Multidisciplinary treatment of desmoid tumours in Gardner’s syndrome due to a large interstitial deletion of chromosome 5q

Q J Med 2014; 107:521–527 doi:10.1093/qjmed/hcu036 Advance Access Publication 18 February 2014 Translational Medicine Multidisciplinary treatment of desmoid tumours in Gardner’s syndrome due to a large interstitial deletion of chromosome 5q M. CASPER1, E. PETEK2, W. HENN3, M. NIEWALD4, G. SCHNEIDER5, V. ZIMMER1, F. LAMMERT1 and J. RAEDLE6 From the 1Department of Medicine II, Saarland University Medical Center, Homburg, Germany, 2 Institute of Medical Biology and Human Genetics, Medical University Graz, Graz, Austria, 3 Institute of Human Genetics, Saarland University Medical Center, Homburg, 4 Department of Radiotherapy and Radiooncology, Saarland University Medical Center, Homburg, 5 Department of Radiology, Saarland University Medical Center, Homburg and 6 Department of Medicine 3, Westpfalz Hospital, Kaiserslautern, Germany Address correspondence to M. Casper, Department of Medicine II, Saarland University Medical Center, Kirrberger Straße 100, D-66421 Homburg, Germany. email: Received 25 November 2013 and in revised form 10 February 2014 Summary Background and aims: Classic autosomal-dominant familial adenomatous polyposis (FAP) is clinically defined by the development of hundreds to thousands of colorectal adenomas beginning in childhood and adolescence. A variant of FAP characterized by polyposis in combination with osteomas or soft tissue tumours is called Gardner’s syndrome. FAP is caused by germline inactivation of the APC (adenomatous polyposis coli) tumoursuppressor gene located on the long arm of chromosome 5 (5q21–5q22). Cytogenetically visible deletions of chromosome 5q encompassing APC have very rarely been reported. Here, we aimed to phenotypically and genetically characterize a patient with a heterozygous 5q deletion resulting in Gardner’s syndrome. Methods and results: A 26-year-old female patient with mild mental handicap and dysmorphic features due to a cytogenetically visible deletion on chromosome 5q (microscopically estimated region 5q14–5q23) presented at our tertiary referral centre because of mild adenomatous polyposis (<500 polyps). Twenty months after prophylactic proctocolectomy with definitive ileostomy, three rapidly growing desmoids were observed. Tumourassociated complications necessitated a multidisciplinary approach including medical treatment, surgery and radiation therapy. The characterization of the deletionbycomparativegenomichybridizationidentified a large 5q deletion expanding over a 20-Mb region (5q21.3–5q23.3) including the APC gene. Conclusion: Chromosome deletions must be suspected in patients presenting with FAP together with mental handicap and dysmorphic features. This case also impressively shows that FAPassociated desmoids need multimodal treatment taking into account the patient’s individual symptoms, disease progression and tumour location. ! The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: 522 M. Casper et al. Introduction Classic autosomal-dominant familial adenomatous polyposis (FAP) is defined by the development of hundreds to thousands of colorectal adenomas in childhood and adolescence with extremely high risk for colorectal cancer.1 FAP is caused by germline inactivation of the APC (adenomatous polyposis coli) tumour-suppressor gene (NC_000005) located on the long arm of chromosome 5 (5q21–5q22).2 In most cases the disease is inherited as an autosomal-dominant trait with near complete penetrance, but de novo-mutations are responsible for about 25–30% of cases.3 In addition to common truncating mutations, gross alterations such as exon deletions or whole gene deletions have been described.4 However, the prevalence of these large deletions may be underestimated as they are difficult to detect by using standard sequencing methods.5 Besides colorectal adenomas, many benign (e.g. duodenal and small bowel adenomas, gastric fundic gland polyps, osteomas, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium, desmoid tumours, cutaneous lesions) as well as malignant extracolonic manifestations (duodenal adenocarcinoma, thyroid carcinoma, hepatoblastoma, central nervous system tumours) exist.6–8 The specific combination of colorectal adenomatous polyposis with osteomas and soft tissue tumours is called Gardner’s syndrome.6 Here, we present a patient suffering from Gardner’s syndrome due to a large interstitial 5q deletion spanning more than 20 Mb which could be characterized in detail by a comparative genomic hybridization (CGH) array. In addition to a detailed description of the phenotype, we present the patient’s complicated medical history and discuss the treatment options for FAP-related desmoids. Methods and results Case history with regard to FAP A 26-year-old female patient (174 cm, 64 kg) with mild mental handicap and dysmorphic features (Figure 1A1 and A2) presented at our tertiary referral centre because of a positive faecal occult blood test. Colonoscopy uncovered polyposis with <500 colorectal polyps up to 15 mm in size throughout the entire colorectum (histologically tubular and tubulovillous adenomas with low grade and focal high grade intraepithelial neoplasia) (Figure 1B1). When FAP was suspected, oesophagogastroduodenoscopy identified numerous gastric fundic gland polyps (Figure 1B2). Moreover, several small duodenal adenomas (Spigelman stage II) were removed (Figure 1B3). Extensive work-up for extra-intestinal manifestations identified several radiopaque lower jaw lesions representing osteomas, and magnetic resonance imaging (MRI) of the abdomen identified a small adrenal tumour on the right side compatible with endocrine-inactive adrenal adenoma. Two months after diagnosis the patient underwent total proctocolectomy with definitive ileostomy. Twenty months after proctocolectomy a large palpable abdominal mass nearby the ileostomy was detected. MRI revealed a tumour of 10  9  6 cm deriving from the left rectus sheath (Figure 2A1). Two additional tumours with identical characteristics in MRI were found in the right fossa iliaca (Figure 2A1–3) (7 cm in largest diameter) and the mesentery (left paramedian; 2.8 cm in largest diameter) (Figure 2B). As these lesions were compatible with desmoids, an anti-proliferative therapy with celecoxib (200 mg b.i.d.) and tamoxifen (40 mg t.i.d.) was initiated. Imaging 3 months later visualized significant tumour growth (largest diameter 13, 9 and 3 cm, respectively). A developing intestinal obstruction due to compression of the ileostomy between the two largest desmoids and compression of the ureter necessitated surgical treatment 4 months after the initial diagnosis. The ileostomy and 50 cm of the terminal ileum had to be resected together with the two large desmoids (proliferation rate of 5%). The smallest tumour in the mesentery was functionally unresectable. Nevertheless, the patient postoperatively suffered from short bowel (...truncated)