Fine molecular mapping of the 4p16.3 aneuploidy syndromes in four translocation families

EDITOR—Deletions of 4p16.3 have attracted considerable attention, particularly since the introduction of FISH and molecular techniques, and are associated with a variety of clinical pictures. Although all aVected subjects are mentally retarded, this can vary from profound to mild and the physical manifestations may be those of the severe, often fatal, Wolf-Hirschhorn syndrome (WHS) or of the relatively milder, usually non-fatal Pitt-Rogers-Danks syndrome (PRDS). Genotype-phenotype correlations are not consistent except for the broad generalisation that the most severe physical abnormalities are more likely to be seen with the largest deletions. There is less information about 4p16.3 duplications. Before FISH, patients with 4p trisomy or duplications were reported to have profound mental retardation with microcephaly, short stature, and other marked physical abnormalities. By contrast, in two translocation families where we have described index cases with PRDS, those sibs with the 4p16.3 duplication had relatively mild mental retardation and late onset physical overgrowth. Here we describe the fourth family we have encountered with a translocation in which the index case has PRDS. This boy’s father and older brother carried the translocation in a balanced form and his younger brother had an unbalanced karyotype with 4p16.3 duplication. Patient 1 is the proband, born in 1986, who was diagnosed clinically at the age of 10 years. He was born at 35 weeks’ gestation with a birth weight of 1800 g (10th centile). There were early feeding problems and he was in hospital for three months. Pyloric and ureteric stenosis were found and operated on. He was left with only one functioning kidney. In the second year of life, he developed grand mal seizures, up to six per day, but these stopped at the age of 5 years. At 12 years 9 months he was an aVable child with some limited conversation. He had developed some expertise in bowling. His height (136 cm) was below the 3rd centile and his head circumference (HC) was 48 cm, some 3.5 SD below the mean. He had abundant curly hair on the head, apparent hypotelorism, slightly prominent eyes with some fullness of the lower lids and the sclera visible below the iris, a pointed nose, some prominence of the glabella, a short philtrum, wide mouth, and small chin (fig 1). He was very slender with little subcutaneous fat.