Pitt-Rogers-Danks syndrome and Wolf-Hirschhorn syndrome are caused by a deletion in the same region on chromosome 4p 16.3.

Abstract

Recently, a deletion of chromosome 4pter was found in three patients with PittRogers-Danks syndrome. We investigated two of these patients, by means of DNA and FISH studies, together with two additional patients with Pitt-Rogers-Danks syndrome, to determine the critical region of the deletion in these patients and to compare this with the critical region in Wolf-Hirschhorn syndrome.All four patients showed terminal deletions of chromosome 4p of different sizes. One of them appeared to have an unbalanced karyotype caused by a cryptic translocation t(4;8) in the mother, resulting in a deletion of chromosome 4pter and a duplication of chromosome 8pter. The localisation of the Wolf-Hirschhorn critical region has been confined to approximately 1 Mb between D4S43 and D4S115. Our study shows that the deletions in four patients with the Pitt-Rogers-Danks syndrome overlap the Wolf-Hirschhorn critical region and extend beyond this in both directions. This study, combined with the fact that our third patient, who was previously described as a Pitt-Rogers-Danks patient, but who now more closely resembles a Wolf-Hirschhorn patient, makes it likely that Pitt-Rogers-Danks and WolfHirschhorn syndromes are different clinical phenotypes resulting from a deletion in the same microscopic region on chromosome 4p16.

?Tandem? duplication of 4p16.1p16.3 chromosome region associated with 4p16.3pter molecular deletion resulting in Wolf-Hirschhorn syndrome phenotype

“…After the reports of a molecular deletion at the same locus in most PRDS patients [Clemens et al, 1996;Lindeman-Kusse et al, 1996], PRDS and WHS are assumed to be a single genetic disorder. It has been suggested that a PRDS diagnosis represents a milder phenotype [Zollino et al, 1996;Kant et al, 1997;Wright et al, 1998, Battaglia andCarey, 1998]. …”

“…The 3. Partial 4p trisomy is associated with a distinctive multiple congenital anomalies/mental retardation (MCA/MR) syndrome with clinical manifestations including a characteristic nose with a flat bridge and a bulbous tip, often referred to as ''boxer nose,'' abnormal ears, and flexion contractures [Dallapiccola et al, 1977;Gonzales et al, 1977].Haploinsufficiency of 4p16.3 results in WolfHirschhorn syndrome (WHS), characterized by preand postnatal growth retardation, mental retardation, characteristic face with apparent hypertelorism, high nasal bridge and maxillary hypoplasia, asymmetric skull, skeletal abnormalities, seizures, and midline defects [Wilson et al, 1981;de Grouchy and Turleau, 1984].More recently, microdeletions of 4p16.3, only detect- Kant et al, 1997;Wright et al, 1998]. We report on a WHS patient in whom a ''tandem'' duplication of the 4p16.1p16.3 chromosome region was detected in association with a subtle 4p16.3 terminal deletion.…”

Effect of the size of the deletion and clinical manifestation in Wolf-Hirschhorn syndrome: analysis of 13 patients with a de novo deletion

“…These conditions are both caused by deletions in the same region on chromosome 4p16.3. 47 Clinical phenotype is so similar and may change in one person at different ages. Thus, we agree that these conditions are not distinct entities.…”

Microdeletion 4p16.3 in three unrelated patients with Wolf-Hirschhorn syndrome

“…Their case histories and phenotypes seem to be very similar to those of patients with WHS but tend to be clinically less severe (Donnai, 1986;Oorthuys and Bleeker-Wagemakers, 1989;Lizcano-Gil et al, 1995;Clemens et al, 1996;Lindeman-Kusse et al, 1996;Zollino et al, 1996;Kant et al, 1997;Partington et al, 1997). None of the PRDS patients is known to have the severe cardiac problems or midline fusion defects seen in WHS cases.…”

“…Furthermore, it has been shown that both WHS and PRDS can be caused by overlapping 4p deletions (Kant et al, 1997;Wright et al, 1998), and there is enough evidence that PRDS is not a separate clinical entity but may "represent the milder end of the WHS spectrum" (Battaglia and Carey, 1998).…”