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4p- Syndrome Wolf-Hirschhorn syndrome

Ghada M. Mansour, MD

Article Published: May 24, 2002

Cairo, Egypt

Synonyms: 4p Deletion Syndrome, Wolf-Hirschhorn syndrome (WHS), Wolf-Hirschhorn chromosome region (WHCR)[1]

Definition: Chromosomal disorder caused by loss of material from the distal aspect of the short arm of chromosome 41.

Incidence: Around 120 cases reported in the world literature[2], but several times that many are registered in support group.

Etiology: Abnormal chromosome breakage during synapsis and recombination

Recurrence risk: Unknown.

Inheritance: Although it was first thought that the deletion was paternal in origin[3], it has been found recently that it can be of both maternal or paternal origin[4],[5]. Paternal age is not a causal factor[6].

Diagnosis: The prenatal diagnosis is suggested by the presence of severe intrauterine growth retardation associated with midline defects, and a "downturn mouthâ€. The following images are from the case of the week #31.

This baby was seen on 3 examinations. The first at 26 weeks one day, then again at 29 weeks 5 days and 36 weeks 5 days. The following images (head, lips and kidneys) were obtained at 26 weeks:

case0031-4
case0031-7
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case0031-6
 

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The patient declined an amniocentesis. These are the images at 29 weeks

case0031-9
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and finally at 36 weeks, the kidneys

case0031-12
case0031-13
case0031-14
 

case0031-18
case0031-20

a section through the upper arm and the head.

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a representative section of the amniotic fluid

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A Doppler examination of the cord

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This is the growth curve of the baby

case0031-1
 

These are some of the growth measurements (the actual gestational age is under the date): 

 

 October 7
(26 weeks 1 day)

 November 1
(29 weeks 5 days)

 December 20
(36 weeks 5 days)

Biparietal
diameter

 58 mm = 23 weeks 6 days

 69 mm = 27 weeks 4 days

 85 mm = 34 weeks 2 days

Abdominal perimeter

 191 mm = 23 weeks 6 days

 220 mm = 26 weeks 3 days

 278 mm = 31 weeks 6 days

Femur length

 43 mm = 22 weeks 5 days

 51 mm = 27 weeks 1 day    

58 mm = 30 weeks 4 days    

Genetic diagnosis: Although there may be some difficulty in detecting some small deletions by cytogenetics[7], the standard cytogenetics (regular-G-banding[8], high resolution banding[9], PCR typing, Southern blot hybridization and/or fluorescence in situ hybridization (FISH) technique) can all provide the diagnosis[10]. The gene map locus is 4p16.3

Associated anomalies:

Growth
  • Severe growth retardation is the rule
[11],[12],[13],

Achievements
  • Psychomotor delay
13Mental retardation11,13

Central nervous system
  • Dysgenesis of the corpus callosum
  • Abnormal EEG pattern characterized by generalized or unilateral myoclonic seizures followed by brief atypical absences
[14]. Seizure disorders tend to disappear with age2.

Skull
  • Microcephaly

Face
  • Greek-Helmet facial appearance
  • Ear lobe anomalies
  • Low-set ears
  • Anterior eye segment anomalies (extropia, blepharoptosis)
  • Coloboma of the eyes
  • Hypertelorism
  • Downward slanting palpebral fissures
  • Some ophthalmic features of 4p- syndrome are similar to those of 5p-, (Cri-du-Chat syndrome)
[15]. Coracoid nose[16] Facial dysmorphia Cleft lip and palate Downturned mouth Taurodontism[17], which is a dental, trait characterized by teeth with elongated pulp chambers and apical displacement of the bifurcation and trifurcation of roots. It causes eruption delay and congenitally lost teeth[18].

Heart
  • Ventricular septal defect
2

Lungs
  • Pulmonary isomerism
  • Diaphragmatic hernia

Urinary system
  • Renal hypoplasia
  • Polycystic dysplasia
11,12Oligomeganephronia (a rare renal hypoplasia characterized by a reduction in the number of reniculi with compensatory hypertrophy of the glomeruli and proximal renal tubules[19])

Genital
  • Hypospadias

Spine
  • Sacral dimples
11Sacral sinus

Others
  • Skeletal anomalies
13Scalp defects Midline defects Antibody deficiencies (IgA and IgG2) are mentioned in some cases. The association of antibody defects with 4p- suggests a regulatory gene with the deleted chromosome region that affects the B cell system[20]. One 8 months old baby girl developed malignant hyperthermia, after cheiloplasty[21].

Differential diagnosis:

·       PITT syndrome is very closely related to 4p-. PITT syndrome was first described in 1984[22]. Since that only 7 cases have been reported.  PITT syndrome or Pitt-Rogers-Danks syndrome (PRDS) is a rare presumed autosomal recessive syndrome with pre- and postnatal growth retardation, microcephaly, characteristic facial appearance, seizures, unusual palmar creases, and developmental delay[23]. It is also a microdeletion in 4p16.3. It is uncertain if the critical region involves a single locus or multiple loci or to what extent this region overlaps with critical region of 4p-23. It can be considered to be allelic to 4p-[24] and so the clinical differences observed in between 2 syndromes are likely the result of allelic variation in the remaining homologue[25]. 4p- and PRDS in other literature are considered as 2 different clinical phenotypes resulting from a deletion in the same microscopic region on chromosome 4p6[26].

·        Zink finger syndrome is considered as a subfamily of 4p-, however signs and symptoms are different[27].

·        Other aneuploidies: Although 4p- is similar to 5p-, 4p- individuals do not have the distinct cry. The ocular features, which distinguish 4p- from other deletions, include normal tearing, some degree of blepharoptosis, and the preponderance of anterior segment signs15.  

Prognosis: Lethal, however 4 cases has been followed up to 16 years2.

Support groups and web links:

Larry Bentley"s Page - Wolf-Hirschhorn Syndrome

Family Village - Wolf Hirschhorn Syndrome

Additional Information ...

Chromosome Deletion Outreach, Inc.

Ethan"s page

References:

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