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].

• Soft Tissue Swelling

  RESULTS: There were 18 surgical specimens from nine patients, median age 4 years (range 1-9), classified into four main categories: soft-tissue swellings (lipomatous lesions), vascular anomalies (vascular malformation and haemangioma), macrodactyly (hamartomatous [ncbi.nlm.nih.gov]

  Photo 2a Photo 2b Two soft tissue swellings on his anterior abdominal wall and lower anterior chest wall 10x10cm and 5x6 cm, imaging study for those soft tissue swelling revealed fatty tissue suggesting lipoma (photo 3). [pubs.sciepub.com]

• Splenectomy

  The patients' bleeding tendency and hemostatic defects were completely corrected after they successfully underwent splenectomy. [ncbi.nlm.nih.gov]

• Rectal Bleeding

  We describe a case of a 17-year-old girl with Proteus syndrome presented with symptomatic anaemia secondary to chronic rectal bleeding. Computed Tomography Angiogram of Abdomen and Pelvis confirmed the presence of rectal vascular malformations. [ncbi.nlm.nih.gov]

• Abdominal Mass

  Our patient presented with macrodactyly, cerebriform appearance and a huge abdominal mass. A biopsy under laparotomy was performed, and histopathological examination revealed myelolipoma. Tumor resection was performed. [ncbi.nlm.nih.gov]

• Gingival Overgrowth

  In conclusion, oral manifestations of Proteus syndrome may include gingival overgrowth and malposition of teeth, as well as unilateral enamel hypoplasia, as shown in this case report. [ncbi.nlm.nih.gov]

  Oral findings included crowded dentition in 11 patients, a high-arched palate in 10, gingival overgrowth in 9, and prominent tongue papillae in 3. Three patients had heterochromic irides. [jamanetwork.com]

• Prognathism

  The analysis of the radiological evaluation revealed a bialveolar prognathism, a skeletal class III, a dolicocephalic growth pattern and a left convex face scoliosis. [ncbi.nlm.nih.gov]

• Gingival Hypertrophy

  The ENT manifestations of Proteus syndrome are high arched palate, gingival hypertrophy, malocclusion and overcrowding of teeth, hyperostosis of the external auditory meatus, and low nasal bridge. [ncbi.nlm.nih.gov]

• Axillary Freckling

  Neurofibromatosis type 1, a disease caused by mutations in the NF1 gene on chromosome 17 (, 20 ), is inherited in an autosomal dominant pattern and is characterized by Lisch nodules, axillary freckles, multiple café-au-lait spots, and multiple neurofibromas [doi.org]

• Ankylosis

  (c, d) Posteroanterior radiographs of the left hand in another patient at ages 4 years (c) and 16 years (d) show asymmetric and irregular overgrowth of the phalanges, more marked and with accompanying ankylosis of the interphalangeal joints in d. [doi.org]

• Peripheral Neuropathy

  Pediatric peripheral neuropathy in proteus syndrome. Ann Plast Surg. 1998 May. 40(5):528-32. [Medline]. Atherton DJ. Naevi and other developmental defects. Champion RH, Burton JL, Burns DA, eds. [emedicine.com]

• Testicular Mass

  We report the first such case in a 20-month-old child who presented with a left-sided testicular mass that was found on histology to be a serous borderline tumor of the paratestis. [ncbi.nlm.nih.gov]

• Vaginal Bleeding

  A 19-year-old girl with Proteus syndrome presented with vaginal bleeding. The histological examination revealed Müllerian papilloma of the uterine cervix and large bilateral ovarian cystadenomas. [ncbi.nlm.nih.gov]

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].

• Visceromegaly

  In a radiological series with 21 patients, 29% patients had visceromegaly. Other organs involved were kidney and brain. Vascular malformations were reported in seven out of the 21 patients. [idoj.in]

  Conclusions Proteus syndrome is characterized by progressive mosaic overgrowth of skin, bones, muscles, fatty tissues, and blood and lymphatic vessels, as well as by visceromegaly, lung cysts, and predisposition to pulmonary embolism. [doi.org]

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]

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]

There is no cure or specific treatment for Proteus syndrome and treatment involves medical and surgical management of symptoms. [texaschildrens.org]

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]

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]

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]

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]

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]

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

When multiple risk factors are present, such as when someone with Proteus syndrome has surgery, we recommend blood thinners to prevent blood clots. [proteus-syndrome.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]

Management to prevent and monitor for blood clots is needed. Imaging. Imaging studies (x-rays) are often important to assess and monitor areas of overgrowth. No one type of imaging is best for everyone with Proteus syndrome. [texaschildrens.org]

Proteus syndrome treatment includes: detection of abnormalities at an early stage and using symptomatic and preventive treatment multiple orthopedic procedures to control the overgrowth surgery epiphysiodesis (removal or ablation of growth plates in bones [medigoo.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]

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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.