Search :     
Articles » Aneuploidy » 4p-, Wolf-Hirschhorn syndrome

2000-08-17-14 4p- Syndrome Wolf-Hirschhorn syndrome © Mansour www.thefetus.net/


4p- Syndrome (Wolf-Hirschhorn syndrome)

Ghada M. Mansour, MD

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 mouth”. 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:

   

   

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

 

and finally at 36 weeks, the kidneys

   

 

a section through the upper arm and the head.

 

a representative section of the amniotic fluid

A Doppler examination of the cord

This is the growth curve of the baby

 

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

Achievements

  • Psychomotor delay13
  • Mental 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 defect2

Lungs

  • Pulmonary isomerism
  • Diaphragmatic hernia

Urinary system

  • Renal hypoplasia
  • Polycystic dysplasia11,12
  • Oligomeganephronia (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 dimples11
  • Sacral sinus

Others

  • Skeletal anomalies13
  • Scalp 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:


[2] Battaglia A, Carey JC: Health supervision and anticipatory guidance of individuals with Wolf-Hirschhorn syndrome. Am. J. Med. Genet. 1999 Jun 25;89(2):111-5.

[3] Quarell OWJ,Snell RG,Curtis MA,Roberts SH, Harper PS,Shaw DJ. Paternal origin of the chromosomal deletion resulting in Wolf-Hirschhorn syndrome. J. Med. Genet. 1991,28:256-59.

[4] Anvert M; Nordenskjold M;Stolpe L;Johanson L,Brondum-Nielsen K Molecular analysis of 4p deletion associated with Wolf-Hirschhorn syndrome, moving the critical segment towards the telomere. Hum. Genet. 86:481-83,1991.

[5] Thies U, Back E, Wolff G, Schroeder-Kurth T, Hger HD, Schroder K. Clinical cytogenetic and molecular investigations in three patients with Wolf-Hirschhorn syndrome. Clin. Genet. 1992,42:201-5.

[6] Quarell OWJ, Snell RG, Curtis MA, Roberts SH, Harper PS, Shaw DJ. Paternal origin of the chromosomal deletion resulting in Wolf-Hirschhorn syndrome. J. Med. Genet. 1991,28:256-59.

[7] Battaglia A, Carey JC, Viskochil DH, Cederholm P, Opitz JM. Wolf-Hirschhorn syndrome: a history in pictures. Clin dysmorphol. 2000. Jan; 9(1):25-30.

[8] Johnson VP, Altherr MR, Blake JM, Kepper LD,FISH detection of Wolf-Hirschhorn syndrome: exclusion of D4F26 as critical site. Am. J. Med Genet. 1994. Aug. 1;52(1):70-4.

[9] Battaglia A, Carey JC: Health supervision and anticipatory guidance of individuals with Wolf-Hirschhorn syndrome. Am. J. Med. Genet. 1999 Jun 25;89(2):111-5.

[10] Battaglia A, CareyJC, Cederholm P,Viskochil DH,BrothmanAR, Galasso C. Natural history of Wolf –Hirschhorn syndrome,experience with 15 cases. Pediatrics 1999,103:830-6.

[11] Kohlschmidt N, Zielinski J, Brude E, Schafer D, Olert J, Hallerman C, Coerdt W, Arnemann J. Prenatal diagnosis of a fetus with a cryptic translocation 4p;18p and Wolf-Hirschhorn Syndrome (WHS). Prenatal Diagn 2000 Feb;20 (2):152-5.

[12] Tachdjian G, Fondacci C, Tapia S, Huten Y, Blot P, Nessemann C. The Wolf-Hirschhorn syndrome in fetuses. Clin. Genet. 1992, Dec, 62 (6):281-7.

[13] Tan CK, Tsai FJ, lin CC, Wuj Y, Yu MT, Hsu SL, Shi YR, Chang JC, Lai SW. Wolf-hirschhorn 4Pdeletion syndrome : report of one case. Chung Hua Min Kuo Hsiao Erhko 1 Hsueh Hui Tsa Chih 2000. Jan-Feb, 41(1):39-42.

[14] Sgrov Riva E, Canevini MP, Colamaria V, Rottoli A, Minotti L, Canger  R, Dalla Bernardina. (4P-) syndrome a chromosomal disorder associated with a particular EEG pattern. Epilepsia 1995. Dec, 36(12):1206-14.

[15] Wilcox LMJR, Bercovitch L, Howard RO. Ophthalmic features of Chromosome deletion 4p- (Wolf-Hirschhorn syndrome) Am J Ophthalmol. 1978. Dec, 86 (6) : 384-9.

[16] Laziuk GI, Ostrovskasia TI, Lur, e IV, Kirillova IA, Kravtsova GI. Pathologic anatomy of the Wolf-Hirschhorn syndrome Partial monosomy (4p-). Arkh. patol, 1979;41 (8):40-5.

[17] Breen GH. Taurodontism, an unreported dental finding in Wolf-Hirschhorn syndrome(4P-) syndrome. ASDC. J. Dent. Child. 1998. Sept-Oct;65(5):344-5, 356.

[18] Alpoz AR, Eronat C. Taurodontism in children associated with trisomy 21syndrome. J. Clin. Pediatr. Dent. 1997. Fall, 22(1):37-9.

[19] Park SH, Chi JG. Oligomeganephronia associated with 4p deletion type chromosomal anomaly. Pediatr. Pathol. 1993. Nov-Dec;13(6):731-40.

[20] Hanley-Lozez J, Estabrooks LL, Stiehm R antibody defects in Wolf-Hirschhorn syndrome. J. Pediatr. 1998. Jul;133(1):141-3.

[21] Chen JC, Jen RK, Hsu YW, Ke YB, HwangJJ, Wuk H, Wei TT. (4p-)  syndrome (Wolf-Hirschhorn) syndrome complicated with delayed onset of malignant hyperthermia, acase report. Acta Anaesthesiol. Sin. 1994. Dec; 32(4):275-8

[22] Pitt DB, Rogers JG, Danks DM:Mental retardation, unusual face, and intrauterine growth retardation, a new recessive syndrome. Am. J. Med Genet. 1984, 19:307-13.

[23] Clemens M, Martsolf JT, Rogers JG, Mowery-RushtonP, SurtiU, Mcpherson E. Pitt, Rogers, Danks Syndrome:The result of a 4p microdeletion. Am. J. Med. Genet. 1996 Dec. 2;66(1):95-100.

[24] Wright TJ, Costa JL, Naranj OC, Francis-West P, Atherr MR. Comparative analysis of a novel gene from the Wolf –Hirschhorn / Pitt Rogers Danks syndrome. Critical region Genomics. 1999. Jul 15;59(2):203-12.

[25] Wright TJ, Clemens M, Quarell O, Alther MR. Wolf-Hirschhorn Syndrome and Pitt Rogers Danks Syndromes, caused by overlapping 4P deletions. Am. J. med. Genet. 1998 Feb. 3; 75 (4):345-50.

[26] Kant SG, Van Hearnigen A, Bakker E, Stec I, Donnai D, MollevangerP, Beverstock GC, Lindeman Kusse MC, Vanommen GJ. PITT, Rogers, Danks Syndrome and Wolf-Hirschhorn syndrome are caused by a deletion in the same region on chromosome 4p6. 3. J. Med. Genet. 1997 Jul;34(7):569-72.

[27] Tommerup N, Aagaard L, Lund CL, Boel E, Baxendal S, Bates GP, Lehroch H, Vissing H. A zinc finger gene ZNF141 mapping at 4P16. 3/D4590 is a candidate gene for the Wolf-Hirschhorn (4p-) Syndrome. Hum. Mol. Genet. 1993, Oct, 2(10) : 1571-5.

Help Support TheFetus.net :