SEVERE MICROCEPHALY WITH NORMAL INTELLECTUAL-DEVELOPMENT - THE NIJMEGEN-BREAKAGE-SYNDROME

A brother and sister are described with severe microcephaly of prenata l onset, normal intellectual and motor development, chromosomal breaka ge and cellular immunodeficiency, which is characteristic of the autos omal recessive condition, Nijmegen breakage syndrome. The proband was a girl who presented at 15 months, with normal developmental milestone s and an extremely small head circumference of 36 cm. Twenty per cent of her lymphocytes showed spontaneous translocations involving chromos ome 7p13, 7q35, 14q11, and 14q32. The lymphocytes also showed excessiv e x ray induced chromosome damage. She had T cell lymphopenia, but nor mal immunoglobulins, and a normal cr fetoprotein. A brother was born s hortly after her diagnosis was made. He also had extreme microcephaly of 28 cm, with similar spontaneous and x ray induced chromosomal break age, and T cell lymphopenia. Neither child has clinical evidence of im munodeficiency. To test the hypothesis that Nijmegen breakage syndrome and ataxia telangiectasia are allelic disorders, haplotype analysis w as carried out in the family using DNA markers spanning the AT locus o n chromosome 11q22. The affected boy had a different haplotype from hi s affected sister. Thus in this family, the Nijmegen breakage syndrome is not allelic to the ataxia telangiectasia locus on chromosome 11q, and the two conditions are genetically distinct. The normal intellect in these children raises questions about normal brain development in t he presence of severe microcephaly.