Abstract
The so-called Birt–Hogg–Dubé syndrome, an autosomal dominant trait characterized by multiple fibrofolliculomas and extracutaneous cancer proneness, was not first recognized by Birt, Hogg, and Dubé. Hence, the presently used eponymic designation reflects a historical error. In fact, the disorder was discovered in the following way. In 1975, Hornstein and Knickenberg described a “distinct nosological entity” in two sibs with multiple perifollicular fibromas, multiple skin tags, and polyps of the colon with a tendency to malignancy. The father had similar skin lesions and “bilateral kidney cysts” and unilateral lung cysts. In 1976, Hornstein et al. informed, in two additional articles, both geneticists and gastroenterologists about the new autosomal dominant trait. When Birt et al. presented their report in 1977, they knew of Hornstein's first publication but were convinced that they had discovered “a previously unrecognized hereditary pilar hamartoma.” This was a misconception because what they called “fibrofolliculoma” has turned out to be identical with “perifollicular fibroma” as described by Hornstein et al. Moreover, Birt et al. failed to mention any associated extracutaneous cancer proneness, whereas Hornstein et al. had delineated the complete syndrome. For all of these reasons, the new term “Hornstein–Birt–Hogg–Dubé syndrome” appears to be appropriate. © 2012 Wiley Periodicals, Inc.
INTRODUCTION
The disorder that is called today “Birt–Hogg–Dubé syndrome” (OMIM # 135150) is an autosomal dominant trait characterized by multiple fibrofolliculomas, proneness to extracutaneous cancer, and lung cysts giving rise to pneumothorax [Menko et al., 2009; Kluger et al., 2010]. The condition is caused by heterozygous mutations in the FLCN gene encoding folliculin [Nickerson et al., 2002; Schmidt et al., 2005]. The purpose of this article is to tell the story how this phenotype was delineated, and to present arguments why the discoverer's name should be added to the eponymic designation of the syndrome.
THE DESCRIPTION OF THE SYNDROME
In 1975, Otto Paul Hornstein from Erlangen, Germany (Fig. 1) reported, together with his coworker Monika Knickenberg, on “a distinct nosological entity” that had so far been unknown [Hornstein and Knickenberg, 1975]. A 47-year-old woman had multiple perifollicular fibromas on her face, neck, and back (Fig. 2A), multiple skin tags (“pedunculated fibromas”) involving the neck, the axillae, the groins, and the trunk (Fig. 3A), as well as multiple polyps of the colon. One of the colonic tumors showed malignant degeneration. The patient's 42-year-old brother had similar skin lesions and colonic polyps. Their father was reported to have had skin nodules resembling those of his children on his face, neck, and back. Remarkably, he had “died of bilateral kidney cysts (and unilateral lung cysts), hypertension, and cardiac insufficiency.” The authors presented a meticulous description of the cutaneous lesions of the phenotype, including their distinguishing histopathological criteria (Fig. 4A). They asserted that “as a typical feature, the nodules are arranged perifollicularly, as most of them show a small central pore or a minute keratotic plug, respectively.” They stated that such perifollicular fibromas had previously been described by French authors as a distinct cutaneous entity [Burnier and Rejsek, 1925] and that even a familial occurrence of multiple lesions was mentioned in one case [Civatte and Tréguilly, 1971]. As a new message, Hornstein and Knickenberg emphasized that “perifollicular fibromatosis should alert the dermatologist to consider periodic thorough examination for intestinal polyps the more as they may change into malignant growth.” The title of their publication said that the disorder was “a cutaneo-intestinal syndrome sui generis.”
Otto Paul Hornstein, the man who discovered the syndrome that bears the names of Birt, Hogg, and Dubé, although their description of the phenotype was neither new nor complete.
Hornstein–Birt–Hogg–Dubé syndrome. A: “Densely aggregated flat-topped papules…” [Hornstein and Knickenberg, 1975]. Reprinted with permission from Arch Dermatol Res, © Springer Verlag, Berlin. B: “Fibrofolliculomas distributed in sheets over side of face, neck, and ear” [Birt et al., 1977]. Reprinted with permission from Arch Dermatol, © American Medical Association.
Hornstein-Birt-Hogg-Dubé syndrome. A: “Flat-topped papules interspersed with multiple skin tags on neck and shoulders” [Hornstein and Knickenberg, 1975]. Reprinted with permission from Arch Dermatol Res, © Springer Verlag, Berlin. B: “Fibrofolliculomas intermingled with multiple small globoid acrochordons” [Birt et al., 1977]. Reprinted with permission from Arch Dermatol, © American Medical Association.
Hornstein–Birt–Hogg–Dubé syndrome. A: “Biopsy specimen of a perifollicular fibroma shows concentrically arranged fascicles of collagen bundles. Small strands of follicular epithelium are seen below.” [Hornstein and Knickenberg, 1975]. Reprinted with permission from Arch Dermatol Res, © Springer Verlag, Berlin. B: “Lower end of hair follicle surrounded by well-demarcated, relatively acellular mantle of connective tissue placed horizontally in dermis.” [Birt et al., 1977]. Reprinted with permission from Arch Dermatol, © American Medical Association.
In another article, Hornstein [1976] informed the geneticists that he had delineated “a rare, generalized genodermatosis” that was transmitted as “an apparent autosomal dominant trait.” In a third article, gastroenterologists were notified that multiple perifollicular fibromas may herald the presence of colonic polyposis, thus constituting “a peculiar clinical syndrome” [Hornstein et al., 1976].
All three of these articles were written in English and published in journals with an international readership (Table I). The report of Birt et al. [1977] appeared 2 years after Hornstein's first publication.
| Authors | Year of publication | Name of journal | Note on extracutaneous cancer proneness |
|---|---|---|---|
| Hornstein and Knickenberg | 1975 | Arch Dermatol Res | Yes |
| Hornstein | 1976 | Hum Genet | Yes |
| Hornstein, Knickenberg, and Mörl | 1976 | Acta Hepatogastroenterol | Yes |
| Birt, Hogg, and Dubé | 1977 | Arch Dermatol | Noa |
- a Description of the cutaneous phenotype only.
DID BIRT, HOGG, AND DUBÉ DESCRIBE THE DISORDER INDEPENDENTLY?
The phenotype was not reported independently by the Canadian physicians. They referred to the article of Hornstein and Knickenberg [1975] but did not discuss the crucial point that the European authors had postulated a new phenotype heralding cancer proneness. For unknown reasons they cited the title of their article in a mutilated form: “Perifollicular fibromatosis cutis with polyps of the colon,” thus omitting the important additional wording: “—a cutaneo-intestinal syndrome sui generis” [Hornstein and Knickenberg, 1975].
ABSENCE OF HISTOPATHOLOGICAL DISSIMILARITIES
Birt et al. [1977] conceded that the report from Erlangen on perifollicular fibromatosis cutis “describes a similar clinical appearance to fibrofolliculoma, and the histologic description of epithelial strands and fibrous tissue proliferation is also suggestive. However, the presence of hypoplastic sebaceous glands and the situation of some of the nodules deep in the dermis and subcutis are not features of fibrofolliculoma.” Meanwhile, further histopathological studies have shown convincingly that these rather subtle distinguishing criteria do not exist [Schachtschabel et al., 1996; Schulz and Hartschuh, 2000; Frantzen et al., 2001; Vincent et al., 2003]. In other words, the phantom of a fibrofolliculoma (Figs. 2B and 4B) to be distinguished from Hornstein's perifollicular fibroma (Figs. 2A and 4A) and thus representing “a previously unrecognized hereditary pilar hamartoma” [Birt et al., 1977] has vanished into thin air [Schulz and Hartschuh, 1999].
Moreover, the “acrochordons” as noted by the Canadian physicians (Fig. 3B) had already been described, in a meticulous way, in the patients from Erlangen as “soft pedunculated fibromas, resp. skin tags” or “multiple fibromata pendulantia” (Fig. 3A) [Hornstein and Knickenberg, 1975]. Today, some authors think that most of these “acrochordons” turn out to represent, in fact, fibrofolliculomas when examined histopathologically [De la Torre et al., 1999].
On the other hand, both syndromologists and dermatohistopathologists will agree that an occasional occurrence of trichodiscoma in affected family members, as noted by Birt et al. [1977], cannot be taken as a distinguishing feature when compared to the syndrome delineated by Hornstein et al. [1976]. Trichodiscoma and fibrofolliculoma are very similar tumors [Starink et al., 1985]. Notwithstanding, it should be borne in mind that familial multiple trichodiscomas [OMIM # 135150] represent a quite different disorder that is not linked to the FLCN locus [Starink et al., 2012].
THE ISSUE OF COLONIC POLYPS AND CANCER
More recent studies have demonstrated that an increased risk to develop malignant kidney tumors represents, in this syndrome, the most important form of cancer proneness [Toro et al., 1999; Zbar et al., 2002; Schmidt et al., 2005; OMIM, 2012]. Interestingly, Hornstein and Knickenberg [1975] had mentioned that the father of their patients had “bilateral kidney cysts” in addition to unilateral lung cysts. However, the authors from Erlangen categorized the disorder as “a peculiar cutaneo-intestinal syndrome” because of the presence of multiple colon polyps in two sibs, with signs of malignant degeneration in one of them [Hornstein et al., 1976]. Subsequent reports have confirmed that colonic polyps constitute an important part of the syndrome [Binet et al., 1986; Combemale et al., 1988; Rongioletti et al., 1989; Le Guyadec et al., 1998; Monteagudo Sánchez et al., 2004], with an increased risk of colorectal cancer [Sasai et al., 1996; Schulz and Hartschuh, 2000; Frantzen et al., 2001; Khoo et al., 2010].
Paradoxically, Zbar et al. [2002] found in a large cohort of patients no increased risk for the development of colonic polyps or carcinomas. Some years later, however, the same group identified within the same cohort, through medical history, nine individuals with colon polyps/carcinoma [Schmidt et al., 2005]. Hence, there can no longer be any doubt that, at least in some families, colon tumors are part of the syndrome, as postulated by Hornstein et al. [1976]. Interestingly, FLCN mutations have also been found to play a major role in the development of sporadic colorectal tumors [Kahnoski et al., 2003].
DID BIRT, HOGG, AND DUBÉ REDESCRIBE THE COMPLETE SYNDROME?
Birt et al. [1977] exclusively redescribed the cutaneous features of the new syndrome. By studying a large kindred they confirmed that these particular skin lesions can be transmitted as an autosomal dominant trait. They did not refer, however, to any predisposition of their patients to extracutaneous cancer and, remarkably, they did not discuss the cancer proneness as described in the cited article from Erlangen [Hornstein and Knickenberg, 1975].
Admittedly, they found a hereditary proneness to thyroid carcinoma within their proband's sibship, but they emphasized that the “thyroid carcinomas had been inherited from a male antecedent of French Canadian origin, and the multiple skin hamartomas through his wife, who was of English descent” [Birt et al., 1977]. Hence, according to the rules of Mendelian inheritance it is obvious that the thyroid tumors had nothing to do with the cutaneous phenotype.
CONCLUSION
For all of these reasons it seems both logical and historically justified to give credit to Otto Paul Hornstein who was the first who recognized the syndrome and presented a precise description of its distinguishing clinical and histopathological features. On the other hand, it is true that the historically incorrect name “Birt–Hogg–Dubé syndrome” is firmly entrenched in our literature. In view of this fact, I propose to use the new term “Hornstein–Birt–Hogg–Dubé syndrome.” One might argue that this term disregards the name of Hornstein's co-worker Monika Knickenberg. For practical reasons, however, we may accept this form of injustice because otherwise the name of the syndrome would become too longwinded.
Admittedly, humans will never be able to create a world of absolute justice, and this is also true for eponymic designations of nosological entities [Opitz, 1985; Tomb and Grosshans, 2001]. Those who want to keep to the beaten track may cling to the tenuous term “Birt–Hogg–Dubé syndrome,” whereas others may realize that this naming has a trace of nonsensicalness.
