Cosegregation of two genetic conditions in a family we encountered may aid in localization of the responsible genes. The first is the Wolfram or DIDMOAD syndrome (Diabetes Znsipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), considered to be an autosomal recessive disorder [Fraser and Gunn, 19771. All manifestations are seldom seen in one patient; the key symptoms are juvenile-onset diabetes mellitus and optic atrophy [Gunn et al, 19761. The second is brachydactyly E, in which patients have short metacarpals and short stature and which may occur as an autoso-ma1 dominant trait or as a component of several, especially endocrine, disorders; it has not been reported in the Wolfram syndrome [Temtamy and McKusick, 1969; McKusick, 19831. Three sisters, who developed insulin-dependent diabetes mellitus, hearing loss, and impaired vision in early childhood, had optic atrophy and bilateral sensorineural deafness but no history or laboratory findings of diabetes insipidus; further, each had the metacarpal sign [Archibald et al, 19591, short stature, and disproportionately short hands and feet. Their mother and one brother had short fourth metacarpals but no signs of the Wolfram syndrome. One brother was normal.
With the assumption of autosomal recessive inheritance of the Wolfram syndrome and autosomal dominant inheritance of brachydactyly E, this pedigree probably represents cosegregation of the two genes; ie, all three sisters received the chromosome containing the brachydactyly E and Wolfram syndrome genes from their mother, the normal brother received the homologous maternal chromosome, and the brother with brachydactyly E alone received the Wolfram syndrome gene from his mother but not from his father. From these data, the LIPED program [Ott, 19741 calculated a maximum lod score of 0.55 with a recombination fraction of 0, which is suggestive of linkage but not significant at the 5% probability level.
Since both traits are rare, detection of cosegregation in other families is unlikely. However, family studies using standard markers could suggest the chromosomal localization of the brachydactyly E gene and set the stage for mapping the Wolfram syndrome gene. In informative families with one affected child, a closely linked polymorphic gene would allow early detection of this disabling disease in subsequent children or even prenatal diagnosis.