Evidence for locus heterogeneity in the Camurati–Engelmann (DPD1) Syndrome

To the Editor: Camurati–Engelmann Syndrome (DPD1) (MIM 131300) is a rare, autosomal dominant sclerosing bone disorder belonging to the osteopetroses group of bone conditions (1–5). Waddling gait, muscle weakness and wasting, pain and generalized fatigue are characteristic clinical features. Progressive cortical sclerosis involving the diaphyses of the long bones and the base of the skull are the major radiographic findings. The locus for DPD1 has recently been mapped to chromosome 19q13.1-13.3 (6, 7). Subsequently, mutations have been identified in individuals with DPD1 in the human transforming growth factor b1 gene (TGFb1), a candidate gene because of its location on chromosome 19 (8). We report a family with typical DPD1 in which no TGFb1 mutation can be identified, and in which linkage analysis excludes the disease from the region surrounding TGFb1. The multigenerational family with DPD1 is shown in Fig. 1. The DPD1 in affected individual II-1 appears to be the result of a new mutation as he is the first affected individual in his family. He has three affected children with two different women. Individual III-2 (proband) was diagnosed with Camurati–Engelmann Syndrome at 14 years after a 3-year history of lower extremity bone pain. Her musculoskeletal symptoms consist of joint aching, particularly in the lower extremities, as well as pain in the hips predominantly with walking or lying on her side. X-rays documented increased bone density in the petrous and frontal bone of the skull. Femurs and tibias show symmetric expansion of the mid-shaft with undulating cortical thickening, also present in the radius and humeri, bilaterally. Corticosteroids have not significantly improved her clinical symptomatology. All of the affected individuals had onset of symptoms in late childhood or early adolescence and demonstrate the characteristic sclerosing diaphyseal dysplasia (Fig. 2). Linkage analysis was performed using the following PCR STR markers: D19S587, D19S8881, D19S223, D19S400, D19S718, D19S211, D19S913, D19S408, D19S178 (7). Two-point linkage analysis was conducted using MLINK of the package LINKAGE version 5.1 (9). Multipoint analysis was conducted using VITESSE (10). SimWalk2 (11) was used to reconstruct haplotypes from data converted using Mega2 (12). Two point lod scores for all informative markers (markers D19S211 and D19S408 were not informative) were –3.1 at u= 0.0 and –2.1 at u=0.001. Multipoint lod scores over the entire region ranged from –3.2 to –6.2. Haplotypes of the informative markers, as reconstructed with SimWalk2, are depicted in Fig. 1. It has previously been shown that the DPD1 locus lies in the 3.2 cM region flanked by D19S881 and D19S211 (7). As D19S211 was uninformative in this pedigree, D19S913 becomes the next closest flanking marker. The pedigree clearly demonstrates that individual III-3 inherited different chromosome 19 marker alleles from her affected parent II-2 than were inherited by her other two affected siblings, III-1 and III-2. The inter-marker distances are small making a double recombination in the region between two markers unlikely. However, to rule this possibility out, we sequenced TGFb1 to