpha chain that is still incorporated into the molecule, rather than an absent one.

Why dominant, not recessive. Type II collagen is a homotrimer of three alpha-1(II) chains, so even one mutant chain per molecule corrupts the triple helix. A single abnormal allele therefore poisons the assembly of collagen made from the normal allele as well, the dominant-negative or "protein suicide" effect. This is why a heterozygous mutation produces disease, whereas loss-of-function variants can give the milder, haploinsufficiency-type Stickler phenotype.

From molecule to histology. Mis-assembled type II collagen disrupts the cartilage fibrillar network. The growth-plate and epiphyseal cartilage is structurally weak and laden with dilated chondrocyte lacunae, the 'Swiss-cheese' cartilage, and this translates into disordered enchondral growth (broad metaphyses, dumbbell bones, platyspondyly) and the soft, enlarged, stiff joints. The same defective collagen in the vitreous and inner ear produces the myopia, retinal detachment and hearing loss. Type II collagen biology is developed further in Proteoglycans & Collagen and Skeletal Dysplasias.

The examinable skill is distinguishing Kniest from its spectrum siblings, the Stickler and SEDC groups. All three are COL2A1 collagenopathies that share the eye (myopia, retinal detachment) and ear (hearing loss) features, so they separate on stature, joints and the radiographic pattern.

Each of these is developed separately in skeletal dysplasias, Stickler syndrome, the mucopolysaccharidoses, diastrophic dysplasia and short-rib thoracic dysplasias including metatropic.

View larger

View larger

There is no cure, so management is supportive and multidisciplinary:

• Ophthalmology. Regular, lifelong review for high myopia and vitreoretinal degeneration, to detect and treat, or prevent, retinal detachment, a major preventable cause of visual loss.
• Audiology. Monitor and manage the sensorineural and/or conductive hearing loss.
• Orthopaedics. Manage scoliosis and joint contractures, anticipate early osteoarthritis and address limb and joint problems. Assess and protect the cervical spine: like other type II collagenopathies, Kniest can involve the upper cervical spine with odontoid/atlantoaxial instability.
• Airway and anaesthesia. Plan the airway and protect the neck, as set out below.
• Other. Cleft palate repair, respiratory monitoring, and genetic counselling for the autosomal dominant inheritance.

Screening the cervical spine: what to request and what the numbers mean

"Assess the cervical spine before any procedure" needs a method attached, because this is the one instruction whose omission can cost a cord.

What to request. Lateral cervical radiographs in flexion and extension, supervised and taken actively by the child rather than forced, plus an open-mouth odontoid view. MRI is added where there are neurological symptoms, an abnormal radiographic measurement, or a plan for major surgery, since it shows the cord itself and any signal change. Two measurements matter:

• Atlantodens interval (ADI), from the anterior arch of C1 to the front of the dens. Normal is under 3 mm in an adult and under 5 mm in a child; more than 5 mm indicates incompetence of the restraint between C1 and the dens.
• Space available for the cord (SAC, or posterior ADI), from the back of the dens to the anterior edge of the posterior C1 arch. Under 14 mm means the cord is at risk. This is the more important number, because it measures the space the cord actually has.

Steel's rule of thirds (a third dens, a third cord, a third spare) is the reason a large ADI is tolerated until the spare third is used up.

When to stabilise. Neurological symptoms or myelopathy are an absolute indication. An ADI over 10 mm, a SAC under 14 mm or documented progressive instability are relative ones, and posterior C1-C2 fusion is the standard operation. The thresholds and technique are set out in Atlantoaxial Instability.

Ligament or bone. In Down syndrome the instability is ligamentous: a lax transverse ligament with a normal dens. In the skeletal dysplasias it is usually osseous, from a hypoplastic or absent odontoid or an os odontoideum, so the restraint fails because there is nothing for the ligament to hold. Odontoid hypoplasia does not improve with growth and is not excluded by a normal-looking neutral lateral film, so it has to be looked for.

Planning the anaesthetic

Midface hypoplasia, cleft palate and possible cervical instability make airway management and anaesthesia hazardous. The airway and the neck are separate problems that arrive together, and the plan follows from that:

• Anticipate a difficult airway from the midface hypoplasia, a repaired or unrepaired cleft palate, a short neck and restricted mouth opening. Plan for it rather than discovering it, with a senior anaesthetist and difficult-airway equipment available.
• Protect the neck throughout. Avoid forced extension for laryngoscopy and during positioning and transfer. An awake or videolaryngoscopic technique with manual in-line stabilisation is preferable where instability is documented or unassessed.
• Expect restrictive lung physiology from the short trunk and kyphoscoliosis. It lowers the threshold for post-operative respiratory support and makes prolonged procedures less well tolerated.
• Position carefully. Stiff, enlarged joints with fixed contractures do not tolerate being forced into a standard position, and the same collagen defect makes the skin and soft tissues vulnerable to pressure.