Proteus syndrome: An update

Abstract

Proteus syndrome is a complex disorder consisting variably of disproportionate, asymmetric overgrowth of body parts; cerebriform connective tissue nevi; epidermal nevi; vascular malformations of the capillary, venous, and lymphatic types; and dysregulated adipose tissue. Serious complications may ensue, such as pulmonary embolism, cystic lung disease, and various neoplasms. Somatic mosaicism, lethal in the nonmosaic state, is the best working hypothesis. Although Proteus syndrome data are consistent with this hypothesis, it has not been proven. The etiology is unknown to date. Diagnostic criteria are emphasized because misdiagnosis of Proteus syndrome is common. Finally, evaluation and management are discussed. © 2005 Wiley-Liss, Inc.

Proteus syndrome is a complex disorder consisting variably of disproportionate, asymmetric overgrowth of body parts, particularly involving the skeleton; cerebriform connective tissue nevi; epidermal nevi; vascular malformations; and dysregulated adipose tissue. Some possible findings are listed in Table I.

Table I. Possible Findings in Proteus Syndrome

From Cohen [2002a].

Skin

Cerebriform connective tissue nevi

Epidermal nevi

Disproportionate, asymmetric overgrowth

Limbs

Arms/legs/digits

Skull

Hyperostoses

Vertebrae

Megaspondylodysplasia

Viscera

Spleen/thymus

Dysregulated adipose tissue

Lipomas

Lipohypoplasia

Vascular malformations

Capillary malformations

Venous malformations

Lungs

Cystic lung alterations

Central nervous system

Mental deficiency

Seizures

Brain malformations

Other abnormalities (low frequency)

Neoplasms

Facial phenotype with seizures and severe mental deficiency

Epibulbar dermoids

Craniosynostosis

Renal anomalies

IMPORTANT PROTEUS SYNDROME LITERATURE

The subject has been reviewed elsewhere: historical delineation of Proteus syndrome [Cohen and Hayden, 1979; Wiedemann et al., 1983], Joseph Merrick [Cohen, 1986, 1988a,b], general references [Cohen, 1988b, 1993, 2002a; Biesecker, 2001; Turner et al., 2004], somatic mosaicism hypothesis [Happle, 1987; Cohen, 2002a], diagnostic criteria [Biesecker et al., 1999; Turner et al., 2004], problems of misdiagnosis [Biesecker et al., 2001; Cohen et al., 2003, 2004; Turner et al., 2004], premature death [Biesecker, 2000; Cohen, 2001; Slavotinek et al., 2001], cerebriform connective tissue nevus [Cohen and Hayden, 1979; Cohen, 1988b, 1993, 1995, 2002a; Nguyen et al., 2004; Turner et al., 2004], epidermal nevi [Biesecker et al., 1999; Cohen, 2002a; Nguyen et al., 2004; Turner et al., 2004], vascular malformations [Cohen, 1988b, 2002a; Biesecker et al., 1998, 1999], dysregulated adipose tissue [Biesecker et al., 1999; Cohen, 2002a; Nguyen et al., 2004], cutaneous manifestations [Nguyen et al., 2004], skeletal manifestations [Jamis-Dow et al., 2004], tumors [Cohen, 1993, 2002a; Gordon et al., 1995], and management [Biesecker, 2005].

ISSUES AND PROBLEMS

Many issues and problems arise with Proteus syndrome: (1) etiologic hypothesis, (2) natural history, (3) diagnostic criteria, (4) misdiagnosis, (5) medical providers, and (6) psychological impact.

Somatic mosaicism, lethal in the nonmosaic state, is the present hypothesis for Proteus syndrome, and although some of the findings in the syndrome are consistent with this hypothesis, it has not been proven. The etiology is unknown to date (see “Somatic Mosaicism Hypothesis”).

Knowledge about natural history is incomplete because an extensive study has yet to be carried out [Cohen, 1988b]. However, some information is available. Proteus syndrome is rare, and less than 100 bona fide cases have been recorded. The male:female sex ratio is 1.9:1 (n = 96). Some overgrowth and asymmetry are present at birth in 17.5% (n = 97) [Turner et al., 2004]. However, such findings are much more dramatic during postnatal evolution of the disorder. If the category is enlarged to include any signs present at birth (e.g., additional features such as vascular malformations and epidermal nevi), 43.3% are affected (n = 97) [Turner et al., 2004]. Bone overgrowth and soft tissue overgrowth tend to plateau after adolescence, although there are some exceptions; an occasional neoplasm has been noted at age 20, 30, or older [Cohen, 2002a]. Important sequelae in Proteus syndrome include (1) premature death in 20% [Biesecker, 2000; Cohen, 2001; Slavotinek et al., 2001; Turner et al., 2004], particularly from deep venous thrombosis, resulting in pulmonary embolism (see “Causes of Premature Death”) and (2) various tumors [Cohen, 1993, 2002a; Gordon et al., 1995] (see “Tumors”).

Diagnostic criteria for Proteus syndrome [Biesecker et al., 1999; Turner et al., 2004] must be interpreted with exactitude.

Diagnostic criteria for Proteus syndrome must be interpreted with exactitude.

There are two reasons for this. First, the criteria reliably divide high risk Proteus syndrome patients from the more static low risk group of patients, e.g., hemihyperplasia and hemihyperplasia/lipomatosis syndrome, among others [Biesecker, 2005]. When a more extensive study of the natural history becomes available, the results will be meaningful because a specific Proteus syndrome group has been identified. Some information about the natural history is already known (vide supra) and, to date, all cases of Proteus syndrome are sporadic. Thus, patient and family counseling can be meaningful [Biesecker, 2001]. Second, strict diagnostic criteria for any condition, e.g., Proteus syndrome, make an excellent research strategy for studying the molecular basis of a disorder [Cohen and Cole, 1989]. Once the molecular basis is known, it can be determined if the mutations apply to a wider spectrum of patients than presently thought. Furthermore, the possibility of etiologic heterogeneity can be studied in a meaningful way.

Misdiagnosis of Proteus syndrome has been common before and after publication of the diagnostic criteria [Biesecker et al., 1999]. The finding of PTEN mutations with presumed “Proteus syndrome” has been shown to be erroneous because the patients did not have bona fide Proteus syndrome [Cohen et al., 2003, 2004] (see “Misdiagnosis”).

Because Proteus syndrome is rare, most medical providers lack knowledge about the disorder. A few clinicians, particularly those at NIH, have had experience with a large number of patients. Effective evaluation and management require a large and diverse group of medical specialties, including, among others, genetics, pediatrics, neurology, pulmonology, hematology, radiology, gastroenterology, surgery, dermatology, and orthopedic surgery. The diagnosis of Proteus syndrome also has a profound psychological impact on the family [Biesecker, 2001, 2005] (see “Evaluation and Management”).

SOMATIC MOSAICISM HYPOTHESIS

Although the cause of Proteus syndrome is unknown to date, Happle [1987] first postulated that it might be caused by somatic mosaicism, lethal in the nonmosaic state (Fig. 1). This hypothesis has been demonstrated with GNAS1 mutations in McCune–Albright syndrome, polyostotic fibrous dysplasia, and monostotic fibrous dysplasia [Cohen and Howell, 1999]. However, no causal gene mutations are known for Proteus syndrome.

Although the cause of Proteus syndrome is unknown to date, Happle [1987] first postulated that it might be caused by somatic mosaicism, lethal in the nonmosaic state. This hypothesis has been demonstrated with GNAS1 mutations in McCune–Albright syndrome, polyostotic fibrous dysplasia, and monostotic fibrous dysplasia. However, no causal gene mutations are known for Proteus syndrome.

In the somatic mosaicism hypothesis, the disorder is thought to arise from a postzygotic mutation based on (1) mosaic distribution of lesions, (2) sporadic occurrence, (3) exclusively unaffected offspring born to affected individuals, and (4) discordant identical twins. Some findings in Proteus syndrome are consistent with this hypothesis. All cases, to date, have been sporadic and at least three affected adults have given birth to unaffected offspring. Finally, one example of discordant monozygotic twins is known [Cohen, 1993, 2002a; Biesecker, 2005].

Figure 1. Mosaic distribution of lesions depends on (1) the size of the cell mass and (2) which proposed somatic cell mutates.

CAUSES OF PREMATURE DEATH

About 20% of patients with Proteus syndrome have had premature deaths, most commonly from pulmonary embolism, postoperative complications, and pneumonia [Biesecker, 2000; Cohen, 2001; Slavotinek et al., 2001; Turner et al., 2004]. Vascular malformations, relative immobility, and surgical procedures predispose to deep venous thrombosis, resulting in pulmonary embolism [Biesecker, 2000; Cohen, 2001; Slavotinek et al., 2001].

Patients with Proteus syndrome and/or their families should make their health care providers aware of the risk of deep venous thrombosis and pulmonary embolism. Symptoms warranting investigation include calf pain, calf or leg swelling, shortness of breath, and chest pain. Patients undergoing surgical procedures should be evaluated by a hematologist to determine coagulopathic potential and to determine whether antithrombolic prophylaxis is indicated [Biesecker, 2000; Slavotinek et al., 2001].

DISPROPORTIONATE, ASYMMETRIC OVERGROWTH AND SKELETAL ABNORMALITIES

Overgrowth in Proteus syndrome is not only disproportionate and asymmetric, but also progressive, distorting, and relentless (Fig. 2).

Overgrowth in Proteus syndrome is not only disproportionate and asymmetric, but also progressive, distorting, and relentless.

Abnormalities of bone are very different from those observed in hemihyperplasia. Bone defects include (1) hyperostoses of the skull, (2) hyperproliferation of osteoid with variable calcification, resulting in abnormal bony edges, (3) abnormally calcified connective tissue, (4) bony invasion of joint spaces, eventually resulting in immobility of the affected joint, (5) abnormal bone that may be difficult to recognize radiographically, and (6) overgrown long bones, often with abnormally thin cortices and frequently with deficiency of overlying soft tissue [Jamis-Dow et al., 2004; Turner et al., 2004] (Fig. 3). Overgrowth may also include megaspondylodysplasia (Fig. 4) and enlargement of the spleen and/or thymus.

Figure 2. Determining types of overgrowth. Proteus syndrome is associated with asymmetric, disproportionate overgrowth. When asymmetric, disproportionate overgrowth is present and other Proteus diagnostic criteria are satisfactorily met, a diagnosis of Proteus syndrome can be made. It is important to note that the type of overgrowth of body parts in Proteus syndrome is rapid, distorting, and relentless. Modified from Turner et al. [2004].

Figure 3. Asymmetric overgrowth of lower limbs. Note enlargement of the right foot with a cerebriform connective tissue nevus of the plantar surface. Note that overgrowth of long bones is associated with deficiency of overlying soft tissue and immobility of the right knee. From Cohen [2002a].

Figure 4. Rapid progression of the cervical spine overgrowth with enlargement of the vertebral bodies, resulting in fixed hyperextension of the upper cervical spine and hyperflexion of the lower cervical spine. Reduction of neck mobility. Left: age 6 years. Right: 8½ years. From Jamis-Dow et al. [2004].

CEREBRIFORM CONNECTIVE TISSUE NEVUS

The cerebriform connective tissue nevus is very specific with a raised, rugose, cerebriform-like lesion composed of highly collagenized connective tissue. It may occur on the plantar surface of the foot (Fig. 5), the palmar surface of the hand (Fig. 6), and more rarely on the chest (Fig. 7), abdomen, back, lateral and dorsal portions of the fingers, and on the nose (Fig. 8).

The cerebriform connective tissue nevus is very specific with a raised, rugose, cerebriform-like lesion composed of highly collagenized connective tissue. It may occur on the plantar surface of the foot, the palmar surface of the hand, and more rarely on the chest, abdomen, back, lateral and dorsal portions of the fingers, and on the nose.

A cerebriform connective tissue nevus is sufficient for the diagnosis of Proteus syndrome when present. However, some patients do not have this finding [Cohen, 1993, 1995, 2002a; Turner et al., 2004]. Other lesions, such as wrinkling of the plantar surface of the foot or a plexiform neurofibroma in the same location, have often been confused with a cerebriform connective tissue nevus [Cohen, 1995] (Table II).

Figure 5. Evolution of the cerebriform connective tissue nevus on the plantar surface of the foot. Left: Age 5½ years. Center: Second patient at age 12 years. Right: Plaster cast of Joseph Merrick's foot at age 29 years (postmortem). From Cohen [1988b].

Figure 6. Severe digital overgrowth and connective tissue nevus of the palm. From Biesecker et al. [1998].

Figure 7. Normal chest and abdomen of an infant. By 4½ years of age, he developed an extensive cerebriform connective tissue nevus of his chest and abdomen. From Cohen [2002a].

Figure 8. Cerebriform connective tissue nevus of the nose.

Table II. Comparison of Cerebriform Connective Tissue Nevus in Proteus Syndrome and Neurofibroma in Neurofibromatosis

Characteristics	Proteus syndrome (cerebriform connective tissue nevus)	Neurofibromatosis (neurofibroma)
From Cohen [1995].
Surface pattern	Cerebriform	Smooth, creased, or wrinkled
Consistency	Firm	Soft, movable
Histology	Highly collagenized fibrous connective tissue	Delicate connective tissue
Location	Skin	Skin and internal organs
Frequency	Some cases	Rare on foot
Clinical diagnosis	Pathognomonic when present	Almost always suggestive of plexiform neurofibroma on foot

EPIDERMAL NEVI AND OTHER CUTANEOUS MANIFESTATIONS

Epidermal nevi, evident in early life, are tan, brown, or brownish-black in color. They are well demarcated, raised, and pebble-like in texture, often with a streaky appearance. Nevi are asymmetrically located and often multiple; they may be found on the neck, abdomen, flank, or extremities. Histopathological findings consist of acanthosis and hyperkeratosis [Cohen and Hayden, 1979; Cohen, 1988b, 2002a; Nguyen et al., 2004] (Figs. 9 and 10).

Figure 9. Epidermal nevus of the neck. From Cohen and Hayden [1979].

Figure 10. Extensive epidermal nevus of the trunk. From Biesecker et al. [1999].

In three or four instances, an isolated café-au-lait spot has been noted [Cohen and Hayden, 1979; Nguyen et al., 2004]. Patchy areas of dermal hypoplasia and hypopigmentation have also been observed [Nguyen et al., 2004].

VASCULAR MALFORMATIONS

Vascular malformations may be of the capillary, venous, or lymphatic type, or may occur as combined channel anomalies, e.g., capillary and venous channels or capillary, venous, and lymphatic channels. They are developmental anomalies lined by flat endothelium exhibiting a normal, slow rate of turnover. They grow proportionately with the patient: they never regress, but they can expand [Biesecker et al., 1998, 1999; Cohen, 2002a].

DYSREGULATED ADIPOSE TISSUE

Although normal and abnormal adipose tissue can be identified by MRI, histopathological study is necessary to determine various subtypes. Biopsied tissue has been available for study in some patients with Proteus syndrome, but sample size has been limited to date. This discussion of abnormal fat in Proteus syndrome is based on (1) MRI, (2) histopathogical material, (3) general knowledge of pathology involving fat, and (4) speculation. I suggest that four types of abnormal fat may occur in Proteus syndrome: (1) lipomas, (2) lipohypoplasia, (3) fatty overgrowth, and (4) localized fat deposits or partial lipohyperplasia.

Lipomas are benign tumors of mature fat cells. They may occur in subcutaneous tissues, within internal organs, and occasionally within muscle by extension. Lipomas differ from normal fat; they have increased levels of lipoprotein lipase and a larger number of precursor cells than in normal fat. They may be encapsulated or nonencapsulated.

Lipomas in Proteus syndrome may be single or multiple. They may occur subcutaneously or internally (Fig. 11). Lipomas of the abdomen and thorax can be very aggressive despite their benign histology. Biopsied material to date has demonstrated nonencapsulation. Lipoprotein lipase has not been studied nor is it known if precursor cells occur more commonly than in normal fat.

Figure 11. Proteus syndrome in a 5½ year-old boy with large lipomas of the left abdomen and right breast. Also note cerebriform connective tissue of the nostril, enlargement of the right fingers, and an epidermal nevus of the neck. From Cohen [1988b].

In the lipohypoplasia of Proteus syndrome [Happle, 1995], subcutaneous fat may be decreased or absent, most likely the former. It tends to occur on the trunk and limbs, resulting in accentuated bony contours. Dermal hypoplasia with reddish plaques of thinned skin may involve the the lower limbs, resulting in prominently appearing veins [Nguyen et al., 2004] (Fig. 12).

Figure 12. Dermal hypoplasia showing the underlying venous patterning with a varicose vein-like appearance. From Cohen [2002a].

In the asymmetric overgrowth of Proteus syndrome involving the limbs, particularly the lower limbs, MRI comparison of both thighs in cross-section often shows circumscribed, subcutaneous, fatty overgrowth in the enlarged thigh [Jamis-Dow et al., 2004; see their Figs. 8 and 9].

Localized fat deposits or partial lipohyperplasia appear to be different than lipomas or fatty overgrowth (vide supra). Examples include fat deposits within muscles in Proteus syndrome. Adipocytes are normally associated with the epimysium and perimysium and these may exhibit localized hyperplasia. Localized fat hyperplasia of the perimysium can be demonstrated on MRI [Jamis-Dow et al., 2004; see their Fig. 9b]. In contrast, the endomysium does not contain fat cells.

Happle [1995] hypothesized that lipohyperplasia and lipohypoplasia in the same Proteus syndrome patient can be explained by somatic recombination of two alleles at the same locus: one giving rise to a stem cell line that results in hyperplasia, the other giving rise to a stem cell line that results in hypoplasia.

OTHER IMPORTANT FINDINGS

Other important findings include (1) central nervous system manifestations in about 40% and mental deficiency in about 30%, (2) ophthalmologic manifestations in about 42%, particularly strabismus, epibulbar cysts, and epibulbar dermoids, (3) cystic lung disease in about 9%, and (4) renal/urologic abnormalities in about 9% [Turner et al., 2004]. For a complete list of findings, see Turner et al. [2004, their Table II]. Some representative CNS and renal/urologic abnormalities are listed in Table III.

Table III. Other Important Findings: Some CNS and Renal/Urologic Abnormalities

Adapted from Turner et al. [2004]. This list of findings is representative but not complete.

CNS manifestations (∼40%)

Mental deficiency (∼30%)

Seizures

Hydrocephalus

Hemimegalencephaly

Dandy–Walker malformation

Polymicrogyria

Periventricular heterotopias

Porencephalic cyst

Subarachnoid cyst

Periventricular cyst

Cortical atrophy

Cortical thickening

Hypoplastic white matter

Calcifications

Spinal cord stenosis

Fatty matter infiltration

Subependymal nodules

Parenchymal distortion

Renal/urologic manifestations (∼9%)

Renal asymmetry

Renal cysts

Ureteral asymmetry

Hydroureter

Hydronephrosis

Nephrogenic diabetes

CRANIOFACIAL ABNORMALITIES

Craniofacial abnormalities are progressive, and abnormal modes of growth may include hyperostoses, cranial hemihyperplasia (resulting from hemimegalencephaly), craniosynostosis, unilateral condylar hyperplasia (Table IV, Figs. 13 and 14), and, rarely, cerebriform connective tissue nevus (Fig. 8). Low frequency abnormalities may include epibulbar dermoids and hyperostosis of the external auditory canal [Cohen, 1993, 2002a].

Table IV. Types of Abnormal Craniofacial Growth

Typea	Relative frequency	Effect	Comment
From Cohen [1993]. a Four types of abnormal growth can act singly or in various combinations. Facial phenotype accompanying mental deficiency, and in some cases, seizures and/or brain malformations may override severe craniofacial distortion produced by these four modes of abnormal bone growth.
Hyperostoses	Common	Major effect	Progressive enlargement, asymmetry, and disfigurement of skull
Cranial hemihyperplasia	Uncommon	Major effect	Calvarial remodeling secondary to hemimegalencephaly
Craniosynostosis	Rare	Major effect	Usually coronal synostosis; sagittal, metopic, and/or lambdoid involvement are also recorded
Unilateral condylar hyperplasia	Probably common	Usually minor effect; rarely major effect	Overgrowth of condylar cartilage

Figure 13. Evolution of facial abnormalities in a patient with Proteus syndrome. Left: Age 1 month. Center: Age 5 months. Right: Age 5½ years. Note connective tissue nevus on left side of nose. From Cohen [1988b].

Figure 14. Hyperostoses of the skull. Left: age 12 years. Hyperostoses of nasal bridge, left infraorbital region, and mandible. Right: Age 29 years. Skull of Joseph Merrick showing advanced hyperostoses. From Cohen [1988b].

FACIAL PHENOTYPE WITH MENTAL DEFICIENCY

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. 15). These facial features may even override the severe craniofacial distortion produced by bony overgrowth in some cases.

Figure 15. Facial phenotype in a Proteus syndrome patient with mental deficiency and a history of seizures. Note dolichocephaly, long face, mild downslanting palpebral fissures, ptosis of the eyelids, low nasal bridge, anteverted nares, and an open mouth. From Cohen [1993].

TUMORS

Lipomas are the most common type (see “Dysregulated Adipose Tissue”). Several important low frequency tumors are known to occur (Table V). The most frequent of these is ovarian cystadenoma. Well in excess of a dozen cases have been recorded and bilateral instances have been noted at least twice (Figs. 16 and 17). At least six cases of meningioma have also been described. Four testicular tumors have been observed to date, each of a different type. Two young patients with parotid monomorphic adenoma are known. This tumor is usually found in older men in the general population. In some cases, multiple tumors have been found in the same Proteus syndrome patient [Cohen, 1993, 2002a; Gordon et al., 1995] (Table V).

Table V. Uncommon Neoplasms

From Cohen [1993]; Gordon et al. [1995]; and Cohen [2002a]. a Testicular tumors include mesothelioma (tunica vaginalis of testis), papillary adenocarcinoma (testis), bilateral cystadenomas (epididymis), and papillary adenoma (appendix testis).

Tumors

Ovarian cystadenoma (most common; well in excess of 12 cases; bilateral in some instances; also ovarian cysts)

Meningioma (at least 6 cases)

Testicular tumors (4 cases of various types)a

Parotid monomorphic adenoma (at least 2 cases)

Astrocytoma

Optic nerve tumor

Pinealoma

Breast intraductal papilloma

Leiomyoma

Mesothelioma (peritoneal surfaces); see footnote a below for second case

Endometrial carcinoma

Multiple tumors in the same patient

Meningioma and optic nerve tumor

Multiple meningiomas

Multiple meningiomas and leiomyoma (bladder)

Multiple meningiomas and bilateral ovarian cysts

Monomorphic adenoma (parotid) and intraductal papilloma (breast)

Meningioma, multiple leiomyomas (uterus), and ovarian cyst

Meningioma, bilateral cystadenomas (epididymis), and giant cyst (kidney)

Bilateral ovarian cystadenomas (2 cases)

Endometrial carcinoma and unilateral breast hyperplasia

Figure 16. Serous cystadenoma of the ovary from 6½-year-old girl with Proteus syndrome. Mucinous cystadenoma may occur in some instances. See Figure 17. From Cohen [2002a].

Figure 17. Relationship between ovarian surface epithelium, inclusion cysts, serous cystadenomas, and mucinous cystadenomas. From Gordon et al. [1995].

DIAGNOSTIC CRITERIA

Diagnostic criteria have been set forth and discussed by Biesecker et al. [1999] and Turner et al. [2004]. They are summarized in Table VI. To make a diagnosis of Proteus syndrome, all of the general criteria must be present: mosaic distribution of lesions, sporadic occurrence, and progressive course (strikingly relentless, rapid, asymmetric, and disproportionate overgrowth). Specific criteria are as follows: one from category A or two from category B or three from category C. Although individual patients may have findings in two or even three categories, if category A is absent, the mixing of less than the necessary criteria for category B plus less than the necessary criteria for category C does not add up to a diagnosis of Proteus syndrome. Specific criteria for A or B or C discussed above must be met. Further study could conceivably result in modification.

Table VI. Revised Proteus Syndrome Diagnostic Criteria

From Turner et al. [2004]. To make a diagnosis of Proteus syndrome, all general criteria and various specific criteria must be satisfied. a Cerebriform connective tissue nevi are skin lesions characterized by deep grooves and gyrations as seen on the surface of the brain. b Asymmetric, disproportionate overgrowth should be carefully distinguished from asymmetric, proportionate overgrowth (see Fig. 2). c The facial phenotype has been found, to date, only in Proteus syndrome patients who have mental deficiency, and, in some cases, seizures and/or brain malformations.

General criteria

All of the following

Mosaic distribution of lesions

Sporadic occurrence

Progressive course

Specific criteria

Either

Category A or,

Two from category B or,

Three from category C

A. 1. Cerebriform connective tissue nevusa

B. 1. Epidermal nevus

2. Asymmetric, disproportionate overgrowthb

One or more

a. Limbs

Arms/legs

Hands/feet/digits

Extremities

b. Hyperostoses of the skull

c. Hyperostosis of the external auditory meatus

d. Megaspondylodysplasia

e. Viscera

Spleen/thymus

3. Specific tumors before 2nd decade

One of the following

a. Ovarian cystadenoma

b. Parotid monomorphic adenoma

C. 1. Dysregulated adipose tissue

Either one

a. Lipomas

b. Regional lipohypoplasia

2. Vascular malformations

One or more

a. Capillary malformation

b. Venous malformation

c. Lymphatic malformation

3. Lung cysts

4. Facial phenotypec

All

a. Dolichocephaly

b. Long face

c. Downslanting palpebral fissures and/or minor ptosis

d. Low nasal bridge

e. Wide or anteverted nares

f. Open mouth at rest

MISDIAGNOSIS

At least two-thirds of patients diagnosed with Proteus syndrome who have been referred for consultation or for inclusion in the NIH Proteus Research Study failed to meet published diagnostic criteria [Biesecker et al., 1999; Cohen et al., 2003, 2004; Turner et al., 2004]. In an analysis of 205 cases of “Proteus syndrome” from the literature, only 47.3% of the cases actually had bona fide Proteus syndrome. The study was carried out by Turner et al. [2004]. These three investigators, who have extensive experience with Proteus syndrome patients, independently assessed the literature for all articles with the name “Proteus syndrome” in the title. Using established diagnostic criteria [Biesecker et al., 1999], their diagnostic congruence was 97.1%. Discrepancies were resolved by further discussion between the investigators. In all six cases, one or two of us has missed a feature described in the report and when this was pointed out, agreement was readily reached. Thus, for all practical purposes, diagnostic congruence was 100% [Turner et al., 2004].

Several authors have reported patients who were said to have “Proteus syndrome” with PTEN mutations [Zhou et al., 2001; Smith et al., 2002] and others have repeatedly stated that PTEN mutations are a cause of a subset of patients with “Proteus syndrome” [Eng et al., 2001; Eng, 2003; Kirk et al., 2004].

These reported patients do have PTEN mutations, but they do not have Proteus syndrome [Cohen et al., 2003, 2004]. Thirty-four cases of bona fide Proteus syndrome have been studied for PTEN mutations with negative results [Barker et al., 2001; Biesecker et al., 2001; Thiffault et al., 2004]. Direct sequencing was done in 26 cases [Biesecker et al., 2001; Thiffault et al., 2004] with analysis by SSCP in 8 cases [Barker et al., 2001].

Some other recent publications with presumed “Proteus syndrome” are frankly discouraging. Hoeger et al. [2004] reported 22 patients with vascular anomalies and presumed “Proteus syndrome.” They confused Klippel–Trenaunay syndrome with Proteus syndrome. Cardoso et al. [2003] reported a patient with neurofibromatosis as having “Proteus syndrome.” Cekmen et al. [2004] reported a patient with presumed “Proteus syndrome;” no clinical photographs were shown, but juvenile polyposis of the colon was a striking feature.

DIFFERENTIAL DIAGNOSIS

Hemihyperplasia/lipomatosis syndrome is a distinct subset of hemihyperplasia. Cutaneous capillary malformations may occur in some instances. Mild-to-moderate 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].

Wiedemann and Burgio [1986] suggested that encephalocraniocutaneous lipomatosis (ECCL) might represent a more localized form of Proteus syndrome. Comparison of individual cases of ECCL [Al-Mefty et al., 1987; McCall et al., 1992; Rizzo et al., 1993] shows a continuum rather than two distinct entities. For example, in ECCL, cutaneous, craniofacial, and meningeal lipomas occur, but cutaneous lipomas below the head and neck and visceral involvement have been found in some cases. One patient had a moderately sized capillary malformation of the right antecubital fossa extending to the upper arm [Nowaczyk et al., 2000]. Other patients have had mental deficiency, seizures, malformations of the central nervous system, epibulbar dermoids, connective tissue nevi, and focal alopecia. In some instances, hyperostoses of the calvaria have been noted. All of these defects, except possibly focal alopecia, have been seen in Proteus syndrome. Happle [personal communication, 1998] believes that Proteus syndrome and ECCL are separate entities. The association of ECCL with an NF1 mutation, reported by Legius et al. [1995], is coincidental.

Klippel–Trenaunay syndrome is a distinctive condition characterized by vascular malformations of the capillary, venous, and lymphatic types, unusual varicosities of the lower limb, lymphatic vesicles, venous flares, asymmetric limb enlargement (lower limb ∼95%) involving both soft tissue and bone, and macrodactyly, particularly of the toes. On occasion, the disorder has been confused with Proteus syndrome [Cohen, 2000, 2002b].

Finally, it should be noted that vascular malformations can be found in a number of different disorders. The same is true of epidermal nevi.

EVALUATION AND MANAGEMENT

Guidelines for the evaluation of patients are listed in Table VII. High resolution CT may be useful to evaluate pulmonary cystic lesions. Abdominal MRI is important to rule out the possibility of intra-abdominal lipomas, which can behave very aggressively. Skeletal radiographs are necessary to rule out megaspondylodysplasia and/or vertebral body asymmetry. Initial cranial MRI is essential to rule out any CNS anomalies that may be associated with mental deficiency and/or seizures. In addition to the specific consultations listed in Table VII, other consultations may include, as indicated, pediatric neurology, ophthalmology, or hematology [Biesecker et al., 1999].

Table VII. Guidelines for Patient Evaluations

From Biesecker et al. [1999]. a Kim Hoag, Proteus Syndrome Foundation, 4915 Drystone Drive, Colorado Springs, CO 80918. E-mail: [e-mail] Web page: http://www.proteus-syndrome.org/

Serial clinical photography

Initial skeletal survey with targeted follow-up 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

Management issues have been well discussed by Biesecker [2005]. It has already been emphasized that vascular malformations, relative immobility, and surgical procedures predispose to deep venous thrombosis, resulting in pulmonary embolism. Antithrombotic prophylaxis should be considered when undergoing a surgical procedure [Biesecker, 2000; Slavotinek et al., 2001; Cohen, 2001]. Pulmonary cystic lesions should be carefully monitored because atelectasis, pneumonia, or pulmonary insufficiency may develop [Biesecker et al., 1999].

Several procedures should be considered for various skeletal problems. Asymmetric epiphyseal growth can be managed by epiphyseodesis, by curettage, or by stapling. A reduction osteotomy may also be used to shorten and/or straighten a long bone.

Several procedures should be considered for various skeletal problems. Asymmetric epiphyseal growth can be managed by epiphyseodesis, by curettage, or by stapling. A reduction osteotomy may also be used to shorten and/or straighten a long bone.

Shoe lifts can be used for milder instances of leg length discrepancy. Prosthetic joint replacement should be considered for joint immobility. Finally, spinal fusion may be used for overgrown and/or asymmetric vertebrae to avoid development of severe kyphoscoliosis with pulmonary compromise [Biesecker, 2005].

The psychosocial impact of having Proteus syndrome raises a number of important issues. Parents and affected patients commonly report feeling isolated because of the rarity of the disorder and the social stigma of having a progressively disfiguring condition. Inappropriate reactions of others can be very painful for affected children and their parents [Biesecker, 2001].

Parents and affected patients commonly report feeling isolated because of the rarity of the disorder and the social stigma of having a progressively disfiguring condition. Inappropriate reactions of others can be very painful for affected children and their parents.

Symptoms of depression have been reported in about 23% of parents who have affected children [Peters and Biesecker, 2000]. Referral to a family support group (see footnote in Table VII) is very helpful. Families can share experiences, build a support network, and learn about medical management issues from other families [Biesecker, 2001]. When indicated, psychiatric or psychological counseling may be appropriate (Table VII).

Acknowledgements

I wish to thank Leslie G. Biesecker, National Center for Human Genome Research, for helpful discussion. I would also like to acknowledge the efforts of my administrator, Ruth E. MacLean, Halifax.