C O W D E N S Y N D R O M E D I A G N O S E D F O R D E N T A L S U R G E O N
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© 2014 Special Care Dentistry Association and Wiley Periodicals, Inc.
DOI: 10.1111/scd.12081
C A S E H I S T O R Y R E P O R T
Cowden syndrome or multiple
hamartoma syndrome, is a rare genetic condition inherited in an autosomal dominant pattern characterized by cutaneous manifestations, polyps, thyroid gland neoplasias, and macro- cephaly. This report presents the case of a 36-year-old patient who looked for dental treatment for a gingival nodule.
Current and past medical history and oral and facial manifestations led to the diagnosis of Cowden syndrome. This case report emphasizes the role of the dental surgeon in the diagnosis of this systemic disease, based on the analysis of medical history and manifestations in the oral cavity.
A B S T R A C T Cowden syndrome—a case report
emphasizing the role of the dental surgeon in diagnosis
Liana Preto Webber , DDS ; 1* Manoela Domingues Martins , DDS, PhD ; 2 Vinícius Coelho Carrard , DDS, MSc, PhD ; 2 Marco Antônio Trevizani Martins , DDS, MSc, PhD ; 2 Maria Cristina Munerato , DDS, MSc, PhD 3
1 Master degree student, Department of Oral Pathology , School of Dentistry, Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil ; 2 Assistant professor, Department of Oral Pathology, School of Dentistry , Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil ; 3 Assistant professor, Department of Stomatology of Hospital de Clínicas de Porto Alegre , Universidade Federal do Rio Grande do Sul , Porto Alegre , Brazil .
*Corresponding author e-mail: manomartins@gmail.com
Spec Care Dentist 35(1): 51-54, 2015
The diagnosis of CS is based on the criteria defined by The International Cowden Consortium and are divided into pathognomonic, major and minor criteria (Table 1 ). 7 Among these, mucocutaneous lesions like multiple facial verrucous papules (usually trichilemmomas), oral papillomatosis, and macrocephaly are easily detected by the dental surgeon. 6,8 In addition, CS patients are also more prone to develop neoplasias, mainly in the thyroid, breast, and endometrium. 6
This case report describes an occur- rence of CS diagnosed by a dental surgeon based on clinical history and oral cavity manifestations.
C a s e r e p o r t
A 36-year-old female patient, with no children, looked for service in the
Reference Teaching Hospital of the Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil, due to a gingival growth that hindered the use of a dental removable prosthesis.
Clinical history revealed a previous thyroidectomy carried out 15 years before (follicle carcinoma and follicle adenoma). The patient reported having had Hashimoto’s thyroiditis and papules removed from hands and stomach, and was under medical follow-up for gastritis, arthrosis, depression, fibromyalgia, and breast nodules diagnosed as ductal ectasia. Extraoral examination revealed macrocephaly (Figure 1 ). The presence of papules in the perilabial and labial regions was detected (Figure 2 ). Papules were also noticed in hands and in the perinasal, periorbital and preauricular regions.
Intraoral examination revealed papules
In t r o d u c t i o n
Cowden syndrome (CS), also called multiple hamartoma syndrome, is a rare
autosomal dominant genetic condition. This change is associated with mutations in the phosphatase and tensin homologue ( PTEN ) gene, a tumor suppressor located in chromo- some 10q 22–33. 1–4 These mutations may generate changes in derivative tissues of the three germinative layers of the human body, like the skin, gastrointestinal tract, bones, central nervous system, eyes, genitourinary tract, and oral mucosa. 4–6
KEY WORDS: Cowden disease , genetics , hamartoma tumor syndrome , oral papules , PTEN , trichilemmomas
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also on the tongue and oral cavity floor, (Figure 3 ), as well as a single vegetative
nodule with verrucous surface located on the upper alveolar ridge anteriorly to the canine (Figure 4 ). All these findings sug- gested CS or Heck’s Disease. Biopsy of the nodular lesion was carried out, and histopathologic evaluation showed the presence of epithelial hyperplasia (Figure 5 ). The diagnosis of CS was established considering these intra- and
extraoral findings and the patient’s previ- ous medical history. The patient was referred to specialized genetics and der- matology services, which confirmed the diagnosis. Since then, the patient has been under transdisciplinary follow-up for 2 years.
Table 1. Diagnostic criteria proposed by the International Cowden Syndrome Consortium (8).
Pathognomonic Criteria
Mucocutaneous lesions alone if
• There are six or more facial papules of three or more must be trichilemmomas or • Cutaneous facial papules and oral mucosal papillomatosis or
• Oral mucosal papillomatosis and acral keratosis or • Palmoplantar keratosis, six or more
Major Criteria—Two criteria (one of which must be macrocephaly or Lhemitte–Duclos disease Breast carcinoma
Thyroid carcinoma (nonmedullary), especially follicular thyroid carcinoma Macrocephaly
Lhermitte–Daclos disease Endometrial carcinoma Minor criteria—Four criteria Other thyroid lesions Mental retardation
Gastrointestinal hamartomas Fibrocystic disease of the breast Lipomas
Fibromas
Genitourinary malformations or carcinoma
Or One major criterion an three minor criteria may also indicate diagnosis of CS
Figure 1. Frontal aspect of the patient showing macrocephaly.
Figure 2. Extraoral examination reveals multiple papules in the upper lip.
Figure 3. Intraoral examination reveals multiple papules in the tongue.
Figure 4. Verrucous vegetating nodule on the upper right posterior alveolar ridge.
Figure 5. Microphotograph (40 x) of histologi- cal sections stained by hematoxilin-eosin showing the epithelial hyperplasia as a histo- logical finding of excisional biopsy carried out in the gingival nodule.
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D i s c u s s i o n
CS is a rare genetic condition, with esti- mated one case in every 200,000 to 250,000 people. 2 Eighty percent of cases are associated with mutations in PTEN , a gene that regulates cell cycle, migration and apoptosis, and affects the prolifera- tion of the disease. 7 It has been
hypothesized that mutations in PTEN are the reason behind the abnormal prolifer- ation of tissues and the higher chances of carriers to develop neoplasias. 6 This syn- drome has varied genetic expression that often manifest as subtle signs on the skin, which makes it go by misdiag- nosed.
Diagnosis is based on the presence of multiple clinical signs. The International Cowden Consortium has stipulated parameters for the diagnosis of CS (Table 1 ), according to which the confir- mation of one major criterion and of three minor criteria are enough to pro- duce a positive diagnosis. 7 In the present case, the patient presented more than six facial papules, apart from papules in the oral mucosa and on hands (pathogno- monic criteria), thyroid carcinoma, macrocephaly (major criteria), and other lesions on the thyroid and papules in the stomach (minor criteria). However, in spite of all these characteristics and of the fact that the patient was under differ- ent specialties of medical follow-up, the diagnosis of CS had not been produced before her consultation with a dental sur- geon. Ravi Prakash et al. underline that mean age of CS patients is 22 years.
Therefore, early diagnosis and periodical
follow-ups affords to identify the mani- festations of CS, which develop gradually with time. Similarly to the present case, Mukamal et al. reported a similar delay in diagnosis, possibly due to the lack of a proper cross-link of the clinical condi- tions of the patient with CS.
The lesions observed in the oral cavity were papillomatous, and located mainly on the lips, gums and tongue. 9 According to the diagnosis criteria, when six or more papillomatoses are observed, the suspicion of CS should be consid- ered. 7 Here, the dental surgeon
considered these findings in light of the other manifestations of the disease in other organs, and thus proposed the diagnosis of CS. Other manifestations in the head and neck region associated with CS are carcinomas in the parotid and submandibular glands. 6,10 Therefore, when lesions as those described above are observed upon clinical examination, the dental surgeon should review infor- mation pertaining to the patient’s clinical history and conduct a transdisciplinary investigation in search for other lesions, like papules on the skin, thyroid changes, macrocephaly, and gastrointesti- nal polyps to confirm or rule out the diagnosis of CS. 7 This clinical case underlines the importance of the role of the dental surgeon in the diagnosis of CS, and of diseases that affect multiple organs. 9
The main complication of CS is the high prevalence of breast, thyroid, and endometrium neoplasias, since the dis- ease is the manifestation of changes in the PTEN gene, a tumor suppressor. 2,6
Changes in the thyroid are present in between 40% and 60% of the cases, and manifest as hyperthyroidism, benign ade- nomas, and adenocarcinomas. 9,11 In the present case, the patient developed Hashimoto’s thyroiditis and follicle ade- noma followed by follicle carcinoma.
Therefore, CS carriers should be periodi- cally followed-up so as to make it possible to diagnose malignant tumors as early as possible, allowing less invasive treatment approaches. 7,9 Here, the thy- roid neoplasias might have been
diagnosed earlier, if the first clinical signs presented by the patient, such as papillo- matoses in the mouth, had been observed more carefully.
Another neoplasia often observed in CS patients is breast cancer. Thus, women over 25 years of age with CS should carry out the breast self-examina- tion, while women over 30 years old should have mammograms once a year. 7 Polyps in the gastrointestinal tract is also very common, present in 35% to 40% of CS cases. Therefore, it is important to prescribe regular endoscopy to these patients. 11 In this case report, the patient had been submitted to stomach polyp removal surgery before diagnosis of CS was defined.
The differential diagnosis of CS may be carried out together with that of other diseases or syndromes (Table 2 ). 12–14 The Lhermite-Duclos disease is charac- terized by hamartomatous nodules in the cerebellum, and was first considered a separate disease, though today it is seen as a manifestation of CS. 7 The symptoms of the Bannayan-Riley-Ruvalcaba Table 2. Main differential diagnosis with oral manifestations CS.
Similarities with Cowden Syndrome Differences with Cowden Syndrome References Bannayan-Riley-
Ruvalcaba
• Acral Keratoses
• Facial papules
• Lipomas
• Macrocephaly
• Slanting palpebral fissures
• Macrosomia at birth
• Persistent drooling
Wilson et al.
Heck’s disease • Multiple papules or nodules on the oral mucosa
• No systemic manifestations Borborema-Santos
et al.
Multiple endocrinal neoplasia type 2B
• Thyroid cancer
• Multiple papules or nodules on the oral mucosa
• Pheochromocytoma,
• Marfanoid body habitus,
• Ganglioneruomatosis of the gastrointestinal tract
Callender et al .
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syndrome are very similar to those of CS, and include facial papules. However, the difference between the two diseases lies in the fact that gingival hyperplasia is observed in the Bannayan-Riley-
Ruvalcaba syndrome, not in CS. 12,15 The Proteus syndrome and Juvenile Polyposis present a series of clinical manifestations that are similar to CS, though papilloma- tosis in the mouth are not reported. 16
Among the diseases that cause by mouth papillomatous lesions, the main disease that should be included in the differential diagnosis of CS is Heck’s Disease, characterized by diffuse whitish papules in the oral cavity, which, in this case report, were initially considered to be the disease presented by the
patient. 9,13,17 However, this disease does not cause changes in other organs like breast, thyroid and endometrium. The multiple endocrinal neoplasia type 2B also is characterized by multiple oral papules and high prevalence of thyroid carcinomas; however, those papules characterize neuromas histopathologicaly, not epithelial hyperplasia, as in CS.
Moreover, this condition presents other skeletal characteristics, and the manifes- tations in head and neck include marfanoid facies, the presence of neuromas on the eyelids (which causes eversion), and swollen lips. 14,18
Patients with CS require strict medical follow-up to diagnose and treat likely manifestations, as early as possible.
The International Cowden Consortium recommends that CS patients undergo comprehensive annual medical examina- tions from the 18th year of age on, with special care taken to detect any changes in skin and in the head and neck region. 7
The treatment of CS is defined by the severity of clinical manifestations of the syndrome. The patients are considered at high risk for neoplasias. If these patients are followed up at short intervals, the prognosis becomes more favorable, since neoplasias can therefore be diagnosed at their early stages, improving the chances
of success in the treatment.
Muccocutaneous papillomatous lesions may be treated with carbon dioxide, laser, surgical removal, electrosurgery, cryosurgery and interferon 2-alpha and 5-fluorouracyl. 4,10
The case presented in this report emphasizes the role of the dental surgeon in the diagnosis of CS based on a cross- examination of clinical history and the identification of oral lesions during examination.
C o n c l u s i o n
The dental surgeon should know sys- temic diseases that manifest in the oral cavity, like CS, to carry out the early diagnosis of its manifestations, imple- ment efficacious therapeutic measures to ensure a better prognosis.
R e f e r e n c e s
1. Nelen MR , Padberg GW , Peeters EA , et al . Localization of the gene for Cowden disease to chromosome 10q22–23 . Nat Genet 1996 ; 13 : 114 - 6 .
2. Nelen MR , Kremer H , Konings IB , et al . Novel PTEN mutations in patients with Cowden disease: absence of clear genotype- phenotype correlations . Eur J Hum Genet 1999 ; 7 : 267 - 73 .
3. Liaw D , Marsh DJ , Li J , et al . Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome . Nat Genet 1997 ; 16 : 64 - 7 . 4. Leao JC , Batista V , Guimaraes PB , Belo J ,
Porter SR . Cowden’s syndrome affecting the mouth, gastrointestinal, and central nervous system: a case report and review of the liter- ature . Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005 ; 99 : 569 - 72 .
5. Said AK , Leao JC , Fedele S , Porter SR . Focal epithelial hyperplasia—an update . J Oral Pathol Med 2013 ; 42 : 435 - 42 .
6. Uppal S , Mistry D , Coatesworth AP . Cowden disease: a review . Int J Clin Pract
2007 ; 61 : 645 - 52 .
7. Eng C . Will the real Cowden syndrome please stand up: revised diagnostic criteria . J Med Genet 2000 ; 37 : 828 - 30 .
8. Mukamal LV , Ferreira AF , Jacques Cde M , Amorim CA , Pineiro-Maceira J , Ramos- e-Silva M . Cowden syndrome: review and report of a case of late diagnosis . Int J Dermatol 2012 ; 51 : 1494 - 9 .
9. Ravi Prakash SM , Suma GN , Goel S . Cowden syndrome . Indian J Dent Res 2010 ; 21 : 439 - 42 .
10. Patil PB , Sreenivasan V , Goel S , et al . Cowden syndrome- Clinico-radiological illustration of a rare case . Contemp Clin Dent 2013 ; 4 : 119 - 23 .
11. Scheper MA , Nikitakis NG , Sarlani E , Sauk JJ , Meiller TF . Cowden syndrome: report of a case with immunohistochemical analysis and review of the literature . Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006 ; 101 : 625 - 31 .
12. Wilson PH , MacDonald DG , Felix DH . Bannayan-Riley-Ruvalcaba syndrome: report of a family . Oral Dis 2001 ; 7 : 310 - 4 . 13. Borborema-Santos CM , Castro MM , Santos
PJ , Talhari S , Astolfi-Filho S . Oral focal epithelial hyperplasia: report of five cases . Braz Dent J 2006 ; 17 : 79 - 82 .
14. Callender GG , Rich TA , Perrier ND . Multiple endocrine neoplasia syndromes . Surg Clin North Am 2008 ; 88 : 863 - 95 . 15. Flores IL , Romo SA , Tejeda Nava FJ , et al .
Oral presentation of 10 patients with Cowden syndrome . Oral Surg Oral Med Oral Pathol Oral Radiol 2014 ; 117 : e301 - e10 . 16. Sakamoto Y , Nakajima H , Kishi K , Shimizu R , Nakajima T . Management of craniofacial hyperostosis in Proteus syndrome . J Craniofac Surg 2010 ; 21 : 414 - 8 .
17. Segura Saint-Gerons R , Ceballos Salobrena A , Toro Rojas M , Gandara Rey JM . Oral manifestations of Cowden’s disease. Presentation of a clinical case . Med Oral Patol Oral Cir Bucal 2006 ; 11 : E421 - 4 .
18. Usami Y , Takenobu T , Kurihara R , et al . Neural hyperplasia in maxillary bone of multiple endocrine neoplasia type 2B patient . Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011 ; 112 : 783 - 90 .
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