Interstitial deletions of the long arm of chromosome 4 have been reported in 32 cases. Distal interstitial and terminal 4q deletions result in a characteristic phenotype associated with the loss of band 4q31-33; the phenotype of proximal deletions is more variable. We report two male infants with karyotypes 46,XY, del(4)(q21.3q23), and 46,XY, del(4)(q13.2q23), and delineate a clinical chromosome deletion syndrome associated with the loss of band 4q22. Eight of nine patients reported in the literature with deletions involving 4q22 (including two prenatal diagnoses with therapeutic termination) revealed a characteristic phenotype similar to our patients'. In addition, one patient with 4q12q21.1 deletion had a similar phenotype. This clinical syndrome consists of absolute or relative macrocephaly with a characteristic head shape and facial features, profound hypotonia, small hands and feet, short limbs, failure to thrive, metal retardation, and developmental delay. Life expectancy is reduced with death in the first year of life. It affects both sexes (M:F 7:5). Other abnormalities reported include renal cysts, atrioventricular septal defects, coarctation of aorta, partial agenesis of corpus callosum, cerebellar vermis hypoplasia, genital anomalies, complete cleft lip and palate. Two patients developed seizures. Because of lack of the details of breakpoints in the reported patients it is difficult to define the region responsible for the phenotypic features described. Molecular characterization of breakpoints in these patients is required. This syndrome does not include piebaldism (4q12) or Reiger anomaly (4q25), and it is distinct from the distal-terminal (4q33 - qter) deletions.