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Wolf-Hirschhorn Syndrome

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Wolf-Hirschhorn Syndrome Wolf-Hirschhorn syndrome Author: Dr. Dagmar Wieczorek Creation date: September 2003 Scientific editor: Professor Alain Verloes Institut fur Humangenetik, Universitatsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Germany. [email protected] Abstract Key words Disease name and synonyms Excluded diseases Diagnostic criteria/ definition Differential diagnosis Frequency Clinical description Management including treatment Etiology Diagnostic methods Genetic counseling Antenatal diagnosis Unresolved questions References Abstract Wolf-Hirschhorn syndrome (WHS) is caused by a deletion of the band 4p16.3 and this deletion may be submicroscopic. The craniofacial phenotype (microcephaly, hypertelorism, prominent glabella, broad and/or beaked nose, short philtrum, micrognathia, downturned corners of the mouth, dysplastic ears, preauricular tags) in combination with mental retardation, seizures, congenital heart defects, genital and renal anomalies is indicative for the diagnosis. A familial translocation is responsible for 5 – 13% of the patients. The remainder of the patients have de novo deletions, usually on the paternal chromosome 4, or de novo translocations in 1.6 %. Submicroscopic deletions require molecular techniques, e.g. microsatellite analysis, or molecular-cytogenetic techniques, e.g. fluorescence in situ hybridisation (FISH), to detect the deletion. Fluorescence in situ hybridisation of the patient and his parents should be performed to confirm/exclude translocations. Recurrence risk is low in de novo deletions and translocations, but is remarkably increased in familial translocations. Prenatal diagnosis is possible. Key words Wolf-Hirschhorn syndrome, 4p- syndrome, partial deletion 4p, terminal deletion 4p Disease name and synonyms craniofacial gestalt with hypertelorism, prominent Wolf-Hirschhorn syndrome, 4p- syndrome, partial glabella, broad and/or beaked nose, short philtrum, deletion 4p micrognathia, downturned corners of the mouth, cleft lip/palate, dysplastic ears, and preauricular Excluded diseases tags and pits, microcephaly (90%), mental Other chromosomal aberrations retardation (75%), low birth weight (77%), short Diagnostic criteria/ definition stature (25-66%), muscular hypotonia (90%), Wolf-Hirschhorn syndrome (WHS) was first and seizures (50-85%), congenital heart defects (31- independently published in 1965 by Wolf et al., and 45%), colobomata of iris (30%), genital anomalies Hirschhorn et al., It refers to a wide spectrum of (30%), deafness (23%), and renal anomalies (23%). clinical signs in patients with terminal 4p deletions. Mental retardation reaches from mild to profound. The characteristic clinical signs consist of a typical Acquisition of walking without support is between Wieczorek D. Wolf-Hirschhorn syndrome. Orphanet encyclopedia. September 2003: http://www.orpha.net/data/patho/GB/uk-WHS.pdf 1 30 and 60 months, many patients are never able to Later childhood and adolescence walk. Most of the patients do not develop active The facial phenotype is less characteristic in later speech, only a few are able to make complex life. Differentiation from other chromosomal sentences. In those patients, first words were aberrations is much more difficult (Ogle et al., 1996; spoken between 18 and 48 months. The Wheeler et al.,1995; Rauch et al., 2001) described craniofacial phenotype resembles that of a Greek a patient with a small interstitial deletion restricted warrior helmet. The recognizable facial phenotype to the WHSCR who presented only with a partial often leads the clinical geneticist to specific WHS phenotype consisting of low body weight for cytogenetic investigations (conventional height, speech delay, and minor facial anomalies. chromosomal analysis and fluorescence in situ Short stature, microcephaly, seizures and mental hybridisation/ FISH) to prove or exclude this retardation were not present. diagnosis. Management including treatment Differential diagnosis There is no specific treatment. Physiotherapy and Malpuech syndrome (Selicorni and Faravelli, 2000). occupational therapy are recommended. Some patients require physical aids, e.g. wheel chair, Pitt-Rogers-Danks (Wright et al., 1998) and splints, hearing aids etc. Patients with congenital Lambotte (Herens et al., 1997) syndrome were also heart defects, clubfeet, and cryptorchidism have to considered to be separate entities. It is now known be surgically treated. Those with seizures need that they are also caused by deletions of 4p16.3. recurrent EEGs and antiepileptic drugs (Zankl et al., Pitt-Rogers-Danks syndrome is defined as the 2001). milder expression of WHS. Etiology Frequency WHS is caused by a deletion of the region 4p16.3 Incidence is estimated to be about 1:50.000 births on the short arm of one chromosome 4. Most of with a 2:1 female: male ratio. patients with WHS have a de novo deletion, usually on the paternal chromosome (Tupler et al. 1992). Clinical description De novo unbalanced translocations have also been During the first year of life described in 1.6% of WHS patients (Lurie et al., Patients are usually small for gestational age with 1980). The translocation t(4;8)(p16;p23) (Wieczorek an average birth weight of 2000 g at term. Muscular et al., 2000) may be the most frequent after hypotonia is remarkable. The characteristic t(11q;22q), which is the most common reciprocal craniofacial phenotype consisting of microcephaly, translocation in humans (Giglio et al., 2002). A craniofacial asymmetry, high forehead, broad nasal familial translocation is responsible for only 5 – 13 bridge with prominent glabella, hypertelorism, deep- % of cases (Centerwall et al., 1975; Lurie et al., set and dysmorphic ears, preauricular tags, short 1980). WHS is mostly maternally inherited with a philtrum, and downturned corners of the mouth, is 2:1 ratio female to males (Nahara et al., 1984). present at birth and usually gives a clue to the correct diagnosis (Battaglia et al., 1999; Wieczorek Diagnostic methods et al., 2000). Nearly 35% of patients die during the High-resolution chromosomal analysis often detects first year of life, due to congenital heart defects the usually terminal deletion of the short arm of (Shannon et al,. 2001). chromosome 4. Smaller deletions are not visible with a conventional chromosomal analysis. FISH During toddler’s age analysis using probes of the critical region or The usually severe psychomotor retardation microsatellite analysis, which requires blood becomes obvious. Patients have a short stature and samples of the parents, help to identify a hypodontia. The fingers are tapering and submicroscopic deletion. It is often necessary to sometimes ulnar deviated. The feet are confirm a diagnosis suspected on the basis of characterized by camptodactyly and under- and cytogenetic findings with additional techniques. A overriding toes. This period of life is often cryptic rearrangement should be excluded by FISH complicated by respiratory tract infections. Seizures in all patients with detected deletions. often occur in this period of life, medical treatment is often difficult. Only a very few patients with WHS Genetic counseling learn to walk without support during this time. Following detection of the deletion and confirmation Those, who are able to walk, learn it between the of the WHS diagnosis, the occurrence of a age of 3 and 5 years. Active speech is also translocation in both parents has to be excluded uncommon in patients with WHS, only a few using conventional chromosomal analysis and patients are able to speak some words. The first FISH. two years of life mortality rate is 21% (Battaglia et al., 1999; Wieczorek et al., 2000; Shannon et al., De novo deletion/translocation in the patient 2001). Wieczorek D. Wolf-Hirschhorn syndrome. Orphanet encyclopedia. September 2003: http://www.orpha.net/data/patho/GB/uk-WHS.pdf 2 Recurrence risk for another child with WHS is low. deleted in most WHS patients. Genomics 1999, 60: Prenatal diagnosis can be offered in another 218-225 pregnancy as somatic mosaicism cannot be Giglio S, Calvari V, Gregato G, Gimelli G, completely excluded. Camanini S, Giorda R, Ragusa A, Guerneri S, Selicorni A, Stumm M, Tonnies H, Ventura M, Familial translocation Zollino M, Neri G, Barber J, Wieczorek D, Rocchi Recurrence risk for another child with WHS is high. M, Zuffardi O. Heterozygous submicroscopic There is also a risk for an unbalanced translocation inversions involving olfactory receptor-gene clusters carrier with a partial trisomy 4p and a partial mediate the recurrent t(4;8)(p16;p23) translocation. monosomy of the other chromosome involved in the Am J Hum Genet 2002, 71: 276-285 translocation. No accurate data are available, but Herens C, Jamar M, Alvarez-Gonzalez ML et al. the risk for an unbalanced translocation carrier is Private multiple congenital anomaly syndromes high. may result from unbalanced subtle translocations : t(2q ;4p) explains the Lambotte syndrome. Am J Antenatal diagnosis Med Genet 1997, 73: 127-131 Prenatal diagnosis after chorionic villus sampling or Lurie IW, Lazjuk GI, Ussova YI, Presman EB, amniocentesis is possible. Besides a conventional Gurevich DB. The Wolf-Hirschhorn syndrome. I. karyotyping, additional FISH analysis or Genetics. Clin Genet 1980, 17: 375-384 microsatellite analysis should be performed to Nahara K. Himoto Y, Yokoyama Y, Kasai R, Hasta confirm/exclude WHS in the child. A, Kikkawa K, Takahashi Y, Wkita Y, Kimura S, Kimoto H. The critical monosomic segment in 4p- Unresolved questions syndrome: a high-resolution banding study
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