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Wolf-Hirschhorn syndrome (WHS), a multiple congenital malformation syndrome, and Pitt-Rogers-Danks syndrome (PRDS), a rare condition with similar anomalies, were previously thought to be clinically distinct conditions. While WHS has long been associated with deletions near the terminus of 4p, several recent studies have shown PRDS is associated with deletions in 4p16.3. In this paper we evaluate three patients, two described as PRDS and one diagnosed as WHS. We demonstrate that the molecular defects associated with the two syndromes show a considerable amount of overlap. We conclude that both of these conditions result from the absence of similar, if not identical, genetic segments and propose that the clinical differences observed between these two syndromes are likely the result of allelic variation in the remaining homologue.

We describe a patient who was born with flexion contractures and pterygia at the elbows, clubfeet, torticollis, and several rib fractures. During infancy and childhood, multiple fractures of the lower limbs occurred with minimal trauma and led to disabling deformities. When evaluated at age 19 years, he was normally intelligent, but extremely short, with severe kyphoscoliosis compromising his pulmonary function. Pterygia limited elbow extension to 90 degrees, and severe lower limb deformities prevented ambulation. He did not have blue sclerae, dentinogenesis imperfecta, or hearing loss. X-ray studies showed demineralized bones, severe deformity and cystic change at old fracture sites, and vertebral wedging. Collagen studies on skin fibroblasts were normal.

Pitt-Rogers-Danks syndrome (PRDS) is a rare, presumed autosomal recessive, syndrome with pre- and postnatal growth retardation, microcephaly, characteristic facial appearance, seizures, unusual palmar creases and developmental delay. Since the first description in 1984, only 7 cases have been reported. We report the identification of a 4p microdeletion in 2 new patients, who were previously diagnosed with PRDS, as well as the sibs in Pitt et al. [1984]. PRDS can no longer be considered autosomal recessive. Although our cases are attributable to a microdeletion in 4p16, it is uncertain if the critical region involves a single locus or multiple loci or to what extent this region overlaps with the critical region for Wolf-Hirschhorn syndrome.

A chromosomally normal brother and sister shared a lethal pattern of anomalies including bilateral cleft lip and palate, hypertelorism, flat facial profile, flat occiput, complex congenital heart defect, and malrotation of the intestine. The male was large for gestational age, while his sister was normally grown. The girl had bifid thumbs, but the boy had only minor hand anomalies. These findings are not consistent with any previously recognized syndrome and represent a new condition with probable autosomal recessive inheritance.

Three new patients with the Baller-Gerold syndrome bring the number of reported cases to 20. In addition to craniosynostosis involving various sutures and preaxial reduction defects of variable severity, affected patients may have anal, urogenital, cardiac, central nervous system, and vertebral defects. Autosomal recessive inheritance is supported by the presence of affected sibs and parental consanguinity.

We reviewed 45 patients with a deletion of the long arm of chromosome 4. Forty-one were previous reports (25 terminal deletions and 16 interstitial deletions) and 4 are new cases with terminal deletions. Of the 29 patients with terminal deletions, 18 with deletion at 4q31 and 4 at 4q32----qter had an identifiable phenotype consisting of abnormal skull shape, hypertelorism, cleft palate, apparently low-set abnormal pinnae, short nose with abnormal bridge, virtually pathognomonic pointed fifth finger and nail, congenital heart and genitourinary defects, moderate-severe mental retardation, poor postnatal growth, and hypotonia. Six patients with a deletion at 4q33 and one patient with deletion 4q34 were less severely affected. In general, patients with various interstitial deletions proximal to 4q31 had a phenotype that was less specific, although mental retardation and minor craniofacial anomalies were also present. There were 3 patients with piebaldism and one with Rieger syndrome. We conclude that terminal deletion of chromosome 4q (4q31----qter) appears to produce a distinctive malformation (MCA/MR) syndrome in which the phenotype correlates with the amount of chromosome material missing and which differs from the more variable phenotype associated with interstitial deletions of 4q.