Proteus Syndrome: Case Report and Review

Holly Kanavy, DO,* Cindy Hoffman, DO**

*PGY-4, St. Barnabas Hospital, Bronx, NY **Program Director, Dermatology Residency Program, St. Barnabas Hospital, Bronx, NY

Abstract Proteus syndrome (PS) is a rare, progressive hamartomatous disorder characterized by overgrowth and hyperplasia of diverse tissues including connective tissue, bone, skin, adipose, and central nervous system. expression of a post-zygotic somatic mutation in the AKT1 gene results in random distribution of affected tissues and creates significant phenotypic variability among patients. Herein, we describe a case of PS presenting with a cerebriform connective-tissue in a 14-year-old male and review the pathogenesis, clinical presentation and differential diagnosis, management, and prognosis of patients with the disorder.

Introduction of the lesion was performed. Histology revealed mutation results in a greater number of disease Proteus syndrome was first described in 1979 dense connective tissue beneath an acanthotic, manifestations than a late mutation, because the by Cohen and Hayden, and it was named by acantholytic epidermis. Stellate cells and early somatic cell carrying a mutation would give Weidmann et al. in 1983 for the Greek god entrapped adipose tissue were present in the rise to more affected cell lineages. dermis (Figures 2a [2x], 2b [10x]). The patient Proteus, who was capable of assuming many Due to the clinical overlap with other 1,2 was assigned a diagnosis of Proteus syndrome forms. With fewer than 100 confirmed cases hamartomatous disorders, a mutation in the and referred for genetic testing. reported, Proteus syndrome is extremely rare; tumor suppressor gene PTEN was initially its estimated incidence is less than 1:1,000,000 thought to be pathogenic in PS. However, it 3 persons. It is seen twice as frequently in males, is now believed that individuals with PTEN 4 and there is no ethnic predilection. The variable gene mutations and asymmetric overgrowth presentation and rarity of the disease led to do not meet the diagnostic criteria for Proteus frequent misdiagnosis of the disorder until 1999, syndrome. Instead, these individuals are when Biesecker et al. proposed detailed and considered part of a larger group of disorders 3 specific diagnostic criteria. called PTEN tumor syndromes. Other entities in this group include Cowden Case Presentation syndrome, Bannayan-Riley-Ruvalcaba syndrome, A 14-year-old Caucasian male presented with and Proteus-like syndrome.7 AKT1 is activated a slowly enlarging growth on the bottom of his by loss-of-function mutations in PTEN, which left foot that was present for about three years. explains why patients with such mutations and The patient reported some discomfort with those with activating mutations in AKT1 display Figure 2a ambulation due to the increasing size of the overlapping clinical features. lesion. His medical history included chronic macrocytosis and reticulocytopenia, which Clinical Manifestations prompted a bone marrow biopsy at the age of The clinical features of PS arise postnatally with 10. No evidence of hematologic malignancy irregular, asymmetric, progressive overgrowth was found; however, a non-clonal chromosome that can involve many tissues, most commonly 15 deletion: 45 XY del(15)(q11.2) was revealed. bone, connective tissue and fat. Skeletal changes ( deletions have been described include gigantism of the hands and/or feet and in association with myelodysplastic syndrome.) partial or complete hemihypertrophy. Localized The patient also had a history of developmental overgrowths may exert asymmetric forces on the abnormalities and was diagnosed with autism/ spine and result in . Connective-tissue Asperger’s disease. An MRI of the brain from abnormalities, such as cerebriform connective- five years prior revealed encephalomalacia and tissue nevi (CCTN), typically present in the periventricular leukomalacia (localized areas of Figure 2b first or second year of life and tend to evolve necrosis attributed to infarction or ischemia). slowly, in some patients continuing to develop One of the patient’s two brothers had spina bifida. Pathogenesis throughout adolescence.8 The lesion is virtually A full skin examination revealed one café au lait pathognomonic for PS and appears as gyriform Proteus syndrome is a progressive, hamartomatous gross thickenings of cutaneous and subcutaneous macule on the back. The plantar aspect of the left disorder that may involve any germ layer. The foot contained several flesh-colored cerebriform tissues, most commonly on the soles and hypothesized pathogenesis involves a post- occasionally on the hands, abdomen, and nose. papules and nodules (Figure 1). Partial biopsy zygotic somatic mutation in the AKT1 gene (chromosome 14q32.33), which is lethal in the Other dermatological manifestations include non-mosaic state.5 This gene belongs to the AKT linear verrucous epidermal nevi, which tend family of serine/threonine kinases and is involved to develop in the first year of life, and vascular in regulation of multiple cellular processes, malformations that can be either venous, 8 including proliferation and survival, cell size and capillary, lymphatic-type, or mixed. Four types response to nutrient availability, tissue invasion of abnormalities of fat may occur in Proteus and angiogenesis.6 Constitutive activation of syndrome: (1) lipomas, (2) lipohypoplasia, (3) the protein underlies the overgrowth and tumor fatty overgrowth, and (4) localized fat deposits or susceptibility in patients carrying this mutation. partial lipohyperplasia. Lipomas may be single or Mosaic expression of the mutation is what results multiple and occur subcutaneously or internally. in the random distribution of affected tissue and Lipomas of the abdomen and thorax can be very 8 creates significant phenotypic variability among aggressive despite their benign histology. Figure 1 patients. Accordingly, an early post-zygotic Specific facial features have been described in KANAVY, HOFFMAN Page 21 Table 1. Proteus Syndrome Diagnostic Criteria PS is not inherited, so prenatal testing is not indicated. Criteria Category Clinical Characteristics (Diagnosis requires either A, Differential Diagnosis two from B, or three from C) Among the differential diagnoses for Proteus syndrome are those entities described as part of Category A Cerebriform connective tissue nevus PTEN hamartoma tumor syndrome. Bannayan- Riley-Ruvalcaba syndrome is an autosomal- Category B 1. Linear epidermal nevus dominant disorder characterized by , , , polyposis of the colon 2. Asymmetric, disproportionate overgrowth with at least one of and rectum, and pigmented macules of the the following: penis. These patients lack the progressive digital · Affected limbs overgrowth, skull exostoses, epidermal nevi, · Hyperostosis of the skull and palmar or plantar changes seen in Proteus · Hyperostosis of the external auditory canal syndrome. Patients with · Megaspondylodysplasia typically present with facial trichilemmomas, · Viscera: spleen or thymus acral keratoses, papillomatous lesions, lipomas, hemangiomas, and epidermal nevi (Cowden 3. Specific tumors before the second decade: nevus), but do not develop cerebriform · Bilateral ovarian cystadenoma connective-tissue nevi. These patients also · Parotid monomorphic adenoma carry an increased risk for breast, thyroid, and endometrial cancers. Patients with Proteus-like Category C 1. Dysregulated adipose tissue with either of the following syndrome have significant clinical features of PS (either of the following): but do not meet the diagnostic criteria for PS. · Lipomatous overgrowth They are distinguished by macrocephaly, marked · Regional lipohypoplasia lipohypertrophy, and lack of progressive bony overgrowth.7 2. Vascular malformations (one of the following): In SOLAMEN (segmental overgrowth, · Capillary malformation lipomatosis, AVMs, epidermal nevus) syndrome, · Venous malformation patients display thickening of the soles and · Lymphatic malformation increased wrinkling instead of the gyri found · Lung bullae in CCTN. There is segmental proportionate overgrowth with soft-tissue hypertrophy and ballooning effect, as well as lymphatic 3. Facial phenotype (all of the following): 12 · Dolichocephaly and shunting arteriovenous malformations. Proteus syndrome may be distinguished from · Long face by the absence of multiple café · Down-slanting palpebral fissures au lait macules, Lisch nodules, axillary freckling, · Depressed nasal bridge and multiple . Hemihyperplasia · Wide or anteverted nares and multiple lipomatosis syndrome (HHML) is · Open mouth at rest characterized by subcutaneous lipomatosis and asymmetric overgrowth (hemihyperplasia) that is patients with PS and are most commonly seen in pulmonary insufficiency, persistent atelectasis, not as progressive as in PS.3 individuals with cognitive deficits. These include pneumonia, or even death.3 Syndromes characterized by vascular down-slanting palpebral fissures, flattening of Other manifestations include ophthalmologic malformations may also be considered in the the malar bones, a relative lengthening of the findings such as strabismus, epibulbar cysts, differential diagnosis of PS. In Maffucci syndrome, face, low nasal bridge with wide nostrils, and a 3 and epibulbar dermoids (42%); otolaryngologic enchondromatosis, most commonly of the hands persistently open mouth. Our patient did not abnormalities (37%); mental deficiency (30%); and feet, with multiple cavernous hemangiomas display any of these characteristics. 3 non-cystic pulmonary disease (20%); dental are seen. This should not be difficult to Central nervous system abnormalities are seen abnormalities (19%); reproductive/genital non- distinguish from Proteus syndrome owing to the 4 in up to 40% of patients with PS. Dietrich et tumor abnormalities (18%); male reproductive lack of enchondromatosis in Proteus syndrome. al. described 12 children with PS whose CNS tumors (11%) and renal/urologic manifestations Klippel-Trenaunay syndrome is characterized by 7 abnormalities included (9%); and hair and nail abnormalities. the three main features of nevus flammeus (port- (8), hypodense periventricular white matter (4), wine stain), venous and lymphatic malformations, periventricular calcification (3), corpus callosal Diagnosis and soft-tissue hypertrophy of the affected limb. abnormalities (3), atrophic brains (2), and Dandy- The diagnosis of Proteus syndrome is based on There are no CCTN seen, and overgrowth is 9 3 Walker malformation (1). Mental deficiency is clinical findings. Individuals must meet all of the present at birth and more severe than in PS. 3 seen in approximately 30% of cases. general criteria, including mosaic distribution In Parkes Weber, a mutation in the RASA1 of lesions, sporadic occurrence, and progressive While no specific hematologic abnormalities have gene leads to multiple capillary malformations, course, along with certain specific criteria as including AV fistulas that can lead to heart been described in association with PS, studies 3 outlined in Table 1. failure, as well as overgrowth of one limb, most have demonstrated that AKT1 and AKT2 are 3 critical regulators of long-term hematopoietic Although PS is primarily a clinical diagnosis, commonly the leg. In the differential diagnosis stem-cell function.10 It is feasible that an molecular genetic testing for the somatic of the CCTN is isolated plantar collagenoma, a hamartomatous lesion consisting of proliferation AKT1 gene mutation may underlie the chronic mutation in the AKT1 gene can be helpful to 13 macrocytosis and reticulocytopenia observed in confirm the diagnosis. This can be technically of normal collagen tissue. Collagenomas our patient. challenging because blood is not an appropriate are commonly encountered in other genetic source and tissue may show low-level mosaicism. disorders, such as Buschke-Ollendorff syndrome, Patients with PS are prone to developing several Skin scrapings from epidermal nevi in PS a rare autosomal-dominant condition, resulting types of tumors, most commonly monomorphic patients have been shown to be a good source of from nonsense mutation in the LEMD3 gene, adenomas of the parotid gland, ovarian mutant cells and may provide an alternate source which encodes for a potent negative regulator cystadenomas, , and various types of 11 3 for genetic testing. It is important to note that of bone morphogenic protein and transforming testicular tumors. Cystic lung disease may cause growth factor-β signaling pathways. Recently,

Page 22 PROTEUS SYNDROME: CASE REPORT AND REVIEW a mutation in LEMD3 has been reported in with parents and children and refer for counseling Manifestations. Am J Neuroradiol. 1998;19:987– familial cutaneous collagenomas as well.14 and peer-support groups if needed.20 990. 10. Juntilla MM, Patil VD, Calamito M, Joshi Histopathology Prognosis RP, Birnbaum MJ, Koretzky GA. AKT1 and Histopathologically, cerebriform connective- Regarding progression of skin lesions, AKT2 maintain hematopoietic stem cell function tissue nevi are characterized by an irregular Beachkofsky et al. evaluated 36 patients with by regulating reactive oxygen species. Blood. 2010 proliferation of highly collagenized fibrous Proteus syndrome with serial photography for an 15 May 20;115(20):4030–4038. tissue. Biopsies of lipomatous overgrowths average of 53 months. Cerebriform connective- reveal nonencapsulated lobules and mature tissue nevi showed progression in 13 children but 11. Wieland I, Tinschert S, Zenker M. High- adipocytes.16 Vascular malformations are lined by not in 3 adults. Lesions progressed by expansion level somatic mosaicism of AKT1 c.49G>A, flat endothelium, exhibiting a normal, slow rate into previously uninvolved skin, increased mutation in skin scrapings from epidermal of turnover. The flat, organoid type of epidermal thickness, and development of new lesions. nevi enables non-invasive molecular diagnosis nevus in PS shows acanthosis, hyperkeratosis, and Lipomas increased in size and/or number in 8 in patients with Proteus syndrome. Am J Med papillomatosis.16,17 out of 10 children. Epidermal nevi and vascular Genet. 2013;161A:889–891. malformations generally did not spread or 21 12. Caux F. Segmental overgrowth, lipomatosis, Management increase in number. arteriovenous malformation and epidermal The sporadic and unpredictable nature of nevus (SOLAMEN) syndrome is related to Proteus syndrome can pose a challenge for Long-term prognosis varies across patients. mosaic PTEN nullizygosity. Eur J Hum Genet. health care providers. Since PS can affect many Approximately 20% of PS patients suffer 2007;15:767-73. different parts of the body to varying degrees, premature death, most commonly due to venous or pulmonary thromboembolism, pneumonia, or a multidisciplinary approach is important in 8,22 13. Nelson A. Isolated plantar collagenoma not the management and prevention of secondary surgical complications. associated with Proteus syndrome. J Am Acad complications. Serial clinical photography with Dermatol. 2008 Mar;58(3):497-9. an initial skeletal survey and targeted follow-up Conclusion Proteus syndrome is a complex disease that can 14. McCuaig C. Connective tissue nevi in radiographs should be performed to evaluate the involve many areas of the body, especially the children: institutional experience and review. J degree of obstruction or deformation based on 18 skeletal system, connective tissue, fat, and central Am Acad of Dermatol. 2012 Nov;67(5):890-7. the patient’s medical history and physical exam. nervous system. The variable clinical presentation, 15. Cohen MM Jr. Putting a foot in one’s mouth or Other imaging recommendations include rarity of the disorder, and clinical overlap with putting a foot down: nonspecificity v. specificity of intracranial MRI to evaluate for CNS several other diseases has led to significant the connective tissue nevus in Proteus syndrome. malformations that may be associated with confusion and misdiagnosis. Molecular genetic Proc Greenwood Cent. 1995;14:11-13. developmental delay, mental retardation or testing can be performed, with the highest yield seizures. Findings may include multiple from epidermal nevi or tissue specimens. Patients 16. Nguyen D, Turner JT, Olsen C, Biesecker LG, meningiomas, polymicrogyria, and periventricular should be managed with a multidisciplinary Darling TN. Cutaneous manifestations of Proteus heterotopias.3 Abdominal MRI is recommended approach. syndrome. Arch Dermatol. 2004;140:947-953. to exclude intra-abdominal lipomas, regardless of 17. Nazzaro V, Cambiaghi S, Montagnani the presence of symptoms, due to the aggressive References A, Brusasco A, Cerri A, Caputo R. Proteus nature of these lesions. CT of the chest to 1. Cohen Jr MM, Hayden PW. A newly syndrome: ultrastructural study of linear evaluate pulmonary cystic malformations should recognized hamartomatous syndrome. Birth verrucous and depigmented nevi. J Am Acad be carried out if clinically warranted to evaluate Defects Orig Artic Ser. 1979;15:291-296. Dermatol. 1991 Aug;25:377–383. for cystic malformations.3 2. Wiedemann HR, Burgio GR, Aldenhoff P, 18. Biesecker LG. The challenges of Proteus One of the most common causes of death for Kunze J, Kaufmann HJ, Schirg E. The proteus syndrome: diagnosis and management. Eur J patients with PS, including children, is deep syndrome. Partial gigantism of the hands and/ Hum Genet. 2006 Nov;14(11):1151–1157. venous thrombosis and . or feet, nevi, hemihypertrophy, subcutaneous For this reason, perioperative anticoagulant tumors, macrocephaly or other skull anomalies 19. Guidera KJ, Brinker MR, Kousseff BG, Helal is recommended.18 Chronic anticoagulation, and possible accelerated growth and visceral AA, Pugh LI, Ganey TM, Ogden JA. Overgrowth however, is not recommended, particularly since affections. Eur J Pediatr. 1983;140:5-12. management in Klippel-Trenaunay-Weber and many of these patients have underlying vascular Proteus syndromes. J Pediatr Orthop.1993 Jul- 3. Biesecker LG, Happle R, Mulliken JB, Aug;13:459–466. anomalies. Weksberg R, Graham JM Jr, Viljoen DL, Cohen Tumor surveillance is not recommended in PS MM Jr. Proteus syndrome: Diagnostic criteria, 20. Turner J, Biesecker B, Leib J, Biesecker L, patients. These patients appear to be predisposed differential diagnosis, and patient evaluation. Am Peters KF. Parenting children with Proteus to a broad range of malignancies, and it has not J Med Genet.1999;84:389–395. syndrome: Experiences with and adaptation to courtesy stigma. Am J Med Genet. been demonstrated that early detection of tumors 4. Turner JT, Cohen MM Jr, Biesecker LG. 18 2007;143A:2089–2097. in PS improves prognosis. Reassessment of the Proteus syndrome Cerebriform connective-tissue nevus (CCTN) literature: application of diagnostic criteria to 21. Beachkofsky TM, Sapp JC, Biesecker LG, is a common dermatologic overgrowth that is published cases. Am J Med Genet A. 2004 Oct Darling TN. Progressive overgrowth of the usually found at the plantar aspect of the foot. 1;130A(2):111-22. cerebriform connective tissue nevus in patients The grooves in CCTN can be difficult to clean, with proteus syndrome. J Am Acad Dermatol. 5. Lindhurst MJ, et al. A mosaic activating 2010;63:799–804. leading to the accumulation of bacteria and mutation in AKT1 associated with the proteus fungus that may cause infection and a malodor. syndrome. N Engl J Med. 2011;365:611–19. 22. Slavotinek AM, Vacha SJ, Peters KF, Biesecker CCTN can progressively increase in size, grow LG. Sudden death caused by pulmonary on previously non-involved areas of the foot and 6. Altomare DA, Testa JR. Perturbations of thromboembolism in Proteus syndrome. Clin coalesce. This can be disfiguring, painful, and the AKT signaling pathway in human cancer. Genet. 2000;58:386–9. interfere with ambulation.3 Surgical removal of Oncogene. 2005;24:7455–7464. CCTN can lead to disappointing results since 19 7. Blumenthal G. PTEN hamartoma recurrence and painful scarring is possible. tumor syndromes. Eur J Hum Genet. 2008 Correspondence: Holly Kanavy, DO; Dermatological follow-ups and the use of custom Nov;16(11):1289-300. [email protected] orthotics to manage pain, pressure ulcerations, and/or skin breakdown are preferred treatments.1,3 8. Cohen, MM. Proteus Syndrome: An Update. Because patients and their families can undergo a Am J Med Genet C Semin Med Genet. 2005 great deal of stress from this disease, clinicians are Aug 15;137C(1):38-52. encouraged to assess psychosocial issues routinely 9. Dietrich, et al. The Proteus Syndrome: CNS

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