Throughout our lives, the skeleton undergoes constant remodeling. Two types of cells are responsible for this process: osteoclasts break down old bone, while osteoblasts lay down new mineralized bone matrix. The skeleton remains in a state of dynamic balance between bone formation and resorption, and when the delicate balance of these processes becomes upset for any reason, the consequences may be serious, as in the case of osteoporosis.
A number of genetic disorders affecting the skeleton result in either weakened or abnormally thickened bone. Pycnodysostosis is a rare disorder of osteoclast dysfunction in which the bones don't grow normally and are unusually thick, but also fragile and prone to fractures. It was first described by Maroteaux and Lamy in 1962. It is also known as Toulouse-Lautrec syndrome, since it is suspected that the famous French painter Henri de Toulouse-Lautrec (1864-1901) may have suffered from this disorder. It consistently causes short stature. The height of adult males with pycnodysostosis is less than 150 cm (59 inches, or 4 feet 11 inches). Adult females with the syndrome are even shorter.
Henri de Toulouse-Lautrec. Note his short stature and short legs. Image from: Wikipedia.
Pycnodysostosis is inherited in an autosomal recessive manner, meaning that it occurs with an equal frequency in males and in females, and two copies of the defective gene (located on chromosome 1q21 and identified in 1996) are required to cause symptoms. Deficiency of cathepsin K, a cysteine protease (an enzyme that cleaves proteins) in osteoclasts, is known to cause this condition. Cathepsin K became a much sought-after drug target in osteoporosis after the etiology of pycnodysostosis was discovered.
Pycnodysostosis causes abnormally dense bones, short and stubby fingers, and delays the normal closure of the connections of the skull bones in infancy, so that the "soft spot" (fontanelle) on top of the head remains open. People suffering from this syndrome have brittle bones which easily break, especially in the legs and feet. Patients usually present with frequent fractures even after minor trauma.
Other abnormalities involve the head and face, teeth, collarbones, skin, and nails. The front and back of the head are prominent, while the jaw can be small. The palate is narrow and grooved. Mouth breathing and snoring are common. The baby teeth are late coming in and may be lost much later than usual. The permanent teeth can also be slow to appear and are commonly irregular; some may be missing altogether (hypodontia). The collarbones are often underdeveloped and malformed. The skin over the back of the fingers is very wrinkled, and the nails are flat and grooved.
Pycnodysostosis also causes problems that may become evident with time. Aside from the broken bones, the last bones of the fingers and the collarbone can undergo slow progressive deterioration. Vertebral defects may permit the spine to curve laterally resulting in scoliosis. The tooth problems often require orthodontic care, and dental caries is common.
The frequency of pycnodysostosis is estimated as only 1,7 per 1 million births.
Puri et al. describe the case of a 34-year-old, 45-kg female patient from Agra, India who suffered from pycnodysostosis and successfully underwent femur plating under spinal anesthesia (general anesthesia was contraindicated because of anticipated difficulties in intubation, due to a high arched palate, an underdeveloped upper jaw and a large tongue). The patient had a past history of spontaneous fractures which were managed conservatively. Her mental and sexual developments were normal. She had skeletal abnormalities including the characteristic short stature, particularly limbs, short broad hands, bowed legs and chest deformities. The patient's height was 130 cm, her upper limb to lower limb ratio was 60/76, and arm span was 128 cm. Her one elder brother also showed similar symptoms.
X-ray of the legs showing bowed long bones in a female patient with pycnodysostosis.
Image from: Puri et al. (2013)
And now back to the unfortunate French painter. In his early teens, Henri de Toulouse-Lautrec fractured first one thigh bone, then the other, and the breaks never healed properly. His leg bones ceased to grow; he developed an adult-sized torso with very short legs. Mocked for his physical appearance, he drowned his sorrows in alcohol, which contributed to his early death at 36. It is, however, unclear whether he actually suffered from pycnodysostosis or perhaps from another genetic disorder, such as osteogenesis imperfecta. Had he lived in modern times, his fractures could be managed more easily, and molecular diagnostics would identify the faulty gene.
Puri R, Saxena A, Mittal A, Arshad Z, Dwivedi Y, Chand T, Mittal A, Agrawal A, Prakash J, Pilendran S. (2013) Pycnodysostosis: An Anaesthetic Approach to This Rare Genetic Disorder. Case Rep Anesthesiol. 2013: 716756.
Wikipedia: Henri de Toulouse-Lautrec.