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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.

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. [ABSTRACT FROM AUTHOR]

International Society for the Study of Vascular Anomalies classification defines Congenital Limb Overgrowth Vascular Syndromes (CLOS) as a subset of vascular syndromes with other abnormalities that present with unilateral limb overgrowth. It includes Klippel–Trenaunay Syndrome, Parkes–Weber Syndrome, CLOVES (Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Spinal/Skeletal Anomalies/Scoliosis) Syndrome, Proteus Syndrome, PTEN Hamartomatous Syndrome, and Fibroadipose Vascular Anomaly. Due to their rare and complex nature, a multidisciplinary approach to diagnosis and treatment is required. A thorough clinical and radiological workup can go miles in reflecting on the patient’s outcome. Here we report five cases of CLOS with their detailed dermato‑radiological profiles. [ABSTRACT FROM AUTHOR]

Objective: Proteus syndrome, a rare disorder with an incidence of one in a million, is characterized by connective tissue nevi, asymmetric limb overgrowth, and abnormal subcutaneous adipose tissue distribution. Limited awareness of this condition often hinders accurate clinical diagnosis. We report a case of Proteus syndrome with concurrent progressive paralysis in the unilateral lower limb, aiming to enhance understanding of the disease and its associated complications. Methods: The patient, an 11-year-old male, has been conclusively diagnosed with Proteus Syndrome. This diagnosis was established by analyzing clinical manifestations, imaging studies, and laboratory tests. In addition, a literature review was conducted to systematically elucidate the etiology, diagnosis, treatment, and prognosis of this condition. Results: According to the clinical manifestations, we confirmed a case of Proteus syndrome. This example exhibits the general characteristics of patients with severe hemihypertrophy of the bilateral lower limbs, anomalies in hypodermic and adipose distribution, and unilateral lower limb progressive paralysis. Pathological biopsy confirmed the right chest wall mass as a lipoma. Notably, the patient experiences lower limb movement disorders caused by intraspinal disease. At the same time, the gene sequencing results of this Proteus syndrome patient showed mutations in the IDUS gene and SPECC1L gene, which have not been reported before. Conclusion: We diagnosed Proteus Syndrome with lower limb sensorimotor abnormalities, which may be caused by mutations in the IDUS gene or SPECC1L gene. This is the first report of these kinds of gene mutations in association with Proteus Syndrome.

International Society for the Study of Vascular Anomalies classification defines Congenital Limb Overgrowth Vascular Syndromes (CLOS) as a subset of vascular syndromes with other abnormalities that present with unilateral limb overgrowth. It includes Klippel–Trenaunay Syndrome, Parkes–Weber Syndrome, CLOVES (Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Spinal/Skeletal Anomalies/Scoliosis) Syndrome, Proteus Syndrome, PTEN Hamartomatous Syndrome, and Fibroadipose Vascular Anomaly. Due to their rare and complex nature, a multidisciplinary approach to diagnosis and treatment is required. A thorough clinical and radiological workup can go miles in reflecting on the patient’s outcome. Here we report five cases of CLOS with their detailed dermato-radiological profiles.

Abstract Background Proteus syndrome (PS) is a complex and uncommon disorder with as its main feature a patchy or mosaic postnatal overgrowth. A high clinical and radiological variability characterizes it. Case presentation We report the case of a 2-year-old boy presenting with lipomas and diagnosed as PS in front of general criteria (sporadic occurrence, progressive course, and mosaic distribution of lesions) and specific criteria (linear epidermal nevus in the chest and asymmetric and overgrowth in the upper limbs) of Biesecker. The course of the disease was marked by a huge overgrowth of arms despite several surgeries. By the age of 10 years, a painful swelling of the right forearm revealed a venous thrombosis on a venous malformation. Conclusions This case report highlights the variability of clinical findings in PS. It also emphasizes the contribution of routine imaging tools for the diagnosis and the follow-up of this rare disease.

Abstract Background Proteus syndrome is an ultra-rare mosaic overgrowth disorder. Individuals with Proteus syndrome can develop emphysematous and cystic changes of the lung that may lead to progressive respiratory symptoms and require surgical intervention. This retrospective study seeks to quantify the radiographic features of Proteus syndrome-associated lung disease using computed tomography (CT) of the chest. The first method derives a Cystic Lung Score (CLS) by using a computer-aided diagnostic tool to quantify the fraction of cystic involvement of the lung. The second method yields a Clinician Visual Score (CVS), an observer reported scale of severity based on multiple radiographic features. The aim of this study was to determine if these measurements are associated with clinical symptoms, pulmonary function test (PFT) measurements, and if they may be used to assess progression of pulmonary disease. Results One hundred and thirteen imaging studies from 44 individuals with Proteus syndrome were included. Dyspnea and oxygen use were each associated with higher CLS (p = 0.001 and

Introduction:Proteus syndrome (PS) is a rare genetic disorder usually caused by mutations in AKT1 or PTEN genes, characterized by multiple, asymmetric tissue overgrowth with high clinical variability. Sinonasal neuroendocrine carcinomas (SNEC) are exceptionally rare tumors encountered in the ethmoid sinus, nasal cavity, or maxillary sinus.Case Report:We report a 35-year-old patient with PS, who underwent successful surgical removal of a well-differentiated SNEC obstructing his nasal cavity and highlight the role of the otolaryngologist for safe airway management, minimal surgical intervention and coordination of the multidisciplinary care. Histologically, focally hyperplastic mucosal epithelium of respiratory type of the nasal chamber was noticed along with seromucinous glands and capillary congestion of the subepithelial fibrovascular tissue. The limited presence of neoplastic tissue with histomorphological and immunophenotypic features of a neuroendocrine neoplasm was focally observed. Tumor cells grow in the form of islets within a vascular stroma; these neoplastic cells are immunohistochemically positive for synaptophysin, CD56, EMA, Ki67 (low expression, cell proliferation rate: 2%), CD31, chromogranin and pancytokeratin AE1 / AE3 as well as for S-100 protein (weak intensity)Conclusions:This first description of a SNEC in a PS patient, might hint towards a common basis between the two conditions, due to the mosaic AKT1 variant and an activated AKT/PIK3CA/PTEN pathway.

Proteus syndrome is a rare congenital hamartomatous syndrome characterized by the asymmetric and disproportionate overgrowth of limbs, emergence of connective tissue nevi, epidermal nevi, ysregulated adipose tissue, and vascular malformations. The Proteus syndrome is caused by mosaicism of somatic activating mutation in the AKT1 gene which locates at chromosome 14q32.3. This syndrome is extremely rare, making it difficult to diagnose. The most commonly used diagnostic criteria are too complicated to be used in clinical practice. Surgery can partially alleviate the clinical symptoms of overgrowth, but it can't inhibit the progression of the disease. This article summarizes the diagnostic criteria, treatment principles, and perioperative managements for Proteus syndrome in the world. The article proposes the highly suspected morphological manifestations of Proteus syndrome was based on clinical experiences of the author.The article emphasizes using genetic detection of pathological tissue as the gold standard for diagnosis, and suggests targeted therapy as the optimal treatment for Proteus syndrome.

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Introduction: Proteus syndrome (PS) is a rare genetic disorder usually caused by mutations in AKT1 or PTEN genes, characterized by multiple, asymmetric tissue overgrowth with high clinical variability. Sinonasal neuroendocrine carcinomas (SNEC) are exceptionally rare tumors encountered in the ethmoid sinus, nasal cavity, or maxillary sinus. Case Report: We report a 35-year-old patient with PS, who underwent successful surgical removal of a welldifferentiated SNEC obstructing his nasal cavity and highlight the role of the otolaryngologist for safe airway management, minimal surgical intervention and coordination of the multidisciplinary care. Histologically, focally hyperplastic mucosal epithelium of respiratory type of the nasal chamber was noticed along with seromucinous glands and capillary congestion of the subepithelial fibrovascular tissue. The limited presence of neoplastic tissue with histomorphological and immunophenotypic features of a neuroendocrine neoplasm was focally observed. Tumor cells grow in the form of islets within a vascular stroma; these neoplastic cells are immunohistochemically positive for synaptophysin, CD56, EMA, Ki67 (low expression, cell proliferation rate: 2%), CD31, chromogranin and pancytokeratin AE1 / AE3 as well as for S-100 protein (weak intensity). Conclusions: This first description of a SNEC in a PS patient, might hint towards a common basis between the two conditions, due to the mosaic AKT1 variant and an activated AKT/PIK3CA/PTEN pathway. [ABSTRACT FROM AUTHOR]

BACKGROUND: Proteus syndrome (PS) is an extremely rare disorder with ocular manifestations. In this study, we aimed to describe the ophthalmic characteristics and the clinical course of an unusual PS patient to acquire a comprehensive and intensive understanding of ocular PS and highlight the importance of collaborative treatment by ophthalmologists. CASE PRESENTATION: A case of PS with atypical ocular features and syndromes was observed in a Chinese female. Her proptosis and vision impairment were relieved after Endoscope-Navigation system (ENS)-aided optic canal decompression. A 1.5-year follow-up showed that the treatment was temporarily effective, but the disease continued to develop. A review of the literature was conducted: forty-eight patients met the inclusion criteria. Although ocular manifestations play important roles in PS diagnosis, only a limited number of cases have been reported to have ocular abnormalities. And to date, almost none of these reports have described the treatment in detail. Therefore, PS patients with ocular manifestations were reviewed. CONCLUSIONS: PS is a complex disorder with variable characteristics and progressive imbalances. In this paper, the clinical symptoms, molecular characteristics, and differential diagnosis of PS are introduced. More importantly, the ocular manifestations, treatment, and prognosis of PS cases to date are summarized and discussed. This study aimed to acquire a comprehensive and intensive understanding of ocular PS and to reveal the importance of collaborative treatment by ophthalmologists. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Proteus syndrome is a rare genetic disease characterized by an asymmetrical growth of individual parts of the body and has only been described in single cases. This patient presented with recurrent manifestations of a laryngeal and hypopharyngeal lymphangioma, which were treated with laser surgery, systemic therapy, and sclerotherapy. The reported data depict the diagnosis and treatment in the department of otorhinolaryngology, head and neck surgery of the university hospital Heidelberg from 2019 until May 2023. The recurrent endoscopy of the upper airway was performed using a flexible HD‐endoscope and the Visera Elite video tower from Olympus, Hamburg. The 29‐year old female patient initially presented in February 2019 with stridor and exertional dyspnea due to a lymphatic malformation of the left larynx and hypopharynx. In April 2019 there was no improvement by sclerotherapy with Picibanil, so that systemic therapy with the PIK3CA inhibitor alpelisib was initiated (03–07/2020) and discontinued due to a high side effect profile. In the course of 2021–2023, three microlaryngoscopies with laser surgical resection and renewed sclerotherapy of the lymphangioma with Picibanil were carried out due to fluctuating findings. After these interventions a stable disease could be established until May 2023. Laser surgical therapy is currently described as the therapy of choice in lymphangiomas in the head and neck region and also showed the highest effectiveness in our patient. In case of airway obstruction in particular, it can bring rapid symptom relief. Alternatively, and with a lower surgical risk, local improvements have been reported by sclerotherapy, which was less effective in the presented case. Rare syndromic diseases require multidisciplinary collaboration. In the case of laryngeal lymphangiomatosis, other treatment options should be considered in addition to surgical excision, especially in the case of recurrence. [ABSTRACT FROM AUTHOR]

Proteus syndrome is an extremely rare sporadic hamartomatous condition characterized by random overgrowth of connective, epidermal and bony tissue. Involvement of the genitourinary system in PS is extremely rare and if present, are usually caused by enlarging cysts or neoplasms. Infrequent reports of testicular, renal and bladder involvement have been reported. The involvement of the bladder is predominantly due to vascular malformations with only three previous cases reported in literature. We report the fourth case – one of a 14-year-old male with known Proteus syndrome that presented to the emergency unit with life threatening haematuria. He appeared acutely ill in haemorrhagic shock with a haemoglobin of 4.3 g/dL on index presentation. Initial acute management involved aggressive resuscitation of the patient with intravenous fluids and blood transfusion. Cystoscopy revealed an actively-bleeding extensive venous anomalies of the bladder wall that were successfully-sealed with electrocautery. [ABSTRACT FROM AUTHOR]

Key Clinical Message Proteus syndrome is a rare genetic disease characterized by an asymmetrical growth of individual parts of the body and has only been described in single cases. This patient presented with recurrent manifestations of a laryngeal and hypopharyngeal lymphangioma, which were treated with laser surgery, systemic therapy, and sclerotherapy. The reported data depict the diagnosis and treatment in the department of otorhinolaryngology, head and neck surgery of the university hospital Heidelberg from 2019 until May 2023. The recurrent endoscopy of the upper airway was performed using a flexible HD‐endoscope and the Visera Elite video tower from Olympus, Hamburg. The 29‐year old female patient initially presented in February 2019 with stridor and exertional dyspnea due to a lymphatic malformation of the left larynx and hypopharynx. In April 2019 there was no improvement by sclerotherapy with Picibanil, so that systemic therapy with the PIK3CA inhibitor alpelisib was initiated (03–07/2020) and discontinued due to a high side effect profile. In the course of 2021–2023, three microlaryngoscopies with laser surgical resection and renewed sclerotherapy of the lymphangioma with Picibanil were carried out due to fluctuating findings. After these interventions a stable disease could be established until May 2023. Laser surgical therapy is currently described as the therapy of choice in lymphangiomas in the head and neck region and also showed the highest effectiveness in our patient. In case of airway obstruction in particular, it can bring rapid symptom relief. Alternatively, and with a lower surgical risk, local improvements have been reported by sclerotherapy, which was less effective in the presented case. Rare syndromic diseases require multidisciplinary collaboration. In the case of laryngeal lymphangiomatosis, other treatment options should be considered in addition to surgical excision, especially in the case of recurrence.

Proteus syndrome is an extremely rare overgrowth condition caused by a somatic variant of the AKT1 gene. It can involve multiple organ systems though rarely is there symptomatic cardiac involvement. Fatty infiltration of the myocardium has been described but has not been reported to cause functional or conduction abnormalities. We present an individual with Proteus syndrome who suffered a sudden cardiac arrest. [ABSTRACT FROM AUTHOR]

Proteus syndrome is a rare genetic disorder characterized by disproportionate and asymmetric overgrowth of bones and soft tissues. It is caused by a mutation in the AKT1 gene and manifests with various dermatological criteria such as connective tissue nevi and vascular malformations. This article presents a case study of a 3-year-old girl with Proteus syndrome, highlighting the important role of dermatologists in diagnosis and care coordination. Early childhood diagnosis is crucial for active surveillance and improving the patient's quality of life. A multidisciplinary approach involving various medical specialties is recommended to minimize complications. [Extracted from the article]

Proteus syndrome (PS) is a rare syndrome characterized by asymmetric limb overgrowth, vascular malformation, and hamartomas. In this study we report a case of PS in a 13‐year‐old girl with chief complaint of a new cutaneous lesion that was diagnosed and treated as leishmaniasis. [ABSTRACT FROM AUTHOR]

Abstract Background Clinical outcome assessments are important tools for measuring the natural history of disease and efficacy of an intervention. The heterogenous phenotype and difficult to quantity features of Proteus syndrome present challenges to measuring clinical outcomes. To address these, we designed a global clinical assessment for Proteus syndrome, a rare mosaic overgrowth disorder. The Clinical Gestalt Assessment (CGA) aims to evaluate change over time in this phenotypically diverse disorder. Results We gathered paired serial photographs and radiographs obtained at 12-to-36-month intervals from our natural history study of Proteus syndrome. The chronologic order of each set was blinded and presented to clinicians familiar with overgrowth disorders. They were asked to determine the chronologic order and, based on that response, rate global clinical change using a seven-point scale (Much Worse, Worse, Minimally Worse, No Change, Minimally Improved, Improved, Much Improved). Following a pilot, we tested the inter-rater reliability of the CGA using eight cases rated by eight clinicians. Raters identified the correct chronologic order in 53 of 64 (83%) of responses. There was low inter-rater variance and poor to moderate reliability with an intraclass correlation coefficient of 0.46 (95% CI 0.24–0.75). The overall estimate of global change was Minimally Worse over time, which is an accurate reflection of the natural history of Proteus syndrome. Conclusions The CGA is a tool to evaluate clinical change over time in Proteus syndrome and may be a useful adjunct to measure clinical outcomes in prospective therapeutic trials.

Abstract Proteus syndrome (PS) is a rare syndrome characterized by asymmetric limb overgrowth, vascular malformation, and hamartomas. In this study we report a case of PS in a 13‐year‐old girl with chief complaint of a new cutaneous lesion that was diagnosed and treated as leishmaniasis.

Rationale: Limited information is available regarding cystic lung disease in Proteus syndrome, a rare overgrowth disorder caused by a somatic activating variant in AKT1. Objectives: To define the phenotype of cystic lung disease in Proteus syndrome. Methods: Medical records, pulmonary function tests, and chest computed tomography of 39 individuals with Proteus syndrome evaluated at a single center were retrospectively reviewed. Lung histopathology from five affected individuals was examined. Results: Cystic lung disease affected 26 (67%) of 39 individuals. The mean age of affected individuals was 17.1 years. The lung cysts varied in size and location. Focal regions of heterogeneous lung parenchyma resembling emphysema were found in 81% of affected individuals. Mass effect was seen in 12% of affected individuals; pneumothorax occurred in one. Dyspnea and respiratory infections were reported by 38% and 35% of affected individuals, respectively. Abnormal pulmonary function and scoliosis were found in 96% of affected individuals. Lung disease progressed in seven of 10 affected individuals, and all five affected individuals younger than 20 years of age had progressive cystic lung disease. Three affected individuals had symptomatic improvement after lung resection. Histopathology showed cystic air space enlargement of varying severity. Conclusions: Cystic lung disease is common in Proteus syndrome and is likely to progress in affected individuals younger than 20 years of age. Screening asymptomatic individuals with Proteus syndrome for cystic lung disease is indicated. Surgical lung resection is a therapeutic option for affected individuals with severe disease. Clinical trial registered with www.clinicaltrials.gov (NCT00001403). [ABSTRACT FROM AUTHOR]

Proteus syndrome (PS) is a rare disorder (< 1/1000000), marked by progressive overgrowth commonly impacting the skeleton, skin, adipose tissue, and central nervous system. Clinical criteria were established in 2019. PS arises from a somatic activating variation in the AKT1 gene. We report the second case of PS diagnosed prenatally using whole exome sequencing (WES). A 34-year-old woman was referred for nonvisualized anterior brain structures and genital anomalies. At 21 weeks of gestation (WG), ultrasonography confirmed brain anomalies, genital anomalies, and macrosomia. Array-CGH revealed no pathogenic imbalances (arr(X,1-22)×2). Follow-up ultrasound (25 WG) and MRI (27 WG) also showed a megalencephaly, leading to WES on amniocytes. The reported mosaic variation in AKT1 was identified. Medical termination of pregnancy occurred at 30 + 1 WG. We present a case of PS confirmed prenatally via WES. To date, six cases of prenatal PS suspicion have been reported, four of which lacked molecular diagnosis. Calculating prenatal clinical scores indicate PS could not be definitively diagnosed without molecular confirmation. Certain features, such as limb malformation and gray matter heterotopia, seem to be significant in prenatal diagnosis. WES, with an average coverage depth of 130X, is valuable for diagnosing suspected PS., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Proteus syndrome (PS) is a rare segmental overgrowth disorder caused by a mosaic activating variant in AKT1. The features of PS are often not present at birth but develop during the first few years of life. We describe a 55‐year‐old female, whose first symptom of overgrowth, a cerebriform connective tissue nevus, occurred at 19 years of age. We report the identification of the AKT1 c.49G > A p.(Glu17Lys) variant in this progressive lesion, the bony overgrowth, and recurrence after surgical intervention. In the sixth decade of life, this individual developed intraductal papillomas within her right breast which were confirmed to contain the same activating AKT1 variant as the connective tissue nevus. While similar neoplasms have been described in an individual with Proteus syndrome, none has been evaluated for the presence of the AKT1 variant. The tumor also contained two likely pathogenic variants in PIK3R1, c.1392_1403dupTAGATTATATGA p.(Asp464_Tyr467dup) and c.1728_1730delGAG p.(Arg577del). The finding of additional genetic variation putatively affecting the PI3K/AKT pathway in the neoplastic tissue may provide preliminary evidence of a molecular mechanism for tumorigenesis in PS. The late onset of symptoms and molecular characterization of the breast tumor expand the clinical spectrum of this rare disorder. [ABSTRACT FROM AUTHOR]

Background: Clinical outcome assessments are important tools for measuring the natural history of disease and efficacy of an intervention. The heterogenous phenotype and difficult to quantity features of Proteus syndrome present challenges to measuring clinical outcomes. To address these, we designed a global clinical assessment for Proteus syndrome, a rare mosaic overgrowth disorder. The Clinical Gestalt Assessment (CGA) aims to evaluate change over time in this phenotypically diverse disorder.Results: We gathered paired serial photographs and radiographs obtained at 12-to-36-month intervals from our natural history study of Proteus syndrome. The chronologic order of each set was blinded and presented to clinicians familiar with overgrowth disorders. They were asked to determine the chronologic order and, based on that response, rate global clinical change using a seven-point scale (Much Worse, Worse, Minimally Worse, No Change, Minimally Improved, Improved, Much Improved). Following a pilot, we tested the inter-rater reliability of the CGA using eight cases rated by eight clinicians. Raters identified the correct chronologic order in 53 of 64 (83%) of responses. There was low inter-rater variance and poor to moderate reliability with an intraclass correlation coefficient of 0.46 (95% CI 0.24-0.75). The overall estimate of global change was Minimally Worse over time, which is an accurate reflection of the natural history of Proteus syndrome.Conclusions: The CGA is a tool to evaluate clinical change over time in Proteus syndrome and may be a useful adjunct to measure clinical outcomes in prospective therapeutic trials. [ABSTRACT FROM AUTHOR]

Proteus syndrome is a rare progressive multisystem disorder characterized by asymmetric, disproportionate overgrowth of bone, skin, and other tissue types. Molecular pathogenesis has been identified as somatic activating mutations of the AKT1 gene. The presentation of Proteus syndrome is exceptionally variable. Respiratory complications include emphysematous lung disease and predisposition to pulmonary emboli, the latter of which is a significant source of mortality. Pulmonary hypertension due to longstanding hypoxic lung disease as well as chronic thromboembolic events has been observed in this population. In contrast, precapillary pulmonary arterial hypertension in the absence of chronic pulmonary emboli and parenchymal lung disease has not been described in the literature on patients with Proteus syndrome. We report such a case in a young patient with Proteus syndrome, reviewing subsequent management and emphasizing the need for a detailed investigation of dyspnea. [ABSTRACT FROM AUTHOR]

Abstract Background Isolated macrodactyly is a severe congenital hand anomaly with functional and physiological impact. Known causative genes include PIK3CA, AKT1 and PTEN. The aim of this study is to gain insights into the genetics basis of isolated macrodactyly. Results We enrolled 24 patients with isolated macrodactyly. Four of them were diagnosed with Proteus syndrome based on skin presentations characteristic to this disease. Targeted next-generation sequencing was performed using patients’ blood and affected tissues. Overall, 20 patients carry mosaic PIK3CA pathogenic variants, i.e. p.His1047Arg (N = 7), p.Glu542Lys (N = 6), p.Glu545Lys (N = 2), p.His1047Leu (N = 2), p.Glu453Lys (N = 1), p.Gln546Lys (N = 1) and p.His1047Tyr (N = 1). Four patients who met the diagnostic criteria of Proteus syndrome carry mosaic AKT1 p.Glu17Lys variant. Variant allele frequencies of these mosaic variants obtained through next-generation sequencing range from 10 to 33%. In genotype–phenotype correlation analysis of patients with PIK3CA variant, we found that patients with the macrodactyly of the lower limbs tend to carry PIK3CA variants located in the helical domain (P = 0.005). Conclusions Mosaic PIK3CA and AKT1 variants can be found in all of our samples with isolated macrodactyly. Insights into phenotypic and genetic spectrum of isolated macrodactyly may be helpful in perusing a more precise and effective management of isolated macrodactyly.

Abstract Proteus syndrome is a rare progressive multisystem disorder characterized by asymmetric, disproportionate overgrowth of bone, skin, and other tissue types. Molecular pathogenesis has been identified as somatic activating mutations of the AKT1 gene. The presentation of Proteus syndrome is exceptionally variable. Respiratory complications include emphysematous lung disease and predisposition to pulmonary emboli, the latter of which is a significant source of mortality. Pulmonary hypertension due to longstanding hypoxic lung disease as well as chronic thromboembolic events has been observed in this population. In contrast, precapillary pulmonary arterial hypertension in the absence of chronic pulmonary emboli and parenchymal lung disease has not been described in the literature on patients with Proteus syndrome. We report such a case in a young patient with Proteus syndrome, reviewing subsequent management and emphasizing the need for a detailed investigation of dyspnea.

Proteus syndrome is a rare disease manifested by progressive segmental overgrowth involving the skeletal, Cutaneous, subcutaneous, and nervous systems. We report the case of a 24-year-old female who was born with no obvious abnormality at birth. From the age of 1 year, she developed asymmetric enlargement of her left upper limb and bilateral lower limbs leading to enlargement of the right-hand phalanges with radial deviation, enlargement of the right big toe, lateral deviation of left foot, and discrepancy in the length of lower extremities and kyphoscoliosis. She had become bed-bound for the last few years due to increasing disability. She was diagnosed with Proteus syndrome based on clinical features of progressive course, mosaic distribution, and sporadic occurrence of the lesions. [ABSTRACT FROM AUTHOR]

Proteus syndrome is a rare, sporadic, congenital syndrome that causes asymmetric and disproportionate overgrowth of limbs, connective tissue nevi, epidermal nevi, alteration of adipose tissue, and vascular malformations. Genetic mosaicism, such as activating mutations involving protein kinase AKT1, phosphoinositide 3 kinase (PI3-K), and phosphatase and tensin homolog (PTEN), may be important causes of Proteus syndrome. However, many patients have no evidence of mutations in these genes. Currently, the diagnosis is clinical and based on phenotypic features. This article reports a case of Proteus syndrome in a 14-year-old female patient who presented with linear epidermal nevi, viscera anomalies, and adipose tissue dysregulation. She showed an asymmetric progressive overgrowth of the right lower limb after birth bringing relevant functional and esthetic consequences. Therefore, she asked a plastic surgery consultation and a surgical treatment with a combined technique was planned. With our approach, we were able to reduce leg diameter and improve joint mobility reliably and safely with satisfying esthetic results. [ABSTRACT FROM AUTHOR]

Proteus syndrome is a rare, multi-system, genetic syndrome characterised by atypical and excessive growth of skeletal tissue. Clinical presentations include abnormal musculoskeletal growth and cutaneous lesions. Due to its rarity, there have been a limited number of published case reports of Proteus syndrome. This is the first case report on the management of Proteus syndrome in pregnancy. We present the case of a pregnant woman with Proteus syndrome in her first pregnancy in a large teaching hospital and discuss the considerations and challenges faced in her antenatal, intrapartum and postnatal care. [ABSTRACT FROM AUTHOR]

Proteus syndrome is a rare overgrowth disorder caused by postzygotic activating variants in AKT1. Individuals may develop a range of skin, bone, and soft tissue overgrowth leading to functional impairment and disfigurement. Therapy for this disorder is limited to supportive care and surgical intervention. Inhibitors of AKT, originally designed as cancer therapeutics, are a rational, targeted pharmacologic strategy to mitigate the devastating morbidity of Proteus syndrome. We present the 5-yr follow-up of an 18-yr-old male with Proteus syndrome treated with miransertib (MK-7075), an oral pan-AKT inhibitor. At completion of a planned 48-wk phase 1 pharmacodynamic study, the individual derived sufficient benefit that the study was amended to permit continued use and assess the long-term safety of miransertib. The treatment has been well-tolerated with mild treatment-attributed side effects including headache, transient hyperglycemia, and transient elevations of aspartate aminotransferase, alanine aminotransferase, and bilirubin. The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi. This case report supplements the data from our prior study extending those findings out to 5 years. It shows that at the doses used, miransertib has a favorable safety profile and durable benefit of improving symptoms of pain and slowing progression of overgrowth in Proteus syndrome in a single individual. Although an uncontrolled single report cannot prove safety or efficacy, these data lend support to the encouraging preliminary data of our prior phase 1 pharmacodynamic study. [ABSTRACT FROM AUTHOR]