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2011-01-18-10 Wolf-Hirschhorn syndrome © Cuillier www.TheFetus.net  
Wolf-Hirschhorn syndrome


Fabrice Cuillier
, MD.


Department of Gynecology, Félix Guyon Hospital, 97400 Saint-Denis, Ile de la Réunion, France.

Introduction

Wolf-Hirschhorn syndrome demonstrates in the antenatal period with some characteristic findings:

  • Severe intrauterine growth restriction
  • Facial dysmorphic features, midline defects (hypertelorism, labial or labio-palatine defects, corpus callosum agenesis)
  • Cardiac septal defects
  • Urinary tract malformations
  • Brain anomalies
 


During postnatal life, neurodevelopmental delay and epilepsy can reveal this chromosomal abnormality.

Case report

We diagnosed the four following cases of Wolf-Hirschhorn syndrome prenatally.

Case 1

A 23-year-old G1 P0, was scanned at our antenal unit at 30 weeks of gestation for a severe intrauterine growth restriction. Patient had non-contributive family or personal history. The ultrasound scan at 22 weeks did not reveal any anomaly.
At 30 weeks of gestation we detected a intrauterine growth restriction, without abnormal Doppler. The ultrasound findings included the following: microcephaly, flat fetal profile, a big toe and curved penis. An amniocentesis was performed. The result showed a normal karyotype 46 XY. Fluorescent hybridization in situ (FISH) detected a deletion of the short arm of chromosome 4 (4p-), which was consistent with Wolf-Hirschhorn syndrome.
Patient agreed with the pregnancy termination at 35 weeks of gestation.

Images 1,2: Images of the flat profile.



Images 3,4: Image 4 shows a big toe (arrow). Image 4 shows a curved penis.

 


Case 2

A 23-year-old, G1 P0, was scanned at our antenal unit at 32 weeks of gestation for an intrauterine growth restriction. We detected a flat fetal profile. The amniocentesis result confirmed deletion of the short arm of chromosome 4, 4p-. Patient decided for the pregnancy termination at 33 weeks of gestation.    

Images 5,6: Flat profile, prenasal edema. 



Image 7,8: Image 7 shows an ear. Image 8 shows a fetal biometry at 32 weeks of gestation, the estimated fetal weight was 1206 grams corresponding with 29 weeks of gestation.



Case 3

A 30-year-old patient was referred to our department at 30 weeks of gestation for a severe intrauterine growth restriction. The fetal profile was flat. The amniocentesis with FISH showed a deletion of the short arm of chromosome 4. Patient opted for the pregnancy termination at 32 weeks of gestation. 

Images 9,10: Image 9 shows an abnormal fetal profile. Image 10 shows a fetal biometry at 30 weeks of gestation, estimated fetal weight was 770 grams corresponding with 26 weeks of gestation.

 

Case 4

A 28-year-old patient was seen in our antenatal unit at 24 weeks of gestation for intrauterine growth restriction. The ultrasound scan at 27 weeks of gestation showed a microcephaly and prefrontal edema. The facial profile was flat. The amniocentesis and FISH confirmed a Wolf-Hirschhorn syndrome.

Images 11
: Image 11 shows a fetal profile with prefrontal edema.



Images 12,13:
Image 12 shows a biparietal diameter (red cross) and head circumference (red dots), all the values are below the 5th percentile. Image 13 shows the length of the long bones, x-axis shows weeks of gestation and y-axis bone length, all values are below the 5th percentile.




Image 14,15: Pictures of the fetus after pregnancy termination, note the typical facial features " Greek warrior helmet appearance", the broad nasal bridge continuing to the forehead, high forehead, microcephaly, hypertelorism, short philtrum, downturned mouth, malformed ears.  

 

Discussion


Monosomy 4p- is a rare chromosomal aberration frequently diagnosed after birth after development of the
psychomotor retardation, epileptic seizures and growth retardation with hypotonia. 
Prenatally, it is usually characterized by a severe intrauterine growth restriction and fronto-nasal dysmorphy described as
a "Greek warrior helmet appearance". Microcephaly is always present (87 % of cases according to  Haentjens). 

The diagnosis is confirmed by a detection of a deletion of the Wolf-Hirschhorn syndrome critical region (WHSCR, within chromosome 4p16.3) of the short arm of the chromosome 4.

The frequency of Wolf-Hirschhorn syndrome is very low: 0.01-0.2:10000.  Haentjens-Verbeke wrote in 1996 that there were 180 cases of
Wolf-Hirschhorn syndrome described in the literature, but in most cases diagnosed after delivery. Hirschhorn described the first child affected by Wolf-Hirschhorn syndrome in the year 1961. In 1963, Lejeune described three children, with a deletion of the short arm of chromosome 5, 5p- (Cri-du-chat syndrome). In 1965, Wolf published another cases of Wolf-Hirschhorn syndrome. Wolf and Hirschhorn described together this dysmorphy in 1965 and afterwards, with a development of cytogenetics, the mechanism of this condition was discovered as well.

Wolf-Hirschhorn syndrome is caused by deletion of the WHSCR of chromosome 4p16.3 by one of several genetic mechanisms. About 50%-60% of individuals have a de novo deletion of 4p16 and about 40%-45% have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. These unbalanced translocations may be de novo or inherited from a parent. Risks of inheritance depends on the mechanism of the deletion. Prenatal testing is possible for families in which one parent is known to be a carrier of a chromosome rearrangement involving 4p16.3.
 
Prenatal discovery of
Wolf-Hirschhorn syndrome is possible if we know the characteristic ultrasound findings, usually facial dysmorphic features with microcephaly and intrauterine growth restriction with normal Doppler. Detailed scan of the fetal face, including 3D imaging is helpful.
According to Talmant, fetal profile analysis should be precise and relies on the objective signs. We should carefully analyze the following:

  • Forehead, not too flat nor protuberant
  • Frontonasal angle, approximately 130°
  • Nasal bone is of the same length as the cartilage
  • The philtrum and nasal columna are of the same length
  • The inferior lip is separate from the superior lip
  • The chin prominence is in the level of the fronto-nasal plane
  • The tongue is not protruding

 
Conclusion

When we discover a flat facial profile with an abnormal fronto-nasal angle (> 140°) and intrauterine growth restriction, 4p deletion, Wolf-Hirschhorn syndrome must be included into differential diagnosis. Levaillant et al. emphasized the importance of 3D sonography to described the facial dysmorphic features.

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