Cancer-Associated Genodermatoses: a Personal History

Home , Sebaceous carcinoma

Experimental Dermatology 2006: 15: 653–666 Copyright The Author 2006. Journal compilation 2006 Blackwell Munksgaard Blackwell Munksgaard . Printed in Singapore Experimental Dermatology doi: 10.1111/j.0906-6705.2006.00463.x ISSN 0906-6705

Review Article Cancer-associated genodermatoses: a personal history

Burgdorf WHC. Cancer-associated genodermatoses: a personal Walter H. C. Burgdorf history. Department of Dermatology, Ludwig Exp Dermatol 2006: 15: 653–666. The Author 2006. Journal Maximilian University, Munich, Germany compilation 2006 Blackwell Munksgaard.

Abstract: Cancer-associated genodermatoses are a group of genetic Key words: basal cell nevus syndrome – Birt– Hogg–Dube´ syndrome – cancer-associated disorders inherited in an autosomal-dominant fashion in which unique genodermatoses – Carney complex – Cowden cutaneous ﬁndings are a reliable marker for the risk of developing syndrome – Muir–Torre syndrome internal malignancies. The historical, clinical and dermatopathological aspects of basal cell nevus syndrome, Muir–Torre syndrome, Cowden Walter Burgdorf, MD Traubinger Str. 45A syndrome, Carney complex and Birt–Hogg–Dube´syndrome are 82327 Tutzing reviewed in a personal and informal fashion. The latest advances in Germany the molecular genetics of the disorders are also summarized. Tel.: +49 8158 7159 e-mail: [email protected] Accepted for publication 9 June 2006

Introduction stimulated my interest in clinical genetics, Bob David Bickers and I are of roughly the same Gorlin. He in turn was introduced to clinical age and our paths have crossed many times genetics by a dermatologist, Helen Ollendorff over the years. Our special interest is nourish- Curth, a long-time clinical faculty member at ing German–American interactions in derma- Columbia, who was an international expert on tology. As our scientific interests have never acanthosis nigricans. overlapped, I instead offer, for David’s 65th birthday, a personal recollection of the Why bother? progress which has been made in bringing cancer-associated genodermatoses from early As I have lectured across the USA and Eur- warning signs for systemic malignancies to ope about cancer-associated genodermatoses extensively researched genetic disorders, whose over the past 30 years, the almost invariable responsible genes have given important question is ‘Why bother with such rare dis- insights into the molecular biology of cancer. eases?’. One of the great attractions of derma- My two special interests have been genoder- tology for me was the possibility to walk into matoses and dermatopathology – not two sub- a room, glance at a patient and make a pro- jects one instinctively links – but I will also nouncement such as ‘You ought to have your try to show how in this group of disorders thyroid checked; you have a increased risk of they fit together nicely. a medullary thyroid carcinoma.’ In many Another link, which David and I have, is instances, cutaneous findings precede systemic Columbia University. I certainly would not be tumors by many years and the possibility for here today but for the fact that a red-headed either careful monitoring, prophylactic treat- Alabamian grade school teacher and a young ment or genetic counselling of relatives at risk German law student both lived at International is available. In addition, it has been clear House 1 year in the 1930s while pursuing since the days of Warthin (1) a century ago advanced degrees at Columbia. The two met, that familial cancer has the potential to offer got married, and I am their only child. My insights into sporadic cancer. In no field has other Columbia link is through the man who this played out to be more true than in

653 Burgdorf cancer-associated genodermatoses. As a der- the next few years, I had the honour of curet- matopathologist, one fascinating aspect is that ting or excising many of her lesions. She taught multiple cutaneous tumors, usually adnexal me to always listen to the patient, as she could neoplasms, often indicate a genodermatosis, find a new BCC better than any physician. The while a solitary but microscopically identical second patient with BCNS was L.P., who pre- lesion is of little significance (2). sented in an extraordinary way. Working in a pet shop, he was bitten by a poisonous snake, which had been given to Owen Wangensteen, Basal cell nevus syndrome the revered Chairman of the Department of Surgery at Minnesota. A friend in the store Abbreviation BCNS took L.P. to the hospital on his motorcycle and OMIM 109400 they were involved in an accident. When Bob Gene PTCH at 9q22.3 Gorlin first met L.P., the latter not only had a Cutaneous Multiple basal cell carcinomas, palmo-plantar pits findings fractured femur but also a funny-shaped head Systemic Medulloblastoma, ovarian fibrosarcoma and lots of skin cancers. malignancies The next lesson I learned was as a junior fac- Other clinical Macrocephaly, odontogenic keratocyst, cardiac findings fibroma, ovarian fibroma, fetal rhabdomyoma, calci- ulty member in Oklahoma. The residents fication of falx cerebri showed me a 7-year-old boy with a few tiny tel- Synonyms Gorlin syndrome, Gorlin–Goltz syndrome, angiectatic papules on his fingers. They were nevoid basal cell carcinoma syndrome disturbingly confident and I was totally con- fused, offering ‘treated warts’ as a diagnosis. My first introduction to basal cell nevus syn- The answer was BCNS – tiny papules in a child drome (BCNS) happened in 1974 as a first year with palmar pits and fairly obvious frontal dermatology resident at the University of Min- bossing. The residents were so sure because they nesota. A delightful lady, M.S. (Fig. 1), was a had been treating the child’s mother, grand- regular patient of my chairman, Bob Goltz. She mother and great-grandfather for years. In this was the first patient Bob Gorlin and he had family, ‘little skin cancers’ were nothing extra- described in their classic paper on BCNS in the ordinary, and surely no indication for getting New England Journal of Medicine in 1960 (3). excited. M.S. has had hundreds of basal cell carcinomas The relevant dermatopathology question here (BCC) removed, most superficial, and was very is – can one see anything microscopically to fussy about allowing residents to work on her. indicate which BCC are taken from patients She, for unclear reasons, accepted me, and for with BCNS? The answer was long ‘Yes, lesions from syndrome patients are more likely to cal- cify.’ This surely has not been my experience and in any case, looking at a patient is a much quicker way to ascertain association. Once the gene had been identified, then this question became more interesting and we will return to it. A dermatologist was part of the research team that helped identify the PTCH gene, a homologue of the patched gene in Drosophila. Erwin Epstein Jr from UC-SF, a close personal friend of David’s, moved from clinical practice back into the laboratory to associate with a worldwide group of researchers and produce a classic paper in 1996 (4). Since then, the world of PTCH has become incredibly complex and linguistically challenging. In a simplified form, PTCH encodes a transmembrane protein Ptch which interacts with Smoh protein (from SMOH or smoothened gene) to serve as receptor for the sonic hedgehog signalling molecule Figure 1. M.S. Gorlin and Goltz’s first patient with basal cell nevus syndrome with scars where hundreds of basal cell carci- Shh (5). When Shh is missing, Ptch suppresses nomas had been removed over the years. Smoh; when Shh binds, Smoh is freed from

654 Cancer-associated genodermatoses inhibition with increased signal transduction and activation of target genes. Thus, PTCH is, in one sense, a tumor-suppressor gene and SMOH is a proto-oncogene. Mutations in both are important in the development of sporadic BCC (6); thus, understanding this rare syndrome has done what I and many others suggested would be possible – given us an insight into the most common human malignancy (7,8). Returning to the microscopic appearance of the tumors, it became clear in the 1990s that BCC were derived from hair germ in most Figure 3. Mark Allen Everett, Robert J. Gorlin, Walter Burg- cases, not from ordinary basal layer keratino- dorf, Robert W. Goltz; Albuquerque NM, 1993. cytes. The UC-SF group with Erv Epstein and Phil LeBoit noted that PTCH +/) mice develop follicular neoplasms which resemble trichoblastomas, but when they are exposed was very impressed that I actually knew to UV or ionizing radiation, the tumors Gorlin and Goltz; he soon demanded to see evolve in BCC (9). The human equivalent only me, the temporary help. I brought in a may well be the infundibulocystic BCC des- picture (Fig. 3) of the three of us together cribed by Tozawa and Ackerman in 1987 with Mark Allen Everett and after that he (10), and expanded upon by Walsh and Ack- was in awe of my knowledge, which had not erman a few years later (Fig. 2) (11). They radically changed. Then, I decided to ask emphasized that any type of BCC could be both Bob Goltz and Bob Gorlin how they found in BCNS patients with nodular being preferred to have their syndrome named. Bob most common, but pointed out that when a Gorlin in a modest way said he identiﬁed biopsy was encountered where virtually every more with BCNS than with any other of his infundibulum was associated with a small syndromes; in the fourth edition of Syndromes infundibulocystic BCC, the diagnosis was BCNS of the Head and Neck (14), he used the title – or perhaps in rare cases multiple hereditary Gorlin (nevoid BCC) syndrome. Bob Goltz infundibulocystic BCC without other features of said he was happy to be associated in any BCNS (12). A most important parallel clinical way. point is that 10% of patients with BCNS have Finally, in contrast to the other syndromes absolutely no BCC (13). mentioned below, systemic malignancies are A picture is still worth 1000 words. One not a great problem in BCNS. The main risk afternoon a few years ago, I was moonlight- is childhood medulloblastomas. The exact ing in a dermatology practice in Munich when risk is hard to determine because medullobla- a bus driver came in. He had BCNS, known stoma is the most common childhood brain in Germany as Gorlin–Goltz-Syndrom and tumor, accounting for about 25% of such lesions (15). Only 3% of all medulloblastomas occur in patients with BCNS, while about 5% of BCNS patients develop medulloblastoma. Returning to the laboratory, the activation of the Shh pathway predisposes neural progen- itor cells to develop into medulloblastomas by inactivating the retinoblastoma tumor-suppressor gene (Rb) and inducing the proto-oncogene N-myc (16). The main clinical factor is that radiation therapy is the treatment of choice for medulloblastoma; often children are irradiated before the diagnosis of BCNS has been made. As the skin of BCNS patients is exquisitely radio-sensitive, such unfortunate Figure 2. Infundibulocystic basal cell carcinoma (photomicro- individuals often develop thousands of BCC graph courtesy of Peter Soyer, MD, Graz, Austria). in the radiation ﬁelds.

655 Burgdorf Muir–Torre syndrome York Dermatologic Society with several gastrointestinal tumors, prolonged survival and a collection of peculiar cutaneous tumors including Abbreviation MTS an ‘epidermoid cyst with squamous cell carci- OMIM 158320 Genes Mismatch repair genes noma’ and multiple poorly defined sebaceous MSH2 at 2p22–p21 tumors (17). In the interval between Torre’s MLH1 at 3p21.3 presentation and the publication of the meeting Cutaneous findings Multiple sebaceous tumors (especially cystic sebaceous tumors), proceedings in the Archives of Dermatology, multiple keratoacanthomas E. G. Muir, a surgeon, and his colleagues from Systemic malignancies Carcinomas of colon, endometrium, London described a Maltese patient with mul- ovary and many other organs Synonyms Hereditary non-polyposis colorectal cancer, tiple keratoacanthomas, sebaceous neoplasms Lynch syndrome, cancer family syndrome and gastrointestinal tumors (18). Dr Helwig and his fellow Dave Rulon, a dermatopatholo- In 1979, Aly Fahmy, a general pathologist at gist, had also recently written about the associ- the Oklahoma City Veterans Administration ation of sebaceous neoplasms and visceral Hospital, asked me to come by and look at tumors but had lacked sufficient information to some slides which he and his colleague Jan diagnose our case (19). Pitha found interesting. They were from a About this time, two exogenous factors patient whom I already had seen in clinic; R.S. forced me to become further interested in had had lots of funny cutaneous tumors (Fig. 4), MTS. First, my chairman, Mark Allen Everett but I knew little else about him. Aly and Jan (also shown in Fig. 3), had agreed to arrange were way ahead of me. In those days, before a dermatopathology meeting in New Orleans computers, they had little index cards containing and simply told me I would be presenting all the previous pathological diagnoses on each ‘something’ there. I asked Aly if he would patient and R.S.’s card was most interesting. In help me and he did. We identified two other addition to keratoacanthomas and sebaceous veterans with multiple malignancies, and I tumors, he had already multiple primary gastro- then had a ‘moment of understanding’, recall- intestinal carcinomas at a relatively early age. ing a patient I had presented to Hermann Dr Elson B. Helwig at the Armed Forces Insti- Pinkus a few months before. J.M. was a tute of Pathology had agreed that they were all young lady with a personal history of thyroid primary tumors. R.S. died several years later cancer, a family history of gastrointestinal from radiation-induced pneumonia, but was cancer and a single red papule on her thigh. tumor-free after having nine primary systemic The lesion was a small basaloid tumor with a malignancies over more than a decade. few sebaceous cells scattered throughout; I was still in the dark, but Aly and Jan knew Pinkus had been stumped but identified the the answer – Muir–Torre syndrome (MTS). sebocytes. She became our fourth MTS Douglas Torre, one of the pioneers in dermato- patient. All fit the pattern – multiple systemic logical cryotherapy and a private practitioner in tumors, early onset and relatively long survi- Manhattan, had presented a patient at the New val. After our paper on R.S. written by Bob Schosser, our dermatopathology fellow, had been accepted by Cancer (20), Wolf-Ingo Worret, a young German visiting dermatopathologist, helped us write up all four patients in the German literature. Because of the vagaries of publishing schedules, the paper in Hautarzt appeared first with the initial Ger- man-language mention of MTS (21). Next, Henry Lynch asked me to write a chapter in a book, he and Ramon Fusaro were editing, entitled Cancer-associated Genoderma- toses. My assignment was ‘Dermatopathologic aspects of cancer-associated genodermatoses’ (22). This chapter in 1982 convinced me that I was not wasting my time trying to combine Figure 4. R.S. My first patient with Muir–Torre syndrome; notice the sebaceous carcinoma of the chin, as well as the typ- dermatopathology and clinical genetics. I had ical paranasal lesions and scars. the opportunity to learn from another master

656 Cancer-associated genodermatoses clinician-geneticist, Henry T. Lynch of Omaha. matopathologist in Friedrichshafen, Germany, Henry shared his insights into MTS with me who had a long interest in MTS and had provi- and convinced me that MTS was simply part of ded much of the pathological material for the cancer family syndrome (CFS), today known Roland’s studies. as hereditary non-polyposis colorectal cancer 1 I agreed to bring my collection of biopsies to and 2 (HNPCC1 and HNPCC2) (Lynch syn- Friedrichshafen, where Arno and I spent a day drome 1 and 2) (23–25). He had several large looking at funny sebaceous lesions. We decided pedigrees of CFS, some of which he had inher- that the most distinctive tumor was what we ited from Warthin’s files at the University of then designated a cystic sebaceous tumor Michigan (26). In this collective, Henry had (CST), a deep cystic sebaceous proliferation already identified a few patients with sebaceous (Fig. 5) (38). I had identified such lesions in neoplasms (27,28), whom we would now identify passing a decade earlier, but now Arno found as either MTS or HNPCC2 with colonic and at least one in half the patients in his much lar- extracolonic tumors. HNPCC is caused by ger collective. Prospectively, we identified sev- mutations in a variety of DNA mismatch repair eral patients who had only a CST, but (MMR) genes; MSH2 (29) is almost always investigation revealed a personal or family his- responsible for HNPCC2 (MTS), while MLH1 tory that strongly suggested MTS and then (30) is equally important in HNPCC1. The germline DNA repair gene mutations were revised Bethesda guidelines incorporate much of found (39). the carefully acquired clinical and genetic data Mathiak, Ru¨tten and others refined the pro- from Lynch and his colleagues (31). cess even further. Their group employed com- Our first patient nicely summarizes the entire mercial monoclonal antibody stains with which HNPCC story; he developed multiple tumors, the presence of MSH2 or MLH1 protein had primarily gastrointestinal, but also involving been identified in gastrointestinal biopsy sec- other organs, at a relatively early age but sur- tions (40). In CST and other tumors with vived far longer than age-matched controls with microsatellite instability, in most instances, similar sporadic tumors (32). Another distin- there was no staining for the appropriate gene guishing feature is that the colon carcinomas products in the cutaneous tumors. Thus, it was are far more likely to be on the right side, as in possible to exactly identify the gene harbouring our case, than in familial adenomatous polypo- the germline mutation responsible for a whole sis (FAP) with its cutaneous marker, Gardner spectrum of problems simply by staining the syndrome. By then, I had numerous biopsies right skin biopsy in the right way. This is truly from our four patients with MTS and had an elegant combination of dermatopathology received cases in consultation from around the and genetics. country. So, I had a burgeoning collection. I was becoming more and more convinced that the cutaneous lesions in MTS frequently defied classification, often showed overlaps between sebaceous tumors and keratoacanthomas and on occasion were most distinctive. All this information I published with Jan and Aly in an article in American Journal of Dermatopathology in 1986 (33). Some 15 years later, Roland Kruse, a young German dermatologist at that time working in the genetics department in Bonn, called me to discuss MTS. His group made many new dis- coveries about MTS, showing they had the same spectrum of MMR gene mutations as HNPCC (34), although MSH2 was more likely to be involved (35). They also showed the presence of microsatellite instability in skin tumors (36) and demonstrated that the loss of hetero- zygosity (LOH) was not the preferred mode of Figure 5. Cystic sebaceous tumor, deep in dermis with obvi- tumor development in MTS (37). Roland ous glandular areas (histological material courtesy of Arno placed me in contact with Arno Ru¨tten, a der- Ru¨tten, MD, Friedrichshafen, Germany).

657 Burgdorf Cowden syndrome asked Bob to write down these events and now I quote… It was the case of a woman who had lots of Abbreviation CS bumps on her lips, gingiva and skin, who had OMIM 158350 Gene PTEN at 10q23.31 huge breasts and breast cancer. About six Cutaneous findings Facial, acral and oral mucosal papules; months later Lauren Ackerman contacted me lipomas, haemangiomas, and said, ‘Bob I have a patient with this, this, pigmented macules Systemic malignancies Carcinomas of breast, thyroid; this and this.’ I said, ‘My goodness, Lauren, I hamartomatous polyposis with just (saw slides) of a gal with almost the identi- low risk of colon cancer cal findings.’ Other clinical findings Macrocephaly, cerebellar dysfunction Synonyms Multiple hamartoma syndrome The doctors caring for the first case were two young internal medicine residents in Youngs- town, OH, Kenneth Lloyd and Macey Dennis. They published their case in Annals of Internal I first learned about Cowden syndrome (CS) Medicine in 1963 (42), choosing the name Cow- under the wrong name – multiple hamartoma den syndrome to honour their patient Rachel syndrome. Peyton Weary, Bob Gorlin, Bill Cowden, who later died of metastatic cancer. Gentry (my favourite clinical teacher at Minne- Ken Lloyd went on to become a dermatologist sota) and several of Peyton’s colleagues from and still practises today in Youngstown. Virginia published a paper on this disorder in Carcinoma of the breast remains the major 1972 (41). As it was a Minnesota-Virginia risk for CS patients. About 75% of female paper, I accepted it as the whole answer. I saw patients have fibrocystic disease or other several of Bill Gentry’s patients and many biop- breast changes and fully a quarter develop sies but never grasped the essence of the dis- carcinoma. Prophylactic mastectomy is often ease. In 1976, Bob Goltz took me with him to recommended (43). In addition, recent evi- the Michigan Dermatologic Society meeting dence shows that male individuals with CS held one spring weekend in Dearborn Village are also at risk for breast cancer (44). Around near Detroit. My most vivid memory of the 50% of patients have hamartomatous polyps meeting is a case discussed by Amir Mehregan of the gastrointestinal tract, but the risk of in which the patient had a baffling array of malignant degeneration is very small. Simi- cutaneous tumors – lipomas, hair follicle tum- larly, about two-thirds have thyroid disease, ors, warts and peculiar fibrous lesions – and but once again, malignant change is rare. was introduced under a complex new name Theo Starink, a dermatologist in Amsterdam, which I have forgotten. Bob Goltz was one of accumulated considerable data from several the guest discussants and in his inimitable way large Dutch pedigrees (45). praised the clinicians, praised Amir, indicated Cowden syndrome evolved into an even more this was just about the most puzzling thing he interesting dermatopathological issue. The facial had ever seen, but asked if he could pose a lesions were identified as trichilemmomas possible alternative diagnosis – multiple hamar- (46,47), and the dermal lesions occasionally toma syndrome. The minute he said it, everyone showed a peculiar cut-onion layered pattern in the audience simultaneously clapped their which was designated as sclerosing fibroma foreheads in the ‘Oh, why didn’t I think of (48). Although multiple sclerotic fibromas were that?’ routine, and I became a fan of this first described, soon solitary sporadic ones were disorder. identified (49). Two giants of dermatopathology, I went to the library immediately on the fol- Marty Brownstein and Bernie Ackerman, lowing Monday to read about my new interest argued for years whether the trichilemmomas and as always bumped into Bob Gorlin, the were warts or not. Bernie was sure all trichi- most conspicuous user of Diehl Hall (the med- lemmomas were warts (50), and Marty was just ical library) at the University of Minnesota. He as sure they were not (51). reminded me that Ken Lloyd in Youngstown, While at the University of New Mexico, I OH, had first described the syndrome and told saw a college freshman, who had presented as me of his personal first encounter with CS. He an infant with an enlarged head but did not was visiting the Armed Forces Institute of have hydrocephalus and now in college, was Pathology and was shown a tray of slides by having trouble concentrating and developing Dr Southern Hooker, a descendent of General lots of warts. The referring physician had Fighting Joe Hooker of Civil War fame. I later already thought of CS, so I could only agree,

658 Cancer-associated genodermatoses but I learned that many patients are originally I met Jo¨rg Schaller, a dermatopathologist evaluated by paediatricians for increased head in Duisburg, Germany, about this time. It circumference. I also found out that Lhermitte– turned out that he had been in the Depart- Duclos syndrome (52), a form of cerebellar ment of Dermatology at the University of hypertrophy, was closely associated with CS Leipzig when I lectured there during the deep- (53). est days of the German Democratic Republic The next major jump in our knowledge of CS (East Germany) but had missed my talk. At occurred at Columbia University. The group of one meeting, Jo¨rg presented the data he and Ramon Parson in the Institute for Cancer Gen- Angela Rohwedder had produced, indicating etics reported, in early 1997 in Science, on the that many solitary trichilemmomas contain finding that the PTEN gene, a member of the human papillomavirus (HPV) DNA (62). It protein tyrosine phosphatase family, is mutated seemed to me more and more likely that all in human brain, breast and prostate cancers the cutaneous lesions in CS represented differ- (54). Parson’s group had already joined efforts ent stages in the same pathological process with the group of Monica Peacocke in David involving follicular proliferation and perifolli- Bicker’s dermatology department. Together, cular fibrosis. Clinically, everything fits with these researchers found out that mutations in warts – white mucosal papules; papillomatous the PTEN gene are also responsible for CS facial and acral tumors, sometimes involving (55). Subsequently, diagnostic criteria were hair follicles; and palmo-plantar papules. Peter established for CS and everything seemed clear Itin, Stephan Lautenschlager and I collected (56). The diagnostic criteria included mucocuta- biopsies from seven patients with CS which neous lesions: we studied histologically with Jo¨rg Schaller, 1. six or more facial papules are present, of while Angela Rohwedder looked for HPV which three or more must be trichilemmomas; DNA. We learned that only a small percent- 2. cutaneous facial papules and oral mucosal age of facial papules in CS are trichilemmo- papillomatosus are present; mas; our batting average was abysmal, even 3. oral mucosal papillomatosus and acral though we chose typical wart-like facial keratoses are present; lesions (Fig. 6). We were able to confirm that 4. six or more palmoplantar keratoses are there is a spectrum between wart, seborrheic present. keratosis-like lesion, trichilemmoma and scler- Mutations in PTEN are responsible for a otic fibroma (Fig. 7), but the HPV search befuddling list of syndromes, which are some- taught us another lesson. The incidence of times given the group name Bannayan–Riley– HPV in facial skin of adults, especially in the Ruvalcaba (57) and at other times further hair follicles, is so high that to obtain statisti- subdivided into Bannayan–Zonana syndrome cally significant results, we would have had to (58), Riley–Smith syndrome and Ruvalcaba– study more CS-related skin lesions than had Myhre–Smith syndrome. Even the names are ever been biopsied, probably by a factor of confusing – two different Smiths were involved; thousand or even million. Thus, our frequent Harris ‘Pete’ Riley was a long-time Chairman of finding of HPV DNA did not help answer Pediatrics at Oklahoma and kind to me when I the question (63). Personally, I wonder if ran paediatric dermatology clinics at Oklahoma Children’s Hospital. Today, we know all these alphabet soup syndromes are caused by PTEN mutations (59) and can be viewed as ‘PTENosis’ or paediatric variants of CS, featuring haemangiomas, lipomas, juvenile polyps, macrocephaly and the classic pigmented macules of the penis (speckled pecker sign). In addition, mutations in PTEN also cause Lhermitte–Duclos syndrome. The association with juvenile polyposis syndrome has been more confusing; latest information suggests that PTEN mutations should exclude this diagnosis (60), while two other caus- ative genes for JPS have been identified. The Figure 6. Elderly woman with Cowden syndrome and verru- diagnostic criteria are now more comprehensive cous facial papules (photograph courtesy of Peter Itin, MD, and address the PTEN spectrum (61). Basel, Switzerland).

659 Burgdorf ing information for lectures or review papers. The minute I read his classic paper (64), I real- ized that he was correct to lump together both NAME (65) and LAMB (66) syndromes which were clearly describing the same patients with slightly different choice of words and emphasis. I was sure that when I saw a patient, I would immediately recognize the admixture of freckles and blue nevi and promptly make a brilliant diagnosis. It turned out differently. In the midst of a busy clinic, a resident called me in to look at some molluscum before he cur- etted them. J.H. was a tall teenage boy, accom- panied by his mother, a hospital employee whom I knew in passing. The resident said, ‘J. has a few molluscum. I’m going to curette them and not get pathology, as there is no need of wasting the family’s money.’ (In defense of the resident, we rarely submitted molluscum for pathology). But…J. had two little glassy papules on his eyelids (Fig. 8). I knew they were not molluscum but was totally stumped. I briefly looked at the rest of his skin; he had nothing else. Then his mom asked ‘Could this have anything to do with his bilateral large-cell calcifying Sertoli cell tumor of the testes?’ I Figure 7. Trichilemmoma with papillomatous or warty chan- said, ‘Just that these are myxomas in Carney ges. complex.’ Histological examination of the tan- gentially excised papules proved me correct PTEN mutations can somehow lead to an (Fig. 9). I examined J. again; he had absolutely epidermal growth pattern which resembles that no pigmented lesions. I ran back to my office induced by HPV; I have asked lots of PTEN and called Dr Carney. He excitedly told me that experts and never received an answer. Any he was doing a paper on myxomas of the eye- suggestions? lids and external ear as almost dead-certain markers for CNC. Soon thereafter, Ferreiro Carney complex and he published their findings in this area (67). The extraordinary finding in my first cases was the lack of pigmented lesions. Seventy Abbreviation CNC per cent of patients have either freckles or OMIM CNC1 160980 CNC2 605244 lentigines; the matter has never been resolved. Genes CNC1: PRKAR1A at 17q23–q24 CNC2: CNC2 at 2p16 Cutaneous findings Myxomas, multiple freckles or lentigines, blue nevi Systemic malignancies Large-cell calcifying Sertoli cell tumor, psammomatous melanotic schwannoma Other clinical findings Cardiac myxoma, pigmented nodular adrenocortical disease with Cushing syndrome, myxoid mammary fibroadenoma Synonyms NAME syndrome, LAMB syndrome

For many years, I read about Carney complex (CNC) and saw cases at meetings, but never personally diagnosed or followed a patient. I had written to J. Aidan Carney, a pathologist Figure 8. J.H. My ﬁrst patient with Carney syndrome with at the Mayo Clinic, a number of times request- conjunctival myxomas.

660 Cancer-associated genodermatoses (75); they metastasize in about 10% of cases. The breast tumors are benign (76). Carney complex was one of the first diseases to turn out to be caused by mutations in at least two different genes, without discernible differences in clinical appearance. Mutations in PRKAR1A (77), a protein kinase, at 17q23–q24 and a not characterized gene at 2p16 (78) cause exactly the same problems. Who would have thought 30 years ago that two different genes could cause exactly the same autosomal-dominant disorder? The possibility never crossed my mind. Recently, I was lucky enough to be able to join Dr Carney in writing the section on CNC in the latest World Health Organization Figure 9. Myxoma with lacy epithelial strands originating book on skin tumors (79). from central follicle. Birt–Hogg–Dube´syndrome The ‘E’ in NAME refers to ephelides, while the ‘L’ in LAMB indicates lentigines; in my Abbreviation BHDS experience there are both. The most striking OMIM 135150 cutaneous findings are the myxomas (68), Gene FLCN (folliculin) at 17p11.2 Cutaneous findings Multiple perifollicular fibromas nodules with lacy epithelial strands and lakes and trichodiscomas of mucin. They are almost pathognomonic of Systemic malignancies Renal cell carcinomas CNC. Another unusual feature is epithelioid (unusual histological types) Other clinical findings Spontaneous pneumothoraces blue nevi which should suggest CNC (69) but Synonyms Hornstein–Knickenberg syndrome may be sporadic (70). I stayed in touch with Dr Carney and learned much from him. First of all, one must say Carney complex, because Carney triad I go back a very long way with Birt–Hogg–Dube´ refers to gastric (epithelioid) leiomyosarcoma, syndrome (BHDS). Arthur Birt was a dermatol- functioning extra-adrenal paraganglioma and ogist in Winnipeg, Canada, who frequently vis- pulmonary chondroma (71). In CNC, the pre- ited the University of Minnesota for state valence of cardiac myxomas is 70% and that dermatology meetings or occasionally just Friday of Cushing syndrome is 30%. Carney spent a afternoon grand rounds. He was often accom- great deal of time trying to track down panied by his colleague Arthur Anhalt, father of Harvey Cushing’s first patient, Minnie G., Grant Anhalt (who needs no further introduct- with what is now known as Cushing ion to readers of this journal). This trip alone syndrome; it appears likely that Minnie G. shows the devotion of Dr Birt to dermatological actually had CNC (72). Similarly, William education; the two cities are 450 miles (720 km) Young re-evaluated the first patient with pri- apart. Dr Birt was Winnipeg through and mary pigmented nodular adrenocortical disease through. His father and grandfather had been 50 years later and she too had CNC (73). mayors of the city. He completed his entire med- The main problem in CNC is the cardiac ical training there and then practised in the same myxomas, which are histologically benign, but office for over 50 years. The syndrome which potentially life-threatening. In a familial made Winnipeg famous was initially identified patient, the myxomas tend to occur at earlier by Jim Dube´, a endocrinologist originally from age than in a sporadic case, more often are Trinidad who discovered a family with multiple multiple, involve any chamber and tend to thyroid cancers and funny skin lesions. He recur. They may cause emboli or cardiac fail- referred the family to Arthur Birt who biopsied ure and the surgery itself is risky, so that per- the lesions and sent the specimens to Georgina haps 25% of CNC patients die from their Hogg, a pathologist. She identified them as folli- myxomas. Psammomatous melanotic schwan- cular tumors but sought help from Herman nomas usually involve the gastrointestinal Pinkus who was able to provide an almost-cor- tract (74) but have been reported in the skin rect diagnosis, as discussed below. She also sent

661 Burgdorf slides to Bob Goltz and I still have some of the original slides which she shared with me. The Canadians then published their description of the syndrome in 1977 (80). My first encounter with a patient with BHDS was at the University of Oklahoma. I was sitting in my office at Oklahoma Children’s Hospital reading a paper by Otto Hornstein and Monika Knickenberg on a new syndrome (81). The phone rang and Dennis Weigand was calling from the Veterans Administration Hospital across the street. He said ‘I have a patient who has been boarded out of the service with the diagnosis of acne scars, but he has something else. Could you take a look?’ I walked over, entered the room and saw a man who looked identical to the pic- Figure 11. Fibrofolliculoma with branching lacy epithelial tures I had been glancing at a few minutes strands arising from follicle and surrounded by perifollicular before. I confidently said, ‘He’s got Hornstein– fibrosis. Knickenberg syndrome.’ This tour de force convinced Dennis and the residents that perhaps the new faculty member was not so bad. There are still divided opinions, but to me it is clear that Hornstein and Knickenberg were describing the same syndrome as Birt, Hogg and Dube´; they clearly published first – 2 years earlier. C.P. had hundreds of small white dome- shaped perifollicular papules most prominent on face and chest, clearly not acne scars (Fig. 10). I biopsied 10 lesions; five showed perifollicular fibrosis with lacy epithelial strands (fibrofolliculoma) (Fig. 11) and five showed a disc-shaped subepidermal proliferation of spindle cells (trichodiscoma) (Fig. 12). We referred Figure 12. The original trichodiscoma described by Birt, the patient for internal medicine work-up Hogg and Dube´(histological material courtesy of Georgina because Hornstein and Knickenberg had men- Hogg, MD, Winnipeg, Canada). tioned a risk of gastrointestinal carcinoma, while Birt and colleagues had suggested a poss- I saw several more patients clinically, but the ible association with thyroid cancer. Nothing most interesting question was the nature of the was found, but he died a few years later of met- lesions under the microscope. The hair disc is a astatic colon carcinoma. well-established sensory structure, prominent on cat and rabbit lips, and especially well seen in gloves made from the hide of the peccary, a pig- like mammal of the Southwestern Desert of the USA locally known as javelina. Felix Pinkus first described the ‘Haarscheibe’ (German for hair disc) in 1902 (82) and even identified it in peccar- ies (83). It consists of an acanthotic epidermis overlying a spindle-shaped proliferation; the epidermis is rich in Merkel cells and the dermal ele- ments are neural, as the hair disc is a highly specialized neuroreceptor. Felix’s son, Hermann Pinkus, identified cutaneous tumors resembling hair discs which he named trichodiscomas (84). Initially Burnier and Rejsek (85) and later Figure 10. C.P. My first patient with Birt–Hogg–Dube´syn- Zackheim and Pinkus (86) had described drome. Numerous follicular papules. perifolliculomas. With this background, it had

662 Cancer-associated genodermatoses been relatively easy for Hermann Pinkus to sug- My most fascinating contact with BHDS – gest a diagnosis for the slides sent to him by even though I contributed nothing – was a Hogg. Because of the presence of perifollicular phone call from Burton Zbar at the National fibrosis interlaced with thin epithelial strands or Institutes of Health perhaps 10 years ago. Paul fingers, the Winnipeg group as well as Weintraub Duray, one of my oldest (better said, longest and Pinkus (87) proposed the name fibrofollicu- serving) friends, with whom I worked at Henne- loma. pin County Hospital in the spring of 1975, had Unfortunately, the issue was more complex told Burt I was an expert on BHDS. The story and Pinkus was not 100% correct. I met one of had evolved as follows: the NIH had become my best friends over this issue. Gerd Plewig, interested in families with multiple, often bilat- when he was Chairman of the Department of eral, renal cell carcinoma, often with unusual Dermatology in Du¨sseldorf, Germany, became histological types (usually chromophobe, onco- interested in the trichodiscomas; he and his cytic or overlap, with the common sporadic co-workers clearly showed that they were fibrous clear cell carcinoma found in only 10%). Maria proliferations, not neural, in a poster presented Turner and other clinicians at the NIH noticed at the American Academy of Dermatology in immediately that many of these patients had 1987 (88). I visited Gerd in Du¨sseldorf on one of cutaneous findings – multiple perifollicular my German trips just to see these slides and we papules which on biopsy were mantleomas, so became close friends. Even though clinical pro- they knew that BHDS was the answer (91). fessorships are almost non-existent in Germany, In 2002, Zbar’s group was successful in iden- I have one enabling me to work closely with tifying mutations in the folliculin (FLCN) gene Gerd in the Department of Dermatology at the underlying BHDS (92). Folliculin is a cytoplas- Ludwig Maximilian University in Munich since mic protein with a predicted size of 64 kDa. 1993, editing and translating several books, as Alternative splicing of the FLCN gene results in well as taking numerous hikes and bike trips. two isoforms, a full-length form and one that The next step in understanding these lesions uses an initiation codon in intron 6. Although was made by Bernie Ackerman who often lec- the precise function of folliculin and its alter- tured about what I call ‘Ackerman’s rule of nate splice variant is not clear, it is thought to multiple adnexal neoplasms’. I paraphrase, but be a tumor suppressor with LOH initiating he stated, ‘If a patient has multiple lesions tumor formation. All germline mutations in which are interpreted with two different histo- patients suffering from BHDS described so far pathological diagnoses, but a good clinician are splice-site mutations or insertions/deletions cannot tell them apart, then the lesions are that result in putative protein truncation and probably variants on a single process.’ This is haplo-insufficiency. surely the case in MTS where the sebaceous Today, it appears that Birt’s suggestions of lesions and keratoacanthomas overlap and in associated thyroid carcinoma and Hornstein’s CS where trichilemmomas and fibromas merge of gastrointestinal carcinoma were incorrect; together; it is also true in BHDS where the best the major tumor risk is that of renal cell carci- name is probably that proposed by Charlie noma, as well as of spontaneous pneumothorax Steffen – mantleoma (89). The sebaceous mantle and pulmonary cysts (93). The picture may be consists of strands of epithelial cells that eman- more complex. My last contact with BHDS was ate from the infundibulum of a hair follicle and just a few weeks ago. One of the junior faculties drop down aside the follicle in the form of a in Gerd Plewig’s department called to tell me mantle or skirt; sebocytes appear at the tips of she and colleagues in Nuremburg were follow- these chords and evolve into sebaceous lobules ing twin sisters with BHDS and dysplastic and glands. Later, the mantle and sebaceous nevus syndrome, whose mother had similar skin glands involute with fibrosis. Thus, perifollicu- lesions but had died of melanoma. One of the lar fibrosis, lacy strands and finally pure fibrosis patients has an endometrial carcinoma. Who occur. The connection between this normal pro- knows where this trail will lead? cess and the microscopic appearance of fibrofolliculomas and trichodiscomas is obvious. Two My big question German workers, Tilman Schulz and Wolfgang Hartschuh, took things a step further and One thing fascinates me about these disorders – showed that if one sectioned carefully, features the unexplained paradox about why they cause of both the epithelial proliferation and fibrosis malignant systemic tumors and very often could be found in the same specimens (90). benign cutaneous tumors. Of course, in BCNS,

663 Burgdorf the skin tumors are malignant, but generations 5. Stone D M, Hynes M, Armanini M et al. The of dermatologists have argued about the terms tumour-suppressor gene patched encodes a candidate receptor for sonic hedgehog. Nature 1996: 384: 129– ‘basal cell carcinoma’ and ‘basal cell epitheli- 134. oma’ because of the almost 0% lifetime risk of 6. Reifenberger J, Wolter M, Knobbe C B et al. Somatic metastasis. In MTS, only a very rare sebaceous mutations in the PTCH, SMOH, SUFUH and TP53 tumor is malignant. Our first patient had a genes in sporadic basal cell carcinomas. Br J Dermatol small-cell sebaceous carcinoma of the soft tissue 2005: 152: 43–51. 7. Cohen M M Jr. The hedgehog signaling network. Am of the chin, mimicking a Merkel cell tumor J Med Genet A 2003: 123: 5–28. under the microscope. When I presented the 8. Taipale J, Beachy P A. The hedgehog and Wnt sig- case, Richard Winkelmann, a superb dermato- nalling pathways in cancer. Nature 2001: 411: 349– pathologist among his other considerable tal- 354. ents, doubted it was a carcinoma. Several 9. Aszterbaum M, Epstein J, Oro A et al. Ultraviolet and ionizing radiation enhance the growth of BCCs months later, the patient had jaw metastases. In and trichoblastomas in patched heterozygous knock- CS, CNC and BHDS, the cutaneous lesions are out mice. Nat Med 1999: 5: 1285–1291. completely benign. I have no explanation. Once 10. Tozawa T, Ackerman A B. Basal cell carcinoma with again, maybe, a young experimentally oriented follicular differentiation. Am J Dermatopathol 1987: reader of this journal can solve this puzzle for 9: 474–482. 11. Walsh N, Ackerman A B. Infundibulocystic basal cell me. carcinoma: a newly described variant. Mod Pathol My purpose in writing this highly anecdotal 1990: 3: 599–608. account has not been to highlight my own 12. Requena L, Farina M C, Robledo M et al. Multiple achievements. They have been minimal and of hereditary infundibulocystic basal cell carcinomas: a interest to no one, not even to my mother. genodermatosis different from nevoid basal cell carcinoma syndrome. Arch Dermatol 1999: 135: 1227– Instead, I present them just to show how if one 1235. remains alert, communicates with everyone 13. Gorlin R J. Nevoid basal-cell carcinoma syndrome. possible and always tries to learn something Medicine (Baltimore) 1987: 66: 98–113. new, there are many interesting adventures to 14. Gorlin R J, Cohen M M Jr, Hennekam R C M. be had in the field of cancer-associated genoder- Syndromes of the Head and Neck, 4th edn. New York: Oxford University Press, 2001. matoses. Over the 30 some years, David and I 15. Campbell R M, Mader R D, Dufresne R G Jr. Men- have been active in dermatology. These five ingiomas after medulloblastoma irradiation treatment syndromes have advanced from being odd dis- in a patient with basal cell nevus syndrome. J Am eases set aside for the ‘stamp collectors’ to fas- Acad Dermatol 2005: 53: S256–S259. cinating diseases, giving us new insights into 16. Sanai N, Alvarez-Buylla A, Berger M S. Neural stem cells and the origin of gliomas. N Engl J Med 2005: cutaneous and systemic tumor development. 353: 811–822. 17. Torre D. Multiple sebaceous tumors. Arch Dermatol 1968: 98: 549–551. Acknowledgements 18. Muir E G, Bell A J, Barlow K A. Multiple primary Many old friends and some new acquaintances helped me carcinomata of the colon, duodenum, and larynx asso- refresh my memory and expand my knowledge. This hope- ciated with kerato-acanthomata of the face. Br J Surg fully complete list includes: Grant Anhalt, J. Aidan Car- 1967: 54: 191–195. ney, Michael Flaig, Jorge Frank, Robert Goltz, Robert 19. Rulon D B, Helwig E B. Multiple sebaceous neo- Gorlin, Wolfgang Hartschuh, Robert Jackson, Peter Itin, plasms of the skin: an association with multiple vis- Roland Kruse, Peter Lane, Kenneth Lloyd, Ingrid Moll, ceral carcinomas, especially of the colon. Am J Clin Eileen Murray, Gerd Plewig, Julia Reifenberger, Arno Pathol 1973: 60: 745–752. Ru¨tten, Jo¨rg Schaller, Jack Toole and Peyton Weary. 20. Fahmy A, Burgdorf W H, Schosser R H et al. Muir– Torre syndrome: report of a case and reevaluation of the dermatopathologic features. Cancer 1982: 49: References 1898–1903. 21. Worret W I, Burgdorf W H, Fahmy A et al. Torre– 1. Warthin A S. Heredity with reference to carcinoma. Muir syndrome. Sebaceous gland neoplasms, kerato- Arch Intern Med 1913: 12: 546–555. acanthomas, multiple internal cancers and heredity. 2. Burgdorf W H, Koester G. Multiple cutaneous tum- Hautarzt 1981: 32: 519–524. ors: what do they mean? J Cutan Pathol 1992: 19: 22. Burgdorf W. Dermatopathologic aspects of cancer- 449–457. associated genodermatoses. In: Lynch H T, Fusaro R 3. Gorlin R J, Goltz R W. Multiple nevoid basal-cell epi- M, eds. Cancer-associated Genodermatoses. New thelioma, jaw cysts and bifid rib. A syndrome. N Engl York: Van Nostrand, 1982: 145–170. J Med 1960: 262: 908–912. 23. Lynch H T, Kimberling W, Albano W A et al. Hered- 4. Johnson R L, Rothman A L, Xie J et al. Human itary nonpolyposis colorectal cancer (Lynch homolog of patched, a candidate gene for the basal syndromes I and II). I. Clinical description of cell nevus syndrome. Science 1996: 272: 1668–1671. resource. Cancer 1985: 56: 934–938.

664 Cancer-associated genodermatoses 24. Lynch H T, Lanspa S, Smyrk T et al. Hereditary non- nohistochemical analysis as a screening test. Am J polyposis colorectal cancer (Lynch syndromes I & II). Surg Pathol 2002: 26: 338–343. Genetics, pathology, natural history, and cancer con- 41. Weary P E, Gorlin R J, Gentry W C Jr et al. Multiple trol, Part I. Cancer Genet Cytogenet 1991: 53: 143– hamartoma syndrome (Cowden’s disease). Arch Der- 160. matol 1972: 106: 682–690. 25. Lynch H T, de la Chapelle A. Hereditary colorectal 42. Lloyd K M 2nd, Dennis M. Cowden’s disease. A cancer. N Engl J Med 2003: 348: 919–932. possible new symptom complex with multiple system 26. Lynch H T, Krush A J. Cancer family ‘‘G’’ revisited: involvement. Ann Intern Med 1963: 58: 136–142. 1895–1970. Cancer 1971: 27: 1505–1511. 43. Walton B J, Morain W D, Baughman R D et al. 27. Lynch H T, Lynch P M, Pester J et al. The cancer Cowden’s disease: a further indication for prophylactic family syndrome. Rare cutaneous phenotypic linkage mastectomy. Surgery 1986: 99: 82–86. of Torre’s syndrome. Arch Intern Med 1981: 141: 44. Fackenthal J D, Marsh D J, Richardson A L et al. 607–611. Male breast cancer in Cowden syndrome patients with 28. Lynch H T, Fusaro R M, Roberts L et al. Muir–Torre germline PTEN mutations. J Med Genet 2001: 38: syndrome in several members of a family with a variant 159–164. of the cancer family syndrome. Br J Dermatol 1985: 45. Starink T M, van der Veen J P, Arwert F et al. The 113: 295–301. Cowden syndrome: a clinical and genetic study in 21 29. Fishel R, Lescoe M K, Rao M R et al. The human patients. Clin Genet 1986: 29: 222–233. mutator gene homolog MSH2 and its association with 46. Brownstein M H, Mehregan A H, Bikowski J B. hereditary nonpolyposis colon cancer. Cell 1993: 75: Trichilemmomas in Cowden’s disease. JAMA 1977: 1027–1038. 238: 26. 30. Papadopoulos N, Nicolaides N C, Wei Y F et al. 47. Brownstein M H, Mehregan A H, Bikowski J B et al. Mutation of a mutL homolog in hereditary colon can- The dermatopathology of Cowden’s syndrome. Br J cer. Science 1994: 263: 1625–1629. Dermatol 1979: 100: 667–673. 31. Umar A, Boland C R, Terdiman J P et al. Revised 48. Starink T M, Meijer C J, Brownstein M H. The cuta- Bethesda guidelines for hereditary nonpolyposis colo- neous pathology of Cowden’s disease: new findings. rectal cancer (Lynch syndrome) and microsatellite J Cutan Pathol 1985: 12: 83–93. instability. J Natl Cancer Inst 2004: 96: 261–268. 49. Metcalf J S, Maize J C, LeBoit P E. Circumscribed 32. Myrhoj T, Bisgaard M L, Bernstein I et al. Hereditary storiform collagenoma (sclerosing fibroma). Am J non-polyposis colorectal cancer: clinical features and Dermatopathol 1991: 13: 122–129. survival. Results from the Danish HNPCC register. 50. Ackerman A B. Trichilemmoma. Arch Dermatol Scand J Gastroenterol 1997: 32: 572–576. 1978: 114: 286. 33. Burgdorf W H, Pitha J, Fahmy A. Muir–Torre syn- 51. Brownstein M H. Trichilemmoma. Benign follicular drome. Histologic spectrum of sebaceous prolifera- tumor or viral wart? Am J Dermatopathol 1980: 2: tions. Am J Dermatopathol 1986: 8: 202–208. 229–231. 34. Kruse R, Rutten A, Lamberti C et al. Muir–Torre 52. Lhermitte J, Duclos P. Sur un ganglioneurome diffus phenotype has a frequency of DNA mismatch- du cortex du cervelet. Bull Assoc Fr Cancer 1920: 9: repair-gene mutations similar to that in hereditary non- 99–107. polyposis colorectal cancer families defined by the 53. Padberg G W, Schot J D, Vielvoye G J et al. Lher- Amsterdam criteria. Am J Hum Genet 1998: 63: 63–70. mitte–Duclos disease and Cowden disease: a single 35. Kruse R, Lamberti C, Wang Y et al. Is the mismatch phakomatosis. Ann Neurol 1991: 29: 517–523. repair deficient type of Muir–Torre syndrome confined 54. Li J, Yen C, Liaw D et al. PTEN, a putative protein to mutations in the hMSH2 gene? Hum Genet 1996: tyrosine phosphatase gene mutated in human brain, 98: 747–750. breast, and prostate cancer. Science 1997: 275: 1943– 36. Kruse R, Rutten A, Schweiger N et al. Frequency of 1947. microsatellite instability in unselected sebaceous gland 55. Liaw D, Marsh D J, Li J et al. Germline mutations of neoplasias and hyperplasias. J Invest Dermatol 2003: the PTEN gene in Cowden disease, an inherited breast 120: 858–864. and thyroid cancer syndrome. Nat Genet 1997: 16: 37. Kruse R, Rutten A, Hosseiny-Malayeri H R et al. 64–67. ‘‘Second hit’’ in sebaceous tumors from Muir–Torre 56. Eng C. Will the real Cowden syndrome please stand patients with germline mutations in MSH2: allele loss up: revised diagnostic criteria. J Med Genet 2000: 37: is not the preferred mode of inactivation. J Invest 828–830. Dermatol 2001: 116: 463–465. 57. Arch E M, Goodman B K, Van Wesep R A et al. 38. Rutten A, Burgdorf W, Hugel H et al. Cystic seba- Deletion of PTEN in a patient with Bannayan–Riley– ceous tumors as marker lesions for the Muir–Torre Ruvalcaba syndrome suggests allelism with Cowden syndrome: a histopathologic and molecular genetic disease. Am J Med Genet 1997: 71: 489–493. study. Am J Dermatopathol 1999: 21: 405–413. 58. Marsh D J, Dahia P L, Zheng Z et al. Germline 39. Kruse R, Rutten A, Malayeri H R et al. A novel mutations in PTEN are present in Bannayan–Zonana germline mutation in the hMLH1 DNA mismatch syndrome. Nat Genet 1997: 16: 333–334. repair gene in a patient with an isolated cystic 59. Marsh D J, Kum J B, Lunetta K L et al. PTEN muta- sebaceous tumor. J Invest Dermatol 1999: 112: 117– tion spectrum and genotype–phenotype correlations in 118. Bannayan–Riley–Ruvalcaba syndrome suggest a single 40. Mathiak M, Rutten A, Mangold E et al. Loss of entity with Cowden syndrome. Hum Mol Genet 1999: DNA mismatch repair proteins in skin tumors from 8: 1461–1472. patients with Muir–Torre syndrome and MSH2 or 60. Waite K A, Eng C. Protean PTEN: form and func- MLH1 germline mutations: establishment of immu- tion. Am J Hum Genet 2002: 70: 829–844.

665 Burgdorf 61. Pilarski R, Eng C. Will the real Cowden syndrome cardiac and cutaneous myxomas. Am J Surg Pathol please stand up (again)? Expanding mutational and 1991: 15: 713–721. clinical spectra of the PTEN hamartoma tumour syn- 77. Kirschner L S, Carney J A, Pack S D et al. Mutations drome. J Med Genet 2004: 41: 323–326. of the gene encoding the protein kinase A type I-alpha 62. Rohwedder A, Keminer O, Hendricks C et al. Detec- regulatory subunit in patients with the Carney com- tion of HPV DNA in trichilemmomas by polymerase plex. Nat Genet 2000: 26: 89–92. chain reaction. J Med Virol 1997: 51: 119–125. 78. Matyakhina L, Pack S, Kirschner L S et al. Chromo- 63. Schaller J, Rohwedder A, Burgdorf W H et al. Identi- some 2 (2p16) abnormalities in Carney complex fication of human papillomavirus DNA in cutaneous tumours. J Med Genet 2003: 40: 268–277. lesions of Cowden syndrome. Dermatology 2003: 207: 79. Burgdorf W, Carney J A. Carney complex. In: LeBoit P 134–140. E, Burg G, Weedon D et al., eds. Pathology and Genet- 64. Carney J A, Gordon H, Carpenter P C et al. The ics of Skin Tumors. Lyon: IARC Press, 2006: 291–292. complex of myxomas, spotty pigmentation, and endo- 80. Birt A R, Hogg G R, Dube W J. Hereditary multiple crine overactivity. Medicine (Baltimore) 1985: 64: 270– fibrofolliculomas with trichodiscomas and acrochor- 283. dons. Arch Dermatol 1977: 113: 1674–1677. 65. Atherton D J, Pitcher D W, Wells R S et al. A syn- 81. Hornstein O P, Knickenberg M. Perifollicular fibro- drome of various cutaneous pigmented lesions, myx- matosis cutis with polyps of the colon – a cutaneo- oid neurofibromata and atrial myxoma: the NAME intestinal syndrome sui generis. Arch Dermatol Res syndrome. Br J Dermatol 1980: 103: 421–429. 1975: 253: 161–175. 66. Rhodes A R, Silverman R A, Harrist T J et al. Muco- 82. Pinkus F. U¨ber einen bisher unbekannten Nebenappa- cutaneous lentigines, cardiomucocutaneous myxomas, rat des Menschen: Haarscheiben. Dermatol Z 1902: 9: and multiple blue nevi: the ‘‘LAMB’’ syndrome. J Am 465–469. Acad Dermatol 1984: 10: 72–82. 83. Pinkus F. U¨ber die Haarscheiben des Nabelschweins 67. Ferreiro J A, Carney J A. Myxomas of the external (Pekari-Dicotyles). Zugleich ein Beitrag zur Kenntnis ear and their significance. Am J Surg Pathol 1994: 18: der Muskulatur der Haare. Arch Dermatol Syphiligr 274–280. 1933: 169: 379–396. 68. Carney J A, Headington J T, Su W P. Cutaneous 84. Pinkus H, Coskey R, Burgess G H. Trichodiscoma. A myxomas. A major component of the complex of benign tumor related to haarscheibe (hair disk). myxomas, spotty pigmentation, and endocrine overac- J Invest Dermatol 1974: 63: 212–218. tivity. Arch Dermatol 1986: 122: 790–798. 85. Burnier M, Rejsek P. Fibromes sous-cutanes peripil- 69. Carney J A, Ferreiro J A. The epithelioid blue nevus. aires multiples du cou. Bull Soc Fr Dermatol Syphiligr A multicentric familial tumor with important associa- 1925: 32: 242–243. tions, including cardiac myxoma and psammomatous 86. Zackheim H S, Pinkus H. Perifollicular fibromas. melanotic schwannoma. Am J Surg Pathol 1996: 20: Arch Dermatol 1960: 82: 913–917. 259–272. 87. Weintraub R, Pinkus H. Multiple fibrofolliculomas 70. O’Grady T C, Barr R J, Billman G et al. Epithelioid (Birt–Hogg–Dube) associated with a large connective blue nevus occurring in children with no evidence of tissue nevus. J Cutan Pathol 1977: 4: 289–299. Carney complex. Am J Dermatopathol 1999: 21: 483– 88. Ro¨dder O, Schulz-Ehrenburg U, Veh R W, Plewig G. 486. Hair disk (Haarscheibe) and trichodiscoma (Poster). 71. Carney J A, Sheps S G, Go V L et al. The triad of In: 46th Annual Meeting, American Academy of Der- gastric leiomyosarcoma, functioning extra-adrenal matology. San Antonio, 1987. paraganglioma and pulmonary chondroma. N Engl J 89. Steffen C. Mantleoma. A benign neoplasm with man- Med 1977: 296: 1517–1518. tle differentiation. Am J Dermatopathol 1993: 15: 72. Carney J A. The search for Harvey Cushing’s patient, 306–310. Minnie G., and the cause of her hypercortisolism. Am 90. Schulz T, Hartschuh W. Birt–Hogg–Dube syndrome J Surg Pathol 1995: 19: 100–108. and Hornstein–Knickenberg syndrome are the same. 73. Young W F Jr, Carney J A, Musa B U et al. Familial Different sectioning technique as the cause of different Cushing’s syndrome due to primary pigmented nod- histology. J Cutan Pathol 1999: 26: 55–61. ular adrenocortical disease. Reinvestigation 50 years 91. Toro J R, Glenn G, Duray P et al. Birt–Hogg–Dube later. N Engl J Med 1989: 321: 1659–1664. syndrome: a novel marker of kidney neoplasia. Arch 74. Carney J A. Psammomatous melanotic schwannoma. Dermatol 1999: 135: 1195–1202. A distinctive, heritable tumor with special associa- 92. Nickerson M L, Warren M B, Toro J R et al. Muta- tions, including cardiac myxoma and the Cushing syn- tions in a novel gene lead to kidney tumors, lung wall drome. Am J Surg Pathol 1990: 14: 206–222. defects, and benign tumors of the hair follicle in 75. Carney J A, Stratakis C A. Epithelioid blue nevus and patients with the Birt–Hogg–Dube syndrome. Cancer psammomatous melanotic schwannoma: the unusual Cell 2002: 2: 157–164. pigmented skin tumors of the Carney complex. Semin 93. Zbar B, Alvord W G, Glenn G et al. Risk of renal Diagn Pathol 1998: 15: 216–224. and colonic neoplasms and spontaneous pneumotho- 76. Carney J A, Toorkey B C. Myxoid fibroadenoma and rax in the Birt–Hogg–Dube syndrome. Cancer Epi- allied conditions (myxomatosis) of the breast. A herit- demiol Biomarkers Prev 2002: 11: 393–400. able disorder with special associations including

666