DR [page 6] [Dermatology Reports 2010; 2:e3] Proteus syndrome: a case report and a case study review in China Xi-Bao Zhang,1 Chang-Xing Li,2 Yu-Qing He,1 San-Quan Zhang,1 Yan-Xia Cai1 1Guangzhou Institute of Dermatology, Guangzhou, China; 2Dongguan Institute of Dermatology, Dongguan, China Abstract Proteus syndrome (PS) is a rare and spo- radic disorder characterized by overgrowth of multiple tissues and a propensity to develop particular neoplasms. The clinical manifesta- tions of PS include macrodactyly, vertebral abnormalities, asymmetric limb overgrowth and length discrepancy, hyperostosis, abnor- mal and asymmetric fat distribution, asymmet- ric muscle development, connective tissue nevi, and vascular malformations. We report a 16-year old female patient who manifested a number of these complications and review the Chinese literature about the diagnosis, natural history, and management of PS. Introduction The malformations in PS can involve skin, subcutaneous tissue, connective tissue (in - clud ing bone), the central nervous system, and viscera. The main clinical manifestations of PS include hemihypertrophic macrodactyly, sub- cutaneous tumors, palmar and metatarsal cerebriform connective tissue nevi, lipomas, exogenesis bone mammilla, epidermal nevi, vascular malformations, lipohypoplasia, and dermalhypoplasia.1 In this article, we report a PS case that has a number of clinical manifes- tations, and review the literature on this unique disorder in China. Case report A 16-year old Chinese girl was born to non- consanguineous parents. The pregnancy and delivery were uneventful. Her mother denied any drug use, radiation exposure, or infections during pregnancy. She presented to our insti- tute at the age of 16 with facial dysmorphism and verrucous hyperplasia on the right side of her body. She was born with deafness of the right ear and dry, rough, light brown color pat- terns on the right trunk. As she grew, the patient developed more abnormalities, includ- ing right face, ear, tongue, and lip hyperplasia and overgrowth. The skin of the right trunk thickened and darkened, as the left side remained normal. Her parents, 3 sisters and brother are all normal, and there was no other similar disorder in her family. Physical examination The patient was noted to have normal intel- ligence. Her height and weight were 153 cm and 44 kg, respectively. Her vital signs were within normal limits. The patient showed sev- eral anomalies. There was hemihypertrophy involving the entire right side of the head, including the skull, face, ear, palate, tongue, lip and neck. There was an epidermal nevus on the right side of the body, showing general cornification pachydermia. Hyperpigmented swirled and linear skin lesions were present on the right side of the neck and trunk, and verru- cous epidermal nevi were seen on the right side of neck. She had malocclusion of the teeth, papillomarous hyperplasia of the tongue, hypertrophy of the right auricle, obstruction of the right auditory meatus, and a vascular malformation and lipomas on the right of the face. The distal right maniphalanx was enlarged and hammer-like. The right plan- ta had an amber hyperplastic plaque that was moderately hard in texture and lacked pain sensation (Figures 1 and 2). Laboratory and auxiliary examination Computer tomography scan of the patient’s head and face showed a large lipoma in the right face, but there were no abnormalities of the brain. Plain radiographs showed hyperpla- sia and hypertrophy of the jaw bone. There was a mild protrusion on the side of the thorax and the left tibia was mildly thickened. Electro - cardiography was within normal limits. Ultrasounds for the other organs, such as liver, kidney, spleen, pancreas, uterus and both adnexa, were all within normal limits. The histopathological changes in the epi- dermis were hyperplastic and affected chiefly the stratum corneum and stratum malpighii. Evaluation of the firm nodule adjacent to the right nasal ala revealed dense collagen consis- tent with a connective tissue nevus or linear verrucous epidermal nevus. Discussion Etiology of Proteus syndrome The cause of PS is still unknown, but a genetic mutation that is viable only in a mosa- ic state has been postulated.2 Such a mutation might affect local production or regulation of tissue growth factor receptors. This theory would explain the sporadic nature of the syn- drome, its occurrence in various ethnic groups and both sexes, and its interindividual vari- ability, as well as the mosaic pattern of lesion distribution in all who are affected. In recent years, some authors have suggest- ed that PS may be caused by germline muta- tions within the PTEN gene.3 The presence of a germline PTEN mutation in a subset of Dermatology Reports 2010; volume 2:e3 Correspondence: Xi-Bao Zhang, Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou 510095, Guangdong Province, P R of China. E-mail: lilichangxing@163.com Key words: Proteus syndrome, clinical manifes- tation, diagnosis Acknowledgments. The authors are deeply grate- ful to Dr. T Joseph and Dr. C Helena for their kind suggestions. Conflict of Interest: the authors have no con- flicts of interest to declare. Received for publication: 2 November 2009 Revision received: 23 December 2009 Accepted for publication: 28 December 2009 This work is licensed under a Creative Commons Attribution 3.0 License (by-nc 3.0). ©Copyright X-B. Zhang et al., 2010 Licensee PAGEPress, Italy Dermatology Reports 2010; 2:e3 doi:10.4081/dr.2010.e3 Figure 1. There was hemihypertrophy involving the entire right side of the head,including the skull, face, ear, palate, tongue, lip and neck. No n- co mm er cia l u se on ly [Dermatology Reports 2010; 2:e3] [page 7] patients with PS has been confirmed by the identification of a de novo PTEN mutation in a patient with classical PS conforming to the cri- teria described by Biesecker et al.4 Manifestations of Proteus syndrome PS is a rare and sporadic disorder that caus- es postnatal overgrowth of multiple tissues in a mosaic pattern.5 While patients with PS have a variable clinical appearance, they exhibit a defined constellation of skin abnormalities. Extracutaneous manifestations were divided into the following categories: skeletal over- growth, visceral overgrowth, other overgrowth, tumors, cysts, vascular abnormalities, deformi- ty, and hypoplasia/maldevelopment.6-8 Infants affected by the disorder usually appear normal or show only mild asymmetry at birth but pro- gressively develop the characteristic features of the disease during childhood.9 Complications of PS include, among others, progressive skeletal deformities, invasive lipo- mas, benign and malignant tumors, and deep venous thrombosis with pulmonary embolism. Progressive skeletal abnormalities such as macrodactyly, scoliosis, asymmetric over- growth, and limb length discrepancy are the most frequent and striking findings in patients with PS, followed by soft-tissue abnormalities such as fatty, muscular, and vascular malfor- mations. Visceral anomalies such as spleno - megaly, asymmetric megalencephaly, white- matter abnormalities, and nephromegaly as well as masses other than fatty, muscular, and vascular malformations are less common.10 The diagnosis of PS was based on published criteria.4 The current situation of investiga- tion on Proteus syndrome in China All 8 patients reported11-18 in China had at least 2 different skin abnormalities and had other abnormalities, including lipomas, telang- iectatic nevi or other vascular lesions, plantar cerebriform connective tissue nevi, or linear lesions of an epidermal nevus. Remarkably, connective tissue nevi were also found on the Article Figure 2. Verrucous epidermal nevi were seen on the right side of neck. T ab le 1 . Su m m ar y o f 8 c as es w it h P ro te u s sy n d ro m e in C h in a. C as e 1 C as e 2 C as e 3 C as e 4 C as e 5 C as e 6 C as e 7 C as e 8 Se x fe m al e fe m al e fe m al e fe m al e m al e fe m al e m al e fe m al e Ag e 30 y ea rs 12 y ea rs 6 ye ar s 16 y ea rs 9 ye ar s 30 y ea rs 28 y ea rs 26 y ea rs Ab no rm al ity Le ft th um b Le ft h an d Le ft li m b Ri gh t f ac e, Ri gh t f ac e Le ft le g Le ft fa ce Le ft fi ng er an d le g he m ih yp er - he m ih yp er -, ea r, to ng ue , an d no se he m ih yp er - an d he ad an d ri gh t f oo t he m ih yp er - tr op hy , tr op hy , an d ec to la bi um he m ih yp er tr op hy , tr op hy , b ot h he m ih yp er - he m ih yp er tr op hy , tr op hy , b on e ep id er m al n ev i, le ft h an d gi an t he m ih yp er tr op hy , ep id er m al n ev i, lo w er , e xt re m ity tr op hy , c on ne ct iv e ri gh t l ow er e xt re m ity th ic ke ni ng , fib ro ne ur om a fin ge r, ep id er m al ri gh t f ac e lip om as , co nn ec tiv e tis su e ve no us tis su e ne vu s, ve no us m al fo rm at io ns , co nn ec tiv e of h ea d an d fa ce , ne vi , l ef t a rm ri gh t f ac e ne vu s, b on e m al fo rm at io n, fib ro lip om a, ep id er m al n ev i, tis su e ne vi , ao rt ic op ul m on ar y an gi om a, h ig h te la ng ie ct at ic th ic ke ni ng co nn ec tiv e tis su e se ba ce ou s cy st , gi an t h em an gi om as o f le ft fi rs t fis tu la o r w in do w, ar cu s pa la tin us ne vi , d en te s ne vu s, li m b bo ne th ic ke ni ng , th e sp le en ph al an x m ic ro m an di bu la r m al oc cl us io n, le ng th lim b le ng th ex og en es is de fo rm ity , f ro nt al ri gh t a ud ito ry di sc re pa nc y di sc re pa nc y m am m ill a an tr um n ul li- m ea tu s ob st ru ct , de ve lo pm en t, au ri cu la ri s m ag nu s de nt es en la rg em en t, m al oc cl us io n, ri gh t h yp er pl as ia ja w b on e of p ar ot id g la nd , ex og en es is ep id er m al n ev i, m am m ill a co nn ec tiv e tis su e ne vi , j aw b on e ex og en es is m am m ill a, si de p ro tr ud in g th or ac ic v er te br a No n- co mm er cia l u se on ly [page 8] [Dermatology Reports 2010; 2:e3] palms, forearms, trunk, and face. Epidermal nevi were examined histopathologically in all 8 patients (Table 1). The reported cases were 6 females and 2 males; the youngest was six years old and the oldest was 30 years old. That only 8 cases have been reported in China suggests that many cases of PS may go unrecognized. China, as the most populated country on the globe at 1.2 billion people, should have more cases than have already been reported. The problem might be that both the clinical manifestations and diagnostic criteria are not familiar to der- matologists. Moreover, medical services are not as accessible to citizens because of China’s status as a developing country. For these rea- sons, many cases may have been misdiag- nosed or undiagnosed. Although progress is being made in the clin- ical understanding of PS, much remains to be done. 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