Zurich Open Repository and Archive. Severe clinical course of Hirschsprung disease in a Mowat-Wilson syndrome patient

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1 University of Zurich Zurich Open Repository and Archive Winterthurerstr. 190 CH-8057 Zurich Year: 2010 Severe clinical course of Hirschsprung disease in a Mowat-Wilson syndrome patient Smigiel, R; Szafranska, A; Czyzewska, M; Rauch, A; Zweier, C; Patkowski, D Smigiel, R; Szafranska, A; Czyzewska, M; Rauch, A; Zweier, C; Patkowski, D (2010). Severe clinical course of Hirschsprung disease in a Mowat-Wilson syndrome patient. Journal of Applied Genetics:1-3. Postprint available at: Posted at the Zurich Open Repository and Archive, University of Zurich. Originally published at: Journal of Applied Genetics 2010, :1-3.

2 Severe clinical course of Hirschsprung disease in a Mowat-Wilson syndrome patient Abstract We present a clinical case of a female infant with multiple anomalies and distinctive facial features, with an exceptionally severe clinical course of Hirschsprung disease. The girl was also diagnosed with Mowat-Wilson syndrome, confirmed by molecular analysis as a heterozygous deletion of the ZEB2 gene. Moreover, molecular karyotyping revealed a deletion involving further genes (KYNU, ARHGAP15, and GTDC1).

3 J Appl Genet 51(1), 2010, pp Case report Severe clinical course of Hirschsprung disease in a Mowat-Wilson syndrome patient R. Smigiel 1, A. Szafranska 2, M. Czyzewska 2, A. Rauch 3, Ch. Zweier 3, D. Patkowski 4 1 Genetics Department, Wroc³aw Medical University, Poland 2 Neonatology Department, Wroc³aw Medical University, Poland 3 Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany 4 Paediatric Surgery Department, Wroc³aw Medical University, Poland Abstract. We present a clinical case of a female infant with multiple anomalies and distinctive facial features, with an exceptionally severe clinical course of Hirschsprung disease. The girl was also diagnosed with Mowat-Wilson syndrome, confirmed by molecular analysis as a heterozygous deletion of the ZEB2 gene. Moreover, molecular karyotyping revealed a deletion involving further genes (KYNU, ARHGAP15, and GTDC1). Keywords: Mowat-Wilson syndrome, Hirschsprung disease, ZEB2 gene, ZFHX1B gene, genotype-phenotype correlation. Mowat-Wilson syndrome (MWS) is a recently delineated syndrome with multiple congenital anomalies and mental retardation (Amiel et al. 2001; Cacheux et al. 2001; Mowat et al. 1998; Wakamatsu et al. 2001; Zweier et al. 2002). MWS is characterized by distinctive facial features, short stature, and structural anomalies, including Hirschsprung disease (HD), genitourinary anomalies, congenital heart defects, agenesis or hypogenesis of the corpus callosum, and eye defects, as well as moderate to severe intellectual disability and severe speech impairment. We present a young female with a clinical diagnosis of MWS, confirmed by molecular analysis, presenting a severe course of HD. The proband was born to a G2,P1 healthy mother at 36 weeks of gestation. The parameters at birth were: weight 2600 g, length 52 cm, OFC 31 cm. Heart murmur, delayed meconium passage, and enterocolitis, were diagnosed after birth. Echocardiography showed a Fallot tetralogy. Radiographic barium enema studies suggested HD, which was confirmed by immunohistochemistry. During the operative procedure a short segment of aganglionosis was found and sigmoid colostomy was created. The postoperative course was complicated by multiple eventrations and severe sepsis. At the age of 18 months, the Duhamel procedure was planned. However, during the operation the Swenson procedure was performed, because of severe adhesions and difficult tissue preparation. The course of the disease was complicated again by leakage at the level of colorectal anastomosis, which required temporal protective ileostomy. Two days later the girl was reoperated because of severe haemorrhage from the rectum and through the peritoneal drain, but the source of bleeding was not found and she developed a sepsis. Ten days later ileal mechanical obstruction occurred. The ileostomy was closed 2 months later. The subsequent course was complicated by an incisional hernia. No congenital and acquired immunological defects were detected. However, hepatic cell lesion and -1 antitrypsin deficiency (ATD) were revealed. The microscopic evaluation Received: May 5, Accepted: June 23, Correspondence: R. Smigiel, Department of Genetics, Wroc³aw Medical University, Marcinkowskiego 1, Wroclaw, Poland; smigiel@gen.am.wroc.pl

4 112 R. Smigiel et al. of hepatic cells showed liver cirrhosis in the course of ATD. Clinical evaluation of the child in 6th, 12th and 18th month of life revealed hypotrophy, delayed psychomotor development, hypotonia, and a variety of dysmorphic features, including microcephaly, square-shaped face, hypertelorism, deep-set eyes, wide nasal bridge with a rounded nasal tip, strabismus, prominent and thickened ears, high palate, open mouth, full lips, and pointed chin (Figure 1). Genitourinary tract examination revealed mild hydronephrosis and vesicoureteric reflux. MRI of the brain showed agenesis of corpus callosum and cerebral atrophy. Seizures started at the age of 15 months. The overall clinical picture suggested the diagnosis of MWS. Cytogenetic analysis revealed a normal karyotype. FISH for 22q11.2 excluded the common microdeletion. Molecular analysis of the ZEB2 gene was performed by sequencing and multiplex ligation-dependent probe amplification (MLPA), using the MRC-Holland P169 assay. Sequencing of the whole region of the ZEB2 gene showed normal results, but MLPA analysis revealed a heterozygous deletion of all exons of the ZEB2 gene (Figure 2). Additional molecular karyotyping (Affymetrix GeneChip Mapping 6.0) confirmed a heterozygous deletion of the ZEB2 gene and revealed a 3.6-Mb deletion (chr2: ; UCSC hg18), including further genes (KYNU, ARHGAP15 and GTDC1). MWS, which involves multiple congenital defects, was first clinically described in 1998 and molecularly delineated in 2001 as heterozygous deletions or truncating mutations of the ZEB2 (ZFHX1B) gene (Amiel et al. 2001; Cacheux et al. 2001; Ishihara et al. 2004; Mowat et al. 1998; Wakamatsu et al. 2001; Zweier et al. 2002; Zweier et al. 2003; Zweier et al. 2005). Only about 160 cases have been reported in the literature so far (Dastot-Le Moal et al. 2007). HD occurs in 57% cases of MWS (Dastot-Le Moal et al. 2007). The outcome of surgical treat- Figure 1. The phenotype of Mowat-Wilson syndrome in the 12-month-old patient Figure 2. MLPA result: heterozygous deletion of exons 1-10 of the ZEB2 (ZFHX1B) gene

5 Hirschsprung disease in Mowat-Wilson syndrome 113 ment of HD is usually satisfactory with good prognosis. However, long-term complications can appear, such as chronic constipation and soiling. There were no reports presenting a severe, unexpected course of HD in MWS. We have observed in our case a severe course of HD and numerous complications during surgical treatment, derived from severe infections with difficult healing of tissues (multiple eventrations, leakage at anastomosis, incisional hernia), which are very rare in children with HD. The clinical diagnosis of MWS in our patient was confirmed by MLPA, revealing a deletion of all exons of the ZEB2 gene, which occurs in 19% of MWS patients (Dastot-Le Moal et al. 2007). It is presumed that cases with deletions of the ZEB2 gene are similar to those with point mutations with nonallelic modifiers explaining clinical variability (Zweier et al. 2005). However, larger deletions, involving several megabases, are associated with a more severe course (Ishihara et al. 2004). Accordingly, the 3.5-Mb deletion in our patient with a severe course of HD, includes 3 further genes, for which no disease is known so far. Therefore it is tempting to speculate that the genes other than ZEB2, involved in the deletion of our patient, can play a crucial role in the process of tissue regeneration. Our case allows us to speculate that the large deletion of the ZEB2 locus can influence the course of congenital aganglionosis. Nevertheless, it is possible that the complicated surgical course occurred independently. A systematic clinical follow-up of MWS patients with HD is proposed to anticipate the complications. REFERENCES Amiel J, Espinosa-Parrilla Y, Steffann J, Gosset P, Pelet A, Prieur M, et al Large-scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures. Am J Hum Genet 69: Cacheux V, Dastot-Le Moal F, Kääriäinen H, Bondurand N, Rintala R, Boissier B, et al Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease. Hum Mol Genet 10: Dastot-Le Moal F, Wilson M, Mowat D, Collot N, Niel F, Goossens M, ZFHX1B mutations in patients with Mowat-Wilson syndrome. Hum Mutat 28: Ishihara N, Yamada K, Yamada Y, Miura K, Kato J, Kuwabara N, et al Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFHX1B mutations and deletions at 2q22-q24.1. J Med Genet 41: Mowat DR, Croaker GDH, Cass DT, Kerr BA, Chaitow J, Ades J, et al Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23. J Med Genet 35: Wakamatsu N, Yamada Y, Yamada K, Ono T, Nomura N, Taniguchi H, et al Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nature Genetics 27: Zweier C, Albrecht B, Mitulla B, Behrens R, Beese M, Gillessen-Kaesbach G, et al Mowat-Wilson syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene. 108: Zweier C, Temple IK, Beemer F, Zackai E, Lerman Sagie T, Weschke B, et al Characterisation of deletions of the ZFHX1B region and genotype-phenotype analysis in Mowat-Wilson syndrome. J Med Genet 40: Zweier C, Thiel CT, Dufke A, Crow J, Meinecke P, Suri M, et al Clinical and mutational spectrum of Mowat-Wilson syndrome. Eur J Med Genet 48: