Wolf-Hirschhorn Syndrome

A number sign (#) is used with this entry because Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion syndrome associated with a hemizygous deletion of chromosome 4p16.3.

Description

Wolf-Hirschhorn syndrome is a congenital malformation syndrome characterized by pre- and postnatal growth deficiency, developmental disability of variable degree, characteristic craniofacial features ('Greek warrior helmet' appearance of the nose, high forehead, prominent glabella, hypertelorism, high-arched eyebrows, protruding eyes, epicanthal folds, short philtrum, distinct mouth with downturned corners, and micrognathia), and a seizure disorder (Battaglia et al., 2008).

Clinical Features

The Wolf-Hirschhorn syndrome is characterized by severe growth retardation and mental defect, microcephaly, 'Greek helmet' facies, and closure defects (cleft lip or palate, coloboma of the eye, and cardiac septal defects) (Hirschhorn et al., 1965; Wolf et al., 1965).

In 2 mentally retarded sisters and 2 other unrelated patients (1 male, 1 female), Pitt et al. (1984) reported a seemingly distinctive syndrome: intrauterine growth retardation with subsequent dwarfism, and unusual, characteristic facies. Short upper lip, prominent and slanting eyes, telecanthus, wide mouth, and microcephaly were described. Donnai (1986) and Oorthuys and Bleeker-Wagemakers (1989) described single similar cases. Lizcano-Gil et al. (1995) described a similar case of what was then called the 'Pitt-Rogers-Danks syndrome (PRDS)' or 'Pitt syndrome,' with the additional feature of optic atrophy. The father was 37 years old, prompting Lizcano-Gil et al. (1995) to suggest new dominant mutation with paternal age effect. Clemens et al. (1995, 1996) described a patient thought to have Pitt syndrome in whom fluorescence in situ hybridization analysis using the D4S96 probe specific for the WHS region at 4p16.3 revealed microdeletion in 20 of 20 metaphase cells tested. Donnai (1996) and Lindeman-Kusse et al. (1996) also found microdeletions of 4p16.3 in 4 patients previously diagnosed as having Pitt syndrome. Moreover, 2 sisters originally reported by Pitt et al. (1984) showed 46,XX,-4 +der 4 t(4;8)(p16.3;p23.1) pat. Although Donnai (1996) and Zollino et al. (1996) noted that 4p deletions had not been demonstrated in all cases of Pitt syndrome, the possibility remained that these cases had small deletions within the critical WHS region.

Wittwer et al. (1996) reported a family in which 3 males related as first cousins through carrier sisters were thought to have a novel X-linked mental retardation syndrome. Typical features included prenatal and severe postnatal growth retardation, blindness due to microphthalmia or optic atrophy, moderate to severe hearing loss, dysmorphic features, epilepsy, and severe mental retardation with absence of speech. Urogenital anomalies, malrotation of the gut, and abnormal segmentation of the lungs were also observed. Wieland et al. (2003) restudied this family and concluded that there were also typical skeletal changes. In 1 patient, radiographic examination showed dysplastic lesions in the proximal femurs and the vertebrae. These lesions were progressive and were assumed to be present in another patient because osteochondroma-like changes were mentioned in clinical reports. The patients never achieved walking. They also had white hair in early childhood, which contrasted with the hair color of their relatives. Haplotype analysis and investigation with microsatellite and EST markers suggested a disease locus in a region of Xp22, but no evidence for deletion indicative of a contiguous gene deletion syndrome was found. In a clinical and genetic reevaluation of the 2 living affected sibs in this family, Wieland et al. (2014) concluded that the disorder, previously called Wittwer syndrome, is a variant of Wolf-Hirschhorn syndrome (see CYTOGENETICS).

Kant et al. (1997) studied the patients with Pitt syndrome reported by Lindeman-Kusse et al. (1996) and Oorthuys and Bleeker-Wagemakers (1989) as well as an additional patient. They demonstrated that in each case there was a deletion of 4p16 that overlapped and extended beyond the WHS critical region in each direction. The minimal deleted region in these 4 patients extended from D4S126 to the telomere, with the largest deletion being from D4S394 to the telomere. As a result of their study, Kant et al. (1997) considered it likely that the Pitt and Wolf-Hirschhorn syndromes result from deletion in the same region of 4p16.

Wright et al. (1998) came to a similar conclusion from analysis of a patient with WHS and 2 patients with PRDS. They analyzed the patients at the molecular level, using a series of cosmids across a 4.5-Mb region of 4p16.3. They found that the molecular defects associated with the 2 syndromes show considerable overlap. They concluded that the 2 conditions result from the absence of similar, if not identical, genetic segments and proposed that the clinical differences observed between them are likely the result of allelic variation in the remaining homolog. Battaglia and Carey (1998) also argued that the Pitt-Rogers-Danks syndrome is essentially the same as Wolf-Hirschhorn syndrome, i.e., a 4p deletion syndrome. Wright et al. (1999) further defended the conclusion that WHS and PRDS represent clinical variation of a single disorder. They concluded that WHS and PRDS should no longer be considered separately but instead referred to as WHS (the original name). The prognosis for patients will be determined by the range and severity of symptoms present in the individual cases.

Battaglia et al. (1999) evaluated 15 patients with the 4p- syndrome (12 females, 3 males) in 3 centers. Follow-up spanning 16 years was achieved in 4 of the cases. Thirteen cases were detected by cytogenetics (regular G-banding in 10; high-resolution banding in 3), while the remaining 2 required fluorescence in situ hybridization. Of the 15 patients, 5 (33.3%) had heart lesions; 7 (47%) had orofacial clefts; 13 (87%) had a seizure disorder that tended to disappear with age; and all 15 had severe/profound developmental retardation. One Italian patient had sensorineural deafness and 1 Utah patient had a right split-hand defect. Of note, 2 Utah patients were able to walk with support (at 4 and 12 years of age, respectively), whereas 3 Italian patients and 1 Utah patient were able to walk unassisted (at 4, 5, 5 years 9 months, and 7 years of age, respectively). Two of the 3 Italian patients also achieved sphincter control by day. Eight patients receiving serial electroencephalogram studies showed fairly distinctive abnormalities, usually outlasting seizures. A slow, but constant progress in development was observed in all cases during the follow-up period.

Shannon et al. (2001) reported a study of 159 cases of WHS. Of the 146 cases in which it was possible to collect status, 96 were alive, 37 had died, and 13 were detected on prenatal diagnostic tests. The authors estimated a minimum birth incidence of 1 in 95,896. The crude infant mortality rate was 23 of 132 (17%), and in the first 2 years of life the mortality rate was 28 of 132 (21%). Cases with large de novo deletions (proximal to and including p15.2) were more likely to have died than those with smaller deletions (odds ratio = 5.7; 95% confidence interval 1.7 to 19.9). A comparison of the survival curves for de novo deletions and translocations did not show a statistically significant difference. Shannon et al. (2001) concluded that the mortality rate for WHS was lower than previously reported and that there was a statistically significant relationship between deletion size and overall risk of death in de novo deletion cases.

By telephone survey of 27 adults with WHS ranging in age from 17 to 40 years and their parents, Worthington et al. (2008) found that most patients had cessation of seizures in childhood. A seizure had not occurred in 3 years in 18 (66%) patients, and the mean age of the last seizure in those who were seizure-free was 11.3 years. In addition, many parents commented that seizures were triggered by fever. Worthington et al. (2008) noted that these findings may have relevance in genetic counseling.

Verbrugge et al. (2009) reported 2 unrelated patients with genetically confirmed WHS associated with growth retardation, craniofacial abnormalities, heart defects, and other anomalies. MRI showed tethered spinal cord in both patients. A literature review of 22 reports of neuroimaging findings in WHS indicated that the most common findings were corpus callosum abnormalities (71%), focal white matter signal abnormalities (46%), lateral and third ventricle enlargement (42%), white matter volume reductions (42%), and periventricular cysts (29%). Periventricular cysts were associated with the first year of life, but then appeared to fuse with the frontal horns during late infancy with enlargement of the frontal horns.

Diagnosis

Prenatal Diagnosis

Tachdjian et al. (1992) described prenatal diagnosis of 5 cases of WHS studied because of severe intrauterine growth retardation detected on routine ultrasound. At autopsy, the fetuses showed typical craniofacial dysmorphia without microcephaly. Major renal hypoplasia was the only constant visceral anomaly. Midline fusion defects were found in all, ranging from minor abnormalities such as scalp defect, hypertelorism, pulmonary isomerism, common mesentery, hypospadias, and sacral dimple, to cleft palate, corpus callosum agenesis, ventricular septal defect, and diaphragmatic hernia. Delayed bone age was present in all.

Population Genetics

The frequency of Wolf-Hirschhorn syndrome is estimated at 1/20,000 to 1/50,000 births, with a female predilection of 2:1 (Battaglia et al., 1999; Maas et al., 2008).

Cytogenetics

The critical zone for development of WHS is located distal to the Huntington disease-linked G8 (D4S10) marker. Although Gusella et al. (1985) found apparent deletion of D4S10 when they tested 7 unrelated patients with WHS, McKeown et al. (1987) reported a family in which 2 children with WHS retained the D4S10 locus on the deleted chromosome. WHS in the 2 sibs was the result of unbalanced segregation of a reciprocal 4;12 translocation in the mother.

Altherr et al. (1991) described a molecular deletion in 4p due to a subtle, inherited translocation between chromosomes 4 and 19, leading to the Wolf-Hirschhorn syndrome phenotype.

Gandelman et al. (1992) described a subtle deletion of 4p in a patient with WHS. Using probes from 4p16.3, they demonstrated a deletion of approximately 2.5 Mb with the breakpoint located approximately 80 kb distal to D4S43.

In 7 cases of WHS, Quarrell et al. (1991) found that there was de novo deletion or rearrangement of 4p; in each case the abnormality had arisen on the paternal chromosome. A paternal age effect was not observed, however.

Anvret et al. (1991) reported molecular studies in 2 patients with WHS which showed that the critical region was within 4p16.3. The deletion was of maternal origin in one patient and of paternal origin in the other.

Goodship et al. (1992) described a 2-year-old girl who presented with developmental delay and subtle dysmorphic features suggesting Wolf-Hirschhorn syndrome: hypertelorism, prominent glabella, short philtrum, and carp-shaped mouth. Although high resolution chromosome analysis was normal in the child and in both parents, molecular analysis indicated that the child had not inherited a maternal allele of probes from 4p16. Prenatal diagnosis in the next pregnancy showed that again the fetus had no maternal allele for probes mapping to 4p16. Fluorescence in situ hybridization (FISH) in the mother showed a submicroscopic translocation between chromosomes 4 and 10.

Estabrooks et al. (1992) reported 2 families with a satellited chromosome 4 short arm. Satellites and stalks normally occur on the short arms of acrocentric chromosomes. Although satellited nonacrocentric chromosomes, presumably resulting through translocation from an acrocentric chromosome, had been reported, this was the first report of involvement of 4p. By Southern blot analysis and FISH, deletion of material mapping approximately 150 kb from 4pter was discovered. Notably, the phenotype was normal with no signs of WHS. Estabrooks et al. (1992) speculated that homology between subterminal repeat sequences on 4p and sequences on the acrocentric short arms may explain the origin of the rearrangement.

Thies et al. (1992) reported 3 apparently de novo deletion cases of WHS. Molecular studies indicated that the deleted segment was of paternal origin in 2 and maternal in the other.

Partington et al. (1997) reported individuals from 3 families in which there was a translocation involving 4p16.3. Nine individuals had clinical features of Pitt syndrome, and a deletion of 4p16.3 was shown by fluorescence in situ hybridization analysis in all 8 patients so studied. Eleven patients had a 'new' syndrome consisting of overgrowth with heavy facial features and mild to moderate mental retardation. A duplication of 4p16.3 was found in the 4 subjects studied. Partington et al. (1997) suggested that the growth abnormalities in these 2 families could be explained by a dosage effect of the FGFR3 gene (134934), with a single dose leading to growth failure and a triple dose to physical overgrowth.

Wright et al. (1997) presented a transcript map of the WHS critical region (WHSCR1), an approximately 165 kb region (about 2 Mb from the telomere, defined by D4S166 and D4S3327) that is gene dense.

Zollino et al. (2003) proposed a new critical region for WHS, a 300- to 600-kb interval on 4p16.3 between D4S3327 and D4S98-D4S168 (WHSCR2; at 1.9 Mb from the telomere), contiguous distally with the WHSCR1 defined by Wright et al. (1997).

Wieland et al. (2014) reevaluated the 2 living males from the family reported by Wittwer et al. (1996) and Wieland et al. (2003) in which 3 males related as first cousins through carrier sisters were thought to have a novel X-linked mental retardation syndrome. Array-based molecular karyotyping revealed a cryptic genomic rearrangement in both patients involving deletion of about 8.4 Mb on 4p16.3p16.1 and duplication of about 3.9 Mb on 17q25.3. FISH confirmed the array results and identified the derivative chromosome der(4)t(4;17) in the patients and the balanced translocation in both female carriers. Wieland et al. (2014) noted that the key features of the patients met the description of WHS, including variable additional manifestations that may be explained in part by the size of the deletion in 4p16.3. They concluded that the disorder in this family, previously called Wittwer syndrome, falls within the phenotypic and genotypic spectrum of WHS.

Molecular Genetics

Zollino et al. (2000) reported the findings in 16 WHS patients. In 11 patients, hemizygosity of 4p16.3 was detected by conventional prometaphase chromosome analysis; in 4 patients, it was detected by molecular probes on apparently normal chromosomes. One patient had normal chromosomes without a detectable molecular deletion within the WHS critical region. In each patient with a deletion, the deletion was demonstrated to be terminal by FISH. The proximal breakpoint of the rearrangement was established by prometaphase chromosome analysis in cases with a visible deletion. The breakpoint was within the 4p16.1 band in 6 patients, apparently coincident with the distal half of this band in 5 patients. The authors used a set of overlapping cosmid clones spanning the 4p16.3 region to establish the extent of each of the 4 submicroscopic deletions. Variations were found in both the size of the deletions and the position of the breakpoints. The precise definition of the cytogenetic defect permitted an analysis of genotype/phenotype correlations in WHS, leading to the proposal of a set of minimal diagnostic criteria. Deletion of less than 3.5 Mb resulted in a mild phenotype, in which malformations were absent. The absence of a detectable molecular deletion was still consistent with the diagnosis of WHS. Based on these observations, a 'minimal' WHS phenotype was inferred, the clinical manifestations of which are restricted to the typical facial appearance, mild mental and growth retardation, and congenital hypotonia.

The t(4;8)(p16;p23) translocation, in either the balanced or unbalanced form, has been reported several times (Wieczorek et al., 2000). Giglio et al. (2002) considered that the t(4;8)(p16;p23) translocation may be undetected in routine cytogenetics, and suggested that it may be the most frequent translocation after t(11q;22q), which is the most common reciprocal translocation in humans (Kurahashi et al., 2000; see 609029). Giglio et al. (2002) showed that subjects with der(4) had WHS, whereas subjects with der(8) showed a milder spectrum of dysmorphic features. Two pairs of the many olfactory receptor (OR) gene clusters are located close to each other, on both 4p16 and 8p23. Giglio et al. (2001) demonstrated that an inversion polymorphism of the OR region at 8p23 plays a crucial role in the generation of chromosomal imbalances through unusual meiotic exchanges. Their findings prompted Giglio et al. (2002) to investigate whether OR-related inversion polymorphisms at 4p16 and 8p23 might also be involved in the origin of the t(4;8)(p16;p23) translocation. In 7 subjects (5 of whom represented de novo cases and were of maternal origin), including individuals with unbalanced and balanced translocations, Giglio et al. (2002) demonstrated that breakpoints fell within the 4p and 8p OR gene clusters. FISH experiments with bacterial artificial chromosome (BAC) probes detected heterozygous submicroscopic inversions of both 4p and 8p regions in all 5 mothers of the de novo subjects. Heterozygous inversions on 4p16 and 8p23 were detected in 12.5% and 26% of control subjects, respectively, whereas 2.5% of them were scored as doubly heterozygous.

To define the distinctive WHS phenotype, and to map its specific clinical manifestations, Zollino et al. (2003) studied a total of 8 patients carrying a 4p16.3 microdeletion. The extent of each deletion was established by FISH, with a cosmid contig spanning the entire genomic region from MSX1 (142983) in the distal half of 4p16.1 to the subtelomeric locus D4S3359. The deletions were 1.9-3.5 Mb, and all were terminal. All of the patients presented with a mild phenotype, in which major malformations were usually absent. Head circumference was normal for height in the 2 patients with the smallest deletions (1.9 and 2.2 Mb). The theretofore accepted WHS critical region, a 165-kb interval on 4p16.3 defined by the loci D4S166 and D4S3327 (Wright et al., 1997) was fully preserved in the patient with the 1.9-Mb deletion, in spite of a typical WHS phenotype. The deletion in this patient spanned the chromosome region from D4S3327 to the telomere. Clinically, the distinctive WHS phenotype was defined by the presence of typical facial appearance, mental retardation, growth delay, congenital hypotonia, and seizures. These signs represent the minimal diagnostic criteria for WHS. This basic phenotype was found by Zollino et al. (2003) to map distal to the critical region accepted at that time. Zollino et al. (2003) proposed a new critical region for WHS, which they designated WHSCR2, as a 300- to 600-kb interval on 4p16.3 between D4S3327 and D4S98-D4S168, contiguous distally with the WHSCR defined by Wright et al. (1997). Among the candidate genes already described for WHS, the authors considered LETM1 (604407) likely to be pathogenetically involved in seizures. On the basis of genotype-phenotype correlation analysis, they recommended dividing the WHS phenotype into 2 distinct clinical entities, a 'classical' and a 'mild' form.

Nieminen et al. (2003) examined the dentition and the presence of the MSX1 (HOX7) gene (142983) in 8 Finnish patients with abnormalities of 4p, including 7 with WHS. Five of the WHS patients presented with agenesis of several teeth, suggesting that oligodontia may be a common, although previously not well-documented, feature of WHS. By FISH analysis, the 5 patients with oligodontia lacked 1 copy of MSX1, whereas the other 3 had both copies. One of patients in the latter group was the only one who had cleft palate. Nieminen et al. (2003) concluded that haploinsufficiency for MSX1 serves as a mechanism that causes selective tooth agenesis but by itself is not sufficient to cause oral clefts.

Van Buggenhout et al. (2004) reported 6 patients with small deletions of chromosome 4p covering or flanking the WHS critical region, 5 of whom presented with mild phenotypic features of WHS. Two patients with small interstitial deletions allowed further refinement of the phenotypic map of the region. These analyses pinpointed hemizygosity of the WHSC1 (602952) gene as the cause of the typical WHS facial appearance. The results indicated that the other key features (microcephaly, cleft palate, and mental retardation) probably result from haploinsufficiency of more than 1 gene in the region and are thus true contiguous gene syndrome phenotypes. The breakpoints in the 3 terminal deletions identified in this study coincided with gaps in the human genome draft sequence. Van Buggenhout et al. (2004) demonstrated that 1 of these gaps contains an olfactory receptor gene cluster, suggesting that low copy repeats not only mediate ectopic meiotic recombinations but are also susceptibility sites for terminal deletions.

Rodriguez et al. (2005) reported a 4-year-old girl with a subtelomeric deletion of 4p16.3 who had a typical WHS facial appearance, growth and psychomotor delay, and 2 episodes of febrile seizures. FISH revealed that the 1.9-Mb deletion in this patient was from marker D4S3327 to the telomere, thus supporting the more distal WHS critical region (WHSCR2) proposed by Zollino et al. (2003).

Maas et al. (2008) used high-resolution array comparative genomic hybridization to analyze DNA from 21 WHS patients with pure 4p deletions, including 8 with a cytogenetically visible deletion and 13 with a submicroscopic deletion. Eight patients had previously been reported. Six had classic terminal 4p deletions ranging in size from 1.9 to 30 Mb, but 1 patient with mild clinical features had a 1.4-Mb deletion, the smallest ever reported. Interstitial deletions were identified in 4 patients. By comparison of the phenotypes and deletions, Maas et al. (2008) positioned the genes causing microcephaly and growth retardation between 0.3 and 1.4 Mb in the 4pter region.

Pathogenesis

Kerzendorfer et al. (2012) studied 3 WHS patient cell lines with different deletions of chromosome 4p16. The cell lines showed variable deletion of the SLBP (602422) and/or NELFA (606026) genes, depending on the size of the deletion, as evidenced by protein expression studies. Both of these genes are involved in histone biogenesis. All patient cell lines showed delayed progression from S-phase to M-phase of the cell cycle as well as reduced levels of chromatin-associated histones after DNA replication compared to wildtype cells, consistent with underexpression of the SLBP and NELFA genes. This was associated with increased expression of the non-chromatin-associated histone chaperone H3 (see, e.g., HIST1H3A, 602810). Patient cells also showed defective DNA replication and enhanced sensitivity to camptothecin, which induces double-strand DNA breaks. The findings provided a mechanism for altered cell-cycle progression and impaired DNA replication that may contribute to the clinical features of WHS, such as growth retardation and microcephaly.

Animal Model

In mice, the homologs of genes involved in WHS map to chromosome 5 in a region of conserved synteny with human 4p16.3. Naf et al. (2001) generated and characterized 5 mouse lines bearing radiation-induced deletions spanning the WHSCR syntenic region. Similar to WHS patients, these animals were growth-retarded, susceptible to seizures, and showed midline (palate closure, tail kinks), craniofacial, and ocular anomalies (colobomas, corneal opacities). Other phenotypes included cerebellar hypoplasia and a shortened cerebral cortex. Expression of WHS-like traits was variable and influenced by strain background and deletion size.

Nimura et al. (2009) showed that the H3K36me3-specific histone methyltransferase Whsc1 (602952) functions in transcriptional regulation together with developmental transcription factors whose defects overlap with the human disease WHS. Nimura et al. (2009) found that mouse Whsc1, 1 of 5 putative Set2 homologs, governed H3K36me3 along euchromatin by associating with the cell type-specific transcription factors Sall1 (602218), Sall4 (607343), and Nanog (607937) in embryonic stem cells, and Nkx2-5 (600584) in embryonic hearts, regulating the expression of their target genes. Whsc1-deficient mice showed growth retardation and various WHS-like midline defects, including congenital cardiovascular anomalies. The effects of Whsc1 haploinsufficiency were increased in Nkx2-5 heterozygous mutant hearts, indicating their functional link. Nimura et al. (2009) proposed that WHSC1 functions together with developmental transcription factors to prevent the inappropriate transcription that can lead to various pathophysiologies.

McQuibban et al. (2010) identified the Drosophila gene CG4589 as the ortholog of LETM1 (604407), which they considered a candidate gene for seizures seen in WHS. The authors assayed the effects of downregulating the CG4589 gene, which they renamed DmLETM1, on mitochondrial function in vivo and in vitro. Conditional inactivation of DmLETM1 function in specific tissues resulted in roughening of the adult eye, mitochondrial swelling, and developmental lethality in third-instar larvae, possibly the result of deregulated mitophagy. Neuronal-specific downregulation of DmLETM1 resulted in impairment of locomotor behavior in the fly and reduced synaptic neurotransmitter release. DmLETM1 complemented growth and mitochondrial K+/H+ exchange (KHE) activity in yeast deficient for LETM1. The authors proposed that DmLETM1 functions as a mitochondrial osmoregulator through its mitochondrial K+/H+ exchange activity and may explain part of the pathophysiologic WHS phenotype.

History

De Die-Smulders and Engelen (1996) described a 50-year-old woman with kyphoscoliosis and typical clinical manifestations of Pitt syndrome who was found to have duplication of the segment 11q22-q23. Other family members were not karyotyped.