AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Cooper and Hirschhorn first documented Wolf-Hirschhorn syndrome in 1961.¹ They described a child with midline fusion defects, and subsequent cytogenetic studies revealed a chromosomal deletion of the short arm of chromosome 4. In 1965, back-to-back publications in Humangenetik by Hirschhorn et al and Wolf et al brought the disease to the attention of geneticists and other medical professionals.^{2, 3} Numerous cases were subsequently published. Clinical features include mental retardation, seizures, distinct facial appearance, and midline closure defects.

Pathophysiology

Wolf-Hirschhorn syndrome results from the deletion of the distal short arm of chromosome 4. Deletion of the terminal band (4p16.3) is essential for full expression of the phenotype.

A large deletion several megabases (Mb) in length, easily detected using conventional chromosome analysis, is usually associated with severe phenotypic expression, including multiple malformations. However, a microdeletion of band 4p16.3, detected only by molecular probes, is usually associated with a milder phenotype without malformations.

Most phenotypic manifestations in this syndrome reflect a contiguous gene syndrome, leading to a phenotypic map of chromosome arm 4p. However, similar genetic rearrangements in this syndrome may determine variable phenotypic effects, most likely as a consequence of allelic variation in the homologous 4p region. The former Pitt-Rogers-Danks syndromes, caused by overlapping 4p deletions, are now considered to be a part of Wolf-Hirschhorn syndrome.

Frequency

United States

The incidence rate is estimated at 1 in 50,000 births.

Mortality/Morbidity

Mortality rate is estimated at 34% in the first 2 years of life. However, because many affected children die before the anomaly is diagnosed or suspected, the mortality rate is underestimated. The usual cause of death is a heart defect, aspiration pneumonia, infection, or seizure.

• Prenatal mortality rate of Wolf-Hirschhorn syndrome is not significantly augmented because 4p deletions are not reported as an increase in spontaneous abortions.
• Associated adulthood morbidity includes congenital heart defect; marked growth failure; contracture of hands, wrists, and feet; poor development of secondary sexual characteristics; and severe growth and intellectual impairment.

Race

Wolf-Hirschhorn syndrome has no ethnic predilection.

Sex

Wolf-Hirschhorn syndrome is more common in females than in males, with a male-to-female ratio of 1:2.

Age

Usually, the condition is detected in the newborn period because of dysmorphic features.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Pregnancy history
• • Intrauterine growth retardation
  • Decreased fetal movements
  • Hypotrophic placenta
• Developmental history
• • Delayed psychomotor development
  • Difficulty in ambulation, often with ataxic gait
  • Seizures (50%)
• Behavior history
• • Stereotypes (holding the hands in front of the face, hand-washing or flapping, patting self on chest, rocking, head-shaking, stretching of legs)
  • Absence of speech
  • Babbling or guttural sounds, occasionally modulated in a communicative way
  • Comprehension limited to simple orders or to a specific context
  • Affect disorder that improves over time
  • Walking with or without support
  • Self-feeding
  • Helps in dressing and undressing self
  • Improved abilities and adaptation to new situations
  • Communicative abilities and verbal comprehension with extension of the gesture repertoire and decreased occurrence of withdrawal and anxiety behaviors

Physical

• Growth - Severe growth retardation (short stature)
• CNS - Profound mental retardation, microcephaly, seizures, congenital hypotonia with muscle hypotrophy particularly of the lower limbs, hypoplasia of cerebellum, cavum or absent septum pellucidum, agenesis of corpus callosum, hypoplasia or absence of olfactory bulbs and tracts, microgyria, migration defects, hydrocephalus
• Skull - Frontal bossing, high frontal hairline, hemangioma over forehead or glabella, scalp defect with or without underlying bony defect
• Face - Characteristic dysmorphic features including prominent glabella, hypertelorism, broad beaked nose, and frontal bossing, collectively described as "Greek warrior helmet" facies
• Eyes - Hypertelorism, down-slanting palpebral fissures, epicanthal folds, strabismus, coloboma, proptosis due to hypoplasia of orbital ridges, ectopic pupils, exotropia, ptosis, microphthalmia, megalocornea, sclerocornea, cataracts, hypoplastic anterior chamber and ciliary body of iris, persistence of lenticular membrane, hypoplastic retina with formation of rosettes, cup-shaped optic discs, congenital nystagmus, Rieger anomaly
• Nose - Broad or beaked nose, nasolacrimal duct stenosis or atresia
• Mouth - Short upper lip, short philtrum, cleft lip or palate, bifid uvula, carplike mouth, micrognathia, retrognathia
• Teeth - Hypodontia
• Ears - Low-set ears; large, floppy, or misshapen ears; microtia; preauricular dimples; chronic otitis media with effusion; sensorineural hearing loss
• Cardiovascular - Atrial septal defect, ventricular septal defect, persistent left superior vena cava, valve abnormalities, complex cardiac defects
• Pulmonary - Bilateral bilobed or trilobed lungs, lung hypoplasia secondary to diaphragmatic hernia
• GI - Diastasis recti, umbilical or inguinal hernias, accessory spleens, absent gallbladder, diaphragmatic hernia, intestinal malrotation
• Genitourinary - Hypoplastic kidneys, cystic dysplastic kidneys, unilateral renal agenesis, hydronephrosis, exstrophy of bladder, hypoplastic external genitalia, cryptorchidism and hypospadias in males, hypoplastic müllerian derivatives (ie, agenesis of vagina, cervix, or uterus; hypoplastic uterus; ovarian streaks) in females
• Skeletal - Long slender fingers with additional flexion creases, long narrow chest, hypoplastic widely spaced nipples, hypoplasia or duplication of thumbs and great toes, talipes equinovarus, hypoplasia of pubic bones, vertebral and rib anomalies, defective calvaria ossification, scoliosis, kyphosis, osteoporosis, delayed bone maturation, sacral dimple
• Immune system - Infection-prone, immunodeficiency
• Dermatoglyphics - Hypoplastic dermal ridges, transverse palmar creases (25%), excess of digital arches, t or t'
• Fetal phenotype
• • Minor anomalies - Scalp defect, hypertelorism usually with a prominent glabella, pulmonary isomerism, common mesentery, hypospadias, sacral dimple
  • Major anomalies - Intrauterine growth retardation, microcephaly, cleft palate, corpus callosum agenesis, ventricular septal defect, diaphragmatic hernia, renal hypoplasia

Causes

• Wolf-Hirschhorn syndrome is caused by a deletion in the terminal band of the short arm of chromosome 4 (band 4p16.3). The cause in 87% of cases is a de novo interstitial deletion of preferential paternal origin. The remaining 13% are due to unbalanced product of a parental chromosomal rearrangement, usually of a reciprocal translocation. The number of translocations may be higher because fluorescence in situ hybridization (FISH) has demonstrated submicroscopic translocations in cytogenetically normal parents and affected offspring.
• A new mechanism of familial recurrence of a microdeletion syndrome has been described. Faravelli et al reported a case of familial recurrence of Wolf-Hirschhorn syndrome involving a previously unreported expansion of the deletion during the mother-to-son transmission. The report described a mother with partial Wolf-Hirschhorn syndrome, facial "gestalt,” borderline mental delay, a few episodes of seizures as a child, normal weight and head circumference, height at the lower limit of the reference range, and a smaller 4p deletion that spanned the 1.5-Mb region from locus D4S96 to the telomere.⁴
• Molecular analysis of various patients localized the critical region to the approximate 450-700 kb between D4S168/FGFR3 and D4S166/D4S43. The chromosome band 4p16.3 region also contains a gene called DFNA6, which encodes for autosomal dominant nonsyndromic hereditary hearing loss.
• Using genotype-phenotype correlation analysis in 8 informative patients, Zollino et al (2003) characterized the following minimal diagnostic criteria for this condition: presence of typical facial appearance, mental retardation, growth delay, congenital hypotonia, and seizures.⁵ They also mapped this basic phenotype outside the currently defined Wolf-Hirschhorn syndrome critical region (WHSCR) and designated a new critical region, WHSCR-2.

DIFFERENTIALS

Section 4 of 11  

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• Introduction
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• Differentials
• Workup
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Other Problems to be Considered

Duplication 4p syndrome: This syndrome is characterized by interstitial direct duplication of 4p (4p16.1-3), large low-set ears, microcephaly, a prominent glabella, broad nasal bridge, bulbous nose (often referred to as box nose), growth deficiency, severe mental retardation, seizures, scoliosis, fifth finger clinodactyly, flexion contractures, and hypospadias.

Other autosomal monosomy syndromes and trisomy syndromes

Other multiple congenital anomalies and mental retardation syndromes

Pitt-Rogers-Danks syndrome (OMIM #262350): This is a rare disorder, presumed to have autosomal recessive inheritance, that is characterized by prenatal and postnatal growth retardation, microcephaly, characteristic facial appearance, seizures, unusual palmar creases, and developmental delay. Microdeletion of chromosome band 4p16 has been reported.

Proximal 4p syndrome: This syndrome is characterized by deletion of the proximal half of chromosome arm 4p (4p11->4p15), moderate mental deficiency, normal height, short palpebral fissures, abnormal ears, large nose, broad hands, microcephaly, short fingers, and congenital heart defects.

Seckel syndrome (OMIM #210600): This syndrome is also known as bird-headed dwarfism or microcephalic primordial dwarfism type I.

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Conventional cytogenetic studies
• • These are the most common studies used to detect chromosome arm 4p deletions.
  • Small chromosome arm 4p deletions may be missed.
• High-resolution cytogenetic studies
• • Smaller deletions of chromosome band 4p16.3 may be detected with this study.
  • Very small rearrangements, especially subtle translocation, can be very difficult to detect, even with high-resolution chromosome analysis.
• Fluorescence in situ hybridization
• • Molecular cytogenetic studies using FISH allow the diagnosis to be made in patients with very small deletions or cryptic translocations.
  • FISH uses genetic markers that have been precisely localized to the area of interest.
  • The absence of signal from either the maternal or paternal allele for the marker indicates monosomy for that chromosomal region.
  • Commercially, D4S96 or D4Z1 chromosome band 4p16.3–specific probe (Wolf-Hirschhorn region, Vysis, Inc) is available for FISH study.
• Microarray-based comparative genomic hybridization analysis: This study is faster and more convenient in detecting a large deletion region than other studies.
• Immune workup: Patients should be assessed for common variable immunodeficiency, immunoglobulin A (IgA) and immunoglobulin G2 (IgG2) subclass deficiency, IgA deficiency, impaired polysaccharide responsiveness, and normal T-cell immunity.

Imaging Studies

• Radiography may reveal delayed bone maturation, microcephaly, hypertelorism, micrognathia, anterior fusion of vertebrae, fused ribs, dislocated hips, proximal radioulnar synostosis, and club feet.
• Echocardiography may be helpful in detecting heart defects.
• Renal ultrasonography is used to detect renal anomalies.
• MRI and CT scanning may reveal underlying brain pathology, including agenesis of corpus callosum and ventriculomegaly.

Other Tests

• EEG for seizure monitoring
• Swallowing study for feeding difficulty
• Comprehensive audiologic and otologic evaluation to rule out possible hearing impairment
• Ophthalmologic examination
• Developmental testing and referral to early intervention and appropriate school placement

Procedures

• Gastrostomy may be necessary in infancy to protect the airway of patients with major feeding difficulty.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Medical care is supportive. The underlying disorder has no known treatment.

• Seizure control
• Multidisciplinary team approach
• Genetic counseling
• • Recurrence risk is negligible unless a parent is a translocation carrier.
  • Reassessing patients with abnormal phenotypes previously reported as cytogenetically normal is imperative because the precise diagnosis in the propositus has important reproductive implications.
  • FISH can demonstrate submicroscopic translocations in cytogenetically normal parents and affected offspring.

Consultations

• Clinical geneticist
• Developmental pediatrician
• Neurologist
• Cardiologist
• Ophthalmologist
• Orthopedist
• Physical therapist
• Occupational therapist
• Speech language pathologist
• Audiologist

Diet

No special diet is required.

Activity

Activities are limited because of profound mental retardation and physical limitations.

MEDICATION

Section 7 of 11  

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• Differentials
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• Follow-up
• Miscellaneous
• Multimedia
• References

Medical care is supportive. No medications are used to treat the underlying disorder.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Prognosis

• Wolf-Hirschhorn disease is associated with frequent stillbirths, perinatal deaths, and death within the first year of life.
• If patients survive beyond infancy, their development progresses slowly but constantly.

Patient Education

• Up-to-date information about the syndrome should be made available to the families through the following organizations:
• • National Organization for Rare Disorders, Inc. (NORD)
    55 Kenosia Avenue
    PO Box 1968
    Danbury, CT 06813-1968
    Tel: (800) 999-6673
    Fax: (203) 798-2291
    email: orphan@rarediseases.org
  • Chromosome Deletion Outreach, Inc.
    PO Box 724
    Boca Raton, FL 33429-0724
    Tel: (561) 395-4252
    email: info@chromodisorder.org

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to identify characteristic symptoms and signs
• Failure to refer to a geneticist for evaluation and genetic counseling
• Failure to request chromosome analysis of clinically diagnosed patients and their parents to rule out familial translocation
• Failure to offer prenatal diagnosis after having an affected child
• Failure to reassess patients with abnormal phenotypes previously reported as cytogenetically normal (The precise diagnosis in the propositus has important reproductive implications.)  
• Failure to recognize and inform parents about the psychomotor potential of a child with Wolf-Hirschhorn syndrome to allow informed decisions concerning home rearing or institutional placement

Special Concerns

• Prenatal diagnosis
• • Two-dimensional ultrasonography: This may reveal the distinct phenotype in utero. Findings include severe intrauterine growth retardation; microcephaly; hypertelorism, usually with prominent glabella; cleft lip and palate; and diaphragmatic hernia. These findings should lead to karyotyping.
  • Three-dimensional ultrasonography:  This depicts the prenatal appearance of the fetal face in a fetus affected with a genetic syndrome. In particular, the depiction of the “Greek warrior helmet” sign is striking. In addition, the associated anomalies, such as hypospadias, which presents as a "tulip sign." are clearly visible.
  • Amniocentesis, chorionic villi sampling, or fetal blood sampling

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  A child with Wolf-Hirschhorn syndrome. Note the characteristic dysmorphic facial features, including prominent glabella, hypertelorism, beaked nose, and frontal bossing, collectively described as "Greek warrior helmet" facies.
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Media file 2:  A fetus with Wolf-Hirschhorn syndrome. Note the presence of "Greek warrior helmet" facies.
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Media type:  Photo

Media file 3:  The result of a fluorescence in situ hybridization (FISH) study of a patient with Wolf-Hirschhorn syndrome. FISH photograph shows deletion of a locus-specific probe for the Wolf-Hirschhorn critical region (absence of a probe signal at 4p16.3).
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Media type:  Photo

Media file 4:  G-banded karyotype showing deletion of a distal part of the short arm of a chromosome 4 [del(4)(p15.2)].
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
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• Differentials
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• Follow-up
• Miscellaneous
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• References

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Article Last Updated: Aug 3, 2007