Fetal and Pediatric Pathology, 31:145–153, 2012

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ISSN: 1551-3815 print / 1551-3823 online
DOI: 10.3109/15513815.2012.656830

Proteus Syndrome: Three Case Reports with a

Review of the Literature

Jenna L. Thomason, BS,1 C.R. Abramowsky, MD,1 Richard R. Rickets,

MD,2 John H. Culbertson, MD,3 Matthew S. Clifton, MD,2
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and Bahig M. Shehata, MD1

1
Department of Pediatrics and Pathology; 2 Division of Pediatric Surgery; 3 Division of
Plastic Surgery, Emory University School of Medicine

Proteus syndrome (PS) is a rare, progressive disorder that manifests as asymmetric, disproportion-
ate overgrowth affecting tissues derived from any germline layer. Cases of PS from 2005–2010
were retrieved from the pathology files at our institution. Two confirmed cases and one possible
case of PS were identified. All patients came from different ethnic backgrounds. Patient 1 displayed
classic skin and overgrowth lesions. Patient 2 displayed various features, particularly vascular mal-
formations. Patient 3 demonstrated a cerebriform connective tissue nevus alone. These patients
demonstrate the spectrum of presentations of PS. Much is left to learn about this disfiguring dis-
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ease.
Keywords Proteus Syndrome (PS), overgrowth, vascular malformation, proteus

INTRODUCTION
Proteus syndrome (PS) is an exceedingly rare, progressive disorder that manifests as
asymmetric, disproportionate overgrowth affecting tissues derived from any germline
layer. It is characterized by macrodactyly, vertebral anomalies, hyperostosis, abnor-
mally distributed adipose tissue, asymmetric muscle development, connective tis-
sue and epidermal nevi, and vascular malformations. The disease manifests in a
mosaic pattern. Cohen and Hayden first described the syndrome in 1979 [1]; how-
ever, the name “Proteus Syndrome” was designated by Wiedemann et al. in 1983,
after the Greek god, Proteus [2]. Like Proteus, this syndrome is capable of assum-
ing many forms, which commonly results in misdiagnosis. Although the etiology
of this disfiguring disease remains unknown, somatic mosaicism is currently the
most acceptable hypothesis [3]. Because of the rarity of this disease, less than 100
cases have been recorded in the literature, and therefore the natural history has yet
to be completely delineated [4]. In this study, we report three cases of PS at our
institution.

CASE REPORTS
After obtaining Institutional Review Board (IRB) approval, cases of PS from 2000–2010
were retrieved from the pathology files at Children’s Healthcare of Atlanta. Clinical
presentation, imaging, and pathologic findings were reviewed.

Address correspondence to Dr. Bahig M. Shehata, Department of Pathology, Children’s Healthcare

of Atlanta and Emory University School of Medicine, 1405 Clifton Road NE, Atlanta, GA 30322
USA. E-mail: bshehat@emory.edu

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  B.M. Shehata

Family histories for all cases were negative for overgrowth syndromes.

Patient 1
At birth, this Hispanic male displayed enlarged third and fourth fingers on the right
hand, enlarged second and third toes on the left foot, and hyperpigmented patches
on his neck. At 2 years of age, an x-ray of the hand (Figure 1) showed soft tissue
and bony enlargement and abnormal ossification. Klippel-Trenaunay-Weber (KTS),
Sturge-Weber, and Proteus Syndromes were all initially included in the differential di-
agnosis. However, the differential quickly narrowed within the next year as the patient
exhibited progressive macrodactyly of the right hand, particularly elongation and de-
viation of the right third finger, subcutaneous nodules on his left hand, macrodactyly
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of both feet, and cerebriform soft tissue prominences of both palms and soles (Fig-
ure 2). Besides the hyperpigmented patches over his neck, he developed additional
lesions over his trunk and extremities; they appeared as brown and red patches with
several streaky, vertical, verrucoid hyperpigmented plaques. The patient was defini-
tively diagnosed with PS at 3 years and 4 months of age. At this time, he was making
good developmental gains and was able to ambulate appropriately.
At 4 years of age, the patient underwent amputation of his left second toe, debulk-
ing of his left first (great) toe, and excision of the cerebriform soft tissue prominence
on the sole of his left foot. Histopathologic examination of the soft tissue prominence
revealed highly collagenized fibrous connective tissue, consistent with a cerebriform
connective tissue nevus (CCTN). Five months later, the patient underwent amputation
of his distal right third finger, rotational osteotomy of his ulnar deviated right fourth
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FIGURE 1 X-ray of right hand of Patient 1. This radiograph was taken at 2 years of age and demon-
strates soft tissue and bony enlargement, particularly of the third and fourth fingers. Abnormal os-
sification was also present.

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FIGURE 2 Macrodactyly and CCTN of Patient 1. These photographs demonstrate the extensive in-
volvement of both palms and soles, bilaterally.

finger, excision of the palmar hamartoma on the ulnar aspect of the hand, and debulk-
ing of both palmar connective tissue nevi.

Patient 2
At birth, this African-American female dizygotic twin was noted to have a curved, thick
left second finger and several small subcutaneous nodules in her left forearm. The
other twin showed no evidence of disease. At 3 months of age, the patient was di-
agnosed with KTS. By 6 months, her abnormalities had increased in size and were
accompanied by enlargement of her left thumb, right fifth finger, and a tender sub-
cutaneous nodule on her right forearm (Figure 3). The skin overlying her left forearm
lesions became bluish in color, suggesting that the nodules likely represented vascu-
lar malformations. The subcutaneous nodule in her right forearm was found to repre-
sent a lipoma; with this finding, the diagnosis of PS became clear. Subsequently, other
supporting features were identified, including an enlarged thymus. Her condition has
continued to progress and now includes developmental delay, diffusely ectatic veins
in the chest and left upper extremity, several vascular malformations, subglottal tra-
cheal stenosis, benign soft tissue masses in the left anterior chest wall and right sub-

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  B.M. Shehata
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FIGURE 3 Left hand of Patient 2. Note the macrodactyly and deviation of the second finger and
mild macrodactyly of the thumb.

scapular area, diffuse dilation of the esophagus with distal esophageal wall thickening,
scoliosis, and seizures. The patient has visited the emergency department on multiple
occasions for pneumonia and asthma exacerbations. Hyperexpansion and atelectasis
have been noted repeatedly on chest x-rays.
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At the age of 3, the patient underwent surgical excision of subcutaneous masses

from her upper back, bilaterally, and from her left posterior forearm. Histologic exam-
ination of the upper back masses revealed primarily venous malformations, while the
mass removed from her arm was found to be a vascular malformation consisting of
blood and lymphatic vessels. At 5 years of age, the patient underwent surgical resec-
tion of a hemorrhagic cystic hygroma from the right posterior neck triangle (Figure 4).
A vascular malformation was simultaneously removed from the patient’s right axilla;
this lesion recurred within the next month and required re-excision.

Patient 3
This Caucasian male was noted prenatally to have a soft tissue growth on his posterior
scalp which prompted a cesarean section at 36 weeks gestation. After birth, a CT scan
of his head showed an “exophytic cauliflower-like soft tissue growth” without intracra-
nial extension. Clinically, the lesion was diagnosed as a posterior scalp hemangioma.
The surgeon originally planned to remove the lesion at 12 months of age; however, the
lesion continued to grow and seemed to irritate the child, so the patient underwent
surgical excision of the 3.5 × 3.5-cm mass at 4 months of age. Histopathologic exami-
nation revealed a CCTN suggestive of PS (Figure 5).

DISCUSSION
Proteus Syndrome occurs more often in males, with a ratio of approximately 2:1, but
does not appear to have a predilection for any particular ethnic group [5, 6]. The ge-
netic mutation that results in PS has yet to be elucidated. Mutations of the PTEN gene
have been proposed as the underlying etiology for PS and “Proteus-like Syndrome”
[7–9]; however, this theory has been discredited in more recent literature [10–12].
The currently accepted pathogenetic model was suggested in 1987 by Happle, who
proposed that PS results from a somatic mutation that is lethal in the nonmosaic state

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FIGURE 4 Hemorrhagic cystic hygroma of Patient 2. This photograph was taken prior to excision
and shows the location of the cystic hygroma in the right posterior neck triangle.
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[13]. Mosaicism of the gene results in random distribution of affected tissues, which
is characteristic of PS [14]. This theory is also supported by the lack of recurrence in
offspring of affected patients or in siblings, even monozygotic twins [5, 15]. As our
cases demonstrate, a large degree of variation in severity between patients exists;
with the mosaic theory, we may conjecture that an early postzygotic mutation would
result in more disease manifestations than a late mutation, because the early somatic
cell carrying a mutation would give rise to more affected cell lineages [16].

FIGURE 5 Gross CCTN of Patient 2. This lesion was removed from the posterior scalp at 4 months
of age.

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  B.M. Shehata

Because no genetic diagnostic test exists, and because of the significant overlap of
PS with other dysmorphic diseases, adherence to a strict set of diagnostic criteria is
imperative. The diagnostic criteria include three general criteria and three specific cri-
teria categories, A through C (Table 1) [5, 17]. The patient must meet all of the general
criteria, which include mosaic distribution of lesions, sporadic occurrence, and pro-
gressive course. The single category A sign, two signs from category B, or three signs
from category C are sufficient to meet the specific criteria requirement [5, 16].
The single sign in category A, a cerebriform connective tissue nevus (CCTN), is al-
most pathognomonic for PS. If Patient 3 progresses to fulfill all general criteria, he will
represent the first case, to our knowledge, where a CCTN was noted prenatally; even
cases where this lesion presents at birth are exceedingly rare [18]. This lesion typically
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presents in the first or second year of life and evolves slowly, in some patients contin-
uing to develop throughout adolescence [3, 18]. The nevus appears as gyriform gross
thickening of cutaneous and subcutaneous tissues, most commonly present on the
soles, but can occasionally be found on the hands, abdomen, and nose. Patient 1 is
unique in that he exhibited severe involvement of both palms and soles, bilaterally.

TABLE 1 Diagnostic criteria [5]

General criteria (diagnosis includes all of the following):
• Mosaic distribution of lesions
• Sporadic occurrence
• Progressive course
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Specific criteria categories (Either Category A or 2 from Category B or 3 from category C)

A. 1. Cerebriform connective tissue nevus (skin lesions characterized by deep grooves and
gyrations as seen on the surface of the brain)
B. 1. Linear epidermal nevus
2. Asymmetric, disproportionate overgrowth (asymmetric, disproportionate overgrowth should
be carefully distinguished from asymmetric, proportionate overgrowth) One or more of:
a. Limbs: Arms/legs/hands/feet/digits
b. Skull (hyperostosis)
c. External auditory meatus (hyperostosis)
d. Vertebra (megaspondylodysplasia)
e. Viscera: Spleen and/or thymus
3. specific tumors before 2nd decade
One of the following:
a. Ovarian cystadenoma
b. Paratid monomorphic adenoma
C. 1. Dysregulated adipose tissue
Either one:
a. Lipomas
b. Regional absence of fat
2. Vascular malformations
One or more:
a. Capillary malformation
b. Venous malformation
c. Lymphatic malformation
3. lung cysts
4. facial phenotype (this criteria has been found, to date, only in PS patients who have mental
deficiency, and in some cases, seizures and/or brain malformations)
All:
a. Dolichocephaly
b. Long face
c. Down slanting palpebral fissures and/or minor ptosis
d. Low nasal bridge
e. Wide or anteverted nares
f. Open mouth at rest

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Connective tissue nevus on the soles of the feet result in significant morbidity since
they commonly cause difficulty in walking, may be painful, pruritic, or malodorous,
and are prone to ulceration and infection [15, 18, 19].
Category B includes a linear epidermal nevus, disproportionate overgrowth, and
specific tumors before the second decade of life. The hyperpigmented patches with
streaky, vertical verrucoid lesions exhibited by Patient 1 representing a linear epider-
mal nevus. This lesion may be present at birth in the form of subtle macular lesions, as
in our case, or it may develop within the first year of life. The nevus may be found on
the neck, abdomen, flank, or extremities and is typically thick, rough, dark brown to
black, patchy, and typically follows the lines of Blaschko [3, 4, 15]. The disproportion-
ate overgrowth seen in PS patients usually develops post-natally, must be asymmetric,
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and must involve the limbs, skull, vertebrae, or viscera. X-rays may reveal hyperostosis,
abnormal epiphyses, and bony growth into joint spaces [20]. Affected bone often loses
its normal architecture and can even become unrecognizably distorted [3, 5]. Com-
monly involved viscera include the spleen and the thymus. The tumors listed in cate-
gory B include ovarian cystadenoma and parotid monomorphic adenoma. Although a
wide variety of tumors have been reported in patients with PS, these particular tumors
have been incorporated into the diagnostic criteria because of their specificity.
Category C includes dysregulated adipose tissue, vascular malformations, lung
cysts, and the specific facial phenotype. Dysregulated adipose tissue may present as
localized overgrowth (lipomas) or regional atrophy (lipohypoplasia). Vascular mal-
formations include capillary, venous, lymphatic malformations, or combined chan-
nel anomalies. These lesions differ from classical vascular tumors in that they are
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larger, softer, more disseminated, and have a higher incidence of complications such
as thrombosis, thrombocytopenia, and phlebitis. They typically grow along with the
patient and never regress [21]. Cystic lung disease, characterized by bulla formation
and hyperexpansion, is found in approximately 9% of PS patients and can lead to pul-
monary insufficiency, persistent atelectasis, pneumonia, or even death [22–24]. Dys-
regulated adipose tissue and vascular malformations are the features of PS that most
commonly overlap with other overgrowth conditions. The specific facial phenotype
manifests with dolichocephaly (long head), long face, down-slanting palpebral fis-
sures, and/or minor ptosis, low nasal bridge, wide or anteverted nares, and an open
mouth at rest. The facial phenotype is rare and has, so far, only been found in PS pa-
tients with cognitive deficiency, seizures, and/or brain malformations [3, 5].
The manifestations of PS extend far beyond the above diagnostic criteria. Scolio-
sis develops in the majority (60%) of patients as a result of local overgrowth creating
asymmetrical forces on the spine [25]. Ophthalmologic findings (42%) are numerous
and include strabismus, epibulbar cysts, and epibulbar dermoids [5]. Central nervous
system abnormalities, particularly seizures, are found in 40% of patients. Mental de-
ficiency has been observed in approximately one-third of patients. Other notewor-
thy findings include otolaryngologic abnormalities (37%), noncystic pulmonary dis-
ease (20%), dental abnormalities (19%), reproductive/genital nontumor abnormali-
ties (18%), male reproductive tumors (11%) and renal/urologic manifestations (9%)
[5]. Some patients may exhibit abnormalities of hair and nail growth [15].
Because of the inherent complexity of this condition, a multidisciplinary approach
to management is essential [5]. A diverse group of medical specialists should be in-
volved in the care of PS patients, including geneticists, pediatricians, neurologists, pul-
monologists, hematologists, radiologists, gastroenterologists, surgeons, psychiatrists,
and dermatologists [4]. Baseline imaging at diagnosis, including a skeletal survey and
an MRI of the brain, chest, abdomen, and all other clinically affected areas is recom-
mended [4]. No data exists demonstrating that early detection of tumors in PS im-
proves prognosis; therefore, routine imaging surveillance for tumors is not recom-

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  B.M. Shehata

mended at this time [3]. Surgical intervention is generally reserved for symptomatic
lesions in order to minimize operations and avoid possible surgical complications;
the exceptions to this rule are lesions occurring in the ovaries and testes because of
a high incidence of gonadal neoplasms. Such lesions should be managed more ag-
gressively [22]. Research has shown that craciofacial hyperostoses are more likely to
recur after surgical reduction in prepubertal patients as opposed to patients in whom
overgrowth has stabilized [26]. It is possible that this rule may extend to all PS lesions,
as we witnessed recurrence of Patient 2’s axillary hemangiolymphangioma at 5 years
of age. Only time and close follow-up will reveal whether the rest of the surgical inter-
ventions carried out on our patients will be definitive. Lastly, because of the incredible
psychological burden that such a disease can place on a patient and his/her family, all
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of these individuals should receive psychological attention as needed, and should be

referred to the Proteus Syndrome Foundation for support [4, 27].
Long-term prognosis varies across patients. Approximately 20% of PS patients suf-
fer premature death, most commonly due to venous thromboembolism or pulmonary
embolism, pneumonia, or surgical complications [4]. Because thrombosis and em-
bolism rarely occur in children, all who participate in the care of PS patients should
be educated about these complications and encouraged to seek immediate medical
attention should they occur [5, 28].

CONCLUSION
Our three patients demonstrate the spectrum of clinical and histopathologic presenta-
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tions of PS, and alert us to the fact that there is much left to discover about this elusive
condition. Molecular analysis of a large pool of patients might shed some light on the
molecular-genetic basis of this syndrome. With continued attention on this disease,
we may advance our understanding of its genetic mechanism, further delineate the
natural history, refine the diagnostic criteria if necessary, and improve management
and prognosis for all of those affected by this disfiguring disease.

Declaration of Interest
The authors did not receive any outside funding or grants in support of their research
for or preparation of this work. Neither they nor a member of their immediate families
received payments or other benefits or a commitment or agreement to provide such
benefits from a commercial entity.

REFERENCES
[1] Cohen MM Jr, Hayden PW. A newly recognized hamartomatous syndrome. Birth Defects Orig Artic
Ser 15(5B):291–6, 1979.
[2] Wiedemann HR, Burgio GR, Aldenhoff P, Kunze J, Kaufmann HJ, Schirg E. The Proteus Syndrome:
partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macro-
cephaly, or other skull anomalies and possible accelerated growth and visceral affections. Eur J Pe-
diatr 140:5–12, 1983.
[3] Biesecker L. The challenges of Proteus syndrome: diagnosis and management. Eur J Hum Genet
14(11):1151–7, 2006.
[4] Cohen MM Jr. Proteus syndrome: an update. Am J Med Genet C Semin Med Genet 137C(1):38–52,
2005.
[5] Turner JT, Cohen MM Jr, Biesecker LG. Reassessment of the Proteus syndrome literature: application
of diagnostic criteria to published cases. Am J Med Genet A 130A(2):111–22, 2004.
[6] Satter E. Proteus Syndrome: 2 case reports and a review of the literature. Cutis 80(4):297–302, 2007.
[7] Zhou XP, Marsh DJ, Hampel H, Mulliken JB, Gimm O, Eng C. Germline and mosaic PTEN mutations
associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous
malformations and lipomatosis. Hum Mol Genet 9:765–8, 2000.

Fetal and Pediatric Pathology

 Macrodactyly and CCTN of palms and soles 

[8] Zhou X, Hampel H, Thiele H, Gorlin RJ, Hennekam RC, Parisi M, Winter RM, Eng C. Association of
germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes.
Lancet 358(9277):210–1, 2001.
[9] Smith JM, Kirk EP, Theodosopoulos G, Marshall GM, Walker J, Rogers M, Field M, Brereton JJ,
Marsh DJ. Germline mutation of the tumour suppressor PTEN in Proteus syndrome. J Med Genet
39(12):937–40, 2002.
[10] Barker K, Martinez A, Wang R, Bevan S, Murday V, Shipley J, Houlston R, Harper J. PTEN mutations
are uncommon in Proteus syndrome. J Med Genet 38(7):480–1, 2001.
[11] Cohen MM Jr, Turner JT, Biesecker LG. Proteus syndrome: misdiagnosis with PTEN mutations. Am
J Med Genet A 122A(4):323–4, 2003.
[12] Biesecker LG, Rosenberg MJ, Vacha S, Turner JT, Cohen MM. PTEN mutations and proteus syn-
drome. Lancet 358(9298):2079–80, 2001.
[13] Happle R. Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects
Fetal Pediatr Pathol Downloaded from informahealthcare.com by Technische Universiteit Eindhoven on 01/08/15

involving the skin. J Am Acad Dermatol 16(4):899–906, 1987.

[14] Happle R. Cutaneous manifestation of lethal genes. Hum Genet 72(3):280, 1986.
[15] Brockmann K, Happle R, Oeffner F, König A. Monozygotic twins discordant for Proteus syndrome.
Am J Med Genet A 146A(16):2122–5, 2008.
[16] Nguyen D, Turner JT, Olsen C, Biesecker LG, Darling TN. Cutaneous manifestations of proteus syn-
drome: correlations with general clinical severity. Arch Dermatol 140(8):947–53, 2004.
[17] Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr, Viljoen DL, Cohen MM Jr. Pro-
teus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet
84(5):389–95, 1999.
[18] Satter E. Proteus syndrome: 2 case reports and a review of the literature. Cutis 80(4):297–302, 2007.
[19] Twede JV, Turner JT, Biesecker LG, Darling TN. Evolution of skin lesions in Proteus syndrome. J Am
Acad Dermatol 52(5):834–8, 2005.
[20] Jamis-Dow CA, Turner J, Biesecker LG, Choyke PL. Radiologic manifestations of Proteus syndrome.
Radiographics 24(4):1051–68, 2004.
[21] Hoeger PH, Martinez A, Maerker J, Harper JI. Vascular anomalies in Proteus syndrome. Clin Exp
For personal use only.

Dermatol 29(3):222–30, 2004.

[22] Nakane M, Sato M, Hattori H, Matsumoto Y, Otsuki M, Murakawa M. Perioperative respiratory com-
plications caused by cystic lung malformation in Proteus syndrome. J Anesth 20(1):26–9, 2006.
[23] Lublin M, Schwartzentruber DJ, Lukish J, Chester C, Biesecker LG, Newman KD. Principles for the
surgical management of patients with Proteus syndrome and patients with overgrowth not meeting
Proteus criteria. J Pediatr Surg 37(7):1013–20., 2002.
[24] Li CY, Chang YL, Chen WC, Lee YC. Pulmonary manifestations and management of proteus syn-
drome. J Formos Med Assoc 109(5):397–400, 2010.
[25] Pazzaglia UE, Beluffi G, Bonaspetti G, Ranchetti F. Bone malformations in Proteus syndrome: an
analysis of bone structural changes and their evolution during growth. Pediatr Radiol 37(8):829–35,
2007.
[26] Sakamoto Y, Nakajima H, Kishi K, Shimizu R, Nakajima T. Management of craniofacial hyperostosis
in Proteus syndrome. J Craniofac Surg 21(2):414–8, 2010.
[27] “Proteus Syndrome Foundation,” 2009, http://www.proteus-syndrome.org/ (20 December 2010).
[28] Papadimitriou L, Kavalieratos CS. Proteus syndrome and sudden cardiac arrest; Beware of pul-
monary embolism! Resuscitation 54(3):313–4, 2002.

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