Pycnodysostosis: dense, brittle bones and short stature explained

NORD, the US National Organization for Rare Disorders, describes pycnodysostosis as a rare genetic disorder characterised by distinctive facial features and skeletal malformations. The name refers to dense (pycno) bone. Although the bone is more dense than usual, it is also more brittle, so the disorder is a disease of bone quality rather than bone quantity.

NORD places it among lysosomal storage disorders, and notes it is similar to osteopetrosis, another condition of abnormally dense bones that are brittle and prone to fracture, so the two are sometimes discussed together in the medical literature. A systematic review of orthopaedic treatment describes it as a rare autosomal recessive lysosomal storage disorder of the bone with sclerotic and fragile bone, shortened distal phalanges (the end bones of the fingers) and loss of the normal angle of the jaw.

No UK patient leaflet specific to pycnodysostosis was available when this page was prepared, so the information here is drawn from NORD and a published review. A clinical geneticist or a metabolic bone specialist is the right source for personal advice.

NORD says pycnodysostosis is caused by a change (mutation) in the cathepsin K (CTSK) gene, which produces an enzyme whose job is to break down certain substances in the body, including bone matrix proteins and certain types of collagen. The published review explains that cathepsin K is highly expressed in osteoclasts, the cells that remodel bone, and that without it the bone mineral can be removed but the organic matrix is not adequately degraded.

It is inherited in an autosomal recessive manner. NORD explains that a person must inherit two copies of the abnormal gene, one from each parent, and that carrier parents usually do not show symptoms. For two carrier parents, NORD gives the risk of an affected child as 25% with each pregnancy, and 50% that a child will be a carrier like the parents. In some populations it has occurred in families where the parents are closely related, because close relatives are more likely to carry the same abnormal gene.

NORD stresses that affected individuals may not have all the symptoms, and that the small number of known cases means much about the disorder is not fully understood. The features it lists include the following.

• In infancy, delayed closure of the skull sutures and soft spots, and a skull that is often larger than normal.

• Distinctive facial features: a prominent forehead, a pointed nose, a highly arched palate, prominent eyes with bluish whites, and a small jaw.

• Dental problems: delayed eruption of baby teeth and then persistence of them, delayed eruption of permanent teeth, and sometimes missing teeth.

• Malformation of the collarbone and breakdown of bone in the tips of the fingers and toes, so that the fingers may be small and stubby and the nails absent or small.

• Repeated fractures, most commonly in the legs, and sometimes curvature of the spine or stress fractures of the lower spine.

• Breathing problems related to chest shape or airway, including snoring and sleep apnoea, which can sometimes be severe.

• Growth hormone deficiency and low IGF-1 in some individuals, contributing to short stature.

NORD says diagnosis is based on identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and X-ray studies, which can show many of the characteristic bone changes. Molecular genetic testing can confirm the diagnosis by detecting mutations in the CTSK gene, but is available only as a diagnostic service at specialised laboratories.

NORD adds that the disorder may go undiagnosed or misdiagnosed, which is one reason the true frequency is hard to determine, and it lists osteopetrosis and cleidocranial dysplasia among disorders with similar symptoms that need to be distinguished.

NORD says treatment is directed towards the specific symptoms that are apparent in an individual and may require the coordinated efforts of a team: paediatricians, bone specialists, orthopaedic surgeons, endocrinologists, dental specialists and other professionals. Genetic counselling may benefit affected individuals and their families, and psychosocial support for the whole family is described as essential.

There are no standardised treatment protocols or guidelines. NORD says that individuals will need orthopaedic care when fractures occur, that there are no standard guidelines on the best method of fracture treatment, that specialised dental care should be provided and that craniofacial surgery may be warranted. It also notes that some children have been treated with growth hormone because of short stature, with initial results showing positive effects on final adult height.

The published review notes that fractures in pycnodysostosis have a high propensity to occur spontaneously or with low trauma, with significant delay in healing, and that treatment of orthopaedic fractures is a controversial topic in the literature.

NORD says pycnodysostosis can potentially complicate the use of anaesthesia in some people because of abnormalities affecting the jaw and the roof of the mouth, and that affected individuals should be evaluated before undergoing procedures that require anaesthesia. In practice this means telling the surgical and anaesthetic team about the diagnosis well in advance of any planned operation or dental procedure.

NORD says the disorder is not believed to be life-threatening and that intelligence is not affected, but that severity, including the frequency of fractures, final adult height and specific symptoms, varies greatly among affected individuals. Day-to-day care focuses on preventing fractures where possible, managing dental and airway issues, supporting growth and providing psychological and practical support.