Exclusion of the chromosomal 1p21 region in a large pedigree with a phenotypic variant of type II autosomal dominant osteopetrosis

Purpose. To describe a large family including nine subjects with a mild phenotypic variant of type II autosomal dominant osteopetrosis (ADO II). Methods. Clinical and radiological description. Results are compared to those previously obtained in 42 patients (23 families) with classical ADO II. The present family was haplotyped with five markers from the chromosomal 1p21 region, which was previously shown to be linked to ADO II in one out of five tested families. Results. Radiological manifestations included isolated vertebral endplate thickening (22% vs 6% in ADO II), or isolated ‘bone in bone’ sign (22% vs 0% in ADO II), or both (33% vs 94% in ADO II), or a high bone density without segmentary osteosclerosis (lumbar or femoral Z-score above +4 SD) (22% vs 0% in ADO II). Radiographic penetrance was estimated to be 47% (90% in ADO II). Fractures were rare (0.67 vs 3.3/patient in ADO II) and occurred after significant trauma. Non-insulin-dependent diabetes occurred in 11 family members, without obvious co-segregation with osteopetrosis. Linkage analysis excluded the mutated gene in this family from being located in the chromosomal 1p21 region. Conclusion. In the absence of a clear alternative diagnosis, the nine subjects reported here most likely have a mild form of ADO II, with a variable radiological expression. No definite evidence for this hypothesis can be provided until ADO II mutation(s) have been identified.