Genetic disorders of bone - An historical perspective.

Individuals with constitutional diseases of the skeleton attract attention because of their smaller size, because of deformities, and/or because of the disproportion between body parts. Individuals with achondroplasia, a common skeletal short stature condition, have short arms and legs, a head that is usually larger than normal, and a typical facial appearancewith a prominent forehead and a sunken nasal bridge. They are usually healthy (at least as children and young adults) and are said to bewitty. Although there is no scientific data to confirm the latter claim, their personal perspective on life may lead to particular insights. Perhaps for these reasons, individuals with achondroplasia (along with individuals with other deformities) have often played special social roles in human societies – from being members of royal courts, to participating in circus shows or other public entertainments. Shortstatured individuals have also fueled the fantasy ofwriters, and indirectly of the public, like in Swift's “Gulliver's Travels”. The misconception of a separate race (such that of the Lilliputians) was frequent in the past and still lingers even in the present time. Around the turn of the twentieth century, in Paris (France), there existed an institution called “le jardin d'acclimatation” where short-statured individuals (with diverse diagnoses ranging from achondroplasia to growth hormone deficiency) were offered a place to live; perhaps an act of charity, but certainly also one of segregation [1]. The halo around individuals with short stature, deformity or disproportion has thus stood in the way of a scientific or medical approach to the definition of their conditions; so much so, that still in 1886, when the French physician Joseph Marie Jules Parrot described a short-limb patient and coined the name “achondroplasie”, he believed that achondroplasia was a manifestation of rickets, and that rickets itself was a consequence of hereditary syphilis [2]. As late as in 1912, the Dutch orthopaedist Murk Jansen supported the concept that achondroplasia was caused by “amnionpressure” [3]. Another popular belief was that achondroplasia was caused by “weak semen” (this latter belief may have been prompted by the observation that achondroplasia individuals are often the youngest sibs – in accordance with the paternal age effect on de novo FGFR3mutations). The strong aura surrounding little people, or dwarfs, or Lilliputians, is surprising and in contrast with the notion that the genetic difference between an individual with achondroplasia (or pseudoachondroplasia, or spondylo-epiphyseal dysplasia congenita) and a normal-stature individual is a single nucleotide at heterozygosity!