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

Abstract

Chromosome imbalance affecting the short arm of chromosome 4 results in a variety of distinct clinical conditions. Most of them share a number of manifestations, such as mental retardation, microcephaly, pre- and post-natal growth retardation, anteverted and low-set ears, that can be considered as nonspecific signs, generally attributable to gene dosage impairment. On the other hand, more distinctive phenotypic traits correlate with the segmental aneuploidy. Duplications of the distal half of 4p give rise to the partial trisomy 4 syndrome, characterized by a "boxer" nose configuration and deep-set eyes. These signs are usually observed even in cases of small terminal duplications. Haploinsufficiency of 4p16.3 results in the so-called Wolf-Hirschhorn (WH) syndrome, a contiguous gene syndrome characterized by maxillary hypoplasia, large and protruding eyes, high nasal bridge, skeletal abnormalities, and midline defects. The smallest overlapping deletion described so far as a cause of this condition is only 165 kb long, suggesting that one or a few genes in this region act as "master" regulators of different developmental pathways. A "tandem" duplication of 4p16.1p16.3 was detected in association with a subtle deletion of 4p16.3pter on the same chromosome in a patient with the WH phenotype. The 3.2 Mb deletion, spanning the genomic region from the vicinity of D4S43 to the telomere, encompasses the recently delimited "WHS critical region" [Wright et al., 1997: Hum. Mol. Genet. 6:317-324]. This unusual chromosome rearrangement resulted in WH phenotype, clinical manifestations of partial 4p trisomy being mild or absent. This observation led us to speculate that the regulatory gene/genes in the critical WH region affect the expression of other genes in a dose-dependent manner. Haploinsufficiency of this region could be more deleterious than various partial trisomies.

Subtelomeric study of 132 patients with mental retardation reveals 9 chromosomal anomalies and contributes to the delineation of submicroscopic deletions of 1pter, 2qter, 4pter, 5qter and 9qter

“…This patient's phenotype was relatively mild and correlated with some patients previously described with similar 4p16.3 microdeletions [21,22]. Some patients have been designated Pitt syndrome (Pitt-Rogers-Danks syndrome, PRDS), but recently it was argued that Pitt and Wolf-Hirshhorn syndromes represent phenotypic variations of the same microdeletion [23]. …”

Clinical Manifestations of Partial Trisomy 4p

“…Duplications of the distal half of 4p characterized by a boxer nose configuration and deep-set eyes. These signs are usually observed even in cases of small terminal duplications [9]. The smallest duplicated segment leading to the dup(4p) phenotype was described by Wyandt et al [6] in an 18-month-old infant.…”

Unmasking of a hemizygous WFS1 gene mutation by a chromosome 4p deletion of 8.3 Mb in a patient with Wolf–Hirschhorn syndrome

“…FISH data obtained with probe RP11-34C20 contradicted a tandem duplication 4p16.1p16.3, a translocation between 4p16.2 and 11p15.5, or a translocation between 4p16.3 and 8p23. 4,16 Moreover, our patient did not show the clinical features found in patients with a tandem duplication of 4p16.1 -4p16.3. 16 Thus, these data do not support a contribution of a possible position effect due to a putative translocation 1 to the observed clinical phenotype of our patient.…”