Progressive Diaphyseal Dysplasia:A Three-Generation Family With MarkedlyVariable Expressivity

Jorge M. Saraiva*Consulta de Genetica, Hospital Pediatrico de Coimbra, Coimbra, Portugal

Progressive diaphyseal dysplasia was foundin a 3-generation family including 18 af-fected individuals. We describe the clinicaland radiographic manifestations in 6 of 18patients with this autosomal-dominant bonedysplasia and the good symptomatic re-sponse to corticosteroid treatment in one ofthese. The variability of manifestations ofthe disease in this family and in others pre-viously described seems to depend on thesex of the patient and the parental origin ofthe mutation. The patients with more severesymptoms are males who inherited an alleleof paternal origin. We suggest that the pro-gressive diaphyseal dysplasia gene has afunction in endochondral bone formationand that its mutation is a dynamic one withrepeat expansion enhanced in father-to-sontransmission. Am. J. Med. Genet. 71:348–352,1997. © 1997 Wiley-Liss, Inc.

KEY WORDS: progressive diaphyseal dys-plasia; Camurati-Engelmanndisease; expression variabil-ity; gametic imprinting; an-ticipation

INTRODUCTION

Progressive diaphyseal dysplasia (PDD) or Camu-rati-Englemann disease is an autosomal-dominantbone dysplasia (MIM 131300) [McKusick, 1994]. It wasfirst described by Cockayne [1920], followed by Camu-rati [1922] and Engelmann [1929] 7 years later.

Over 100 cases of PDD have been published [Navehet al., 1984], and its prevalence is under 1 × 106

[Wynne-Davies et al., 1985].Manifestations are variable and may start as early

as age 4 months, often before the age 10 years, and

almost always before age 30 years. Presenting mani-festations usually include limb pain, reduced musclemass, weakness, and awkward gait. Radiographicchanges include basilar skull sclerosis, periosteal andendosteal sclerosis, and thickening of the long bone di-aphyses [Naveh et al., 1984]. A good response to steroidtherapy was reported in at least 16 patients [Allen etal., 1970; Naveh et al., 1985; Royer et al., 1967].

The hereditary nature of PDD was first suggested byCamurati [1922], and several large families have beenreported [Naveh et al., 1984]. The wide range of sever-ity of the disease is well-recognized but still unex-plained [Sparkes and Graham, 1972].

We report on a Portuguese family with 18 affectedindividuals in 3 generations, and we discuss possibleexplanations for the marked variability in expressionof the disease.

CLINICAL REPORT

The propositus (IV-3 in Fig. 1) was the third child ofnonconsanguineous Portuguese parents (mother age49, father age 51). He was born at 39 weeks of gestationfollowing an uncomplicated pregnancy; birth lengthwas 50 cm (50th centile), weight 3,400 g (75th centile),and head circumference (OFC) 35 cm (75th centile).

At age 4 years he complained of pain in the lowerlimbs and easy tiredness. Symptoms became more se-vere during the following years.

He was presented to us at age 9 years with severecrippling. Intelligence and stature were normal (height131 cm, 50th centile, and OFC 50.5 cm, 10th centile),but he had poor appetite, severe pain in the lowerlimbs, easy weariness, and waddling gait; he refused torun. He had reduced muscle mass (weight was 21,700g, <5th centile), gena valga, and tightly stretched skinover thick and prominent tibiae (Fig. 2).

A bone radiographic survey showed sclerosis of thebase of the skull (Fig. 3) and symmetrical sclerosis andthickness of the diaphyseal cortices of the long bones,as shown in both femora (Fig. 4). Spine, ribs, hands,and feet were not affected.

Hemoglobin was 13.5 g/dl, white blood cell count10,800 × 109/l, erythrocyte sedimentation rate 35 mm/1hr, and alkaline phosphatase 265 U/l. Karyotype wasnormal (46,XY).

*Correspondence to: Dr. Jorge M. Saraiva, Consulta de Ge-netica, Hospital Pediatrico de Coimbra, Avenida Bissaya-Barreto,3000 Coimbra, Portugal.

Received 17 September 1996; Accepted 4 February 1997

American Journal of Medical Genetics 71:348–352 (1997)

© 1997 Wiley-Liss, Inc.

A diagnosis of PDD was made and a course of pred-nisone was started with an initial dose of 1 mg/kg/dayon an alternate-morning schedule. The dose was ta-pered off to 0.3 mg/kg/day with disappearance of limbpain, improvement of fatigue, and ability to run, butwithout change in appetite or the waddling gait, evenafter 14 months of treatment.

The pedigree is given in Figure 1. We were able toexamine 5 other affected individuals (III-1, III-4, IV-1,IV-9, and IV-10 in Fig. 1). The symptoms, signs, andlaboratory and radiographic investigations of the 6 pa-tients tested by us are shown in Table I and in Figures3–8.

A history of symptoms compatible with this disorderwas obtained in another 12 individuals (II-1, II-3, II-5,II-6, III-7, III-8, III-10, IV-12, IV-16, IV-17, IV-18, andIV-20 in Fig. 1).

DISCUSSION

In the differential diagnosis of PDD, other sclerosingbone dysplasias with normal stature should be consid-ered: osteopetrosis is a generalized sclerotic process;endosteal hyperostosis often presents with enlarge-ment of face, particularly the mandible and forehead;metaphyseal dysplasia shows gross metaphyseal ex-pansion only; in craniometaphyseal dysplasia there iscranial hyperostosis and metaphyseal undermodellingin spite of the fact that in early childhood it is thediaphysis that shows thickening and sclerosis; fronto-metaphyseal dysplasia shows patchy sclerosis of thewhole skull and metaphyseal flare; in craniodiaphysealdysplasia the outstanding differential trait is the mas-sive involvement of the facial bones and cranium; andPaget disease is asymmetrical.

In PDD the basic lesion involves sclerotic thickeningof the base of the cranium and the diaphyseal cortex ofthe long bones, principally the humeri, radii, ulnae,femora, tibiae, and fibulae. Morphological bone exami-

Fig. 2. Propositus (IV-3 in Fig. 1) with gena valga and thick and promi-nent tibiae.

Fig. 3. Lateral view of skull (IV-3 in Fig. 1), showing marked severesclerosis of base of skull. There is no pneumatization of the frontal sinuses.

Fig. 1. Pedigree showing 5 generations of one family with 18 cases of progressive diaphyseal dysplasia.

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nation shows rapid bone formation with woven osteoidand lack of Haversian system development [Wirth etal., 1982], but this aspect was said to be normal inanother bone biopsy [Yoshioka et al., 1980]. The distri-

bution of the bone involvement suggests that a goodcandidate gene for this autosomal-dominant diseaseshould have a function in endochondral bone formationand not in intramembranous bone formation.

Muscular atrophy and weakness have been noted inmany patients with PDD, and the muscular changeshave been shown by biopsy to be selective atrophy oftype II fibers without any degenerative change[Yoshioka et al., 1980]; decreased muscle carnitine con-tent was described once [Bye et al., 1988].

In PDD the sclerotic changes of the base of the skullmay lead to narrowing of the cranial foramina and cra-nial nerve compression, as the narrowing of the med-ullary canals may explain the occasional anemia. Noneof these anomalies was found in our patients, and inone of them (IV-3 in Fig. 1) the beneficial effects ofcorticosteroids were demonstrated once again. Cortico-steroids appear to stimulate osteoclasis and decreaselamellar bone deposition, and to provide radiologicalimprovement [Minford et al., 1981] and relief of crip-pling symptoms [Naveh et al., 1985]; in our patientonly the latter was seen. Surgery may be needed toalleviate cranial nerve compression [Yen et al., 1978]and to correct bone deformities [Clawson and Loop,1964]. This is being considered in patient IV-3 (Fig. 1)due to the worsening of his gena valga.

The marked variability in expression remains unex-plained. Even the clinical and radiological manifesta-tions of the disease may lack correlation [Griffiths,1956; Hundley and Wilson, 1973], as seen in the pa-tients described here. In spite of the fact that the boneinvolvement is much more severe in patient IV-1 (Fig.6) than in his brother IV-3, the latter was the patientwith more severe clinical manifestations of the disease(Table I). The symptoms can be severe early on, andthere can be spontaneous remission, but the past his-tory of these patients was in accordance with their pre-sent status.

Variability of expression of an autosomal-dominanttrait can be explained above all on the basis of epige-netic/epistatic factors, but also by sex-limitation, ga-metic imprinting, or dynamic mutations inducing an-ticipation. In this pedigree it is likely that one of thegreat-grandparents of the propositus (I-1 or I-2 in Fig.1) was affected, the possibility of gonadal mosaicismbeing remote. The greater expression of the disease ina boy (IV-3 in Fig. 1) who inherited it from the fatherwould most likely be due to bias of ascertainment.

TABLE I. Clinical, Laboratory, and Radiographic Data From 6 Patients With Progressive Diaphyseal Dysplasia*

Patient III-1 IV-1 IV-3 III-4 IV-9 IV-10

Age at onset of symptoms (year) 20 8 4 15 18 13Age at examination (year) 51 23 9 42 20 16Pain in limbs PMi PMo PS PMi A AEasy fatigability A PMo PS PMi A PMiHeadache A A A PMi PMi APoor appetite A A PS PMi A APoor muscle mass A A PS A A AWaddling gait A PMo PS A A ARadiographic bone changes PMo PS PMo PMo PMi PMiHemoglobin (g/dl) 14.9 13.3 13.5 12.9 13.9 14.7Erythrocyte sedimentation rate (mm/1 hr) 1 6 35 3 10 4Alkaline phosphatase (U/l) 81 203 265 24 46 71

*III-1, III-4, IV-1, IV-3, IV-9, and IV-10 in Figure 1. P, present; A, absent; S, severe; Mo, moderate; Mi, mild.

Fig. 4. Anteroposterior view of both femora (IV-3 in Fig. 1), showingdiaphyses widened and undermodelled and with irregular cortical thick-ening.

350 Saraiva

However, the mean age of onset of PDD in the familydescribed here, excluding the propositus, was 18 yearsfor generation III and 13 for generation IV. In anotherextended family with known ages of onset of the dis-ease [Naveh et al., 1984], once again the mean age ofonset of PDD, excluding the propositus, was 18 yearsfor generation III and 4 for generation IV.

The 2 more severely affected patients (IV-1 and IV-3in Fig. 1) both inherited the disease from the father,and in most other families reported with PDD the sameseems to be true (in the family described by Naveh etal. [1984] all those with more severe involvement in-herited the disease from the father, as in the casesreported by Kumar et al. [1981], Ribbing [1949] andSparkes and Graham [1972]), and most of the propositiare males.

The disease distribution with the prediction of an-ticipation, particularly in males and with alleles of pa-ternal origin, suggests the presence of a dynamic mu-tation with repeat expansion enhanced in father-to-sontransmission. There is some evidence that a similarphenomenon exists in another triplet repeat amplifica-tion disease, i.e., a higher level of expansion in mother-to-son transmissions of CGG triplet repeats in theFMR1 gene [Loesch et al., 1995]. In spite of the diffi-culty in classifying the severity of the disease in eachpatient due to the variability of the clinical and radio-logical manifestations, anticipation seems to be therule. There is one exception to this: in the case reportedby Ramon and Buchner [1966], the father was muchmore severely affected than the offspring. However,other factors such as interaction with other genes andenvironmental factors cannot yet be disregarded.

Mapping the gene of PDD by linkage analysis, taking

Fig. 5. Lateral view of skull (III-1 in Fig. 1), showing marked severesclerosis of cranial bones and base of skull. Mandible is also involved.

Fig. 6. Anteroposterior view of both tibiae and fibulae (III-1 in Fig. 1),showing wide and sclerotic diaphyses and cortical thickening.

Fig. 7. Lateral view of skull (IV-1 in Fig. 1), showing marked severesclerosis of cranial bones and base of skull. There is no pneumatization ofthe frontal sinuses.

Progressive Diaphyseal Dysplasia 351

advantage of extended families like the one describedhere, or a candidate gene strategy, should be feasible inthe near future and should be able to identify the geneand discover the basic detect of this disease. If there istrue anticipation in PDD, a dynamic mutation could bepredicted to be the cause of the disease, and a noveltechnique called repeat expansion detection should behelpful in genomic screening to identify the potentiallypathological trinucleotide repeat sequences.

ACKNOWLEDGMENTSWe thank the patients’ family for their cooperation

and Dr. Margarida Briosa (Anadia, Portugal) for con-tributing data.

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Fig. 8. Anteroposterior view of both tibiae and fibulae (IV-1 in Fig. 1),showing extremely wide and sclerotic diaphyses and cortical thickening.

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