eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Wolf-Hirschhorn Syndrome: Differential Diagnoses & Workup

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

Differential Diagnoses

Cri-du-chat Syndrome
Patau Syndrome
Smith-Lemli-Opitz Syndrome
Trisomy 18

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. The syndrome is now considered to be a part of Wolf-Hirschhorn syndrome.
  • 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

Laboratory Studies

The following studies may be useful in Wolf-Hirschhorn syndrome:

  • 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.
  • Conventional and high-resolution cytogenetic analysis: This detects approximately 60-70% of the deletions in Wolf-Hirschhorn syndrome.
  • Fluorescence in situ hybridization (FISH) 
    • FISH using a WHCR probe detects more than 95% of deletions in Wolf-Hirschhorn syndrome.
    • 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.
  • Subtelomeric FISH15
    • This is probably the most sensitive and specific way to identify a derivative chromosome 4 because most translocations involve the subtelomeric regions.
    • This study is used to identify the chromosomal origin of the additional segment.
  • Spectral karyotyping (SKY)/M-FISH
    • This is used to identify the translocation partner in cases in which conventional cytogenetic studies reveal the additional material has been translocated to 4p.16,17
    • This study may miss small segments (<5-10 Mb).
  • Deletion/duplication analysis using DNA from lymphocyte cell lines hybridized to a panel of BAC clones that span the terminal region of 4p16.3
    • This 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.18,19
  • 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.

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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