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].

• Splenectomy

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

• Tonsillar Hypertrophy

  We report a rare case of Proteus syndrome which presented with dysphagia due to unilateral tonsillar hypertrophy. [ncbi.nlm.nih.gov]

  Nuyen, Aria Jafari and Javan Nation, Refractory sleep-disordered breathing due to unilateral lingual tonsillar hypertrophy in a child with Proteus Syndrome, International Journal of Pediatric Otorhinolaryngology, 95, (114), (2017). M. Barreau and A. [doi.org]

• Exertional Dyspnea

  This report documents a 25-year-old man with Proteus syndrome who presented with progressive exertional dyspnea and asymmetric overgrowth of his extremities. He underwent left pneumonectomy and his postoperative course was uneventful. [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]

• 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]

• Periodontitis

  Neither periodontal pockets nor alveolar bone destruction were detected. [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]

• Genu Valgum

  Orthopaedic problems include macrodactyly, hindfoot deformity, limb length inequality, genu valgum and scoliosis. Usually, scoliosis does not respond to bracing, and surgical intervention may be required. [ncbi.nlm.nih.gov]

  Other radiographic features include enlarged and dysplastic vertebral bodies, scoliosis, cranial exostosis, osteomas, osteochondromas, enchondromas and genu valgum may also occur. [radiopaedia.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].

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.