American Journal of Medical Genetics 84:389–395 (1999)
Proteus Syndrome: Diagnostic Criteria, Differential Diagnosis, and Patient Evaluation Leslie G. Biesecker,1 Rudolf Happle,2 John B. Mulliken,3 Rosanna Weksberg,4 John M. Graham, Jr.,5 Denis L. Viljoen,6 and M. Michael Cohen, Jr.7 1
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 2 Department of Dermatology, University of Marburg, Marburg, Germany 3 Division of Plastic Surgery, Children’s Hospital, Boston, Massachusetts 4 Department of Genetics, Hospital for Sick Children, Toronto, Ontario, Canada 5 Medical Genetics Birth Defects Center, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, SHARE’s Child Disability Center, University Affiliated Program, International Skeletal Dysplasia Registry, UCLA School of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 6 Department of Human Genetics, Medical School, University of Cape Town, Cape Town, South Africa 7 Departments of Oral and Maxillofacial Sciences, Pediatrics, Community Health and Epidemiology, Health Services Administration, Sociology and Social Anthropology, Dalhousie University, Halifax, Nova Scotia, Canada
Proteus syndrome is a complex disorder comprising malformations and overgrowth of multiple tissues. The disorder is highly variable and appears to affect patients in a mosaic manner. This intrinsic variability has led to diagnostic confusion associated with a dearth of longitudinal data on the natural history of Proteus syndrome. To clarify some of these issues, a workshop on Proteus syndrome was held in March 1998 at the National Institutes of Health, and participants developed recommendations for diagnostic criteria, differential diagnosis, and guidelines for the evaluation of patients. This is a review of those recommendations. Am. J. Med. Genet. 84:389–395, 1999. © 1999 Wiley-Liss, Inc. KEY WORDS: connective tissue nevus; epidermal nevus; hyperostosis; megaspondylodysplasia; disproportionate overgrowth; Klippel-Trenaunay syndrome; hemihyperplasia/multiple lipomatosis syndrome
Contract grant sponsor: National Institutes of Health; Contract grant sponsor: National Cancer Institute of Canada; Contract grant number: 009148; Contract grant sponsor: UCLA Intercampus Training Program; Contract grant number: GM08243; Contract grant sponsor: U.S. Public Health Service; Contract grant number: PO1 HD22657-06. *Correspondence to: M. Michael Cohen, Jr., D.M.D., Ph.D., Dalhousie University, Halifax, Nova Scotia, Canada B3H 3J5. Email:
[email protected] Received 2 December 1998; Accepted 13 February 1999
© 1999 Wiley-Liss, Inc.
INTRODUCTION Proteus syndrome was originally described in two patients by Cohen and Hayden [1979] as a newly recognized disorder characterized by overgrowth of multiple tissues, connective tissue nevi, epidermal nevi, and hyperostoses. The disorder was designated Proteus syndrome by Wiedemann et al. [1983] to denote its variability of clinical expression. Happle [1987] hypothesized that the syndrome resulted from a somatic alteration of a gene leading to mosaic effects that would be lethal if the mutation were carried in nonmosaic fashion. This potentially explains the variability among and within patients, but has led to diagnostic confusion. Intrinsic variability invites overdiagnosis, and reports in the literature include patients who have a number of other conditions. The goal of this conference was to refocus diagnosis on a single condition. The major problems requiring resolution in Proteus syndrome include frequent misdiagnosis, lack of diagnostic criteria, and lack of longitudinal data on natural history. The First National Conference on Proteus Syndrome for Parents and Families was held at the National Institutes of Health in Bethesda, Maryland from March 18 to March 20, 1998. In this report, the opinions of the attendees were combined as recommendations on diagnostic criteria, differential diagnosis, and guidelines for evaluating patients. Although much has been learned about Proteus syndrome in recent years [Cohen, 1993; Biesecker et al., 1998], knowledge is evolving rapidly. Thus, these recommendations should be considered tentative because future clinical and molecular studies may necessitate modification. DIAGNOSTIC CRITERIA Clinical diagnostic criteria are summarized in Table I. Although many manifestations have been recorded
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in Proteus syndrome [Cohen, 1993], only those thought to be of diagnostic value are listed. General Criteria The general characteristics of mosaic distribution of lesions, progressive course, and sporadic occurrence (Table I) are considered mandatory, regardless of specific manifestations in a given patient. Happle [1987] initially postulated that Proteus syndrome, like other conditions that are lethal in the nonmosaic state, is caused by somatic mosaicism. This idea as applied to Proteus syndrome gained some clinical support from the work of Schwartz et al. [1991] and Cohen [1993]. All cases are sporadic. Two purported instances of transmission from parent to child [Goodship et al., 1991; Kru¨ger et al., 1993] are not convincing. Happle [1992, 1993] discussed the possibility of “paradominant inheritance,” should a rare example of familial Proteus syndrome be recorded in the future. According to this hypothesis [Happle, 1992], heterozygosity for a paradominant mutation would confer phenotypic normality and the allele may be transmitted unperceived for generations. The gene carrier would exhibit Proteus syndrome when a somatic mutation occurred during embryogenesis, giving rise to a cell line
that would be either hemizygous, from allelic loss, or homozygous, from a point mutation. On rare occasions, more than one relative might be affected. Because the trait is neither simply mendelian nor entirely nonmendelian but sometimes tends to imitate dominant transmission, Happle [1992] proposed the term “paradominance.” Our clinical impression is that somatic growth during adolescence and final height attainment are normal in Proteus syndrome. Tissue overgrowth is progressive in nature, but usually appears to plateau after adolescence [Clark et al., 1987; Cohen, 1993; Gordon et al., 1995]. Specific Criteria A category A abnormality, if present, suffices for the diagnosis of Proteus syndrome (Table I). Connective tissue nevi are common, and are facultative but not obligatory; i.e., they may or may not be present. They have been recorded most frequently on the plantar surface of the feet, but can also be on the abdomen, hands, and nose [Cohen, 1993]. When present, a connective tissue nevus (Fig. 1) is almost pathognomonic for Proteus syndrome.
TABLE I. Diagnostic Criteria for Proteus Syndrome For Diagnosis: General Criteria (Mandatory) + Mosaic distribution of lesions Progressive course Sporadic occurrence
C.
a
Either one from A or Two from B or Three from C
Manifestations
Relative frequencya
1. Connective tissue nevus 1. Epidermal nevus 2. Disproportionate overgrowth (one or more) Limbs Arms/legs Hands/feet/digits Skull Hyperostoses External auditory meatus Hyperostosis Vertebrae Megaspondylodysplasia Viscera Spleen/thymus 3. Specific tumors before end of second decade (either one) Bilateral ovarian cystadenomas Parotid monomorphic adenoma 1. Dysregulated adipose tissue (either one) Lipomas Regional absence of fat 2. Vascular malformations (one or more) Capillary malformation Venous malformation Lymphatic malformation 3. Facial phenotype Dolichocephaly Long face Minor downslanting of palpebral fissures and/or minor ptosis Low nasal bridge Wide or anteverted nares Open mouth at rest
C C
Category signs A. B.
Specific Criteria (Category Signs)
C, common; U, uncommon.
C C C U C U U U C C C C C U
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Fig. 1. Cerebriform surface of connective tissue nevi in Proteus syndrome. Left: Plantar surface of one patient. Center: Plantar surface of another patient. Right: Abdominal surface of a third patient. From Cohen [1995].
Histologically, connective tissue nevi are characterized by highly collagenized connective tissue. They are easily distinguished from neurofibromas (Fig. 2) [Cohen, 1988b, 1995]. A few isolated examples of connective tissue nevi have been recorded but the patients have subsequently been shown to have had Proteus syndrome [Uitto, 1986; see his Fig. 2 (middle)]. If there are isolated examples, particularly involving the feet,
Fig. 2. Comparative connective tissue patterns. Left: Highly collagenized connective tissue nevus of Proteus syndrome. Right: Delicate connective tissue of neurofibroma. Note cellular component. From Cohen [1995].
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they must be extremely rare. Botella-Estrada et al. [1991] reported such a case but showed no photomicrographs. Furthermore, these authors used the term collagenoma and suggested that it may appear as an acquired lesion, as a hereditary trait, or as part of tuberous sclerosis. The lack of histopathological confirmation and the heterogeneity described casts doubt on whether these authors were discussing the same lesion as that found in Proteus syndrome. Hyperostosis of the external auditory canal is uncommon in Proteus syndrome. It can also occur in surfers or as an isolated abnormality of unknown cause. Nevertheless, when present with a few other manifestations of Proteus syndrome, its diagnostic value can have great significance in mildly affected patients [Cohen, 1993; Smeets et al., 1994] (Table I). Disproportionate overgrowth, commonly asymmetric in nature, can involve the arms, legs, hands, feet, and digits. Cohen [1988b, 1993] termed the bone lesions found in the skull as hyperostoses. The terms exostoses and osteomas are to be avoided because both have somewhat different patterns of osseous organization. A radiograph of megaspondylodysplasia is shown in Figure 3. Although limb overgrowth is most common in Proteus syndrome, we suspect that any organ may be involved. An uncommon manifestation, found in four patients, is pronounced splenomegaly (Fig. 4); one instance was associated with a history of reduced platelet counts [Biesecker et al., 1998]. Another uncommon manifestation is enlargement of the thymus.
Fig. 3.
Megaspondylodysplasia of cervical vertebrae.
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Fig. 4. Huge spleen removed at surgery from a patient with Proteus syndrome who had thrombocytopenia.
Epidermal nevi are causally heterogeneous and pathogenetically variable [Happle, 1991]. The flat, nonorganoid type is found in Proteus syndrome (Fig. 5). It is soft rather than hard like the verrucous type, which is not found in this syndrome. Histologically, the lesion is characterized by hyperorthokeratosis, acanthosis, and papillomatosis [Nazzaro et al., 1991] (Fig. 6). Adnexal hyperplasia is absent.
Fig. 5.
Epidermal nevi in patient with Proteus syndrome.
Fig. 6. Histological sections of epidermal nevus from Proteus syndrome showing hyperorthokeratosis intermingled with some areas of parakeratosis, acanthosis, and papillomatosis (hematoxylin and eosin ×10). From Nazzaro et al. [1991].
Cohen [1993] and Gordon et al. [1995] showed that several unusual types of tumors are occasionally associated with Proteus syndrome: ovarian cystadenoma (most commonly unilateral), various types of testicular tumors, central nervous system tumors (particularly meningiomas), and monomorphic adenoma of the parotid gland. Other overgrowth syndromes are also known to be associated with uncommonly occurring tumors; e.g., embryonal rhabdomyosarcoma in WiedemannBeckwith syndrome. Bilateral cystadenomas of the ovary are rare in children and adolescents and therefore of diagnostic value in Proteus syndrome. In adults, bilateral ovarian involvement is found in a significant percentage of cystadenocarcinomas [Gordon et al., 1995]. Monomorphic adenoma of the parotid gland is very uncommon, occurring most frequently in elderly men. The presence of this tumor in two adolescent girls with Proteus syndrome [Cohen and Hayden, 1979; Cohen, 1993; Gordon et al., 1995] is highly significant. Lipomas in Proteus syndrome are composed principally of mature adipocytes. Decreased and increased fat can be found in the same patient at different sites in the body, indicating dysregulation of adipose tissue (Fig. 7) [Clark et al., 1987; Hotamisligil and Ertogan, 1990; Cohen, 1993; Skovby et al., 1993; Happle, 1995]. Lipomas may be confined or infiltrative. Although histopathologic examination always shows benign adipose-tissue cells, the location of lesions is of great importance. Superficial lesions tend to be confined and may be self-limited in growth, although this is not always the case. On the other hand, intra-abdominal and intra-thoracic lipomas have increased potential for invasive behavior, despite benign histologic appearance. Proteus syndrome is also characterized by vascular malformations. The term “hemangioma” does not apply and “lymphangioma” is synonymous with lymphatic malformation. The distinction between vascular tumors and malformations has been discussed elsewhere [Mulliken and Glowacki, 1982; Mulliken, 1993; Cohen, 1998b]. Hemangioma refers to a common tumor of in-
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Fig. 7. Dysregulation of adipose tissue in patient with Proteus syndrome. Note long thin neck. From Skovby et al. [1993].
fancy characterized by rapid postnatal growth (cellular hyperplasia) and slow spontaneous regression in early childhood (programmed cellular death). Vascular malformations are developmental anomalies composed of channels lined by flat endothelium exhibiting a normal, slow rate of turnover. They grow proportionately with the patient; they never regress and they can expand. Vascular malformations can be single-channel type (e.g., capillary, lymphatic, or venous) or combined (e.g., capillary and venous channels or capillary, venous, and lymphatic channels). So-called combined tumors such as “angiolipomas” probably do not occur; they probably represent lipomas with a vascular stroma. So-called “lymphohemangioma” is a misnomer for combined lymphatic-capillary malformation. Cohen [1993] described a facial phenotype in Proteus syndrome patients with mental deficiency and, in some cases, seizures and/or brain malformations. Manifestations include dolichocephaly, long face, minor downslanting of the palpebral fissures and/or minor ptosis, low nasal bridge, wide or anteverted nares, and an open mouth at rest (Fig. 8) (Table I). These facial manifestations may even override the severe craniofacial distortion produced by bony overgrowth in some cases. Patients with this facial phenotype who have severe mental deficiency, sometimes with seizures and/or brain malformations, are illustrated in several publications: Cohen [1988b; see his Case 2, Fig.
Fig. 8. Facial phenotype in Proteus syndrome patient with mental deficiency and a history of seizures. Note dolichocephaly, long face, mild downslanting of palpebral fissures, ptosis, low nasal bridge, anteverted nares, and open mouth.
5, right], Cohen [1993; see his Case 1, Fig. 1], Mayatepek et al. [1989], and Rizzo et al. [1990]. Diagnostic criteria for Proteus syndrome are summarized in menu form in Table I. General criteria are mandatory and specific criteria, based on category signs A, B, or C, must be met. The single category sign in A appears to be sufficient for diagnosis. Either two category signs from B or three from C also appear to be sufficient for diagnosis. At the present time, we do not recommend the use of combined partial criteria from B and C. For example, we are not certain that one category sign from B combined with two category signs from C would be sufficient to establish diagnosis. DIFFERENTIAL DIAGNOSIS Various syndromes considered in differential diagnosis are listed in Table II, but not in order of importance. Rather, they are grouped for convenience as vascular syndromes, syndromes with pigmentation, and lipomatoses. The two disorders most commonly confused with Proteus syndrome are Klippel-Trenaunay syndrome and hemihyperplasia/lipomatosis syndrome. Misdiagnosis of these two conditions as Proteus syndrome is
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Biesecker et al. TABLE II. Differential Diagnosis Klippel-Trenaunay syndrome Parkes Weber syndrome Maffucci syndrome Neurofibromatosis, type 1 Epidermal nevus syndromea (formerly epidermal nevus syndrome or Solomon syndrome) Bannayan-Riley-Ruvalcaba syndrome Hemihyperplasia/lipomatosis syndrome Familial lipomatosis Symmetrical lipomatosis Encephalocraniocutaneous lipomatosis
ized form of Proteus syndrome. Some case reports described hyperostoses of the skull and visceral lipomas, suggesting overlap. Cohen [1993] pointed out that focal alopecia might be an exception, being found only in ECCL. One of us (R.H.) thinks that Proteus syndrome and ECCL are separate entities. The problem in lumping and splitting will be resolved when the basic defect for Proteus syndrome is known. We regard the association of ECCL with an NF1 mutation, reported by Legius et al. [1995], as coincidental. GUIDELINES FOR PATIENT EVALUATION
a Known to be causally heterogeneous and clinically variable rather than being a single entity [Happle, 1991].
common primarily because of confusion about the variability of Proteus syndrome. Of 16 patients referred to the NIH Proteus Evaluation Study, the diagnosis could be confirmed in ten cases; the other six had KlippelTrenaunay syndrome or hemihyperplasia/multiple lipomatosis syndrome [Biesecker et al., 1998]. Hemihyperplasia with multiple lipomas is a distinct subset of hemihyperplasia. Cutaneous capillary malformation may occur in some instances. Mild-tomoderate signs are present at birth. Progressive overgrowth does not occur. Rather, it tends to be commensurate with growth of the child [Biesecker et al., 1998]. Other disorders with vascular malformations and soft tissue/skeletal overgrowth include KlippelTrenaunay, Parkes Weber, and Maffucci syndromes. Klippel-Trenaunay syndrome is a “slow flow” vascular malformation involving lower or upper limbs and/or trunk. The vascular malformations are always combined: capillary, lymphatic, and venous. Magnetic resonance imaging (MRI) with gadolinium can differentiate venous and lymphatic anomalies. Overgrowth is also present at birth and is commonly severe in contrast to Proteus syndrome in which overgrowth is usually mild or absent at birth. Parkes Weber syndrome is a “fast flow” vascular malformation involving the upper/lower limbs and characterized by a diffuse, often confluent, capillary blush, warmth, and underlying arteriovenous shunts. In Maffucci syndrome, the vascular anomalies are venous and occur together with enchondromas. These tumors have not been found in Proteus syndrome [Mulliken and Glowacki, 1982; Mulliken, 1993; Cohen, 1998a]. Type I neurofibromatosis and Bannayan-RileyRuvalcaba syndrome are distinct from Proteus syndrome and are understood at the molecular level, mutations occurring respectively in the NF1 gene and the PTEN gene [Cohen, 1998a]. Neurofibromas have not been reported in Proteus syndrome, although there was a long-standing confusion between type 1 neurofibromatosis and Proteus syndrome [Cohen, 1986, 1988a,b]. Bannayan-Riley-Ruvalcaba syndrome is characterized by macrocephaly, lipomas, capillary malformations, polyposis of the colon and rectum, pigmented macules of the penis, and Hashimoto thyroiditis [Gorlin et al., 1992]. Wiedemann and Burgio [1986], Cohen [1993], and Rizzo et al. [1993] suggested that encephalocraniocutaneous lipomatosis (ECCL) might represent a local-
Guidelines for evaluation of patients are listed in Table III. High resolution chest computed tomography (CT) may be useful to evaluate pulmonary cystic malformations. This is particularly true for patients who develop persistent atelectasis or pneumonia or symptoms of pulmonary insufficiency. Newman et al. [1994] estimated that 12 to 13% of patients have cystic lung abnormalities which, in some cases, may lead to cystic emphysematous pulmonary disease. Abdominal MRI even in the absence of symptoms is important to rule out intra-abdominal lipomas which, if present, can be aggressive. Cranial MRI may be useful to characterize central nervous system (CNS) anomalies associated with seizures or developmental delay. Chromosome analysis may possibly show a translocation or deletion that might suggest a candidate gene. Finally, other consultations may include, as indicated, pediatric neurology, ophthalmology, or hematology. All participants agreed that coordination of care by an experienced geneticist and genetics counselor is useful because the rarity of Proteus syndrome precludes familiarity of its manifestations by many specialists. ACKNOWLEDGMENTS We are particularly grateful to Ruth E. MacLean (Halifax, Nova Scotia) for her organizational skills in arranging material for this paper. We are extremely grateful to Kathryn F. Peters (National Human Genome Research Institute, Bethesda, Maryland) for her work with patients and her organizational skills, and to Kimberly Hoag (Blue Springs, Missouri) for her inspired founding and managing of the Proteus Syndrome Foundation. We wish to thank Paul Meltzer (Laboratory of Cancer Genetics, National Human Genome Research Institute, National Institutes of TABLE III. Guidelines for Patient Evaluation Serial clinical photography Initial skeletal survey with targeted followup radiographs MRI of all clinically affected areas; chest and abdomen in absence of symptoms Dermatology consultation; biopsy when indicated Orthopedic consultation; operation when indicated Ongoing genetic/pediatric management Other consultations as indicated Referral to family support groupa a
Ms. Kimberly Hoag, Proteus Syndrome Foundation, 609 East Mount Vernon Drive, Blue Springs, MO 64014. E-mail:
[email protected]. www.kumc.edu/gec/support/proteus.htm
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Health, Bethesda, Maryland) for his clinical and laboratory efforts on behalf of the patients. We appreciate generous support from Intramural Research on Proteus Syndrome, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland; National Cancer Institute of Canada, grant no. 009148; SHARE’s Child Disability Center; Steven Spielberg Pediatric Research Center; UCLA Intercampus Training Program grant no. GM08243, National Institutes of Health; and grant no. PO1 HD22657-06, U.S. Department of Health and Human Services, Public Health Service. REFERENCES Biesecker LG, Peters KF, Darling TN, Choyke P, Hill S, Schimke N, Cunningham M, Meltzer P, Cohen MM Jr. 1998. Clinical differentiation between Proteus syndrome and hemihyperplasia: description of a distinct form of hemihyperplasia. Am J Med Genet 79:311–318. Botella-Estrada RB, Alegre V, Sanmartin O, Ros C, Adolfo A. 1991. Isolated plantar cerebriform collagenoma. Arch Dermatol 127:1589–1590. Clark RD, Donnai D, Rogers J, Cooper J, Baraitser M. 1987. Proteus syndrome: an expanded phenotype. Am J Med Genet 27:99–117. Cohen MM Jr. 1986. The Elephant Man did not have neurofibromatosis. Proc Greenwood Genet Cent 6:187–192. Cohen MM Jr. 1988a. Invited historical comment: further diagnostic thoughts about the Elephant Man. Am J Med Genet 29:777–782. Cohen MM Jr. 1988b. Understanding Proteus syndrome, unmasking the Elephant Man, and stemming elephant fever. Neurofibromatosis 1: 260–280. Cohen MM Jr. 1993. Proteus syndrome: clinical evidence for somatic mosaicism and selective review. Am J Med Genet 47:645–652. Cohen MM Jr. 1995. Putting a foot in one’s mouth or putting a foot down: nonspecificity v. specificity of the connective tissue nevus in Proteus syndrome. Proc Greenwood Cent 14:11–13.
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Gordon PL, Wilroy RS, Lasater OE, Cohen MM Jr. 1995. Neoplasms in Proteus syndrome. Am J Med Genet 57:74–78. Gorlin RJ, Cohen MM Jr, Condon LM, Burke BA. 1992. Bannayan-RileyRuvalcaba syndrome. Am J Med Genet 44:307–314. Happle R. 1987. Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J Am Acad Dermatol 16:899–906. Happle R. 1991. How many epidermal nevus syndromes exist? A clinicogenetic classification. J Am Acad Dermatol 25:550–556.
Uitto J. 1986. Biochemistry of collagen diseases. Ann Intern Med 105:740– 756. Wiedemann H-R, Burgio GR, Aldenhoff P, Kunze J, Kaufmann HJ, Schirg E. 1983. The Proteus syndrome, partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly, skull anomalies and possible accelerated growth and visceral affections. Eur J Pediatr 140:5–12. Wiedemann H-R, Burgio GR. 1986. Letter to the editor: Encephalocraniocutaneous lipomatosis and Proteus syndrome. Am J Med Genet 25: 403–404.
