Heterozygous manifestations in the heritable disorders of the skeleton

Many heritable disorders of the skeleton are transmitted as autosomal recessive (AR) traits. During the past two decades, family studies have been undertaken in conditions of this type in order to detect any structural manifestations in obligate and potential heterozygotes. The positive findings that emerge from this long-term investigation are reported. In numerous other AR skeletal disorders family investigations failed to reveal any significant abnormalities in relatives of affected persons. A review of the literature elicited additional examples of heterozygote manifestation. The skeletal abnormalities in the heterozygotes are usually inconsistent and often innocuous, but they have a number of important implications: (a) identification of heterozygotes for family screening or for genetic counseling; (b) identification of heterozygotes for conventional and molecular linkage studies; (c) problems with pedigree analysis; variable expression of an autosomal dominant trait versus heterozygous manifestations in an AR disorder; (d) problems with diagnosis, e.g., does a congenital Madelung anomaly always represent the heterozygous form of Langer mesomelic dysplasia? What proportion of persons with isolated brachydactyly are heterozygotes for Grebe chondrodysplasia? It is likely that close scrutiny of first-degree relatives of persons with other AR skeletal disorders will reveal examples of heterozygous manifestations.