eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Wolf-Hirschhorn Syndrome

Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center
Contributor Information and Disclosures

Updated: Jun 16, 2009

Introduction

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.
  • The genotype-phenotype correlation is as follows:4
    • Clinically, the minimal diagnostic criteria for Wolf-Hirschhorn syndrome (ie, ‘‘core’’ phenotype) consists of typical facial appearance, mental retardation, growth delay, and seizures (or EEG anomalies).
    • Three different categories of the Wolf-Hirschhorn syndrome phenotype are defined and generally correlate with the extent of the 4p deletion.
      • The first is composed of a small deletion (£ 3.5 Mb) that is usually associated with a mild phenotype, lacking major malformations. This category is likely under-diagnosed.
      • The second and far more frequent category is identified by large deletions that average 5-18 Mb and cause the widely recognizable Wolf-Hirschhorn syndrome phenotype.
      • The third clinical category results from a very large deletion that exceeds 22–25 Mb, causing a severe phenotype that can hardly be defined as typical Wolf-Hirschhorn syndrome.
    • Factors involved in prediction of prognosis include the extent of the deletion, the occurrence of complex chromosome anomalies, and the severity of seizures.
    • The core phenotype maps within the terminal 1.9 Mb region of chromosome 4p. Therefore, WHSCR-2 should be considered the critical region for this condition.
    • Pathogenesis of Wolf-Hirschhorn syndrome is multigenic.

Frequency

United States

  • The frequency is estimated to be 1 case per 50,000 births to 1 case per 20,000 births.5,6

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

History

The following may be observed in patients with Wolf-Hirschhorn syndrome:

  • 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

Studies of large samples of individuals, including those with submicroscopic deletions and those with a derivative chromosome 4,7 have led to the recognition of a more complete continuum of the phenotype, pointing out a much wider clinical spectrum than previously thought.8,9

  • Growth - Prenatal onset growth deficiency followed by postnatal growth retardation (short stature)
  • CNS - Developmental delay and mental retardation of varying degree, 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

    A child with Wolf-Hirschhorn syndrome. Note the c...

    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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    A child with Wolf-Hirschhorn syndrome. Note the c...

    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.



    A fetus with Wolf-Hirschhorn syndrome. Note the p...

    A fetus with Wolf-Hirschhorn syndrome. Note the presence of "Greek warrior helmet" facies.

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    A fetus with Wolf-Hirschhorn syndrome. Note the p...

    A fetus with Wolf-Hirschhorn syndrome. Note the presence of "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) and is considered a contiguous gene syndrome.8 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.

    The result of a fluorescence in situ hybridizatio...

    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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    The result of a fluorescence in situ hybridizatio...

    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).

  • 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.10 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.
  • 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.11 They also mapped this basic phenotype outside the currently defined Wolf-Hirschhorn syndrome critical region (WHSCR) and designated a new critical region, WHSCR-2.
  • LETM1 has been proposed as a candidate gene for the neuromuscular aspects of the Wolf-Hirschhorn syndrome phenotype. Its position immediately distal to the critical region means that it is deleted in almost all affected individuals. In yeast, it has been shown to be involved in mitochondrial potassium homeostasis.12,13
  • A patient with developmental delay and several facial characteristics reminiscent of Wolf–Hirschhorn syndrome who carries a terminal 4p16.3 deletion of 1.691 Mb minimally and 1.698 Mb maximally was reported.14 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 patients with 4p16.3 deletion.

More on Wolf-Hirschhorn Syndrome

Overview: Wolf-Hirschhorn Syndrome
Differential Diagnoses & Workup: Wolf-Hirschhorn Syndrome
Treatment & Medication: Wolf-Hirschhorn Syndrome
Follow-up: Wolf-Hirschhorn Syndrome
Multimedia: Wolf-Hirschhorn Syndrome
References
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References

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Further Reading

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Keywords

Wolf-Hirschhorn syndrome, chromosome 4p deletion syndrome, 4p- syndrome, monosomy 4p syndrome, Wolf syndrome, Pitt-Rogers-Danks syndrome, mental retardation, seizures, distinct facial appearance, midline closure defects, congenital heart defect, marked growth failure, contracture of hands, contracture of wrists, contracture of feet, hypotrophic placenta, microcephaly, congenital hypotonia, hypoplasia of the cerebellum, agenesis of corpus callosum, microgyria, migration defects, hydrocephalus, frontal bossing, high frontal hairline, hemangioma, prominent glabella, hypertelorism, broad beaked nose, epicanthal folds, strabismus, coloboma, proptosis

ectopic pupils, exotropia, ptosis, microphthalmia, megalocornea, sclerocornea, hypoplastic anterior chamber, congenital nystagmus, Reiger anomaly, Reiger’s anomaly, hypodontia, chronic otitis media, atrial septal defect, ventricular septal defect, lung hypoplasia, diastasis recti, umbilical hernia, inguinal hernia, accessory spleen, hypoplastic kidney, cystic dysplastic kidneys, unilateral renal agenesis, cryptorchidism, hypospadias, hypoplastic müllerian derivatives, talipes equinovarus, cleft palate, treatment, diagnosis

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Contributor Information and Disclosures

Author

Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center
Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Human Genetics, and Teratology Society
Disclosure: Nothing to disclose.

Medical Editor

Erawati V Bawle, MD, FAAP, FACMG, Division of Genetic and Metabolic Disorders, Children's Hospital of Michigan; Professor (Clinician-Educator), Department of Pediatrics, Wayne State University School of Medicine
Erawati V Bawle, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Robert Anthony Saul, MD, Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center
Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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