Although Proteus syndrome is rarely encountered in clinical practice, several distinct signs are recognized in the affected population. Tissue overgrowth is, by far, the most important feature of this disorder and the skeletal system seems to be most severely affected [1] [2] [3] [4] [5] [6]. After an apparently normal birth, first signs usually appear in late infancy and early childhood (6-18 months of age), but a delayed presentation up to puberty has been encountered [1] [4]. Skeletal changes affect the limbs in most cases in an evidently disproportionate, asymmetric, and often severe and rapidly progressing fashion (leg length discrepancy of up to 20 centimeters has been reported) [1] [4]. The connective tissues and fat are also affected by this phenomenon, but atrophy of the adipose tissue can be simultaneously present in some patients [1] [2] [4]. Furthermore, studies have reported cases with overgrowth of different organs, including the thymus, the gastrointestinal tract, the spleen, and the liver [1] [4]. Vascular malformations involving, the arterial, venous, and/or lymphatic vessels are very frequent and predispose to life-threatening thromboembolic events [1] [2] [4]. Apart from tissue overgrowth, the formation of cutaneous lesions, such as linear verrucous epidermal nevi and cerebriform connective tissue nevi (CCTN) are hallmarks of Proteus syndrome [1] [2] [4] [5]. Other notable findings seen in Proteus syndrome are [1] [2] [3] [4]:

• Facial deformities - Flattening of malar bones, an open mouth at rest, and down-slanting palpebral fissures are seen in a small proportion of patients and intellectual disability may often accompany facial changes [1] [2] [4].
• Neoplasias - Parotid gland adenomas, ovarian cystadenomas, and sometimes meningiomas are tumor types that are strongly correlated with Proteus syndrome.
• Bullous and cystic lung disease [1] [2].

• Disability

  (2) 20th century, play (1) angst, classic (1) angst, drama (1) anthropology, biography (1) award winner, history, movies (1) biography, biology (1) biography, disabilities (1) biography, disease (1) biography, doctor (1) biography, favorite (1) biography [librarything.com]

  It typically manifests in early childhood with asymmetric and progressive skeletal overgrowth that leads to severe distortion of the skeleton and disability. [ncbi.nlm.nih.gov]

• Developmental Delay

  We present a case of a 3½-year-old girl diagnosed as Proteus syndrome with severe cosmetic disfigurement-macrodactyly, hemi-hypertrophy of the face and limbs, megalencephaly, lymph edema of both hands and feet along with severe global developmental delay [ncbi.nlm.nih.gov]

  He has short stature, webbing of his hands, pulmonary stenosis, seizures and hydrocephalus along with developmental delay. [ggc.org]

  delay, lipomas, penile freckling, or vascular anomalies, among other features An unaffected individual with a family history suggestive of PHTS (see above) when an affected individual is unavailable for his or her own genetic testing Lab Method: Capillary [genedx.com]

• Surgical Procedure

  Maxillary disjunction was achieved with a combination of orthodontic treatment and surgical procedure. This represented the initial care for malocclusion treatment and also the preparation for orthognathic surgery. [ncbi.nlm.nih.gov]

  Vascular malformations, relative immobility, and surgical procedures predispose to deep venous thrombosis, resulting in pulmonary embolism. ( Reassessment of the Proteus syndrome literature: application of diagnostic criteria to published cases. 2004 [flipper.diff.org]

  Figure 3. photographs showing the surgical procedure; patient position (a), excision of the mass (star) showing attachment (Arrows) of the mass to the major gluteal muscle (circle) and covering of the site of the exeresis (c). [scirp.org]

  Three surgical procedures were carried out to remove the dorsal tumors. The first procedure was performed when the patient was 11 years old, and used liposuction to remove lipomas. [rbcp.org.br]

• Epilepsy

  In both patients, a refractory epilepsy, compatible with Ohtahara syndrome, as well as hemimegalencephaly, with asymmetric distribution of facial fat, were also diagnosed. [ncbi.nlm.nih.gov]

  The 24-year-old also suffered gigantism, which meant he never stopped growing and also suffered hydrocephalus - a build-up of fluid on the brain - and epilepsy. [dailymail.co.uk]

  There was no history of epilepsy, mental retardation or consanguinity. [ijdvl.com]

  […] hygiene in the affected areas.2,5 Their presence also distinguishes PS from KTS.4 Linear epidermal nevi are also a common manifestation and darken over time.1,5 Central nervous system manifestations occur in 40% of patients, mental deficiency in 30%, and epilepsy [consultant360.com]

• Developmental Disorder

  Proteus syndrome is a rare developmental disorder of unknown aetiology. It is a disorder characterized by postnatal overgrowth affecting multiple tissues. Proteus syndrome is most frequently manifested in skeletal changes. [ncbi.nlm.nih.gov]

  The etiology is obscure and has been postulated to result from an embryonic developmental disorder of mesodermal tissues that affect angiogenesis at different stages, possibly following intra-uterine insult [ 4 ]. [doi.org]

  "Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly". Brain. 140 (10): 2610–2622. doi:10.1093/brain/awx203. PMC 6080423. [wikidoc.org]

• Thrombosis

  Neurological manifestations include intellectual deficit, sinus thrombosis and intracranial lesions. Complications include hemimegalencephaly, bullous pulmonary disease, pulmonary embolism (PE) and deep vein thrombosis (DVT). [orpha.net]

  We conducted a comprehensive review of the medical histories and hematologic evaluations of 57 patients with Proteus syndrome to identify potential risk factors for thrombosis. [ncbi.nlm.nih.gov]

  The arm shows a few lymph vesicles and hardened nodules - likely foci of thrombosis in this limb, which are characterized by foci of vascular channels in Figure 2. The patient presents splenomegaly as a visceral abnormality, shown in Figure 3. [scielo.br]

• Skin Lesion

  BACKGROUND: Proteus syndrome is a rare overgrowth disorder that almost always affects the skin. OBJECTIVE: Our purpose was to evaluate progression of skin lesions in patients with Proteus syndrome. [ncbi.nlm.nih.gov]

  In nevus comedonicus syndrome, the characteristic skin lesion occurs with additional symptoms. These symptoms generally occur on the same side of the body (ipsilateral) as the skin lesion. [rarediseases.org]

  When neuroimaging studies show hemimegalencephaly in a child with pigmented skin lesions, Proteus syndrome should be considered in the differential diagnosis. Copyright © American Society of Neuroradiology [ajnr.org]

  Proteus syndrome is an extremely rare genetic disorder that is characterised by the abnormal growth of bones and blood vessels, and various skin lesions including lipomas, epidermal naevi and café au lait macules. [dermnetnz.org]

• Hyperkeratosis

  […] overgrowth; (ii) bone abnormalities different from those observed in other disorders; (iii) a characteristic cerebriform connective tissue nevus made up of highly collagenized connective tissue; (iv) epidermal nevi in early life, consisting of acanthosis and hyperkeratosis [ncbi.nlm.nih.gov]

  In addition to skeletal defects, PS is characterized by vascular malformations, pulmonary abnormalities, and epidermal nevi with acanthosis and hyperkeratosis [ 2 ]. [imedpub.com]

  Figure 3: Histopathology of nevoid verrucous lesion shows orthokeratotic hyperkeratosis, acanthosis of epidermis with papillomatosis and basal layer hyperpigmentation, and upper dermal scanty perivascular inflammatory infiltrate (H and E, ×100) Click [e-ijd.org]

  Histopathology of the nevus showed mild hyperkeratosis, parakeratosis, acanthosis and papillomatosis, reflecting its epidermal nature. [ijdvl.com]

  […] of people have these symptoms Abnormal lung lobation 0002101 Bronchogenic cyst 0100730 Calvarial hyperostosis Overgrowth of skullcap 0004490 Dolichocephaly Long, narrow head Tall and narrow skull [ more ] 0000268 Finger syndactyly 0006101 Generalized hyperkeratosis [rarediseases.info.nih.gov]

• Keratosis

  Gallego, Acral Keratoses and Inverted Follicular Keratosis Presenting as Cowden Disease, Actas Dermo-Sifiliográficas (English Edition), 98, 6, (425), (2007). [doi.org]

  Oculo-Auriculo-Vertebral (OAV) syndrome / sequence, Facio-Auriculo-Vertebral syndrome, Goldenhar-Gorlin syndrome Harlequin ichthyosis ( 1 Files ) Erkrankung: Harlequin ichthyosis ICD 10: Q80.4 Synonyme: Harlequin baby, ichthyosis congenita, Ichthyosis fetalis, keratosis [orphananesthesia.eu]

• Skin Disease

  Peter Itin and Bettina Burger, Mosaic manifestations of monogenic skin diseases, JDDG: Journal der Deutschen Dermatologischen Gesellschaft, 7, 9, (744-748), (2009). [doi.org]

• Blister

  In addition to growth issues, the syndrome may cause large blisters, lung disease, enlargement of one side of the brain, blood clots and vascular malformations. [uchicagomedicine.org]

  Cutaneous porphyria is a disorder that causes blisters, excess hair, swelling, and necrosis of the skin. It can cause red colored teeth and fingernails, and after exposure to sun, urine can turn purple, pink, brown, or black. [listverse.com]

• Narrow Face

  Café au lait macules are often present Common facial features include: Prominent occiput (enlarged back of the head) Drooping eyelids Low nasal bridge and wide, upturned nostrils Long, narrow face Open mouth at rest Internal organs affected include the [dermnetnz.org]

• Long Narrow Face

  Café au lait macules are often present Common facial features include: Prominent occiput (enlarged back of the head) Drooping eyelids Low nasal bridge and wide, upturned nostrils Long, narrow face Open mouth at rest Internal organs affected include the [dermnetnz.org]

• Prominent Occiput

  Café au lait macules are often present Common facial features include: Prominent occiput (enlarged back of the head) Drooping eyelids Low nasal bridge and wide, upturned nostrils Long, narrow face Open mouth at rest Internal organs affected include the [dermnetnz.org]

Unfortunately, Proteus syndrome is severely debilitating during childhood and adolescence and up to 25% of patients are at risk of not surviving past the beginning of the third decade of life [6]. For this reason, an early diagnosis is essential. To recognize Proteus syndrome, it is first necessary to establish prerequisite criteria - a mosaic pattern of lesions, the absence of a familial component, and a rapidly progressive course of symptoms [1] [4] [5]. During the clinical assessment, use of diagnostic criteria that have been revised in the previous decade should be sufficient to solidify clinical suspicion [1] [4] [5].

• Category A signs - Cerebriform connective tissue nevi.
• Category B signs - Linear verrucous epidermal nevus; Presence of disproportionate and asymmetric overgrowth of the limbs, hyperostosis of the skull or of the external auditory canal, visceral overgrowth, or megaspondylodysplasia; and the presence of either bilateral ovarian cystadenomas or parotid adenomas.
• Category C signs - Abnormal adipose tissue formation (either lipoatrophy or overgrowth), vascular changes, facial deformities, and typical lung disease.

The diagnosis is made when either Category A is fulfilled, when two signs from category B exist, or if three signs from category C are observed [1] [4] [6]. In addition to clinical findings, the revelation of specific mutations involving the AKT1 gene has allowed mutational analysis to be performed in this population [7]; thus genetic testing can be employed as a definitive diagnostic method [1] [3] [4].

Management and treatment Treatment requires a multidisciplinary approach. The interventions used to control overgrowth of tubular bones are epiphysiostasis, epiphysiodesis and amputation in extreme cases. [orpha.net]

What is the treatment for Proteus syndrome? There is no specific treatment for Proteus syndrome. The condition should be managed by identifying early any serious medical problems and providing prophylactic and symptomatic treatment. [dermnetnz.org]

While AKT signaling was suppressed with ARQ 092 treatment, cells retained their ability to respond to growth factor stimulation by increasing pAKT levels proportionally to untreated cells. [ncbi.nlm.nih.gov]

Prognosis Prognosis varies depending on the severity of complications. The documents contained in this web site are presented for information purposes only. [orpha.net]

Prognosis of affected patients may be complicated by premature death, mostly due to pulmonary embolism and respiratory failure. [ncbi.nlm.nih.gov]

This disorder is thought to be caused by a somatic gene mutation, but the exact etiology is unknown. Commonly involved tissues include connective tissue, bone, skin and the central nervous system. [ncbi.nlm.nih.gov]

Etiology Causal mutations of PS have been reported in two components of the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway: PTEN, which make PS a part of the PTEN Hamartoma Tumor Syndrome (PTHS; see this term) and AKT1. [orpha.net]

Summary Epidemiology Approximately 120 cases of PS have been reported to date. The prevalence is estimated to be less than 1/1,000,000 live births. Clinical description Neonates usually appear normal at birth. [orpha.net]

Keywords: Aftercare, Case Report, Human, Infant, Male, Proteus Syndrome, complications,epidemiology,genetics,pathology,surgery, How to cite this article: Alavi S, Chakrapani A, Kher A, Bharucha B A. The Proteus syndrome. [jpgmonline.com]

Epidemiology Frequency International Proteus syndrome is believed to be exceedingly rare, with less than 100 confirmed affected individuals reported worldwide. [5] This suggests that prevalence is less than 1 case per 1,000,000 live births. [emedicine.com]

The principal investigator is Leslie G Biesecker, M.D., Chief of the Medical Genomics and Metabolic Genetics Branch at the National Human Genome Research Institute (NHGRI) who discovered the important role AKT plays in the pathophysiology of Proteus syndrome [raredr.com]

We conclude that the predisposition to thrombosis is likely to be multifaceted with risk factors including vascular malformations, immobility, surgery, additional prothrombotic factors, and possible pathophysiologic effects of the somatic AKT1 mutation [ncbi.nlm.nih.gov]

Pathophysiology Proteus Syndrome is associated with mosaicism for a somatic activating mutation in the AKT1 gene on chromosome 14q32.3. [accessanesthesiology.mhmedical.com]

Pathophysiology A study by Lindhurst et al demonstrated that a somatic mutation in the AKT1 gene is causative for Proteus syndrome. [emedicine.com]

It doesn't run in families, and there is nothing parents can do to prevent it. What Are the Symptoms of Proteus Syndrome? Proteus syndrome symptoms don’t appear right away. [webmd.com]

Research Article Mutation analysis of the tumor suppressor PTEN and the glypican 3 ( GPC3 ) gene in patients diagnosed with Proteus syndrome Department of Human Genetics, McGill University, Montreal, Quebec, Canada Cancer Prevention Centre, Sir MB Davis‐Jewish [doi.org]

Tea tree oil : Tea tree oil is purported to have antiseptic properties, and has been used traditionally to prevent and treat infections. [livingnaturally.com]

To try and prevent her legs from growing further, Katia has started a series of liposuction sessions. Katia's legs grew to a whopping 50 inches in width She said: “Before I had any surgeries, my legs were like 50 to 54 inches.” [barcroft.tv]

1. Biesecker LG, Sapp JC. Proteus Syndrome. 2012 Aug 9. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
2. Cohen MM Jr. Proteus syndrome review: molecular, clinical, and pathologic features. Clin Genet. 2014 Feb;85(2):111-119.
3. Alves C, Acosta AX, Toralles MBP. Proteus syndrome: Clinical diagnosis of a series of cases. Indian J Endocrinol Metab. 2013;17(6):1053-1056.
4. Biesecker L. The challenges of Proteus syndrome: diagnosis and management. Eur J Hum Genet. 2006;14(11):1151-1157.
5. Talari K, Subbanna PKA, Amalnath D, Suri SDK. Proteus syndrome: A rare case report. Indian J Hum Genet. 2012;18(3):356-358.
6. Sapp JC, Hu L, Zhao J, et al. Quantifying survival in patients with Proteus syndrome. Genet Med. 2017 Jun 29.
7. Lindhurst MJ, Sapp JC, Teer JK, et al. A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome. N Engl J Med. 2011;365(7):611-619.