HORMONES 2002, 1(4):260-262
DOI: 10.14310/horm.2002.1177
Historical Note
Pycnodysostosis: Toulouse-Lautrec's and Aesop's disease?
Christos S. Bartsocas

Department of Pediatrics, Faculty of Nursing, University of Athens, Athens, Greece

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Among the several causes of short stature is pycnodysostosis, also known as "Toulouse-Lautrec's disease".1,2 Robert Weismann-Netter is credited with the first description of the disorder which later became known as pycnodysostosis.3 Only a few, however, know that pycnodysostosis was also p¦ssibly Aesop's disease4.


Henri de Toulouse-Lautrec (1864-1901) was initially thought to have had osteogenesis imperfecta. However, following the description of pycnodysostosis as a new genetic skeletal dysplasia, Maroteaux and Lamy5 concluded that this was Toulouse-Lautrec's affliction (Figure1). He, in fact, presented all the clinical features suggestive of this diagnosis, in addition to parental consanguinity. Toulouse-Lautrec had bone fragility leading to fractures with minor trauma, a receding chin and possibly open fontanelles, explaining the artist's insistence on wearing a hat most of the time2.

Figure 1. Toulouse-Lautrec (1864-1901). Printed by permission of Mosby Co and Dr. V.A. McKusick.

Pycnodysostosis was often confused with cleidocranial dysplasia. Both disorders present with multiple Wormian bones and delayed closure of the cranial sutures, particularly the lambdoid and the sagittal. The ramus of the mandible is short and the angle lost, so that this bone is essentially straight and the jaw receding. Bones are fragile and frequent fractures may occur.


Of striking resemblance to Henri de Toulouse-Lautrec (Figure 1) is the representation of Aesop on a 5th century B.C. cylix, presently displayed in the Vatican Museum (Figure 2). A freed slave from Samos, Aesop lived in the 6th century B.C. He was endowed with abundant discernment and wisdom and boasted a rich fund of old myths as well creating his own myths. His ugliness was reported by several ancient authors. Characteristic is the 450 B.C. cylix, now in the Vatican museum, where Aesop is depicted talking to a fox. H.J. Kaufmann (in a letter to the author dated Jan.16, 1973) speculatively suggested that Aesop's characteristics on the black-figured cylix bore the facial features of pycnodysostosis4.

Figure 2. Aesop (6th century b.C.) as he appears on a 5th century b.C. cylix (Vatican Museum). Printed by permission of the Vatican Museum (Monumenti Musei e Gallerie Pontificie).

Aesop is the world-renowned author of a large number of fables, i.e. short narratives making an edifying or cautionary point and often employing as characters animals that speak and act like human beings. The known facts about Aesop are that he was a Greek slave sold by Xanthus to Iadmon, a Samian, later murdered by Delphic priests because he denounced their greed (Aristophanes, Vespae6 1446-8 ). Although a biography of Aesop may have existed already in the 5th century BC, a number of mythical biographies followed much later during Roman times. What has come down to us concerning him are numerous anecdotes about Aesop and his Samian master, the sage Xanthus, and accounts of Aesop's career as adviser in the court of the Lydian King Croesus.


Clinical data

Patients with pycnodysostosis (OMIM:265800) manifest skull deformity, short stature usually reaching a height of a less than 150cm, craniofacial disproportion due to underdeveloped facial bones and a prominence of the frontal and parietal bones, obtuse angle of the mandible, widening of the cranial sutures, persistence of the fontanels and delayed exfoliation of deciduous teeth. Permanent teeth appear on schedule but may be malformed or malpositioned. Other features include a narrow, grooved palate. The clavicles are dysplastic with partial aplasia of the acromial ends. The terminal phalanges of the digits are short with acroosteolysis and wrinkling of the skin over the dorsal surfaces distally, and flattened nails. Radiographic examination shows an increased density of bone of the entire skeleton, osteosclerosis, delayed closure of cranial sutures, wormian bones, open fontanels and hypoplastic facial bones and sinuses. An obtuse mandibular angle and dental irregularities are present on skull films. There is tapering of the distal phalanges with absence of the ungual tufts and segmentation anomalies of the vertebrae. Long bone deformities due to fractures may be present7.

Endocrine data

Soliman et al8 reported defective growth hormone secretion in response to provocation and low IGF-1 concentration in 5 out of 6 patients with pycnodysostosis. Growth hormone replacement in 2 boys succeeded in increasing IGF-1 concentration and improved the linear growth in these children. Normal sexual development, fertility, serum TSH, T4, cortisol, gonadotropins and testosterone were evidence against abnormalities of the hypothalamic-pituitary-gonadal axis.

Genetic data

By linkage analysis, Gelb and coworkers9 demonstrated, in an inbred Arab kindred reported previously by Edelson and co-workers10, that the pycnodysostosis gene (PYCD) is located on chromosome 1q21, also confirmed by Polymeropoulos11 Thirteen of 16 affected individuals were homozygous for the D1S305 allele, which had been previously assigned to the pericentromeric region of chromosome 1. One year later, Gelb and co-workers12, recognizing the fact that cathepsin K, a cysteine protease gene which is highly expressed in osteoclasts, maps in the same region as pycnodysostosis, studied possible mutations of the cathepsin K gene as causes of pycnodysostosis.

Pycnodysostosis patients had nonsense, missense and stop codon mutations of the gene. No immunologically detectable protein was found. A missense mutation ala277 to val inherited only from the father was identified by Gelb and coworkers13 as uniparental disomy for chromosome 1 in a patient with the features of pycnodysostosis. Therefore, Gelb et al12 suggested that cathepsin K, being a major protease in bone resorption, a process mediated by osteoclasts, is characterized by solubilization of inorganic mineral and subsequent degradation of organic matrix, primarily type 1 collagen.

In fact, in pycnodysostosis, the number of osteoclasts is normal but the region of demineralized bone surrounding them is increased. Large, abnormal cytoplasmic vacuoles containing bone collagen fibrils were observed by ultrastructural examination. The conclusion is that although pycnodysostosis osteoclasts function normally in demineralizing bone, they do not adequately degrade the organic matrix.


Lesions on the human genome are the causes of the 4000 or so recognized inherited diseases. The incidence of genetic diseases in the population may indicate the duration of existence of the mutated genes in humanity. Very ancient mutations have the opportunity timewise to spread widely through population migrations. Therefore, the scarcity of the pycnodysostosis gene could indicate a relatively more recent mutation. Nonetheless, it is interesting to note that the resemblance of Aesop's characteristics to those of pycnodysostosis may support the speculation about the existence of the pycnodysostosis gene in ancient Greece.

1. McKusick VA 1972 Heritable Disorders of Connective Tissue , C.V. Mosby Company: St. Louis; pp, 820-821.
2. Maroteaux P, Lamy M, 1965 The malady of Toulouse-Lautrec. JAMA 191: 715- 717.
3. Beighton P, Beighton G 1986 The Man Behind the Syndrome. Spinger-Verlag; p. 231.
4. Bartsocas CS, 1982 An Introduction to Ancient Greek Genetics and Skeletal Dysplasias. Progress in Clinical & Biological Research 104: 3-13.
5. Maroteaux P, Lamy M, 1962 La pycnodysostose. Presse Med 70: 999-1002.
6. Hornblower S, Spawforth T 2000 Who's Who in the Classical World. Oxford University Press: Oxford; pp, 7-8.
7. Bergsma D 1979 Birth Defects Compendium, National Foundation _ March of Dimes, Alan R. Liss, Inc. New York, N.Y
8. Soliman AT, Rajab A, Al Salmi I, Darwish A, Asfour M, 1996 Defective growth hormone secretion in children with pycnodysostosis and improved linear growth after growth hormone treatment. Arch Dis Childh 75: 242-244.
9. Gelb BD, Edelson JG, Desnick RJ, 1995 Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping. Nature Genet 11: 235-237.
10. Edelson JG, Obad S, Geiger R, On A, Arthul HJ, 1992 Pycnodysostosis: orthopedic aspects with a description of 14 new cases. Clin Orthop 280: 263-276.
11. Polymeropoulos MH, Ortiz de Luna RI, Ide SE, Torres R, Rubenstein J, Francomano CA, 1995 The gene for pycnodysostosis maps to human chromosome 1cen-q21. Nature Genet 10: 238-239.
12. Gelb BD, Shi G-P, Chapman HA, Desnick RJ, 1996 Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273: 1236-1238.
13. Gelb BD, Willner JD, Cunn TM, Kardon NB, Berloes A, Poncin J, Desnick RJ, 1998 Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis. Amer J Hum Genet 62: 848-854.

Address correspondence and requests for reprints to:
CS Bartsocas, P.O. Box 17177, GR-10024 Athens, Greece,
Phone: +32.10.7709316, Fax: + 32.10. 3627777,
e-mail: cbartsok@cc.uoa.gr.

Received 11-06-02, Revised 20-06-02, Accepted 01-07-02