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

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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 affected 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.1 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.2 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 affable 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. There was fifth finger clinodactyly and accompanying camptodactyly.

Figure 1

The PRDS proband (left) and his OGS sib, aged 12 years and 5½ years, respectively.

The younger brother was born in 1993. His birth weight (3480 g) was on the 50th centile but his length (52 cm) was above average (85th centile) and head circumference (38 cm) at 2 weeks was on the 90th centile. His physical growth was good with heights and weights at the 70th centile. At 5½ years his HC (53.3 cm) was on the 95th centile. By contrast he was slow to pass his developmental milestones. A formal assessment at the age of 4 years put his mental development at 2½ to 3 years but no more than 2 years for his language. He was an energetic boy with a big head, unruly hair, widely spaced eyes (like his father), a short, upturned nose with a deep saddle, a normal mouth with shed central upper deciduous teeth, and plenty of muscle and fat on his sturdy little body (fig 1). The father was born in 1956; his height (182 cm) was on the 75th centile and he had obvious hypertelorism. The mother, born in 1966, had a height of 173 cm (95th centile) and normal facies. The older brother (born in 1984) had a height at 13 years of 171 cm (95th centile); he had obvious hypertelorism and a HC (56 cm) on the 80th centile.

Cytogenetic studies showed that the proband, parents, and sibs had apparently normal GTG banded karyotypes. By FISH, using the probe D4S96 (Oncor Inc), a cryptic translocation was found in the father and the older brother between chromosomes 4p and 6p. The proband had a deletion of 4p16.3 and the younger brother a duplication (fig 2). The translocations found in all four similar families we have studied have involvement of the 4p16.3 regions with different second chromosomes, 6p25.3 (fig 2) in this family, 1q44 (family 1), 8p23.1 (family 2), and 21q22.3 (family 3) as described previously.2

Figure 2

Family 4. Partial G banded karyotype and FISH using probe D4S96 (Oncor Inc) with marker locus D4S174 of (A) carrier father: 46,XY.ish t(4;6)(p16.3;p25.3)(D4S96-,D4S174+;D4S96+), (B) PRDS proband: 46,XY.ish der(4)t(4;6)(p16.3;p25.3)(D4S96-, D4S174+), and (C) OGS sib: 46,XY.ish der(6)t(4;6)(p16.3;p25.3) (D4S96×3,D4S174×2).

Molecular studies in all four families showed that three different segment sizes were deleted. The smallest translocated region was found in family 1 and this was used in the present study for finer mapping of the breakpoint.

Overlapping cosmids spanning 390 kb, between loci FGFR3 and D4S43 (fig3), were applied on an obligate carrier of family 1. Hybridisation signals for the probes 184d6, 19h1, 27h9, 58b6, 141a8, and 108f12 were seen on the translocated segment. The probe 10d12 was shown to hybridise to the terminal ends of both chromosomes 4 indicating that the breakpoint was at the ends of 108f12 and 10d12, within locus D4S132.

Figure 3

The cosmid contig used in the fine mapping study of family 1; the probes used are in bold. The solid line indicates the region involved in the translocation and localises the proximal breakpoint to be within locus D4S132.

The interpretation of these findings is not straightforward. Differences between WHS and PRDS have been discussed and debated2-4 and the validity of the overgrowth syndrome we found in families 1 and 22 questioned.5Whether the younger brother with the 4p16.3 duplication in this present family will show overgrowth features as an adolescent or adult remains to be seen but his current shape and size suggest that he may.

Phenotypic variation resulting from imprinting or partial trisomy of the other chromosome involved in the translocation was not evident in our families where the probands had PRDS. At the molecular level both WHS and PRDS seem to have very similar deletions as the proximal breakpoint we have found is the same as that recently defined in WHS patients, that is, within D4S132.7

Two recent publications6 7 describe molecular studies of one WHS and six PRDS patients with a deletion of 4p16.3 in all cases. Only one of these resulted from an obvious translocation; no details of molecular family studies were given in the other cases. The breakpoints found were proximal to locus D4S180, that is, similar to the translocation breakpoints in our families 2 and 3 (fig 4). One cell line of a PRDS patient (MA117)7 showed a breakpoint between loci D4S166 and D4S43, similar to our family 1.

Figure 4

Physical map of 4p16.3. The loci used are indicated in bold. Solid patterns indicate the regions translocated and the broken lines show undefined areas. The size of the region involved in each translocation is shown for our families 1, 2, 3, and 4. All deletions overlap with the newly refined WHSCR.7

The overlap in some of the clinical features of WHS and PRDS is probably the result of the overlap in the two critical regions (fig 3). The PRDS critical region may be entirely within the WHS critical region (WHSCR) but smaller, involving fewer gene(s); this could account for the relatively milder phenotype of PRDS compared to WHS. Another explanation might be that the critical regions of WHS and PRDS overlap in the middle, leaving out the distal end of WHS and the proximal end of the PRDS critical regions; the PRDS critical region could then include FGFR3 which may be relevant for overgrowth. It could be that point mutations in different genes or in a different region of the same gene within the overlapped area of the PRDS and WHS critical regions might account for the difference in severity of the two syndromes. So far, WHS families have not been described with 4p translocations that have sibs with the overgrowth resulting from a duplication of 4p16.3.

There are reports of patients with possible WHS/PRDS who were not deleted for locus D4S96.4 8 9 As the critical region of WHS has been recently reduced to 260 kb by WHS patient data,7 this now excludes the locus D4S96 and provides one explanation for these patients. However, as the distal breakpoint for PRDS has not been determined, it may be that D4S96 is not included in the critical region either. Just as the WHSCR has been reduced in size to 260 kb, the same could be done with PRDS patients when such are found with interstitial deletions.


Cosmid clones were obtained from Dr T Wright, Los Alamos National Laboratories (from the laboratory of Dr M Altherr), and VS was supported by an Australian PHRDC Program grant No 954614.