Insights into Clinical Disorders in Cowden Syndrome: A Comprehensive Review.

PTEN Hamartoma Tumour Syndrome (PHTS) encompasses diverse clinical phenotypes, including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like syndrome. This autosomal dominant genetic predisposition with high penetrance arises from heterozygous germline variants in the PTEN tumour suppressor gene, leading to dysregulation of the PI3K/AKT/mTOR signalling pathway, which promotes the overgrowth of multiple and heterogenous tissue types. Clinical presentations of CS range from benign and malignant disorders, affecting nearly every system within the human body. CS is the most diagnosed syndrome among the PHTS group, notwithstanding its weak incidence (1:200,000), for which it is considered rare, and its precise incidence remains unknown among other important factors. The literature is notably inconsistent in reporting the frequencies and occurrences of these disorders, adding an element of bias and uncertainty when looking back at the available research. In this review, we aimed to highlight the significant disparities found in various studies concerning CS and to review the clinical manifestations encountered in CS patients. Furthermore, we intended to emphasize the great significance of early diagnosis as patients will benefit from a longer lifespan while being unceasingly advised and supported by a multidisciplinary team.

Quantification of Proteus syndrome-associated lung disease.

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 < 0.001, respectively) and higher CVS (p < 0.001 and < 0.001). Decreases in percent predicted FVC, FEV1, and DLCO each correlated with increased CLS and CVS. The annual increase of CLS in children, 5.6, was significantly greater than in adults, 1.6. (p = 0.03). The annual increase in CVS in children, 0.4, was similar to adults, 0.2 (p = 0.36). CONCLUSIONS: Proteus syndrome-associated lung disease is progressive. The rate of cystic progression is increased in children. Increased scores in CLS and CVS were associated with clinical symptoms and decreased pulmonary function. Both methods were able to detect change over time and were associated with clinically meaningful outcomes which may enable their use in interventional studies.

Optic nerve compression: a rare ocular manifestation of Proteus syndrome.

Proteus syndrome is characterized by progressive, asymmetric, and distorting overgrowth that involves the skeletal, cutaneous, subcutaneous, and nervous systems. We report the case of a 10-year-old girl with Proteus syndrome and a constellation of ocular signs, including congenital glaucoma, myopia, amblyopia, strabismus, megaloglobus, epibulbar tumors, and right retinal detachment. A decrease in left eye visual acuity coupled with significant deterioration in visual evoked potential response over time prompted urgent neuroimaging, which revealed massive overgrowth of the sphenoid bone, with bilateral optic nerve compression due to optic canal stenosis. Successful removal of the roof of the optic canal along its entire course resulted in optic nerve decompression.

Ophthalmic manifestations and treatments of proteus syndrome: a case report and systematic review.

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.

Proteus Syndrome: A Rare Disease Of Disproportionate And Asymmetric Overgrowth Of Connective Tissue.

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.

Co-occurrence of Proteus syndrome and ventricular tachycardia cardiac arrest in a teenager.

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.

Multimodal ocular imaging in Proteus syndrome.

In this report we illustrate the ophthalmologic assessment of two patients affected by Proteus Syndrome (PS), an extremely rare genetic disorder. Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen. Case #2 describes a 20 year old female patient referred to our Ophthalmology Department for a routine ophthalmologic evaluation after being treated for 3 years with Miransertib (an experimental AKT-pathway inhibitor). Both patients underwent a complete ophthalmologic examination and a multimodal imaging evaluation. The multimodal imaging approach has revealed useful to evaluate both cases in detail and to keep track of disease evolution over time, moreover providing helpful features to further characterize this rare syndrome.

Assessing Cutaneous Mosaicism at the Molecular Level.

Mosaicism results from postzygotic alterations during embryogenesis leading to genetically distinct populations of cells within individuals and has been historically recognized by phenotypes with visible, often patterned manifestations. Before the advent of molecular profiling assays and high-throughput sequencing, it was challenging to study mosaicism in human disease; however, the study of mosaic disorders has recently revealed unexpected and novel pathways for disease pathogenesis. In this paper, we will review the techniques for discovery of disease-causing alleles using Proteus syndrome; phakomatosis pigmentokeratotica; linear porokeratosis; and vacuoles, E1 enzyme, X-linked, autoinflammatory somatic syndrome as models. These tools represent powerful approaches for dissecting the genetic basis for human disorders.

Phenotypic Features of Cystic Lung Disease in Proteus Syndrome: A Clinical Trial.

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).

Progressive frontal intraosseous lipoma: Detection of the mosaic AKT1 variant discloses Proteus syndrome.

Proteus syndrome is a very rare disorder with progressive, asymmetrical, and disproportionate overgrowth of body parts with a highly variable phenotype. It is associated with mosaicism for the recurrent heterozygous somatic gain-of-function variant c.49G>A (p.Glu17Lys) in the protein kinase AKT1. We report on a girl with a progressive intraosseous lipoma of the frontal bone and additional, nonspecific features including mild developmental delay, strabism, and a limbal dermoid of the left eye. She did not fulfill the criteria for a clinical diagnosis of Proteus syndrome. However, mutation analysis of AKT1 in a lipoma biopsy revealed this specific activating variant. Several cases of progressive intraosseous lipoma of the frontal bone have been reported in the literature. Only in two of these observations, a tentative diagnosis of Proteus syndrome was made, based on additional clinical features, although without molecular-genetic verification. We conclude that oligosymptomatic Proteus syndrome should be considered in progressive intraosseous lipoma, as recognition of this diagnosis has relevant implications for genetic counseling and opens novel treatment options with AKT1 inhibitors rather than surgical procedures.

Development of the Clinical Gestalt Assessment: a visual clinical global impression scale for Proteus syndrome.

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.

Late-onset Proteus syndrome with cerebriform connective tissue nevus and subsequent development of intraductal papilloma.

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.

Epidermal Nevi: What Is New.

This article reviews the clinical findings of epidermal nevi and their associated syndromes and provides an update on their pathogenic genetic changes as well as targeted therapies detailed to date.

Proteus Syndrome: Case Report with Anatomopathological Correlation.

Background: Proteus syndrome is characterized by a progressive segmental or patchy growth of bone, skin, adipose tissue, and central nervous system, associated with a wide range of neoplasms, pulmonary pathology, and thrombotic risk. The main histological findings are diffuse patchy overgrowth of skin and subcutaneous tissue, plantar cerebriform connective tissue nevus, and ossification defects. Case report: We present a patient that met the clinical and histological criteria necessary for the diagnosis of the disease. He required multiple surgical interventions, including amputation of the right foot. Genetic evaluation confirmed an AKT1 mutation. Discussion: CLOVES syndrome, neurofibromatosis 1 or PTEN hamartoma tumor syndrome are partially superimposable entities to Proteus syndrome and may generate diagnostic doubt. Although the clinical criteria and histologic findings are indicative, the diagnostic confirmation of this entity is genetic.

Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome.

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.

Dermatologic findings in individuals with genetically confirmed Proteus syndrome.

BACKGROUND/OBJECTIVE: Proteus syndrome, caused by a mosaic activating AKT1 variant, typically presents in toddlers with progressive, asymmetric overgrowth of the skin and bones. We aimed to define the spectrum of dermatologic disease in individuals with genetically confirmed Proteus syndrome. METHODS: We conducted a retrospective review of records from dermatologic examinations of individuals evaluated at the NIH with a molecular diagnosis of Proteus syndrome. The types, prevalence, and localization of dermatologic findings were assessed. RESULTS: Fifty-one individuals (29 males, 22 females, mean age: 9 years) with clinical features of Proteus syndrome had the mosaic c.49G>A, p.Glu17Lys AKT1 variant. Fifty (98%) had at least one cutaneous feature constituting current clinical diagnostic criteria, including vascular malformations in 42 (82%), epidermal nevus in 41 (80%), volar cerebriform connective tissue nevi in 34 (67%), and adipose dysregulation in 30 (59%). Forty-nine (96%) had at least one dermatologic finding not included within the diagnostic criteria, including confluent volar skin-colored to hypopigmented papules or nodules (n = 33, 65%), papules or nodules on the digits or face (n = 27, 53%), and nonlinear epidermal nevi (n = 15, 29%). Other frequently observed features include nail changes (n = 28, 55%), hyperpigmented macules (n = 27, 53%), patchy dermal hypoplasia (n = 18, 35%), gingival/oral mucosal overgrowth (n = 17, 33%), hypopigmented macules (n = 16, 31%), dental enamel changes (n = 9, 18%), acrochordons (n = 6, 12%), and lingual overgrowth (n = 4, 8%). CONCLUSIONS: The range of mucocutaneous features occurring in Proteus syndrome is broader than previously considered. These observations may assist in earlier diagnosis and management and provide novel insights regarding the pathogenesis of the condition.