On two patients with and without the classical Wolf-Hirschhorn syndrome (WHS) sharing the same chromosome 4p16.3 specific probe deletion: evidence of a contiguous gene deletion syndrome

We report here on phenotype-karyotype correlations in two patients with and without complete features of the WHS but sharing the lack of a specific cosmic probe (D4S96/D4Z1) from 4p16.3. These findings indicate that WHS is true a contiguous gene deletion syndrome in nature and expression.     

Parental origin of chromosome 4p deletion in Wolf-Hirschhorn syndrome

We report on molecular studies in 7 patients with Wolf-Hirschhorn syndrome (WHC) not showing an obvious chromosome 4p deletion. Analysis of a set of polymorphic probes mapping in the 4p16.3 region showed the absence of paternal haplotypes in 5 cases, and maternal haplotypes in 2. These observations corroborate evidence for preferential paternal origin of the de novo 4p chromosome deletion. The overall results of molecular studies suggest that the preponderance of paternally derived WHC could be due, rather than to imprinting of this region, to an excess of structural rearrangements in the male meiosis, related to differences between the mechanisms of sperm and egg production. © 1993 Wiley-Liss, Inc.     

De novo del(4) (p15.32) with incomplete expression of the Wolf-Hirschhorn syndrome

A 7 7/12-year-old girl with a de novo deletion 4p15.32----pter without the typical Wolf-Hirschhorn syndrome (WHS) is presented. This observation and others from medical literature suggest that monosomy 4p15.31----4p15.32, rather than 4p16, is the cause of the typical WHS.     

Terminal deletion of chromosome 4p (4p16.3) shows a breakpoint between loci linked to Huntington disease

A 15-year-old boy with a terminal deletion of the short arm of chromosome 4 is described. The patient has a mild clinical phenotype that is incompatible with Wolf-Hirschhorn syndrome. Careful neurological examination including CT scan did not show any signs of Huntington disease. The chromosomal breakpoint was analyzed by means of polymorphic DNA probes localized close to the tentative Huntington (HD) locus. The breakage has occurred between D4S43 and D4S90 loci and thus deletes part of the chromosomal candidate regions for the HD locus. © 1992 Wiley-Liss, Inc.     

Molecular and cytogenetic characterization of a recurrent unbalanced translocation (4;21) (p16.3;q22.1): Relevance to the Wolf-Hirschhorn and Down syndrome critical regions

We report on an aneuploidy syndrome due to the unbalanced segregation of a familial translocation (4;21)(p16.3;q22.1) causing a partial 4p monosomy and a partial 21q trisomy. The three affected children presented with severe failure to thrive, short stature, microcephaly, profound hypotonia, and mental retardation. The face, very similar in the three children, is characterized by frontal bossing, upslanting of the palpebral fissures, short nose, and deep set ears, giving the overall appearance of the Down syndrome. The molecular study has defined the aneuploid segment on both 4p and 21q. Most of the Down syndrome critical region was found to be trisomic, while only part of the candidate Wolf-Hirschhorn syndrome critical region was deleted, suggesting that this region is not critical for the major malformations characteristic for WHS. © 1996 Wiley-Liss, Inc.     

Interstitial deletion of 4p15.32p16.3 in a boy with minor anomalies,hearing loss,borderline intelligence,and oligodontia

We describe an 11-year-old boy of Saudi origin with an interstitial deletion in the short arm of chromosome 4 (p15.32p16.3) as determined by G-banding and fluorescent in situ hybridization. His clinical manifestations were similar but not identical to previously reported cases of interstitial deletion in the same chromosomal region, and were not those associated with Wolf-Hirschhorn syndrome. The boy had normal facial characteristics, short stature, minor anomalies of hands and feet, amblyopia of the right eye, bilateral hearing loss, and hypotonia. On developmental testing, he had borderline intelligence, with a severe sensory integration and motor planning disorder, and severe deficits in the communication domain. In addition, he had severe oligodontia affecting his secondary dentition. This finding supports the presence of one or more genes involved in dentition in this chromosomal region. Am. J. Med. Genet. 86:316–320, 1999. © 1999 Wiley-Liss, Inc.     

Pathologic findings in the Wolf-Hirschhorn (4p-) syndrome

We describe a 1-month-old female with the Wolf-Hirschhorn syndrome. GTG-banding studies disclosed a 46,XX,del(4)(:p15 → qter) in the child and apparently normal chromosomes in the parents. Autopsy at 4 months showed hypoplasia of most organs.     

A complex structural rearrangement of chromosome 4 in a woman without phenotypic features of Wolf-Hirschhorn syndrome

A 32-year-old mentally retarded woman was found to have a complex rearrangement of one chromosome 4. Her karyotype is interpreted as 46,XX,inv(4) (pter----p14::q12----p14::q12----qter) del (4) (pter----15.33::p15.2----qter). Clinically she does not show the features of the Wolf-Hirschhorn syndrome. Her phenotype and cytogenetic findings are compared with 2 other reported cases of 4p-without Wolf-Hirschhorn syndrome.     

Preliminary phenotypic map of chromosome 4p16 based on 4p deletions

We have collected and analyzed clinical information from 11 patients with chromosome 4p deletions or rearrangements characterized by various molecular techniques. Comparing the extent of these patients' deletions with their respective clinical presentations led to the proposal of a preliminary phenotypic map of chromosome 4p. This map consists of regions which, when deleted, are associated with specific clinical manifestations. Nonspecific changes such as mental and growth retardation are not localized, and probably result from the deletion of more than one gene or region. The region associated with most of the facial traits considered typical in Wolf-Hirschhorn syndrome (WHS) patients coincides with the currently proposed WHS critical region (WHSCR), but some anomalies commonly seen in WHS appear to map outside of the WHSCR. The observation of clinodactyly in 2 patients with nonoverlapping deletions allows assignment of these defects to at least 2 separate regions in 4p16. These initial observations and attempts at genotype/phenotype correlation lay the groundwork for identifying the genetic basis of these malformations, a common objective of gene mapping efforts and chromosome deletion studies. © 1995 Wiley-Liss, Inc.     

A familial cryptic subtelomeric deletion 12p with variable phenotypic effect

A 15-year-old-boy and his mother, both carrying a cryptic deletion within 12p13.33, are described. The proband has a mild phenotype with moderate mental retardation and severe behavioural problems. The mother had some learning difficulties at school. Conventional GTL-banded high-resolution chromosome analysis showed normal karyotypes. Subsequent analysis by fluorescence in situ hybridization using a set of probes specific for the subtelomeric regions of all chromosomes, plus a series of probes at 12p13.33 extending from the 12p telomere, showed that both mother and son carry a 1.65 Mb terminal deletion in this region. There are 10 predicted genes within the deleted region. The unanticipated familial nature of the deletion emphasizes the value of family studies in all cases with subtelomeric abnormalities. It also demonstrates the difficulty in making a clinical diagnosis of individuals with this deletion. To the best of the present authors' knowledge, the proband and his mother are the first patients described with a submicroscopic deletion at 12p13.33.     

5p14 deletion associated with microcephaly and seizures

We report on a father and son who have an interstitial deletion of 5p14. The father is clinically and mentally normal while the son has significant clinical involvement including microcephaly, seizures, and global developmental delay. The extent of the 5p14 deletion was determined using fluorescence in situ hybridisation (FISH). The deletion in this present family is smaller than a deletion previously described in a multigenerational family that lacks any clinical phenotype. This report shows that a 5p14 deletion does not always lead to a normal phenotype.     

Wolf-Hirschhorn syndrome facial dysmorphic features in a patient with a terminal 4p16.3 deletion telomeric to the WHSCR and WHSCR 2 regions

We report on a patient with developmental delay and several facial characteristics reminiscent of Wolf-Hirschhorn syndrome, who carries a terminal 4p16.3 deletion of minimally 1.691 Mb and maximally 1.698 Mb. This deletion contains the FGFRL1 gene, but does not include the WHSC1 gene. Given its expression pattern and its involvement in bone and cartilage formation during embryonic development, the FGFRL1 gene represents a plausible candidate gene for part of the facial characteristics of Wolf-Hirshhorn syndrome in 4p16.3 deletion patients.     

Ullrich-turner syndrome associated with interstitial deletion of Xp11.4→p22.31

The full phenotype of the Ullrich-Turner syndrome (UTS) is thought to be due to loss of the short arm of X. We report a 16-year-old girl with lack of secondary sexual development, amenorrhea, and short stature. She had thyroiditis and numerous other UTS manifestations and was found to have a non-mosaic 46,X,del(Xp) chromosome abnormality. Breakpoints occurred at p11.4 and p22.31, with a loss of the intervening segment.     

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

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.     

Two sibs with different phenotypes due to adjacent-1 segregation of a subtle translocation t(4;5)(p16.3;p15.3) mat

High-resolution chromosome banding and in situ hybridization with combined cosmid and alphoid sequence probes were used to delineate a very small reciprocal translocation in a mother and her two children. The first child has a 46,XX,der(4)t(4;5)(p16.3;p15.3)mat and thus has a deletion of 4p16.3→pter and a duplication of 5p15.3→pter (most likely 5p15.31→pter). Clinical findings include marked growth retardation, developmental delay, seizure disorder, microcephaly, unruly hair, broad nasal tip, downturned mouth, narrow palate, 11 pairs of ribs,mild right club foot, and a deep sacral dimple. Thus, this child has only a few non-specific manifestations of Wolf-Hirschhorn syndrome. The second child has a 46,XY,der(5)t(4;5)(p16.3;p15.3)mat; thus a deletion of 5p15.3→pter and a duplication of 4p16.3→pter. He has failure to thrive, developmenatal delay, microcephaly, sparse hair, horizontal nystagmus, short upturned nose with flared nostrils, thin lips with overhanging upper lip, long fingers and toes, and hypertonicity. Findings in the second patient are not suggestive of cri du chat syndrome (del 5p). The mother is phenotypically normal. This translocation will be useful in mapping genes and markers on the 4p and 5p chromosomal regions. © 1993 Wiley-Liss, Inc.     

Syndrome of proximal interstitial deletion 4p15: Report of three cases and review of the literature

We report on two boys and a girl with interstitial deletion in the short arm of chromosome 4 including the segment p15.2p15.33. All had normal growth with psychomotor retardation, multiple minor congenital anomalies, and a characteristic face distinct from that of the Wolf-Hirschhorn syndrome. One of the patients had congenitally enlarged penis. These patients resemble some of the previously reported patients with similar cytogenetic abnormalities and suggests the recognition of a specific clinical chromosome deletion syndrome. © 1995 Wiley-Liss, Inc.