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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Wolf-Hirschhorn syndrome (WHS) is characterized by typical craniofacial features in infancy consisting of 'Greek warrior helmet appearance' of the nose (the broad bridge of the nose continuing to the forehead), microcephaly, high forehead with prominent glabella, ocular hypertelorism, epicanthus, highly arched eyebrows, short philtrum, downturned mouth, micrognathia, and poorly formed ears with pits/tags. All affected individuals have prenatal-onset growth deficiency followed by postnatal growth retardation and hypotonia with muscle under-development. Developmental delay/mental retardation of variable degree is present in all. Seizures occur in 50% to 100% of children with WHS. Other findings include skeletal anomalies (60%-70%), congenital heart defects (~50%), hearing loss (mostly conductive) (>40%), urinary tract malformations (25%), and structural brain abnormalities (33%).
Diagnosis/testing. The diagnosis of WHS is suggested by the characteristic facial appearance, growth delay, psychomotor retardation, and seizures and is confirmed by detection of a deletion of the Wolf-Hirschhorn critical region (WHCR) (chromosome 4p16). Conventional G-banded cytogenetic analysis (routine and high-resolution) detects approximately 60%-70% of the deletions in WHS; fluorescence in situ hybridization (FISH) using a WHCR probe detects more than 95% of deletions in WHS. Testing is clinically available. Most individuals have a deletion with no other cytogenetic abnormality (a so-called 'pure deletion'); some individuals have a more complicated cytogenetic finding such as ring 4 chromosome, 4p- mosaicism, or a derivative chromosome 4 resulting from an unbalanced translocation.
Management. Treatment for individuals with WHS includes: rehabilitation, speech/communication therapy and sign language; valproic acid for atypical absence seizures; benzodiazepines for status epilepticus; "Haberman feeder," gavage feeding, and/or gastrostomy for feeding difficulities. Standard care is recommended for skeletal anomalies, ophthalmologic abnormalities, congenital heart defects, and hearing loss.
Genetic counseling. WHS is caused by deletion of the WHCR of chromosome 4p16 by one of several genetic mechanisms. About 75% of individuals with WHS have a de novo deletion of 4p16, about 12% have an unusual cytogenetic abnormality (such as ring 4), and about 13% have deletion of 4p16 as the result of having inherited an unbalanced chromosome rearrangement from a parent with a balanced rearrangement. Risks to family members depend on the mechanism of origin of the deletion. Prenatal testing is clinically available to families in which one parent is known to be a carrier of a chromosome rearrangement.
The diagnosis of Wolf-Hirschhorn syndrome (WHS) is suggested by the characteristic facial appearance, growth delay, psychomotor retardation, and seizures and is confirmed by detection of a deletion of the World-Hirschhorn critical region (WHCR) (chromosome 4p16.3).
Typical facial features. The facial appearance of individuals with WHS changes with age, exhibiting a typical pattern at each period [Battaglia et al 2000]. Facial features include the 'Greek warrior helmet appearance' of the nose (the broad bridge of the nose continuing to the forehead) recognizable in all individuals from birth to childhood and becoming less evident at puberty. Other craniofacial features are microcephaly, high forehead with prominent glabella, ocular hypertelorism, epicanthus, highly arched eyebrows, short philtrum, downturned mouth, micrognathia, and poorly formed ears with pits/tags [Wilson et al 1981, Estabrooks et al 1995, Battaglia et al 1999a, Battaglia et al 1999b, Battaglia et al 2000, Battaglia & Carey 2000].
Prenatal-onset growth deficiency is followed by postnatal growth retardation in all affected individuals.
Developmental delay/mental retardation of variable degree are present in all. Hypotonia and muscle under-development, mainly of the lower limbs, is observed in all affected individuals.
Cytogenetic analysis. Conventional G-banded cytogenetic studies (routine and high-resolution) detect deletion in the distal portion of the short arm of one chromosome 4 involving band 4p16 in approximately 60%-70% of individuals with WHS.
Most individuals have a deletion with no other cytogenetic abnormality (a so-called "pure deletion"); however, some individuals have a more complicated cytogenetic finding including ring chromosome 4, 4p- mosaicism, or a derivative chromosome 4, resulting from an unbalanced translocation or intrachromosomal duplication or inversion [Takeno et al 2004, Beaujard et al 2005].
Determining whether a cytogenetically visible deletion involves a derivative chromosome 4 resulting from an unbalanced translocation may be accomplished using specialized molecular cytogenetic techniques.
Subtelomeric FISH screening [Knight et al 2000] is probably the most sensitive and specific way to identify a derivative chromosome 4, as the majority of translocations involve the subtelomeric regions. FISH for the subtelomeric regions identifies the chromosomal origin of the additional segment
Spectral karyotyping (SKY)/M-FISH may be used to identify the translocation partner in cases in which conventional cytogenetic studies show that additional material has been translocated to 4p [Schrock et al 1996, Speicher et al 1996]. However, small segments (<5-10 Mb) may be missed with this method.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. Deletion of the Wolf-Hirschhorn critical region (4p16.3) is the only known cause of Wolf-Hirschhorn syndrome.
Uses of clinical testing
Diagnosis
Prenatal diagnosis
Molecular genetic testing: Clinical methods
FISH (fluorescence in situ hybridization). FISH using a probe (e.g., WHSCR probe, LPU 009, Cytocell Ltd) that includes the entire WHCR detects a deletion in more than 95% of individuals with WHS. Note:
Probes used in the past may give a false-negative result as they may fall outside the WHCR.
If a subtelomeric probe kit is used, interstitial deletions may not be detected.
Array genomic hybridization. DNA from lymphocyte cell lines can be hybridized to a panel of BAC clones that span the terminal region of 4p16.3. This technique detects large deletions, including interstitial deletions. Some small gaps in the clone map of this region may preclude exact localization of the breakpoint, but not the initial detection of a deletion [Stevenson et al 2004, Van Buggenhout et al 2004].
Table 1 summarizes genetic testing for this disorder.
| Test Type | Deletion Detected | Detection Rate | Test Availability |
|---|---|---|---|
| Cytogenetic analysis | Deletion of 4p16.3 | ~60-70% | Clinical |
| FISH 1 /array genomic hybridization | Deletion of WHCR | >95% | Clinical
 |
1. Using the WHSCR probe, Catalogue Number LPU 009, Cytocell, Ltd
It is appropriate to test any individual suspected of having WHS with:
Conventional cytogenetic studies to detect large deletions and more complex cytogenetic rearrangements (ring chromosome, unbalanced chromosome translocations);
FISH to detect smaller deletions involving the WHCR.
If needed, subtelomeric FISH screening and possibly array genomic hybridization can be performed to determine if a deletion of the WHCR is the result of an unbalanced translocation.
Rauch et al (2001) reported the first known individuals with a small de novo interstitial deletion restricted to the WHCR, who presented with a partial WHS phenotype consisting of low body weight for height, WHS facial gestalt, and speech delay associated with some neuropsychologic impairments. Microcephaly, short stature, mental retardation, and seizures were absent.
Although previously thought to be separate disorders, it is now recognized that Wolf-Hirschhorn syndrome (WHS) and Pitt-Rogers-Danks syndrome (PRDS) represent the clinical spectrum associated with a single syndrome [Battaglia et al 2001]. PRDS was described in 1984 in four individuals (two of whom are sisters) with intrauterine growth retardation, short stature, microcephaly, a characteristic face, mental retardation, and seizures. Twelve years later, Clemens et al (1995) described a distal 4p microdeletion identical to that seen in individuals with WHS in two previously unreported individuals, as well as in the siblings in the original report. The similarity in the size of the WHS and PRDS critical regions in combination with the phenotypic similarities of these syndromes suggest that PRDS and WHS represent the clinical spectrum associated with a single syndrome [Battaglia & Carey 1998, Wright et al 1998].
Classic WHS. The frequency of the clinical findings associated with WHS is summarized in Table 2.
| Findings | Frequency |
|---|---|
| - Distinctive facial features (see Clinical Diagnosis) - IUGR/postnatal growth retardation - Mental retardation - Hypotonia - Decreased muscle bulk - Seizures and/or distinctive EEG abnormalities - Feeding difficulties | >75% |
| - Skin changes (hemangioma; marble/dry skin) - Skeletal anomalies - Craniofacial asymmetry - Ptosis - Abnormal teeth - Antibody deficiency | 50%-75% |
| - Hearing defects - Heart defects - Eye/optic nerve defects - Cleft lip/palate - Genitourinary tract defects - Structural brain anomalies - Stereotypes (handwashing/flapping, rocking) | 25%-50% |
| Anomalies of the following: - Liver - Gallbladder - Gut - Diaphragm - Esophagus - Lung - Aorta | <25% |
Postnatal growth retardation. All individuals with WHS have marked intrauterine growth retardation, short stature, and slow weight gain later in life despite adequate energy and protein intake [Estabrooks et al 1995, Battaglia et al 1999a, Battaglia et al 1999b, Battaglia & Carey 2000].
Mental retardation. Although it is commonly stated that individuals with WHS are severely/profoundly mentally retarded, do not develop speech, and have minimal communication skills, recent experience has identified a broader range of intellectual abilities in individuals with WHS. Battaglia & Carey (2000) found that the degree of mental retardation was mild in 8%, moderate in 25%, and severe in 67%. Thus, one-third of affected individuals had mild to moderate mental retardation. Expressive language, although limited to guttural or disyllabic sounds in most individuals, was at the level of simple sentences in 6%. Comprehension seems to be limited to a specific context. Intent to communicate appears to be present in most individuals with WHS and improves over time with extension of the gesture repertoire.
About 10% of affected individuals do achieve sphincter control by day, usually between ages eight and 14 years. By age two to 12 years, approximately 45% of affected individuals walk, either independently (25%) or with support (20%) [Battaglia & Carey 2000]. About 30% of children reach some autonomy with eating (10% self-feed), dressing and undressing (20%), and simple household tasks. Slow but constant improvement has been observed over time in all individuals with WHS; these individuals reach more advanced milestones than previously suggested.
Seizures occur in 50%-100% of children with WHS [Battaglia et al 1999a, Battaglia et al 1999b, Battaglia & Carey 2000]. Age at onset varies between three and 23 months with a peak incidence around nine to ten months. Seizures are either unilateral clonic or tonic, with or without secondary generalization, or generalized tonic-clonic from the onset; they are frequently triggered by fever and can occur in clusters and last over 15 minutes. Other seizure types described in a few individuals include tonic spasms, myoclonic seizures, and complex partial seizures [Battaglia & Carey 2005]. Status epilepticus occurs in as many as 58% of individuals. Atypical absences develop between age one and five years in more than 60% of children. Seizures can be difficult to control in some individuals during the early years, but if properly treated tend to disappear with age. Seizures stop by age two to 13 years in 33% of individuals, and 17% of individuals reported recently are not on anti-epileptic drugs (AEDs) [Battaglia & Carey 2000].
Distinctive electroencephalographic (EEG) abnormalities have been found in 70% of individuals with WHS [Battaglia et al 1996, Battaglia et al 2001].
Feeding difficulties may be caused by hypotonia and/or oral facial clefts with related difficulty in sucking, poorly coordinated swallow with consequent aspiration, and/or gastroesophageal reflux. Gastroesophageal reflux, though transitory in healthy infants, usually persists in infants with WHS and results in failure to thrive and respiratory diseases.
Skeletal anomalies found in 60%-70% of individuals with WHS [Battaglia et al 1999a, Battaglia et al 1999b, Battaglia & Carey 2000] include kyphosis/scoliosis with malformed vertebral bodies, accessory or fused ribs, clubfeet, and split hand [Bamshad et al 1998, Sergi et al 1998].
Ophthalmologic abnormalities. Exodeviation, nasolacrimal obstruction, eye or optic nerve coloboma, and foveal hypoplasia are the most common ophthalmic manifestations of WHS [Battaglia et al 2001, Wu-Chen et al 2004]. Eyelid hypoplasia, requiring skin grafting, has occasionally been observed [Battaglia et al 2001]. Glaucoma can be difficult to treat.
Dental abnormalities. Delayed dental eruption with persistence of deciduous teeth, taurodontism in the primary dentition, peg-shaped teeth, and agenesis of some dental elements can be seen in more than 50% of individuals [Battaglia & Carey 2000, Battaglia et al 2001].
Congenital heart defects are noted in about 50% of individuals and are usually not complex. The most frequent is atrial septal defect (27%), followed by pulmonary stenosis, ventricular septal defect, patent ductus arteriosus, aortic insufficiency, and tetralogy of Fallot [Wilson et al 1981, Battaglia et al 1999a, Battaglia et al 1999b, Battaglia & Carey 2000].
Antibody deficiencies (IgA/IgG2 subclass deficiency; isolated IgA deficiency; impaired polysaccharide responsiveness) found in 69% of children studied by Hanley-Lopez et al (1998) seem to be responsible for recurrent respiratory tract infections and otitis media.
Hematopoietic dysfunction has been reported in two children with WHS; dysfunction progressed to refractory cytopenia in one and to acute lymphoblastic leukemia in the other [Sharathkumar et al 2003].
Hearing loss, mostly of the conductive type, can be detected in over 40% of individuals with WHS. Sensorineural hearing loss has been reported in at least seven individuals [Estabrooks et al 1994, Lesperance et al 1998, Battaglia & Carey 2000]. Congenital abnormalities of the middle and inner ear appear to contribute to the hearing impairment [Ulualp et al 2004].
Urinary tract malformations can be seen in 25% of affected individuals and include renal agenesis, cystic dysplasia/hypoplasia, oligomeganephroma (defined as renal hypoplasia characterized by decreased numbers of nephrons and hypertrophy of all nephric elements), horseshoe kidney, renal malrotation, bladder extrophy, and obstructive uropathy. Oligomeganephroma is associated with chronic renal failure. Some of these anomalies can be associated with vesicoureteral reflux [Battaglia & Carey 2000, Grisaru et al 2000].
Hypospadias and cryptorchidism can be seen in 50% of males [Battaglia & Carey 2000].
Absent uterus and streak gonads have been reported in females [Fryns et al 1973, Lazjuk et al 1980, Gonzales et al 1981].
Structural central nervous system defects are present in one-third of affected individuals. These defects mainly include thinning of the corpus callosum associated, in a few cases, with diffusely decreased white matter volume, or marked hypoplasia/agenesis of the posterior lobes of both cerebellar hemispheres. Other reported anomalies are hypoplastic brain with narrow gyri, arhinencephaly, shortening of the H2 area of Ammon's horn, and dystopic dysplastic gyri in the cerebellum [Lazjuk et al 1980, Battaglia & Carey 2000].
Sleeping problems, common in early years, can be easily overcome [Battaglia et al 2001].
Other. A wide variety of congenital defects have been reported in a minority of individuals with WHS [Sergi et al 1998, Battaglia et al 2001].
In order to explain the wide phenotypic variability of WHS, investigators have searched for correlations between size of the 4p deletion and severity of clinical manifestations.
Although Wieczorek et al (2000) and Zollino et al (2000) have respectively suggested a partial or a complete genotype-phenotype correlation, some investigators have concluded that no such correlation exists [Battaglia et al 1999a, Battaglia et al 1999b]. Meloni et al (2000) observed individuals with the 'classic syndrome' with severe mental retardation and a submicroscopic deletion detected only by FISH, as well as individuals with mild to moderate mental retardation and no major malformations with large deletions detected by routine cytogenetic analysis. These observations suggest that the size of the deletion does not correlate with severity of the clinical findings.
Recently, it has been shown that double cryptic chromosome imbalances, initially mistaken as microdeletions, cause large deletions and can be an important factor in explaining phenotypic variability in Wolf-Hirschhorn syndrome [Zollino et al 2004].
Although previously thought to be separate disorders, it is now recognized that WHS and Pitt-Rogers-Danks syndrome (PRDS) represent the clinical spectrum associated with a single syndrome [Battaglia et al 2001].
The prevalence of WHS is estimated to be about 1:50,000 births, with a 2:1 female/male ratio [Lurie et al 1980]. However, this is likely an underestimation because of misdiagnosis and under-recognition of affected individuals [Battaglia et al 2001].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Proximal 4p deletion. Several individuals with an interstitial deletion of 4p have been described. This deletion usually involves bands 4p12-p16, proximal to the critical region for WHS. This disorder is distinct from WHS and is a discrete syndrome [Fryns et al 1989, Chitayat et al 1995, White et al 1995, Petit et al 1996].
WHS phenotype. The clinical phenotype and particularly the facial gestalt of WHS is characteristic; however, some individuals may still be misdiagnosed because of features that overlap with the following disorders:
Seckel syndrome, characterized by pre- and postnatal growth deficiency, microcephaly, beaked/prominent nose
CHARGE syndrome, characterized by coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities, and ear anomalies/deafness. CHARGE syndrome is associated with mutations in CDH7.
Smith-Lemli-Opitz syndrome (SLOS), characterized by pre- and postnatal growth retardation, microcephaly, moderate to severe mental retardation, and multiple major and minor malformations. The malformations include distinctive facial features, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, and 2-3 syndactyly of the toes. SLOS is caused by deficiency of the enzyme 7-dehydrocholesterol reductase. It is an autosomal recessive disorder; diagnosis relies upon clinical suspicion and detection of elevated serum concentration of 7-dehydrocholesterol or an elevated 7-dehydrocholesterol:cholesterol ratio. Molecular genetic testing for mutations in the causative gene, DHCR7, is available.
Opitz G/BBB syndrome, characterized by facial anomalies (ocular hypertelorism, prominent forehead, widow's peak, broad nasal bridge, anteverted nares), laryngo-tracheo-esophageal defects, and genitourinary abnormalities (hypospadias, cryptorchidism, and hypoplastic/bifid scrotum). Developmental delay/mental retardation and cleft lip and/or palate are present in approximately 50%. Malformations present in fewer than 50% of individuals include congenital heart defects, imperforate or ectopic anus, and midline brain defects (Dandy-Walker malformation and agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). Genetic heterogeneity has been demonstrated: an X-linked form is caused by mutations in the gene MID1 (locus Xp22.3) and an autosomal dominant form is linked to 22q11.2.
Malpuech syndrome, characterized by growth retardation, ocular hypertelorism, wide forehead, high-arched eyebrows, urogenital anomalies, and hearing problems
Lowry-MacLean syndrome, characterized by growth failure, mental retardation, cleft palate, congenital heart defect, and glaucoma
Williams syndrome (WS), characterized by cognitive impairment (usually mild mental retardation), a specific cognitive profile, unique personality characteristics, distinctive facial features, and cardiovascular disease (elastin arteriopathy). A range of connective tissue abnormalities is observed and hypercalcemia and/or hypercalciuria are common. WS is caused by the contiguous gene deletion of the WS critical region (at 7q11.23) encompassing the elastin (ELN) gene. More than 99% of individuals with the clinical diagnosis of WS have this contiguous gene deletion, which can be detected using fluorescent in situ hybridization (FISH). It is transmitted in an autosomal dominant manner. Most cases are de novo occurrences.
Rett syndrome, an X-linked dominant disorder that in girls is characterized by normal birth and apparently normal psychomotor development during the first six to 18 months of life followed by a short period of developmental stagnation then by rapid regression in language and motor skills. The hallmark of the disease is the loss of purposeful hand use and its replacement with repetitive stereotyped hand movements. Autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, and acquired microcephaly also occur. The disease becomes relatively stable, but girls will likely develop dystonia and foot and hand deformities as they grow older. Seizures occur in 50% of females with Rett syndrome; generalized tonic-clonic seizures and partial complex seizures are the most common. The incidence of sudden, unexplained death is increased. Males with a 46,XY karyotype may have such a severe neonatal encephalopathy that they die before their second year. The diagnosis rests on clinical diagnostic criteria established for the classic syndrome and/or molecular testing of the MECP2 gene, which is available.
Angelman syndrome (AS), characterized by severe developmental delay/mental retardation, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are common. The diagnosis rests upon a combination of clinical features and molecular genetic testing and/or cytogenetic analysis. Consensus clinical diagnostic criteria for AS have been developed. Analysis of parent-specific DNA methylation imprints in the 15q11.2-q13 chromosome region detects approximately 78% of individuals with AS, including those with a deletion, uniparental disomy, or an imprinting defect; fewer than 1% of individuals have a cytogenetically visible chromosome rearrangement (i.e., translocation or inversion). UBE3A sequence analysis detects mutations in an additional ~11% of individuals. Accordingly, molecular genetic testing (methylation analysis and UBE3A sequence analysis) identifies alterations in about 90% of individuals. The remaining 10% of individuals with classic phenotypic features of AS have a presently unidentified genetic mechanism and thus are not amenable to diagnostic testing.
Smith-Magenis syndrome (SMS), characterized by distinctive facial features, developmental delay, cognitive impairment, and behavioral abnormalities. The facial appearance is characterized by a broad square-shaped face, brachycephaly, prominent forehead, synophrys, upslanting palpebral fissures, deep-set eyes, broad nasal bridge, marked midfacial hypoplasia, short, full-tipped nose with reduced nasal height, micrognathia in infancy changing to relative prognathia with age, and a distinct appearance of the mouth, with fleshy everted upper lip with a "tented" appearance. Cognitive and adaptive abilities are usually in the moderate range of mental retardation. The behavioral phenotype includes significant sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors. Infancy is characterized by feeding difficulties, failure to thrive, hypotonia, prolonged napping or need to awaken for feeds, and generalized lethargy. SMS is caused by an interstitial deletion of the short arm of chromosome 17 band p11.2 (del17p11.2) detectable by G-banded cytogenetic analysis and/or by fluorescence in situ hydridization (FISH). A visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common deletion by a routine G-banded analysis provided the resolution is adequate (550 band or higher). Molecular genetic testing of the causative gene, RAI1, is clinically available for individuals in whom a FISH-detectable deletion has been excluded.
Measurement of growth parameters and plotting on growth charts
Physical and neurologic examination
Evaluation of cognitive, language, and motor development and social skills
Waking/sleeping video-EEG-polygraphic studies in childhood (mainly between one and five years of age) to detect atypical absence seizures that may be subtle [Battaglia & Carey 2000]
Evaluation for feeding problems and gastroesophageal reflux with referral to a dysphagia team
Physical examination for skeletal anomalies (e.g., club foot, scoliosis, kyphosis); if anomalies are present, referral for orthopedic and physical therapy evaluation (including full biomechanical assessment)
Ophthalmology consultation in infancy even in the absence of overt anomalies
Examination of the heart (auscultation, electrocardiogram, echocardiography) in infancy
Testing for immunodeficiency (particularly plasma Ig levels, lymphocyte subsets, and polysaccharide responsiveness); although limited data on immunodefiency in individuals with WHS are available, such testing seems appropriate.
Comprehensive otolaryngologic evaluation and audiologic screening (brainstem auditory evoked responses) as early as possible to allow appropriate interventions
Renal function testing and renal ultrasonography in infancy to detect structural renal anomalies and/or vesicoureteral reflux [Grisaru et al 2000]
Mental retardation. Enrollment in a personalized rehabilitation program with attention to motor development, cognition, communication, and social skills is appropriate [Battaglia & Carey 2000]. Use of sign language enhances communication skills and does not inhibit the appearance of speech. Early intervention and, later, appropriate school placement are essential.
Seizures. Because almost 95% of individuals with Wolf-Hirschhorn syndrome have multiple seizures, most often triggered by fever, and almost two-thirds later develop valproic acid-responsive atypical absences, it is appropriate to start treatment with valproic acid soon after the first seizure [Battaglia & Carey 2000]. Atypical absences are well controlled on valproic acid alone or in association with ethosuccimide.
Sodium bromide has recently been proposed as the initial treatment for the prevention of the development of status epilepticus [Kagitani-Shimono et al 2005].
Clonic, tonic-clonic, absence, or myoclonic status epilepticus can be well controlled by intravenous benzodiazepines (Diazepam) [Battaglia & Carey 2005, Kagitani-Shimono et al 2005].
Because individuals with WHS have distinctive electroencephalographic (EEG) abnormalities not necessarily associated with seizures [Battaglia et al 1996], it seems appropriate to withdraw antiepileptic drugs in individuals who have not experienced seizures for five years [Dean & Penry 1995].
Feeding difficulties. Feeding therapy with attention to oral motor skills is also appropriate. Special feeding techniques or devices such as the "Haberman feeder" can be used for feeding a hypotonic infant/child without a cleft palate or those with a cleft palate prior to surgical repair.
Gavage feeding in individuals with poorly coordinated swallow.
Gastroesophageal reflux should be addressed in a standard manner.
In one study, almost 44% of individuals with WHS were managed with gastrostomy and, occasionally, gastroesophageal fundoplication [Battaglia & Carey 2000].
Skeletal abnormalities (e.g., clubfoot, scoliosis, kyphosis) need to be addressed on an individual basis. Early treatment (both physical therapy and surgery) is suggested.
Ophthalmologic abnormalities are treated in the standard manner.
Congenital heart defects are usually not complex and are amenable to repair.
Hearing loss is treated with a trial of hearing aids.
Sleeping problems. If no medical factors (e.g., otitis media, gastroesophageal reflux, eczema) are involved and if sleeping problems are reinforced by parental attention, the 'extinction of parental attention' is an effective behavioral treatment [Curfs et al 1999].
Other structural anomalies (e.g., diaphragmatic, gastrointestinal, dental) should be addressed in a standard manner.
Antibiotic prophylaxis is indicated for vesicoureteral reflux.
Intravenous Ig infusions or continuous antibiotics may be indicated for those with antibody deficiencies.
Systematic follow-up allows for adjustment of rehabilitation and treatment as skills improve or deteriorate and medical needs change [Ferrarini et al 2003, Battaglia 2005].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Carbamazepine may worsen the electroclinical picture in individuals with atypical absence seizures [Battaglia 2005].
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Wolf-Hirschhorn syndrome (WHS) is caused by deletion of the Wolf-Hirschhorn critical region (WHCR) of chromosome 4p16 by one of several genetic mechanisms.
Risk to family members depends on the mechanism of origin of the deletion.
Parents of a proband
The parents of a proband are unaffected.
About 75% of individuals with WHS have a de novo deletion of 4p16.
In 85% of de novo deletions, the origin of the deleted chromosome is paternal.
About 12% of individuals with WHS have an unusual cytogenetic abnormality (e.g., ring 4).
About 13% of individuals with WHS have deletion of 4p16 as the result of having inherited an unbalanced chromosome rearrangement from a parent with a balanced rearrangement.
In almost two-thirds of individuals with an inherited translocation, the mother carries the rearrangement.
Parents of individuals with WHS should therefore have cytogenetic analysis looking for a translocation involving 4p16 or, more rarely, an inversion involving 4p16. Subtelomeric analysis of both parents of a proband with an apparently de novo deletion is appropriate in order to detect the presence of a cryptic unbalanced translocation involving chromosome 4 in a parent [Reid et al 1996, Zollino et al 2004, South et al 2006].
Sibs of a proband
The risk to the sibs of a proband depends upon the genetic status of the parents.
If the deletion in the proband is de novo, the risk to the sibs of a proband is negligible.
If a parent is a balanced translocation carrier, the risk to sibs of being affected with 4p monosomy (i.e., WHS) or 4p trisomy is increased.
Offspring of a proband. No individual with WHS is known to have reproduced.
Other family members of a proband. If a parent is found to carry a chromosome rearrangement, his or her family members are also at risk of carrying the rearrangement.
Specific counseling issues. Specific empiric risks for translocations involving 4p and another chromosome are unavailable. Genetic counseling is appropriate for families interested in risk of recurrence.
High-risk pregnancy. Prenatal testing is available to families in which one parent is known to be a carrier of a chromosome rearrangement. Cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or amniocentesis usually performed at about 15-18 weeks' gestation can be analyzed by a combination of cytogenetic methods (G-banding, FISH, and whole chromosome painting) depending upon the specific findings in the proband and parent.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Low-risk pregnancy. Three-dimensional (3D) ultrasound may reveal facial features resembling the Greek warrior helmet in fetuses with IUGR [Chen et al 2004].
Preimplantation genetic diagnosis (PGD) may be available for couples at risk of having a pregnancy with WHS caused by an inherited chromosome rearrangement. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Critical Region | Chromosomal Locus | Protein Name |
|---|---|---|
| WHCR | 4p16.3 | Unknown |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 194190 | WOLF-HIRSCHHORN SYNDROME; WHS |
| Critical Region | Entrez Gene |
|---|---|
| WHCR | 7467 (MIM No. 194190) |
For a description of the genomic databases listed, click here.
A molecular approach has been used to define the size of the critical region of Wolf-Hirschhorn syndrome (WHS). A series of cosmids (termed landmark cosmids) spanning 4.5 Mb from the 4p telomere to the marker D4S81 was used to analyze metaphase spreads from individuals with WHS. Using this technique, the WHCR was reduced to 165 kb [Wright et al 1997]. The 165-kb WHCR lies between the markers D4S166 and D4S3327 and contains two genes of unknown function, WHSC1 and WHSC2 [Stec et al 1998, Wright et al 1999]. Using the landmark cosmid set and a series of second-tier cosmids, deletions can be defined with a high degree of confidence. The smallest deletion detected in an individual with WHS is 191 kb [Rauch et al 2001]; thus, it is highly unlikely that deletions are missed when this method is used.
WHSC1is a novel gene that spans a 90-kb genomic region, two-thirds of which maps in the telomeric end of the WHCR [Stec et al 1998]. The temporal and spatial expression of WHSC1 in early development and the protein domain identities suggest that WHSC1 may play a significant role in normal development. Its deletion is likely to be involved in WHS. In two individuals with a ~1.9-Mb deletion that overlaps the current distal breakpoint of the WHCR, it appears that the function of WHSC1 is disrupted.
However, the variation in severity and phenotype of WHS suggests possible roles for genes that lie proximally and distally to the WHCR, including WHSC2 and LETM1 [Zollino et al 2003, Bergemann et al 2005, Rodriguez et al 2005].
WHSC2spans a 26.2-kb genomic region and differs from WHSC1 in several ways. Experiments conducted by Wright et al (1999) confirmed that the gene is ubiquitously expressed. Its location in the WHCR and the identification of a mouse homologue, Whsc2h, suggest that WHSC2 encodes a protein that may play a role in WHS.
LETM1has been proposed as a candidate gene for the neuromuscular aspects of the WHS phenotype. Its position immediately distal to the critical region means it is deleted in almost all affected individuals. In yeast, it has been shown to be involved in mitochondrial potassium homeostasis [Nowikovsky et al 2004, Schlickum et al 2004].
Much work is still needed to identify the function of WHSC1, WHSC2, and LETM1 in both normal development and in individuals with WHS, and to characterize any remaining genes in the WHCR. As detailed analysis of the breakpoints of deletions becomes available, it may become easier to correlate genotype with phenotype for small deletions, possibly elucidating the role that genes outside the WHCR play in WHS. This understanding may be furthered by the generation of a mouse model for WHS. Mice were generated bearing deletions of varying sizes that spanned the WHSCR syntenic region. The phenotype of these animals was variable but included midline, craniofacial, and ocular defects as well as seizures [Naf et al 2001].
WHSCR-2. Zollino et al (2003) proposed a new critical region called WHSCR-2 that is contiguous with and just telomeric of WHSCR and includes the 5' end of WHSC1. WHSCR-2 was defined based on findings in an individual with a mild WHS phenotype and then confirmed in a second person with typical WHS [Rodriguez et al 2005]. Future investigations of additional well-characterized individuals with even smaller deletions will likely define the consensus critical region.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
The 4P-Support Group, Inc
2159 128th St
New Richmond WI 54017
Phone: 715-248-3937
www.4p-supportgroup.org
Associazione Italiana Sindrome Wolf-Hirschhorn
Via Cassiopea 10
20060 Vigliano di Mediglia (Mi)
Italy
Phone: (+39) 0290 600 166
Email: aisiwh@hotmail.com
www.aisiwh.it
Wolf Hirschhorn Syndrome Support Group UK
Phone: (+44) 0 1634 264816
Fax: (+44) 0 1634 264816
Email: whs4p_mjh@hotmail.com
www.whs.webk.co.uk
Chromosome Deletion Outreach, Inc
PO Box 724
Boca Raton FL 33429-0724
Phone: 888-CDO-6880 (888-236-6680); 561-395-4252 (family helpline)
Email: info@chromodisorder.org
www.chromodisorder.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
25 September 2006 (me) Comprehensive update posted to live Web site
6 April 2004 (me) Comprehensive update posted to live Web site
29 April 2002 (me) Review posted to live Web site
2 February 2001 (ab) Original submission
