Proteus Syndrome: Case Report and Updated Literature Review

Proteus syndrome (PS) is an exceptionally uncommon genetic disorder that has been documented in only approximately 250 cases in the literature spanning the past four decades. It is characterized by a disproportionate, asymmetric overgrowth of all types of tissues, provoked by a somatic activating mutation in serine/threonine protein kinase 1. We report a case of PS in a two-year-old female patient with the following clinical features: unilateral overgrowth of connective tissue in the right buttock and right foot, where multiple surgeries were performed to achieve a desirable aesthetic outcome and ensure psychological comfort of the young patient. The insights provided by this case underscore the pivotal role of obtaining pleasing aesthetic outcomes in the surgical management of untreatable genetic disorders, with the aim of nurturing psychological contentment in affected children.


Introduction
Proteus syndrome (PS) is an extremely rare genetic hamartomatous disorder characterized by a disproportionate, asymmetric overgrowth with skeletal deformations, vascular malformations, and dysregulated adipose tissue. 1 It is provoked by a somatic activating mutation in serine/threonine protein kinase 1 (AKT1), causing mutation in the chimeric cells. 2 This activation limits apoptosis and promotes growth among other effects.
It was first described by Cohen and Hayden in 1979. 3A few years later, in 1983, Hans-Rudolf Wiedemann, a German pediatrician named it after sea god Proteus, who could change his shape to evade capture. 4,5The prevalence of this syndrome is believed to be less than 1:1,000,000. 6Symptoms can manifest in various parts of the body and commonly commence during infancy. 7They primarily revolve around skeletal overgrowth, yet this disorder exhibits significant pleiotropy, encompassing central nervous system overgrowth, neuronal migration abnormalities, vascular anomalies, overgrowth of various other organs and tissues, and the development of bullous or cystic lung diseases. 8This syndrome itself is not inherited and does not pass to the offspring, however the life expectancy is short, due to many complications, most common being deep vein thrombosis, as a result of large venous capillary malformations. 5ith fewer than 250 cases documented in the literature, the rarity of its occurrence provides justification for this report. 9This is the case report of a 22-month-old female patient who presented herself at the plastic surgery clinic with a rare case of PS, confirmed by genetic testing.The primary objective of our study is to present the results of the highly radical surgical resection of the overgrown tissue in this rare genetic disorder.overgrowth of connective tissue in the right buttock and the right foot, where overgrowth of bone tissue was also found.When the child was 22 months old, the patient's parents complained of a systematic growth of the right buttock and difficulty in finding fitting shoes for the patient's right foot.
The parents of the patient affirmed that there was no family history of genetic disorders.The patient underwent genetic testing at the age of 20 months with a positive result for a somatic embryonal mutation of AKT1 gene.Due to a high risk of deep vein thrombosis and embolism, additional genetic investigations were conducted (►Table 1).Upon detecting a heterozygous mutation in methylenetetrahydrofolate reductase enzyme gene (MTHFR), the patient was recommended for an annual screening of blood homocysteine levels.Furthermore, the parents were informed about their child's heightened need for vitamin B12 and folic acid.
When the patient was 9 months old, they underwent a surgical procedure at another facility to amputate the distal phalanges of the fourth and fifth toes due to overgrowth.As time progressed, tissue overgrowth persisted, and the aesthetic results of the surgery remained unsatisfactory (►Fig.1).
Physical examination and radiological screening prior to the correction surgery did not reveal any additional abnormalities.Patient's parents gave an informed consent for the surgery of their child.
The patient underwent their initial surgery at our plastic surgery clinic at the age of 5 to address soft tissue hypertrophy in the foot (►Fig.2).The procedure, performed under general anesthesia, was notable for its careful approach.Tissue dissection was performed without ischemia, despite the placement of a tourniquet on the thigh.A skin marker was used to mark the extent of skin excision on the lateral surface of the foot, including the fifth toe and the heel.Once the skin was exposed, masses of adipose tissue located between the dermis and muscle tissue were revealed.Removal of the overgrown adipose tissue along with excess skin from the lateral surface of the heel, the lateral surface of the foot and the fifth toe of the foot was performed (►Fig. 3).After proper hemostasis of the wound bed was achieved, the tissues were sutured, and a layered dressing was applied (►Fig.4).
A year after the reduction of the soft tissues of the foot, the child was qualified for the second procedure, the reduction of hypertrophy of the right buttock (►Fig. 5).Prior to the surgery, the child was prepared with oral laxatives to ensure the best comfort in the postoperative period.The operation was performed under general anesthesia with endotracheal intubation in the prone position.After the preparation of the surgical field, a longitudinal skin incision was planned in the medial quarter of the buttock and a transverse incision around the gluteal fold.After cutting the skin, masses of overgrown A mutation in this gene alters the composition of coagulation cascade factor V, rendering it resistant to the anticoagulant protein C.This mutation elevates the risk of deep vein thrombosis, arterial thrombosis, ischemic stroke, and myocardial infarction.

Ala222Val (C677T)
A mutation in this gene results in elevated levels of homocysteine in blood, potentially raising the susceptibility to cardiovascular diseases and hypercoagulability.In contrast to homozygous mutations, heterozygous mutations often present as asymptomatic.
Fig. 1 Chart presenting the surgical procedures that the patient underwent.
adipose tissue were exposed, which penetrated through the fascial septa toward the gluteal fissure.Reduction of the soft tissue hyperplasia consisted of an excision of a designated dermal fat tissue and removal of an overgrown adipose tissue from between the septum connecting the skin and the muscle fascia (►Fig. 6).The amount of removed soft tissues and the postoperative effect are shown in the pictures (►Fig.7).No drain was left after the procedure.Good hemostasis was achieved during the operation.The wound was sutured in layers and a stabilizing dressing was applied.The child remained in the clinic for 2 days and was discharged in a good general and local condition after the dressing control.
Following both surgeries, the patient received acetaminophen (orally, four times a day, 15 mg/kg).The healing period was uneventful, devoid of complications, and the sutures were removed on the 14th day after the surgery.A significant hypertrophic tendency of scars was observed during the control visits, despite the use of compression therapy (►Fig.8).
There have been no indications of overgrowth recurrence observed in the 2-year-period following the foot reduction surgery.The foot that underwent surgery continue to exhibit consistent proportions with the healthy one, considering the child's growth, without experiencing any unhealthy overgrowth of tissues since the operation (►Fig.8).The second buttock surgery, initially established in the treatment plan, is delayed by 2 years as the current size satisfies both parent and child.In the light of absence of relapse in foot overgrowth, its treatment was limited to observation only.
The overall quality of life, functional and aesthetic outcomes were evaluated 2 years after the foot surgery, using the Pediatric Quality of Life Inventory™ parent and patient report for young children aged 5 to 7 years (►Table 2).Total score of 97.5 for the parent report and 95 for the child report   is very satisfactory and means a high health-related quality of life.

Discussion
PS is a rare asymmetrical and progressive hamartomatous syndrome that may affect many tissues and is barely noticeable at birth.In most cases, this condition initially manifests between 6 and 18 months of age in an irregular, progressively worsening manner, as exemplified by the patient in this report, who exhibited an increasing discrepancy between their body parts as the months passed. 10This genetic disorder has highly variable clinical features, due to mosaic lesion distribution and sporadic occurrence, which can lead to misdiagnosis and confusion with other overgrowth syndromes. 12][13][14][15][16][17][18][19] PS original studies and case reports were selected using PubMed, Embase, and Web of Science, these databases were searched for English language publications published from January 2014 to December 2023.The following search terms were used: (proteus [Title]) AND (syndrome [Title]).The inclusion criteria aimed to select PS studies that described skeletal and soft tissue malformations, limb deformities in cases with confirmed AKT1 mutation, that were treated (surgically and/or pharmacologically) and included a follow-up after treatment.Out of the 115 records initially identified, 80 full-text articles underwent eligibility and quality assessment after exclusion during the abstract review.Nine studies that met the inclusion criteria were included in the analysis.Some of the recent studies [11][12][13][14]17 show results of experimental gene targeting pharmaceutical therapy with sirolimus, ARQ 092, or miransertib-AKT1 inhibitors, originally designed to treat cancer. Whe these papers consistently highlight a reduction in area of cerebriform connective tissue nevus (CCTN), the improvement in the size of limb deformities has not been entirely satisfactory and patients might still require surgery to restore regular function.
There were several studies published concerning diagnostic criteria for PS.In 1999, Biesecker et al 20 developed phenotype-based diagnostic standards, which they subsequently updated and refined in 2006. 21In 2011, Lindhurst et al 2 identified somatic activating mutation in AKT1, as a cause of PS, supporting the hypothesis of somatic mosaicism and implicating the activation of the phosphoinositide-3-kinase/ protein kinse B (PI3K/AKT) pathway in the distinctive clinical manifestations of overgrowth and susceptibility to tumors in this condition.This finding discredited theory proposed earlier in the 21st century that the Phosphatase and TENsin (PTEN) hamartoma syndrome (also known as Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome) and PS had the same cause. 22,23Current understanding reveals that lossof-function mutations in PTEN (located on 10q23.3)activate AKT1, leading to certain shared features with PS.However, this activation results in a separate clinical phenotype. 2n 2019, Sapp et al 24 introduced a novel diagnostic framework for identifying PS based on cases of 75 individuals.This system utilized a weighted, point-based approach to assess phenotypic attributes and subsequently incorporates potential molecular test results, classifying cases into one of the two designations: AKT1-related PS or AKT1-related overgrowth spectrum.We consider this system to be an effective diagnostic tool for PS.It accounts for a wide array of PS manifestations, recognizing the mosaic pleiotropic nature of the disorder, while also considering the presence of pathogenic AKT1 gene variants. 24n the case reported herein, the mutation of ATK1 gene was confirmed by genetic testing.Patient was presented with asymmetric, disproportionate overgrowth of a lower limb, of a fast progressive fashion, as they required two reduction surgeries within a short time interval.There were manifestations of skeletal involvement in the overgrown feet.Dysregulated adipose tissue was found in the affected buttock, as well as vascular malformations.This exact clinical presentation has not been described yet in the literature, [1][2][3][4][5][6][7][8][9][10][20][21][22][23][24][25][26] which implies how this disease can manifest in many ways.
All pleiotropic disorders have phenotypic overlap, and it can be challenging to distinguish them. 24PS must be differentiated from other overgrowth syndromes such as PTEN hamartoma tumor syndrome, Klippel-Trenaunay syndrome, and congenital lipomatous overgrowth, vascular malformations, epidermal nevis, spinal/skeletal anomalies/scoliosis (CLOVES) syndrome, 1 to avoid unnecessary testing and procedures.►Table 4 summarizes the characteristics and distinguishing features of mentioned disorders.In 2007, Sapp et al 26 initially identified CLOVES syndrome in seven individuals previously diagnosed with PS.Distorted skeletal structures in CLOVES patients were primarily associated with major surgical interventions, contrasting with unoperated areas that remained unaffected.Hence surgeons should differentiate these two syndromes, as surgical procedures on the hands or feet in patients with CLOVES syndrome may induce skeletal overgrowth resembling those seen in PS. 1,26 Early surgical procedures of distorted tissues are expected to not only improve aesthetic outcomes but also preserve proper psychological functioning.It is worth noting that there is a lack of evidence on this subject in the literature concerning PS.A study focused on the quality of life of children aged 2 to 12 years with capillary malformations of the lower limbs, particularly those affected by Klippel-Trenaunay syndrome, suggested that venous and orthopaedic complications in children were significantly associated with a decrease in their quality of life. 27This observation remains significant as Klippel-Trenaunay syndrome may exhibit overlapping features with PS, including tissue overgrowth, which demands careful differentiation.Questionnaire evaluated four dimensions of patient's life in the past month.Scores are presented on the scale from 0 to 100.The higher the score, the better health-related quality of life.Another study, which enrolled adult patients, presented similar findings concerning overgrowth syndromes.Within this cohort, 95 patients were diagnosed with psychiatric conditions, 23.2% of the total, with depression (15.1%) and anxiety (5.1%) being the most identified conditions. 28n our study, the strength of our foot reduction surgery lies in the application of a highly radical resection technique, potentially contributing to a lasting outcome.The buttock surgery involved tumor excision in three planes, reducing height, width, and projection.Notably, the procedure extended to subcutaneous removal of extensive adipose tissue clusters, compartmentalized by numerous fibrous septa, reaching toward the gluteal cleft.It enhanced aesthetic results and hygiene maintenance.Limitation is the challenging scarring process.The mid-foot and heel scars improved only after a year, while gluteal scars exhibited excessive growth despite compression therapy, remaining firm and broad.We expect a future relapse of the overgrowth in various body areas, due to progressive nature of the disorder, which is why our patient stays under observation.

Conclusion
Currently there is no effective treatment for this syndrome, however given its monogenic nature, it is an excellent candidate for targeted therapy.We note that the extreme rarity of this disorder limits the researchers' opportunities for finding a favorable pharmacological cure.Considering our experience, we can presume that highly radical resection of pathological tissues may contribute to a longer lasting outcome.This is the first case report of this disease, explaining in such details the surgical approach, followed by a successful long-lasting result in this area of the body.We conclude that early diagnosis of patients with PS and subsequent surgical treatment may improve their quality of life and avoid social stigma.

Fig. 3 A
Fig. 3 A photo showing the amount of tissue removed during foot surgery.

Fig. 2
Fig. 2 Photos of the patient's feet taken before the first tissue reduction surgery at our clinic, after the initial amputation surgery of distal phalange of fourth and fifth toes, performed at a different facility.(A) The picture of the overgrown tissues on the lateral side of the right foot, mostly prevalent in the fourth and fifth toes.(B) The picture of the overgrown tissues of the right heel.

Fig. 4
Fig. 4 Photos (A, B) showing the result of the excess foot tissue removal surgery.

Fig. 5
Fig. 5 Photos (A, B) showing preoperative tissue overgrowth of the right buttock.

Fig. 6
Fig. 6 Photos (A, B) showing postoperative result of tissue reduction.

Fig. 7
Fig. 7 Photo showing the amount of tissue removed from the buttock during surgery.

Fig. 8
Fig. 8 Follow-up photos taken 2 years after the foot surgery and 1 year after the buttock surgery.Photo (A) A photo showing the result of the buttock reduction surgery 1 year after procedure.No significant overgrowth has taken place during this 1-year period.The hypertrophic scar on the buttock is visible.Photos (B-D) showing the state of the patient's feet 2 years after the reduction surgery.No sign of overgrowth has been observed during the follow-up period.

Table 1
Assessed gene mutations and their clinical significance

Table 2
Results of the Pediatric Quality of Life Inventory ™ Generic Core for young children aged 5 to 7 questionnaire