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Anticipation in progressive diaphyseal dysplasia
  1. Consulta de Genética, Hospital Pediátrico de Coimbra, and Serviço de Genética Médica, Faculdade de Medicina de Coimbra, Avenida Bissaya-Barreto, 3000 Coimbra, Portugal, hpcgen{at}

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    Editor—Progressive diaphyseal dysplasia (MIM 131300) is an autosomal dominant osteochondrodysplasia with late onset and marked variability in expression of clinical and radiological features.1 We have recently described a patient with this diagnosis and suggested the presence of anticipation,2 the tendency of a familial disorder to occur earlier in the younger than in the older generations of a family.3

    In order to assess whether this hypothesis were true, we examined 24 other people from the same family (fig 1) who were invited and agreed to participate. We excluded the proband and tried to avoid ascertainment bias by including in the study all family members who were alive in four generations. Although the diagnosis of progressive diaphyseal dysplasia had not been previously recorded in any of them, some family members had assigned to themselves the status of affected or unaffected. This was often discordant with the clinical and radiological data. It is also likely that people with bone complaints were more eager to consent to medical observation.

    Figure 1

    Pedigree showing 15 cases of progressive diaphyseal dysplasia in generations III and IV of one family. Only those personally examined are numbered and included in the statistical analysis.

    All family members were personally examined. The presence or absence and the age of onset of pain in the limbs, easy fatiguability, headache, poor appetite, and difficulty in running were recorded. Height, weight, and OFC were determined. Skull, spine, and limb morphology was examined and exophthalmos, muscle mass and strength, joint movement, tendon reflexes, and walking were assessed. Bone radiographic surveys, haemoglobin, white blood cell count, erythrocyte sedimentation rate, and serum alkaline phosphatase were performed.

    The diagnosis of progressive diaphyseal dysplasia was clinically and radiologically established in 15 family members of the proband (table 1). Five of these have been previously described.2

    Table 1

    Clinical, laboratory, and radiographic data from 15 patients with progressive diaphyseal dysplasia

    We were able to determine the age of onset of the disease in these 15 patients (table 1), five from generation III and 10 from generation IV. Age of onset of the disease was defined as that of the initial symptom. The earlier age of onset in the younger generation was statistically significant (table 2). A similar analysis applying the same criteria to the data previously described in another extended family with progressive diaphyseal dysplasia4 gave identical results (table 2). Other published pedigrees do not describe large families and often do not mention the age of onset of the disease.5-10. However, the available data, excluding once again the probands, is in accordance with the previous results (table2).

    Table 2

    Mean age of onset of progressive diaphyseal dysplasia in the older and younger generations in the family described here (family 1), the family reported by Naveh et al4 (family 2), and other pedigrees.5–10

    A previous suggestion that anticipation was enhanced in father to son transmission2 is not supported by these new data; the patient with the earliest age of onset and one of the most severely affected is a female (IV.12, fig 1, table 1), who inherited the disease from her mother.

    As has been previously pointed out, statistical anticipation without biological anticipation would occur if the disorder reduces fertility.3 However, the mean number of children in the family members of generation III is 2 for those that are healthy and 2.8 for those that are affected. The small number of people of generation IV who have already had children does not merit consideration.

    Another type of bias could be that some of the younger persons might be classed as unaffected but might develop the disease later. This would inevitably increase the mean age of onset as assessed in the younger generation. However, the reported ages of onset of progressive diaphyseal dysplasia are between 4 and 32 years and in 25 patients all but four had ages of onset younger than 20, the exceptions being the ages of 21, 25, 30, and 32 years old.2 4 In order to avoid this bias, we did not include the data on three persons, one of whom is affected, from generation V. The ages of the unaffected persons from generation IV are 16, 23, and 24 years.

    Although anticipation was only accepted as a true biological concept in the last decade, the list of conditions exhibiting it is growing rapidly.3 11 Most of them are neuropsychiatric diseases and trinucleotide repeat expansions are usually suggested to be the cause.

    This report suggests that anticipation occurs in progressive diaphyseal dysplasia and widens the disease spectrum of this concept to bone dysplasias. A dynamic mutation with trinucleotide repeat expansion may or may not be the cause of this osteochondrodysplasia of dense bone with unknown pathogenesis. The search for the molecular explanation of this and other rare genetic disorders that cause dense bones could disclose approaches to more common health problems such as osteoporosis.12


    This work was supported by the Comissão de Fomento da Investigação em Cuidados de Saúde, Ministério da Saúde, Portugal.


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