Ernest Cutz

Hospital for Sick Children

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Herman Yeger

University of Toronto

Philip M. Sherman

University of Toronto

Jie Pan

Guiyang Medical University

Donald G. Perrin

Hospital for Sick Children

Colin A. Nurse

McMaster University

Ron Shaoul

Rambam Health Care Campus

Sharon Dell

University of British Columbia

Margaret Marcon

University of Toronto

Cornelia Thoeni

University of Toronto

Aleixo M. Muise

SickKids Foundation

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428

Hospital for Sick Children

365

SickKids Foundation

285

University College London

University Health Network

Great Ormond Street Hospital

Toronto General Hospital

International Society for Heart and Lung Transplantation

OWL (Spain)

Boston Children's Hospital

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Congenital Cholesteatoma in a Child Carrying a Gene Mutation for Adenomatous Polyposis Coli

Journal of Pediatric Gastroenterology and Nutrition (1999)

Ron Shaoul Blake C. Papsin Ernest Cutz Peter R. Durie

Familial Adenomatous Polyposis (FAP) is an autosomal dominant inherited disorder caused by a germ line mutation of the adenomatous polyposis coli (APC) gene located on the long arm of chromosome 5 in band q21 (1,2). The main clinical feature of FAP is multiple adenomatous polyps throughout the lower gastrointestinal tract, with time of onset ranging from early childhood to adulthood (3-5). Since genetic testing for familial adenomatous polyposis has been available, an APC gene mutation can be identified in approximately 80% of cases of familial adenomatous polyposis (6). If prophylactic colectomy is not performed, colorectal cancer will develop by the third to sixth decade of life in nearly all affected people (5,6). Several cases of onset of colorectal cancer in childhood have been reported (4,7-9). Familial adenomatous polyposis is associated with several extracolonic manifestations. Congenital hypertrophy of the retinal pigment epithelium (CHRPE), known to be associated with FAP (10), was first described in patients with Gardner's syndrome (11). The affected patients have multiple patches of hypertrophy of the retinal pigment epithelium, with lesions composed of enlarged retinal pigment epithelial cells (11,12). In contrast to the colonic polyps, which appear at unpredictable ages beginning at 4 months (13), the ocular findings are usually present at birth (14). Retinal pigment changes affect at least 80% of patients with FAP (10,14). The presence of CHRPE appears to be dependent on the position of the mutation along the coding sequence. Congenital hypertrophy of the retinal pigment epithelium is almost always present if the mutation occurs after exon 9 (15). Gastric polyps occur in up to 60% of patients with FAP. Most of the polyps are hyperplastic fundic glands, but a small proportion are true adenomas (14). Duodenal adenomas are more common than gastric adenomas (14). Adenomas involving the gastric and duodenal mucosa possess premalignant potential similar to that of colonic adenomatous polyps (14). Desmoid tumors comprising slow-growing, locally invasive proliferation of fibroblasts are associated with FAP, with a lifetime risk of 8% in males and 15% in females (14). Up to 90% of cases have osteomas involving mainly the mandible, maxilla, or sinuses. Osteomas can develop before the appearance of colonic adenomatous polyps (14). Epidermoid cysts are also associated with FAP (14). We describe a 6-year-old boy with FAP and congenital cholesteatoma. Congenital cholesteatoma, which has not been previously described in association with FAP, may represent a tumorlike lesion with biologic characteristics resembling other lesions associated with FAP. CASE REPORT A 6-year-old boy was born at term by cesarean delivery because of breech presentation after a normal pregnancy. His birth weight was 4.2 kg. There were no complications in the neonatal period, and his growth and development were normal. Medical attention was sought when he was 4 years of age with a history of intermittent painless hematochezia. He had experienced 10 isolated episodes, always with fresh blood, with normal bowel movements in the intervening periods. Repeated stool samples for bacterial culture and for ova and parasites were negative. He was otherwise healthy. Colonoscopy, performed when he was 6 years of age, showed multiple small sessile polypoid lesions in the sigmoid area and the descending and transverse colon. Histologic examination confirmed adenomatous changes in the crypts of two specimens obtained from the transverse and the descending colon (Fig. 1). Examination of the remaining biopsy specimens showed normal colonic mucosa. Panoramic radiograph of the mandible and maxilla did not show osteoma, odontoma, or epidermoid cyst. Eye examination revealed hyperpigmented retinal lesions in the temporal retina of each eye. The patient was referred to an otolaryngologist at 4 years of age because of unilateral conductive hearing loss. A presumptive diagnosis of middle ear effusion was made, and he was scheduled for myringotomy and tube insertion. However, during surgery, cholesteatoma was observed in the middle ear, and the myringotomy was canceled. After the patient was referred to our institution, computerized tomography showed extensive disease within the middle ear cleft with opacification of the mastoid but no destruction of the septa. During surgery (atticoantrotomy) cholesteatoma occupied the entire left middle ear and had destroyed the stapes and the long process of the incus. The mastoid cavity was pristine. The disease was confined to the middle ear and attic. Despite a history of some ear infections, the surgical findings strongly supported congenital cholesteatoma by virtue of its location and distribution and by the fact that the tympanic membrane was intact and the mastoid air cells uninvolved. The pathologic specimen, which showed fibrous tissue lined by keratinizing squamous epithelium without skin adnexa and focal mixed inflammation, confirmed the diagnosis of cholesteatoma. One year later, the left ear was re-explored, and no residual cholesteatoma was found. A total ossicular reconstruction using a hydroxyapatite prosthesis was performed. He is currently under clinical observation by the otolaryngology service (BP).FIG. 1: Histologic specimen from the transverse colon, showing crypts with adenomatous changes adjoining normal looking crypts (*) (hematoxylin-eosin; magnification, ×100).The patient's mother sought treatment at 22 years of age with intermittent painless rectal bleeding. Colonoscopy was performed when she was 25 years of age. Biopsy confirmed the diagnosis of FAP. She underwent subtotal colectomy and an ileal-rectal pull-through procedure. DNA analysis identified a 5 bp deletion (GAAAG) at codon 1309-1311 (exon 15) of the APC gene. Because of previous diagnosis of FAP in the mother, DNA study of the index case was performed using heteroduplex analysis. It confirmed that the child carries the same mutation as his mother. No other family members are known to be affected. DISCUSSION Cholesteatoma is an abnormal accumulation of keratin-producing squamous epithelium in the middle ear, epitympanum, mastoid, or petrous apex (16). Congenital cholesteatoma has been defined by Derlacki and Clemis (17) as an embryonic rest of epithelial tissue in an ear without tympanic membrane perforation in a patient without a history of ear infection. Although the origin of congenital cholesteatoma is not clearly defined (18), there are several theories concerning its pathogenesis. Aimi (19) postulated that congenital cholesteatoma results from ingrowth of ectoderm from the external canal into the middle ear. He suggested that failure of the tympanic ring to inhibit or restrict such migration may give rise to congenital cholesteatoma. In 1936, Teed (20,21) discovered a small mass of epidermal cells in the dorsolateral epitympanum of a human fetus and postulated that the congenital cholesteatoma may be caused by failure of resorption of these cells. In support of this theory, Michaels (22) demonstrated the presence of fetal epidermoid formation due to a squamous cell rest; this derivative of the first branchial groove, is normally identifiable from 10 to 33 weeks of gestation in the anterior superior lateral wall of the tympanic cavity. After 33 weeks of gestation, epidermoid formation is not normally present, suggesting involution of an embryonic process (20). Thus, failure of epidermoid formation to involute and its later expansion theoretically gives rise to congenital cholesteatoma. Congenital hypertrophy of the retinal pigment epithelium, which is well recognized as associated with FAP (10,14), has several characteristics in common with cholesteatoma: both are caused by abnormal proliferation of a normal epithelium, are congenital in nature, and are believed to develop before birth (20,23). It has been hypothesized that CHRPE develops because of mutations in the APC gene, which may cause disordered control of embryonic growth (24). Congenital cholesteatoma, may develop by a similar mechanism. The normal APC gene appears to play a central role as a tumor-suppressing factor and in controlling normal cell growth and spatial arrangement. Failure of these control mechanism because of a mutation in the APC gene may result in tissue disorganization and abnormal cell growth (24). Specifically, the protein product of the APC gene contains several functional domains, some of which act as binding and degradation sites for β-catenin (24,25). These sites maintain cytoplasmic β-catenin levels in a steady state (24,25). β-Catenin is a 92-kDa protein involved in organization of tissue architecture and polarity (24,25). It is important for activation of E-cadherin, a CA++-dependent adhesion molecule that controls the formation and maintenance of adherens junctions between epithelial cells (24,25). E-cadherin also may control cell motility during embryonic development by affecting cell migration and morphogenesis (24,26). The FAP phenotype seems to vary according to the number of deleted binding sites in the protein product (25). Mutations at codon 1309 or beyond (which is the case in this patient), are associated with early development of adenomatous polyps and a greater risk of malignant disease at an early age (5,27,28). Furthermore, the same mutations are strongly associated with the presence of congenital hypertrophy of the retinal pigmented epithelium (27). Thus, specific mutations in the APC gene may affect normal embryonal development and result in congenital lesions that arise from tissue disorganization and abnormal cell growth, possibly through abnormal function of E-cadherin or other proteins. A recent study by Santucci et al. (29) showed abnormalities in cell proliferation in normal-appearing duodenal biopsy specimens of patients with APC gene mutation. These proliferation abnormalities during embryonal development may cause congenital lesions. The variety of phenotypic expression of a single mutation in the APC gene (30) suggests that modifier genes may also play a role in phenotypic expression. A recent development of mouse models with APC mutation (31,32) may add more to the understanding of genotype-phenotype correlations. In conclusion, expanding knowledge of the function of the normal APC gene, and the effect of mutations on its protein product, may help to elucidate the fundamental mechanisms of tumor development and control of cell growth. In this regard, all manifestations of FAP arising during embryonic development can be reconciled with abnormal control of cell growth and spatial organization. This observation, of a clinical association between FAP and cholesteatoma in this case, may strengthen an association of the role of APC gene mutations with abnormal control of cell growth and spatial organization. Acknowledgment: The authors thank the Mount Sinai Hospital Familial Gastrointestinal Cancer Registry and Dr. B. Bapat for their help and Patricia Jacques for her endless efforts and help. RS is a Canadian Cystic Fibrosis Foundation Research Fellow; he is also supported by grants from the American Physicians Fellowship for Medicine in Israel program, Janssen/Ortho Inc., Canada, and the Postgraduate Dyson Fellowship award from the University of Toronto.

Adenomatous polyposis coli

10.1097/00005176-199901000-00023

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Citations (3)

Colonic Expression of MUC2, MUC5AC, and TFF1 in Inflammatory Bowel Disease in Children

Journal of Pediatric Gastroenterology and Nutrition (2004)

Ron Shaoul Yoshio Okada Ernest Cutz Margaret Marcon

The quantity and quality of mucins are affected in inflammatory bowel disease (IBD) both because of a reduction in the number of goblet cells and a decrease in the number of sugar residues per oligosaccharide side chain. Alteration in the types of mucins and aberrant location may contribute to the underlying pathology by affecting the mucus barrier function or may instead be a response to inflammation. The authors used the periodic acid-Schiff/Alcian blue stain to distinguish neutral and acidic mucins, and used specific antibodies to the mature goblet cell mucin MUC2, MUC2 core antigen, foveolar cell mucin MUC5AC, and gastric trefoil factor (TFF1), to characterize their presence and distribution in colonic tissue sections from patients with IBD.Both core and mature MUC2 were expressed in all colonic goblet cells from patients with ulcerative colitis (UC) and Crohn disease and from healthy controls. MUC5AC and TFF1, which are not normally expressed by colonic tissue, also were expressed in scattered goblet cells, coexpressing with MUC2. In areas of goblet cell depletion, MUC2 was present in cytoplasmic granules of flattened, cuboidal, nongoblet-cell-like surface cells. The staining was more intense and homogenous with the MUC2 core antibody, suggesting expression of relatively immature mucin. Some of these cells also coexpressed MUC5AC but to a lesser extent. These findings are not unique to IBD but were also found in other types of intestinal inflammation.The study confirms earlier observations that MUC2 is the major colonic mucin in IBD. It appears in two forms: mature MUC2 in goblet cells and immature MUC2 especially in secretory granules of cells that are not phenotypically goblet cells. MUC5AC and TFF1 expression in goblet cells is common in IBD and other inflammatory conditions of the colon. These changes may represent a nonspecific repair function of the colon cells to compensate for damage to barrier function.

Inflammatory Bowel Diseases

10.1097/00005176-200405000-00006

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Citations (76)

Loss of ADAM17 is associated with severe multiorgan dysfunction

Human Pathology (2015)

Robert Bandsma Harry van Goor Michael Yourshaw Rudolf K. Horlings Marcel F. Jonkman

Proband

Exome

10.1016/j.humpath.2015.02.010

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Citations (39)

Expression and localization of ABCA3 transporter in neonatal lung disorders

Modern Pathology (2005)

Ernest Cutz Noritoshi Inagaki Jianji Pan William W.‐C. Chan LM Nogee

Source

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PEPCK-C reexpression in the liver counters neonatal hypoglycemia in Pck1 del/del mice, unmasking role in non-gluconeogenic tissues

Journal of Physiology and Biochemistry (2016)

Jana Semakova Petra Hyroššová Andrés Méndez‐Lucas Ernest Cutz Jordi Bermúdez

Gluconeogenesis

Knockout mouse

10.1007/s13105-016-0528-y

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Citations (16)

Editorial

Annales Nestlé (Ed française) (2006)

Philip M. Sherman Ernest Cutz Olivier Goulet Zulfiqar A Bhutta Olivier Goulet

10.1159/000093834

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The Disappearance of Sudden Infant Death Syndrome

JAMA Pediatrics (2016)

Ernest Cutz

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal

10.1001/jamapediatrics.2015.4172

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Dilated cardiomyopathy with neutropenia, short stature, and abnormal carnitine metabolism

The Journal of Pediatrics (1988)

Toshihiro Ino W. G. Sherwood Ernest Cutz Lee Benson Vera Rose

Dilated Cardiomyopathy

10.1016/s0022-3476(88)80642-5

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Citations (44)

Tribute to Laurence Edward Becker, MD, FRCPC (March 30, 1943, to July 14, 2002)

Pediatric and Developmental Pathology (2005)

Ernest Cutz

Tribute

10.1007/s10024-005-3175-9

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Abstract 4400: Novel combination of carbonic anhydrase inhibitor with a phytochemical for treatment of human bronchial carcinoids

Cancer Research (2012)

Reza Bayat Mokhtari Sushil Kumar Sean Zhou Sayed S. Islam Mehrdad Yazdanpanah

Abstract Bronchial carcinoids are pulmonary neuroendocrine cell derived tumors comprising typical (TC) and atypical (AT) malignant phenotypes. The 5-year survival rate in metastatic disease, despite multiple current therapies, is 14-25%. Carcinoids are found in the gastrointestinal tract are more frequent (61%) and also more aggressive; however, 31% of carcinoids are located in bronchopumonary system, which can metastize beyond the longs. Therefore, new strategies are needed for effective treatment of carcinoid malignant progression and metastatic disease. The progenitor neuroendocrine cells are O2/CO2 chemosensory. Hypoxia and hypercapnia stimulate secretion of the neuroendocrine associated bioactive amine, serotonin, which can also serve as an autocrine growth factor. CO2 sensing and metabolism is associated with physiological activities of different carbonic anhydrases (CAs) which function in tumor cell pH homeostasis and therein regulation of growth, survival, and metastasis. CAs are abundantly expressed in lung carcinoids. We postulated that acetazolamide (AZ), a pan CA inhibitor, and the anti-tumor phytochemical sulforaphane (SFN), which can inhibit expression of serotonin receptors could function cooperatively and synergistically to inhibit growth of pulmonary carcinoids. A dose dependent effect of AZ (0-80 µM, 48h) and SFN (0-80µM, 48h) on carcinoid cell lines H727 (TC), H835 (intermediate phenotype) and H720 (AT) was assessed in vitro. Both compounds reduced cell viability (via Alamar Blue) and mitochondrial integrity (via JC-1 mitochondrial staining) dose-dependently in all cell lines. IC50 values for cell viability were 9.29 µM (H727), 16.67 µM (H835) and 30.85 µM (H720) for AZ and 51.93 µM (H727), 5.31 µM (H835) and 10.82 µM (H720) for SFN. The mitochondrial integrity JC1 IC50 values were 50.16 µM (H727), 15.52 µM (H835), 11.93 µM (H720) for AZ and 9.29 µM (H727), 16.67 µM (H835) and 30.85 µM (H720) for SFN treatment. Treatment of H727 subcutaneous xenografts in NOD/SCID mice for 2 weeks demonstrated modest growth inhibition with AZ (7%, 20mg/kg) and SFN (23%, 40mg/kg) alone. However, a highly significant reduction (57%; p=0.02) was shown with the combination treatment. Furthermore, the combination did not show any signs of morbidity in treated mice. Since these doses are at the low end and well within clinical range and bioavailability, our results suggest a potential new therapeutic strategy for the treatment of pulmonary carcinoids. The molecular mechanism underlying this synergistic anti-tumor effect, currently under investigation, suggests a novel targeting of tumor cell homeostasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4400. doi:1538-7445.AM2012-4400

Chromogranin A

10.1158/1538-7445.am2012-4400

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