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].

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].

There is no cure for Proteus Syndrome, so treatment focuses on managing symptoms and complications. This may involve:

• Surgical interventions to correct bone deformities or remove overgrown tissue.
• Physical therapy to improve mobility and function.
• Medications to manage pain or seizures.
• Regular monitoring by a multidisciplinary team to address various health issues as they arise.

The prognosis for individuals with Proteus Syndrome varies widely. Some may experience mild symptoms, while others face significant health challenges. Early diagnosis and comprehensive management can improve quality of life and help manage complications. However, the condition can be life-threatening due to complications such as deep vein thrombosis or pulmonary embolism.

Proteus Syndrome is caused by a mutation in the AKT1 gene, which plays a role in cell growth and division. This mutation occurs after conception, meaning it is not inherited from parents but arises spontaneously in the affected individual. The mutation leads to abnormal cell growth, resulting in the characteristic overgrowth seen in the syndrome.

Proteus Syndrome is extremely rare, with only a few hundred cases reported worldwide. It affects males and females equally and does not appear to be more common in any particular ethnic or geographic group. The rarity of the condition makes it challenging to study and understand fully.

The pathophysiology of Proteus Syndrome involves the mosaic distribution of the AKT1 mutation, meaning not all cells in the body carry the mutation. This results in the patchy and asymmetric overgrowth seen in patients. The mutation leads to uncontrolled cell proliferation and abnormal tissue development, affecting bones, skin, and other organs.

Currently, there is no known way to prevent Proteus Syndrome, as it results from a spontaneous genetic mutation. Genetic counseling may be helpful for families to understand the condition, although the risk of recurrence in siblings is not increased due to the non-hereditary nature of the mutation.

Proteus Syndrome is a rare genetic disorder characterized by asymmetric overgrowth of bones, skin, and other tissues. It is caused by a mutation in the AKT1 gene and presents with a wide range of symptoms. Diagnosis involves clinical evaluation and genetic testing, while treatment focuses on managing symptoms. The condition is not preventable, and its rarity poses challenges for research and understanding.

For patients and families affected by Proteus Syndrome, understanding the condition is crucial. It is important to work closely with a team of healthcare professionals to manage symptoms and monitor for complications. Support groups and resources can provide valuable information and connect families with others facing similar challenges. Regular follow-up and a proactive approach to care can help improve quality of life for those living with Proteus Syndrome.

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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.