Dwarfism with osteosclerosis. Congenital sclerosing
The disease is named after the French painter Henri de
Toulouse-Lautrec, since Maroteaux and Lamy, the first describers of
pyknodysostosis, concluded from complaints found in letters to his friends
and relatives that he was suffering from pyknodysostosis, although this has
been the subject of vivid debate.
NB: Some authors consider pyknodysostosis synonymous with Maroteaux-Lamy
Syndrome. Although it is true that these two French physicians were the
first to describe and name pyknodysostosis, the name Maroteaux-Lamy Syndrome
(which is used for at least four different syndromes) most often refers to
mucopolysaccharidosis type VI.
Nearly 150 cases have been reported.
Autosomal recessive with parental
consanguinity being a known risk factor. The mutation has been mapped to
Pyknodysostosis results from a gene defect
affecting cathepsin K, the only lysosomal cysteine protease with high
expression in osteoclasts. This fact, in combination with the highest type I
collagenolytic, elastinolytic, and gelatinolytic activities of all cysteine
proteases, suggests that cathepsin K plays a key function in bone matrix
resorption. Pyknodysostosis can therefore be considered a skeletal dysplasia
secondary to cathepsin K deficiency, which makes it a lysosomal disease. The
principal site of action for cathepsin K is the subosteoclastic space into
which the enzyme is secreted for bone matrix degradation. The process of
bone resorption is characterized by solubilization of inorganic mineral and
subsequent proteolytic degradation of the organic matrix, primarily type I
collagen. The osteoclast number in pyknodysostosis is normal, but the area
of demineralization surrounding each individual osteoclast is enlarged.
Ultrastructural examination of these osteoclasts shows big, abnormal
intracytoplasmic vacuoles filled with collagen fibrils from bone. It seems
therefore that step one (demineralization) of normal bone resorption is
intact, whereas step two (degradation of the organic matrix) is defective.
The inadequate resorption and remodeling of bones in pyknodysostosis leads
to abnormally dense and brittle bones.
Clinical features and radiologic appearance of bones
(osteosclerosis, increased thickness of the trabecular bone as a result of
Short stature (adult height usually less than 150
cm [59 inches] for males) caused by short limbs, large, disproportionate
head with frontal and occipital bossing, delayed suture closure and
prolonged persistence of fontanels, and lack of frontal sinuses. The midface
is hypoplastic with a prominent nose, grooved palate, and hypoplasia of the
mandibular angles, making these patients prone to obstructive sleep apnea.
The clavicles are affected by partial or complete aplasia. Progressive
acro-osteolytic dysplasia affects the distal phalanges of fingers and toes
with dystrophic, flattened, grooved, and brittle nails. Spondylolysis may
occur at the L4-L5 level and scoliosis is a common finding. Dentition
anomalies include delayed eruption and irregularities of the permanent
teeth, with or without partial anodontia. The brittle bone results in
fractures secondary to minimal trauma and the sometimes blue appearance of
the sclera may initially result ...