Clinical, Pathologic, and Molecular Characterization of Familial Eosinophilic Esophagitis Compared With Sporadic Cases
2008; Elsevier BV; Volume: 6; Issue: 6 Linguagem: Inglês
10.1016/j.cgh.2008.01.004
ISSN1542-7714
AutoresMargaret H. Collins, Carine Blanchard, J. Pablo Abonia, Cassie Kirby, Rachel Akers, Ning Wang, Philip E. Putnam, Sean C. Jameson, Amal Assa’ad, Michael R. Konikoff, Keith Stringer, Marc E. Rothenberg,
Tópico(s)IL-33, ST2, and ILC Pathways
ResumoBackground & Aims: Eosinophilic esophagitis (EE) occurs in families. Methods: Record review confirmed patient kinship and provided clinical information. Slide review confirmed the diagnosis (threshold peak number ≥24 eosinophils/high-power field). Results: Fifty-nine members (41 males, 18 females) of 26 families were 3 months to 47 years of age (mean age, 10.3 y) at diagnosis. The only recorded race was Caucasian. In 4 families a parent of an affected male had EE. The most common complaint at diagnosis was dysphagia (68% of patients). Endoscopy showed esophageal mucosal furrows (93% of patients) and exudates (44%). Fifty-one percent had asthma. Skin prick tests to food and aeroallergens were positive in 76% and 71%, respectively. Familial EE characteristics (clinical, endoscopic, pathologic, and global esophageal transcript expression profile analysis) were similar to sporadic EE, except among patients with mucosal furrows: familial patients had lower peak eosinophil counts in the distal esophagus (P = .03) compared with sporadic patients. The basic characteristics of EE (eg, eosinophil levels, rate of atopy) did not vary with patient age. By using genome-wide microarray analysis, no significant differences (P < .05, false-discovery rate) were observed between familial and sporadic EE. Among all patients, chest pain was more common in females (P = .02), and thickened mucosa was more common in males (P = .006). Conclusions: These data support a familial pattern of inheritance of EE and a pathogenesis shared with sporadic EE. EE should be considered in symptomatic family members of patients who have EE. Background & Aims: Eosinophilic esophagitis (EE) occurs in families. Methods: Record review confirmed patient kinship and provided clinical information. Slide review confirmed the diagnosis (threshold peak number ≥24 eosinophils/high-power field). Results: Fifty-nine members (41 males, 18 females) of 26 families were 3 months to 47 years of age (mean age, 10.3 y) at diagnosis. The only recorded race was Caucasian. In 4 families a parent of an affected male had EE. The most common complaint at diagnosis was dysphagia (68% of patients). Endoscopy showed esophageal mucosal furrows (93% of patients) and exudates (44%). Fifty-one percent had asthma. Skin prick tests to food and aeroallergens were positive in 76% and 71%, respectively. Familial EE characteristics (clinical, endoscopic, pathologic, and global esophageal transcript expression profile analysis) were similar to sporadic EE, except among patients with mucosal furrows: familial patients had lower peak eosinophil counts in the distal esophagus (P = .03) compared with sporadic patients. The basic characteristics of EE (eg, eosinophil levels, rate of atopy) did not vary with patient age. By using genome-wide microarray analysis, no significant differences (P < .05, false-discovery rate) were observed between familial and sporadic EE. Among all patients, chest pain was more common in females (P = .02), and thickened mucosa was more common in males (P = .006). Conclusions: These data support a familial pattern of inheritance of EE and a pathogenesis shared with sporadic EE. EE should be considered in symptomatic family members of patients who have EE. Eosinophilic gastrointestinal diseases (EGID) show increased numbers of eosinophils in one or more parts of the gastrointestinal tract.1Rothenberg M.E. Eosinophilic gastrointestinal disorders (EGID).J Allergy Clin Immunol. 2004; 113: 11-28Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar Primary EGID is diagnosed if a known cause (parasitic infections, allergies, drug reactions, hypereosinophilic syndrome, and so forth) is not identified. Eosinophilic esophagitis (EE), a form of EGID, is a chronic, relapsing inflammatory disease manifesting large numbers of intraepithelial eosinophils in esophageal mucosal biopsy specimens2Rothenberg M.E. Mishra A. Collins M.H. et al.Pathogenesis and clinical features of eosinophilic esophagitis.J Allergy Clin Immunol. 2001; 108: 891-894Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar and characteristic endoscopic findings.3Gupta S.K. Fitzgerald J.F. Chong S.K.F. et al.Vertical lines in distal esophageal mucosa (VLEM): a true endoscopic manifestation of esophagitis in children?.Gastrointest Endosc. 1997; 45: 485-489Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 4Lim J.R. Gupta S.K. Croffie J.M. et al.White specks in the esophageal mucosa: an endoscopic manifestation of non-reflux eosinophilic esophagitis in children.Gastrointest Endosc. 2004; 59: 835-838Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar EE must be distinguished from gastroesophageal reflux disease5Ngo P. Furuta G.T. Antonioli D.A. et al.Eosinophils in the esophagus—peptic or allergic eosinophilic esophagitis? Case series of three patients with esophageal eosinophilia.Am J Gastroenterol. 2006; 101: 1666-1670Crossref PubMed Scopus (273) Google Scholar because EE requires treatment other than or in addition to therapy for gastroesophageal reflux disease.6Kelly K.J. Lazenby A.J. Rowe P.C. et al.Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.Gastroenterology. 1995; 109: 1503-1512Abstract Full Text PDF PubMed Scopus (869) Google Scholar, 7Ruchelli E. Wenner W. Voytek T. et al.Severity of esophageal eosinophilia predicts response to conventional gastroesophageal reflux therapy.Pediatr Develop Pathol. 1999; 2: 15-18Crossref PubMed Scopus (177) Google Scholar, 8Walsh S.V. Antonioli D.A. Goldman H. et al.Allergic esophagitis in children A clinicopathological entity.Am J Surg Pathol. 1999; 23: 390-396Crossref PubMed Scopus (206) Google Scholar, 9Markowitz J.E. Spergel J.M. Ruchelli E. et al.Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents.Am J Gastroenterol. 2003; 98: 777-782Crossref PubMed Scopus (492) Google Scholar, 10Noel R.J. Putman P.E. Collins M.H. et al.Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2004; 2: 568-575Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 11Konikoff M.R. Noel R.J. Blanchard C. et al.A randomized, double blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis.Gastroenterology. 2006; 131: 1381-1391Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar, 12Stein M.L. Collins M.H. Villaneuva J.M. et al.Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis.J Allergy Clin Immunol. 2006; 118: 1312-1319Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar, 13Furuta G.T. Liacouras C.A. Collins M.H. et al.Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment.Gastroenterology. 2007; 133: 1342-1363Abstract Full Text Full Text PDF PubMed Scopus (1351) Google ScholarEE patients frequently are atopic.8Walsh S.V. Antonioli D.A. Goldman H. et al.Allergic esophagitis in children A clinicopathological entity.Am J Surg Pathol. 1999; 23: 390-396Crossref PubMed Scopus (206) Google Scholar, 10Noel R.J. Putman P.E. Collins M.H. et al.Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2004; 2: 568-575Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 11Konikoff M.R. Noel R.J. Blanchard C. et al.A randomized, double blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis.Gastroenterology. 2006; 131: 1381-1391Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar, 14Spergel J.M. Beausoleil J.L. Mascarenhas M. et al.The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis.J Allergy Clin Immunol. 2002; 109: 363-368Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar Atopic disease has a strong familial association, predominantly owing to complex interactions between environmental and genetic factors, the latter accounting for approximately 50% of atopic disease.15Ober C. Perspectives on the past decade of asthma genetics.J Allergy Clin Immunol. 2005; 116: 274-278Abstract Full Text Full Text PDF PubMed Scopus (92) Google ScholarEE has stronger genetic components than other atopic diseases. Families with more than one member with EE have been reported.16Noel R.J. Putnam P.E. Rothenberg M.E. Eosinophilic esophagitis (letter).N Engl J Med. 2004; 351: 940-941Crossref PubMed Scopus (695) Google Scholar, 17Patel S.M. Falchuk K.R. Three brothers with dysphagia caused by eosinophilic esophagitis.Gastrointest Endosc. 2005; 61: 165-167Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 18Meyer G.W. Eosinophilic esophagitis in a father and a daughter (letter).Gastrointest Endosc. 2005; 61: 932Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 19Zink D.A. Amin M. Gebara S. et al.Familial dysphagia and eosinophilia.Gastrointest Endosc. 2007; 65: 330-334Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 20Straumann A. Simon H.-U. Eosinophilic esophagitis: escalating epidemiology?.J Allergy Clin Immunol. 2005; 115: 418-419Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar Based on the estimated prevalence of EE as 4 per 10,000 in the pediatric population,16Noel R.J. Putnam P.E. Rothenberg M.E. Eosinophilic esophagitis (letter).N Engl J Med. 2004; 351: 940-941Crossref PubMed Scopus (695) Google Scholar the sibling risk recurrence ratio for EE is very high, approximately 80,21Blanchard C. Wang N. Rothenberg M.E. Eosinophilic esophagitis: pathogenesis, genetics, and therapy.J Allergy Clin Immunol. 2006; 118: 1054-1059Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar compared with approximately 2 for asthma.15Ober C. Perspectives on the past decade of asthma genetics.J Allergy Clin Immunol. 2005; 116: 274-278Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar EE is linked to a single nucleotide polymorphism in the eotaxin-3 gene based on case-control and transmission disequilibrium test analyses.22Blanchard C. Wang N. Stringer K.F. et al.Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.J Clin Invest. 2006; 116: 536-547Crossref PubMed Scopus (696) Google Scholar We report the clinical and histopathologic characteristics and genetic transcriptome of familial patients compared with EE patients who do not have affected family members (sporadic cases).Materials and MethodsThis study was performed with the approval of the Institutional Review Board at Cincinnati Children's Hospital Medical Center. The database in the Division of Pathology and Laboratory Medicine, which contains pathology cases from 1970 to the present, was searched (by M.H.C.) for biopsies with the diagnosis of EE. Inclusion criteria were a threshold peak count of 24 or more eosinophils/high-power field (hpf) in an esophageal biopsy specimen that was reviewed at the Cincinnati Center for Eosinophilic Disorders (CCED). Biopsy specimens from other sites in the gastrointestinal tract obtained at the same endoscopy as the diagnostic esophageal biopsy specimen were not required for inclusion, and, if those biopsy specimens were obtained, absence of pathology in those biopsy specimens was not required for inclusion.The hospital database was searched to confirm that patients having the same surname resided at the same address. In addition, for all families except one, review of the medical records or query of a gastroenterologist who cared for one or more members of the family confirmed the familial relationships.A relational database of patients treated at the CCED who have EGID was created in 2001 using Microsoft (Redmond, WA) Access with approval from the Institutional Review Board. Only data from patients who consented had their information entered into the database. Data included patient demographics, signs and symptoms, endoscopic findings, pathology diagnosis, results of skin prick tests, pertinent laboratory tests, treatment, and final clinical diagnosis. Information for the database was obtained mainly from hospital records retrospectively. All clinical information used in this study was gathered from the CCED database (by C.K.). One family member of each of the 26 familial patients registered in the database was matched as closely as possible by date of birth and sex to 26 sporadic patients who did not have affected family members. There were insufficient numbers of patients to permit random matching of familial and sporadic patients.Signs and symptoms, endoscopic findings, and results of allergy tests for all patients were obtained from the database. Thick esophageal mucosa diagnosed at endoscopy indicated opaque mucosa in which vascular markings were not visible and that appeared thicker than normal when the biopsy was performed, furrows indicated thick mucosa with evenly spaced vertical lines, exudate indicated patches or plaques of white material on the mucosal surface, stricture indicated small esophageal lumen and a rigid wall, and rings indicated mucosal elevations. For patients whose diagnostic endoscopy was performed at CCED, esophageal cultures were performed if clinically indicated. None of those patients was receiving antibiotics or topical steroid therapy at the time of the diagnostic endoscopy. Evenly spaced white patches or plaques on the vertical lines of abnormal mucosa were considered eosinophilic exudates, but randomly dispersed white patches or plaques were considered suspicious for fungal infection and were cultured. Atopy was defined as reaction to at least one antigen as shown by a skin prick test at the time of EE diagnosis.23Assa'ad A.H. Putnam P.E. Collins M.H. et al.Pediatric patients with eosinophilic esophagitis: an 8-year follow-up.J Allergy Clin Immunol. 2007; 119: 731-738Abstract Full Text Full Text PDF PubMed Scopus (272) Google ScholarAll biopsy specimens were fixed in formalin, and 5-μm–thick slides that were cut from paraffin blocks were stained with H&E. The available slides of esophageal biopsy specimens on which the diagnosis initially was made were re-reviewed to confirm the diagnosis and to quantitate eosinophilic inflammation more extensively for this report (by M.H.C.). The number of intraepithelial eosinophils was counted in all hpfs (400×, 0.30 mm2) in one complete section of a biopsy specimen, and the mean number and SD were calculated. The peak eosinophil number was defined as the greatest number of eosinophils in a hpf. The threshold peak number used to identify EE biopsy specimens was set at 24 or more per hpf.7Ruchelli E. Wenner W. Voytek T. et al.Severity of esophageal eosinophilia predicts response to conventional gastroesophageal reflux therapy.Pediatr Develop Pathol. 1999; 2: 15-18Crossref PubMed Scopus (177) Google Scholar, 10Noel R.J. Putman P.E. Collins M.H. et al.Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2004; 2: 568-575Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 11Konikoff M.R. Noel R.J. Blanchard C. et al.A randomized, double blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis.Gastroenterology. 2006; 131: 1381-1391Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar, 12Stein M.L. Collins M.H. Villaneuva J.M. et al.Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis.J Allergy Clin Immunol. 2006; 118: 1312-1319Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar, 22Blanchard C. Wang N. Stringer K.F. et al.Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.J Clin Invest. 2006; 116: 536-547Crossref PubMed Scopus (696) Google Scholar, 23Assa'ad A.H. Putnam P.E. Collins M.H. et al.Pediatric patients with eosinophilic esophagitis: an 8-year follow-up.J Allergy Clin Immunol. 2007; 119: 731-738Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar Quantitative evaluation of eosinophil number was performed for most patients, but because our clinical practice is composed largely of patients referred from other locales, several initial diagnostic biopsies that had been reviewed at the CCED, confirmed to have the threshold peak eosinophil number and returned to the hospital of origin, could not be obtained for re-review for this study (Table 1).Table 1Characteristics of Familial EE PatientsFamily no.SexPatientsAge at diagnosis, yMean ± SD (peak) eosinophil no.Other biopsiesDistal esophagusProximal esophagus1FemaleProband185.76 ± 6.73 (24)NDNDaMember of family matched to a patient with sporadic disease based on gender and age.MaleBrother183.17 ± 4.13 (17)4.84 ± 7.15 (24)D = eos agg; S = NDAMaleSporadic1513.3 ± 8.62 (32)8.63 ± 7.19 (21)D, S = NDA2FemaleProband710.7 ± 15.03 (42)NDD = eos cryptitis; S = mild chronicaMember of family matched to a patient with sporadic disease based on gender and age.FemaleSister1116 ± 13.11 (38)2.2 ± 4.41 (12)D = NDA; S = MME + MAFemaleSporadic1123.92 ± 14.53 (64)NDD, S = NDA3MaleProband1721.5 ± 14.45 (67)26.6 ± 14.83 (58)D, S = NDAaMember of family matched to a patient with sporadic disease based on gender and age.FemaleSister2016.5 ± 9.36 (32)0.3 ± 0.57 (21)D, S = NDAFemaleSporadic2031.8 ± 17.63 (84)41.83 ± 24.8 (101)D, S = NDA4MaleProband17109.2 ± 51.81 (223)5.6 ± 7.12 (21)D = NDA; S = MEaMember of family matched to a patient with sporadic disease based on gender and age.MaleBrother1175 ± 36.13 (167)53 ± 34.58 (151)D = ME + MA; S = NDAMaleFather4780.3 ± 48.44 (184)41.5 ± 45.62 (148)D = eos cryptitis; S = NDAMaleSporadic958.06 ± 28.36 (108)NDD = NDA5aMember of family matched to a patient with sporadic disease based on gender and age.MaleProband0.0812.7 ± 9 (28)12.7 ± 7.6 (25)D, S, S/R = NDAFemaleMother3622.7 ± 23.2 (111)NDNDMaleSporadic1.522.6 ± 19.3 (69)5.11 ± 5.33 (22)D, S = NDA6MaleProband0.2537 ± 20.5 (74)41.2 ± 20.92 (76)D = ND; S = MEaMember of family matched to a patient with sporadic disease based on gender and age.MaleBrother523.9 ± 14.09 (61)4.5 ± 7.31 (26)D = NDA; S = NDAMaleSporadic5.523.25 ± 15.17 (50)15.5 ± 15.77 (54)D, S, TI = NDA C/A, T/D, S/R = ME7FemaleProband0.587 ± 35.11 (176)NDD = CH; S = NDAaMember of family matched to a patient with sporadic disease based on gender and age.MaleBrother113.8 ± 8.7 (33)45.8 ± 27.2 (110)D, S, TI = NDA C/A, T/D, S/R = MEMaleSporadic136.5 ± 26.7 (86)0.17 ± 0.41 (1)D = NDA8aMember of family matched to a patient with sporadic disease based on gender and age.MaleProbandNA>24NDNDMaleBrotherNA>24NDNDMaleBrotherNA>24NDNDMaleBrotherNA>24NDNDMaleBrotherNA>24NDNDFemaleMother3427.3 ± 21.9 (57)NDNDMaleSporadic51.56 ± 1.26 (4)38.86 ± 28.56 (105) (mid)D, S = NDA9MaleProband21.5 ± 0.5 (2)12 ± 10.37 (28) (mid)NDaMember of family matched to a patient with sporadic disease based on gender and age.MaleBrother543.3 ± 17.66 (82)1.2 ± 1.63 (5)D, S = NDAMaleSporadic317.92 ± 7.42 (34)0.33 ± 0.62 (2)D, S = NDA10FemaleProband89.33 ± 5.91 (22)86.8 ± 53.32 (151)S = NDAaMember of family matched to a patient with sporadic disease based on gender and age.FemaleSister (twin)1532.5 ± 15.57 (64)5.11 ± 9.5 (31)D, S = NDAFemaleSporadic1750 ± 26.29 (106)1.09 ± 1.38 (5) (mid)D = NDA; S = CG11FemaleProband436.9 ± 25.17 (88)35.1 ± 28.14 (88)D = eos cryptitis; S = NDAaMember of family matched to a patient with sporadic disease based on gender and age.MaleBrother339.5 ± 13.41 (62)36.7 ± 25.54 (86)D, S = NDAMaleSporadic233.75 ± 15.26 (54)NDD, S = NDA12MaleProband531.4 ± 22.03 (92)NDS = NDAaMember of family matched to a patient with sporadic disease based on gender and age.MaleBrother113.5 ± 8.9 (39)12.2 ± 14.47 (67)D, S, TI, A/C, T/D, S/R = NDAMaleSporadic266.25 ± 34.38 (160)77.05 ± 48.55 (245)D = eos duodenitis; S = NDA13MaleProband938.5 ± 26.83 (106)7.9 ± 7.74 (26)D, S = NDAaMember of family matched to a patient with sporadic disease based on gender and age.FemaleSister149.4 ± 8.98 (26)27.5 ± 5.36 (36)S = MEFemaleSporadic118.82 ± 8.71 (33)NDND14aMember of family matched to a patient with sporadic disease based on gender and age.FemaleProband121 ± 13.89 (48)0.47 ± 0.7 (26)D, S = NDAMaleBrother717.6 ± 14.88 (61)1.29 ± 1.1 (3)D, S, TI, C/A, T/D, S/R = NDAMaleBrother87.2 ± 9.32 (33)1.3 ± 2.24 (9)D, S, TI, C/A, T/D, S/R = NDAFemaleSporadic15.05 ± 8.81 (33)6.41 ± 8.89 (27)D, S = NDA15FemaleProband632.1 ± 15.77 (78)36.1 ± 14.57 (65)D = NDA; S = MCGaMember of family matched to a patient with sporadic disease based on gender and age.FemaleSister1151.5 ± 27.94 (121)39.1 ± 29.2 (104)D, S = NDAFemaleSporadic718.7 ± 18.53 (62)13.5 ± 10.97 (42)D = eos agg; S = NDA16MaleProband166.5 ± 7.89 (31)13.8 ± 10.26 (31)D = NDA; S = MCGaMember of family matched to a patient with sporadic disease based on gender and age.FemaleSister1814.2 ± 22.4 (100)NDNDFemaleSporadic2028.44 ± 19.46 (70)NDD, S, TI, C/A, T/D, S/R = NDA17MaleProband1136.4 ± 19.62 (85)26.8 ± 10.4 (47)D, S = NDAaMember of family matched to a patient with sporadic disease based on gender and age.MaleBrother (twin)1211.7 ± 11.63 (51)7.6 ± 7.39 (24)D, S, TI, C/A, T/D, S/R = NDAFemaleSister1425.5 ± 24.3 (99)NDD, S = NDAMaleSporadic1134.4 ± 24.41 (79)22.1 ± 20.23 (73)D, S = NDA18FemaleProband175.8 ± 5.2 (18)6.9 ± 8.66 (28)D, S = NDAaMember of family matched to a patient with sporadic disease based on gender and age.MaleBrother2014.6 ± 11.91 (46)6.1 ± 7.93 (38)D, S = NDAMaleSporadic2242.82 ± 35.3 (126)NDD, S = NDA19aMember of family matched to a patient with sporadic disease based on gender and age.MaleProband137.9 ± 7 (27)1.8 ± 3.47 (16)D, S, TI, C/A, T/D, S/R = NDAMaleBrother125.8 ± 4.47 (14)10 ± 10.5 (37)D, S = NDAMaleSporadic1019.45 ± 16.28 (60)33.65 ± 20.56 (69)D, S = NDA20aMember of family matched to a patient with sporadic disease based on gender and age.MaleProband859.8 ± 23.3 (107)28.7 ± 17.15 (86)NDMaleFather216 ± 2.16 (7)39.3 ± 8.99 (52)D, S = NDAMaleSporadic11185 ± 76.8 (349)45.2 ± 43.6 (146)D, S = NDA21MaleProband465.3 ± 28.52 (113)45.7 ± 19.26 (77)D, S = NDAaMember of family matched to a patient with sporadic disease based on gender and age.MaleBrother439.8 ± 20.06 (84)16.8 ± 16.76 (56)D, S = NDAMaleSporadic121.5 ± 16.9 (83)7.88 ± 9.27 (36)D, S = NDA22aMember of family matched to a patient with sporadic disease based on gender and age.MaleProband516.3 ± 11.43 (33)NDD = NDA; S = NAFemaleSister310.5 ± 9.52 (30)8.1 ± 6.57 (26)D = NDA; S = GCMaleSporadic514.7 ± 9.43 (30)NDD, S = NDA23MaleProband752.6 ± 41.99 (140)12.9 ± 21.58 (62)D, S = NDAaMember of family matched to a patient with sporadic disease based on gender and age.MaleBrother1310.7 ± 9.85 (41)8.5 ± 8.45 (27)D = erosive duodenitis; S = NDAMaleSporadic925.39 ± 23.5 (76)20.15 ± 33.51 (132)D = NDA; S = Chem g24aMember of family matched to a patient with sporadic disease based on gender and age.MaleProband412.7 ± 7.49 (34)11.4 ± 6 (24)D, S, TI, C/A, S/R = NDA, T/D = eos aggMaleBrother221.9 ± 8.03 (41)41.6 ± 16.3 (71)D, S = NDAMaleSporadic720.4 ± 27.8 (91)13.4 ± 11.1 (36)D, S = NDA25aMember of family matched to a patient with sporadic disease based on gender and age.MaleProband917.3 ± 19.48 (70)NDD, S = NDAMaleBrother234.6 ± 17.65 (60)NDNDMaleSporadic1139.1 ± 12.9 (55)78.4 ± 33.3 (168)D = reac epi; S = ME26aMember of family matched to a patient with sporadic disease based on gender and age.MaleProband516.4 ± 7.31 (28)11.3 ± 9.92 (33)D = NDAMaleBrother542.8 ± 35.38 (129)21 ± 11.3 (42)D, S = NDAMaleSporadic1.333.5 ± 20.7 (61)12.9 ± 10.2 (35)D, S = NDASporadic, patient with sporadic disease; ND, not done; D, duodenum; Eos agg, eosinophil aggregate in superficial epithelium; S, stomach; NDA, no diagnostic abnormality; Eos, eosinophilic; MME, mild mucosal eosinophilia; MA, mild acute inflammation; ME, mucosal eosinophilia; S/R, sigmoid/rectum; TI, terminal ileum; C/A, cecum/ascending colon; CH, crypt hyperplasia; T/D, transverse/descending colon; NA, not available; mid, midesophagus; CG, chronic gastritis; MCG, mild chronic gastritis; Chem g, chemical gastropathy; Reac epi, reactive epithelial changes. GC, lamina propria giant cell.a Member of family matched to a patient with sporadic disease based on gender and age. Open table in a new tab Reports of biopsy specimens from other sites in the gastrointestinal tract that were obtained during the endoscopy that yielded the initially diagnostic esophageal biopsy specimen were reviewed. Slides or photographs of biopsy specimens that were not reported as normal were re-reviewed. The peak number of eosinophils in normal pediatric gastrointestinal tract biopsy specimens in Cincinnati was used as a guide to distinguish normal from abnormal biopsy specimens.24DeBrosse C.W. Case J.W. Putnam P.E. et al.Quantity and distribution of eosinophils in the gastrointestinal tract of children.Pediatr Develop Pathol. 2006; 9: 210-218Crossref PubMed Scopus (213) Google Scholar For purposes of this study, mucosal eosinophilia designates increased numbers of eosinophils in the lamina propria without eosinophilic cryptitis or other alterations. Eosinophilic cryptitis is the presence of multiple eosinophils in the epithelium of one or more crypts. Eosinophilic enteritis is mucosal eosinophilia plus significant architectural alterations, such as cryptitis, elongated crypts, and reactive epithelial changes.Data were considered absent if neither positive nor negative responses were found in the database or hospital records. Data were analyzed using SAS version 9.1 (SAS Institute, Cary, NC). Simple descriptive statistics were run on each group to obtain N and percentages. The McNemar test was used to test agreement between the familial and nonfamilial groups. The paired t test was used to determine differences between groups. Biserial correlations were used to test correlations between eosinophil counts and endoscopic and atopic findings. A simple t test was used to determine differences among all patients in the study. A P value of .05 or less was considered significant.Several patients reported in this study had participated in a prior study that used esophageal biopsy specimens in a genome-wide DNA microarray analysis.22Blanchard C. Wang N. Stringer K.F. et al.Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.J Clin Invest. 2006; 116: 536-547Crossref PubMed Scopus (696) Google Scholar The available results of the microarray analysis for the familial and sporadic patients were extracted and compared using the Welch t test with and without false-discovery rate (FDR) correction.ResultsEosinophilic Esophagitis Family Member RelationshipsTwenty-six families with more than one affected member were identified. A total of 59 patients in these families had EE (Table 1), 41 males and 18 females, with a mean age of 10.3 years (range, 0.25–47 y) at diagnosis. Affected members were siblings in 85% of families, and children and their parents in 15% of families. Four families had affected members in more than 1 generation. In 2 families, the father of a male proband had EE, in 1 family the mother of a male proband had EE, and in 1 family the mother of a male proband and all 4 of his male siblings had EE.Clinical Features of Familial Eosinophilic EsophagitisAmong all familial patients for whom the information was available, the most common complaint at diagnosis was dysphagia, reported by 68% of patients (Table 2). Emesis, abdominal pain, and heartburn were other common complaints, reported by 62%, 57%, and 45% of patients, respectively. These symptoms varied with patient age. Patients who reported dysphagia had a mean age of 12.9 years at diagnosis, and were significantly older than patients who reported emesis (mean age, 7.99 y; P < .05), or abdominal pain (mean age, 7.96 y, P < .02), but not significantly older than patients who reported heartburn (mean age, 9.76 y).Table 2Clinical CharacteristicsAll familial patients (N = 59)Familial patients matched to sporadic patients (N = 26)Sporadic patients (N = 26)All patients (N = 85)Signs and symptoms Dysphagia36 (68%) N = 5313 (54%) N = 2410 (40%) N = 2546 (59%) N = 78 Emesis32 (62%) N = 5216 (64%) N = 2515 (63%) N = 2447 (62%) N = 76 Abdominal pain27 (57%) N = 4715 (65%) N = 2311 (46%) N = 2438 (54%) N = 71 Heartburn23 (45%) N = 5110 (43%) N = 2314 (58%) N = 2437 (49%) N = 75 Food impaction9 (17%) N = 523 (13%) N = 243 (13%) N = 2412 (16%) N = 76 Chest pain12 (24%) N = 496 (26%) N = 236 (25%) N = 2418 (25%) N = 73 Cough11 (23%) N = 474 (18%) N = 222 (8%) N = 2413 (18%) N = 71 Nausea10 (22%) N = 466 (26%) N = 234 (17%) N = 2414 (20%) N = 70 Diarrhea5 (10%) N = 483 (13%) N = 244 (17%) N = 249 (13%) N = 72 Choking7 (32%) N = 221 (11%) N = 98 (33%) N = 2415 (33%) N = 46 Allergic rhinitis36 (73%) N = 4915 (65%) N = 2313 (57%) N = 2349 (68%) N = 72 Asthma25 (51%) N = 4912 (52%) N = 2313 (54%) N = 2438 (52%) N = 73 Allergic conjunctivitis29 (59%) N = 4911 (48%) N = 2311 (48%) N = 2341 (56%) N = 72 Eczema22 (47%) N = 4713 (57%) N = 238 (36%) N = 2230 (44%) N = 69Endoscopic findings Furrows37 (93%) N = 4019 (95%) N = 2016 (89%) N = 1853 (91%) N = 58 Thickened27 (68%) N = 4013 (68%) N = 199 (69%) N = 1336 (68%) N = 53 Exudate19 (44%) N = 439 (45%) N = 203 (27%) N = 1122 (41%) N = 54 Stricture4 (10%) N = 420 (0%) N = 192 (12%) N = 176 (10%) N = 59 Rings3 (7%) N = 451 (5%) N = 212 (13%) N = 155 (8%) N = 60Skin prick tests Environment27 (71%) N = 3813 (65%) N = 2013 (59%) N = 2240 (67%) N = 60 Food31 (76%) N = 4114 (70%) N = 2016 (80%) N = 2047 (77%) N = 61 Open table in a new tab Endoscopic Features of Familial Eosinophilic EsophagitisDiagnostic endoscopy showed esophageal mucosal furrows in 93% of patients, thick mucosa in 68%
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