Development and validation of an LC-MS/MS assay for the quantification of Miransertib in human plasma and clinical application.

Beyond treatment: What patients and parents expect from care in PROS.

A rare case of a young girl with genital manifestations of Proteus syndrome.

Sinonasal Disease in Proteus Syndrome: A Case Report and Review of the Literature

Proteus syndrome is an uncommon, sporadic disorder characterized by progressive and heterogeneous overgrowth of tissues, resulting in distorted and asymmetric development. In most individuals, Proteus syndrome has minimal to no manifestations at birth but progresses during childhood and adolescence. Clinical manifestations of the disease include isolated asymmetric hemihyperplasia, isolated asymmetric macrodactyly, subcutaneous masses, plantar and palmar cerebriform fibrous overgrowth, exostoses, epidermal nevi, and scoliosis. Cardiothoracic structures are less commonly involved, and the manifestations include cystic lung changes, pulmonary thromboembolism and varicosities, and pulmonary nodules. Patients with Proteus syndrome have an increased risk of early death due to deep venous thrombosis and pulmonary embolism. We report a case of an adult female who was diagnosed with Proteus syndrome at the age of 5 years who had multiple pulmonary manifestations of the disease.

Cerebriform connective tissue nevi (CCTNs) are considered pathognomonic features of Proteus syndrome (PS), a condition characterized by progressive, segmental, or patchy overgrowth that most commonly affects the skeleton, skin, adipose tissue, and central nervous system.CCTNs, which resemble the sulci and gyri of the brain, are rarely observed in infancy and typically emerge during childhood, progressing through adolescence.These lesions are typically found on the soles, hands, nasal alae, ears, and lacrimal puncta. 1) In patients presenting with large plantar CCTNs, periodic dermatologic follow-up is advisable to prevent possible complications such as malodor arising from deep grooves and to manage related issues, including the development of pressure ulcers.Moreover, large plantar CCTNs can interfere with proper shoe fitting and often necessitate pedorthic intervention.This report presents a rare case of PS with a large plantar CCTN on the patient's left foot to enhance recognition of the condition and describes the clinical outcomes following debulking surgery for the lesion, which caused difficulties with shoe fitting and impaired walking.This case report

Proteus syndrome is a rare mosaic overgrowth disorder caused by somatic activating variants in AKT1 , most commonly the c.49G>A p.(Glu17Lys) variant. It predisposes individuals to asymmetric tissue proliferation and an elevated risk for both benign and malignant neoplasms. Among 64 males with genetically confirmed Proteus syndrome enrolled in a longitudinal natural history study, 12 (19%) underwent surgery for paratesticular masses. The average age at surgery was 9 years, most tumors were unilateral, small (median 1.6cm), and slow growing, but 50% showed recurrence or metachronous tumor development, occasionally with progression to more atypical histology. Histologically, these tumors demonstrated a broad spectrum of differentiation. Eight reviewed cases included Müllerian-type papillary cystadenomas and low-grade papillary adenocarcinomas, a Brenner tumor, and one case of a papillary adenocarcinoma with spindle cell transformation. The epithelial components were typically arranged in papillary and glandular architectures, with variable degrees of cytologic atypia. Psammomatous calcifications were common. Immunohistochemistry showed consistent expression of PAX8(7/7), WT1(7/7), estrogen receptor (ER)(7/7), and progesterone receptor (PR)(6/7), supporting Müllerian lineage, while negative staining for germ cell and mesothelial markers excluded common paratesticular differential diagnoses. Four of the 7 tumors were positive for SF-1. All 7/7 sequenced tumors harbored the AKT1 c.49G>A variant with no additional oncogenic alterations identified by exome sequencing. This series is the largest series to date documenting the clinicopathologic features of paratesticular tumors, a poorly understood component of the Proteus syndrome phenotype.

Rationale:Proteus syndrome (PS) is a rare congenital disorder characterized by dysregulated overgrowth and an array of complex skeletal anomalies, including scoliosis. The rehabilitation process following spinal surgery has never been reported.Patient concerns:A 10-year-and-3-month-old patient with PS caused by an serine/threonine protein kinase 1 (AKT1) gene mutation, who was referred to our hospital for bilateral lower extremity weakness following scoliosis surgery.Diagnoses:Proteus syndrome.Interventions:The patient received a comprehensive rehabilitation program, including lower limb muscle strength training, passive-active joint mobilization, and joint manipulation, in conjunction with electronic biofeedback therapy and acupuncture, administered by a multidisciplinary rehabilitation team.Outcomes:The patient’s lower limb mobility has improved compared to the initial presentation upon admission, and no complications have been observed.Lessons:The rehabilitation program presented in this study has demonstrated significant efficacy in mitigating muscle weakness in PS patients following surgical intervention for scoliosis.

Targeted management of vascular anomalies.

Background: Lymphatic malformations (LM) are rare congenital vascular anomalies caused by abnormal development and growth of lymphatic vessels. These malformations can lead to a wide range of symptoms, from mild swelling to more severe complications. Treatment options remain limited, especially for complex cases. Recent research has suggested that PIK3CA mutations play a key role in the pathogenesis of LM, potentially offering new possibilities for targeted treatment strategies. Methods: In this study, a cohort of 36 patients diagnosed with LM, Klippel-Trenaunay syndrome (KTS), and Proteus syndrome was analyzed. PIK3CA mutations were assessed in tissue samples obtained from the LM during clinically indicated procedures using digital droplet polymerase chain reaction (ddPCR), targeting five hotspots. Results: PIK3CA mutations were found in 18 patients (50%). The most frequent mutation was p.E542K (c.1624G>A), found in 19.44% of patients, followed by p.H1047R (c.3149A>G), p.E545K (c.1633G>A), and p.H1047L (c.3140A>T) each occurring in 11.11% of the cases. Mutations were more common in isolated LMs, with 63.16% of patients exhibiting PIK3CA mutations. Conclusions: PIK3CA mutations are common in LM, supporting the potential for targeted therapies like PI3K inhibitors in treating complex cases. This research highlights the importance of genetic analysis in the management of LM and offers a new therapeutic approach.

3D CT cinematic rendering of microcardia and multiple thoracoabdominal venous dilation in Proteus syndrome.

PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome are associated with mosaic tissue overgrowth of varying severity that commonly presents in childhood. The multicenter, open-label, phase 1/2 MOSAIC study (NCT03094832) was designed to evaluate the clinical efficacy and safety of the selective pan-AKT inhibitor miransertib for participants with PROS or Proteus syndrome. Participants ≥ 2years of age with PROS with documented somatic PIK3CA mutations or Proteus syndrome with documented somatic AKT1 mutations were enrolled to receive oral miransertib at a starting dose of 15mg/m2 every day for the first 3 cycles (1 cycle = 28days) and miransertib 25mg/m2 every day thereafter, provided no clinically significant drug-related toxicities were observed. The initial primary objective of the study was to assess clinical response to miransertib. Due to study design and data collection limitations, evaluating efficacy was no longer considered feasible and the primary objective was updated in 2021 to evaluate the safety and tolerability of miransertib. Between May 16, 2017 and January 25, 2021, 49 participants were enrolled and received ≥ 1 dose of study drug, comprising the safety analysis population. Forty-five participants had a diagnosis of PROS and four had a diagnosis of Proteus syndrome. The median (range) age at enrollment was 7years (2-41). Median (range) duration of treatment was 20.5months (9.9-45.6). A total of 23 (46.9%) participants had a drug-related adverse event, most commonly decreased neutrophil count (n = 6, 12.2%), increased blood insulin (n = 5, 10.2%), and stomatitis (n = 5, 10.2%). One (2.0%) participant experienced a grade 3 drug-related adverse event (deep vein thrombosis). No drug-related adverse events led to early study discontinuation or death. Laboratory assessment values remained generally stable throughout the study. Miransertib was safe and tolerable in participants with a confirmed diagnosis of PROS or Proteus syndrome. Future investigations are needed to determine whether patients receive measurable clinical benefit from miransertib. NCT03094832 registered Mar 28, 2017, https://clinicaltrials.gov/ct2/show/NCT03094832 .

Macrodactyly is a rare congenital deformity characterized by hypertrophy of the bones and surrounding soft tissues in one or more digits. The terms “macrodactyly”, “megalodactyly”, and “digital” or “localized gigantism” are often used synonymously [1,2]. The condition seems to affect slightly more boys than girls, and it may occur only on one foot or on both feet, and it may be symmetrical or asymmetrical.Macrodactyly may occur as an isolated defect in either the hand or the foot, or it may present as an element of conditions, such as Proteus syndrome, Klippel-Trenaunay syndrome, Bannayan-Riley-Ruvalcaba syndrome, Maffucci, Ollier’s disease and Milroy’s disease.The enlargement includes skin, subcutaneous tissue, nerve, joint, and bone.The bony involvement is usually limited to phalanges [3]. There are two types of macrodactyly: static and progressive. The progressive variant is more frequently seen in the foot than in the hand. Radiologically, X-ray, computed tomography (CT) and magnetic resonance imaging (MRI) are used to determine the size of lesions, involvement of soft tissue and bone, which are important for surgical treatment planning. In macrodactyly, reconstruction is aimed at decreasing the size of the foot in normal size and shape as much as possible. Many surgical options are available for the treatment of macrodactyly of the foot: amputation, ray amputation, epiphyseal ablation, transverse and longitudinal osteotomies, nerve stripping, and extensive defatting. None of the available methods, however, give ideal functional and cosmetic results [4].Most patients are diagnosed and treated from childhood; however, macrodactyly might become more severe if diagnosis and treatment are delayed for a long time. In this case, we report a rare case of long-term (23 years) macrodactyly of a toe resulting from delayed treatment.

e22598 Background: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PTHS) is a family of related genetic disorders including Cowden Syndrome (CS), Bannayan-Riley-Ruvalcaba Syndrome (BRRS), and Proteus Syndrome (PS) associated with distinct phenotypes and increased CA risk. Germline PTEN PVs remain unidentified in many patients (pts), including 40% w/BRRS, 80% w/PS, and 15% w/CS. Standard DNA testing may fail to identify clinically relevant deep intronic PTEN PVs detectable by comprehensive testing that includes RNA analysis. Using a commercial laboratory database, we identify pts tested by DNA/RNA and found to harbor deep intronic PVs associated with alternative RNA splicing of PTEN and predicted to cause PHTS. Methods: Pts tested by paired DNA/RNA testing (2019-2024, Ambry Genetics) and found to have a deep intronic PV leading to a splice site variant were identified. DNA/RNA results were linked to clinical data from a test requisition form. RNA was isolated using standard methodology and converted to cDNA by RT-PCR. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes followed by PCR and NGS. Absence or presence of RNA transcripts meeting quality thresholds is incorporated as evidence towards classification of DNA variants. Study was IRB reviewed (FCCC IRB #24-9030/Ambry WCG IRB exempt). Results: Index case: 64 yo F w/hx of breast CA (42 & 53) and thyroidectomy for nodules and papillary thyroid CA was referred for genetic counseling following colonoscopy showing extensive ganglioneuromatosis. Exam found macrocephaly (59.5 cm), tongue papules, likely facial trichilemmomas, and axillary acrochordons. RNA testing identified a deep intronic PV at c.209+2047A>G resulting in alternative PTEN splicing. In the combined DNA/RNA testing database (n=489,960), 17 additional individuals/families undergoing PTEN testing were identified with a deep intronic PV/LPV (n=14) or suspicious VUS (n=3). In total, 12 probands reported CA (9 <50 yrs) including cases of early breast (n=4, 38-63 yrs), thyroid (n=1, 25 yrs), salivary (n=1, 31 yrs), uterine (n=1, 46 yrs), bladder (n=1, 29 yrs), prostate (n=1, 66 yrs) and ovary CA (n=3, 28-32 yrs). Other PHTS features reported in probands/families: macrocephaly (n=7), colon ganglioneuromas and/or polyposis (n=7), goiter/thyroid nodules (n=6), penile freckling (n=2), skin findings (n=3), and intellectual disability (n=2). Potentially clinically relevant co-occurring variants were detected in NF1 (x3), GALNT12 (x2), BRCA2 and SDHC . Conclusions: Deep intronic PTEN PVs missed by DNA sequencing but detectable by RNA testing and associated with early-onset CA explain a portion of negative results in pts meeting clinical criteria for CS and/or manifesting phenotypic features of PHTS.

AKT and PI3K inhibitors are more efficient in inhibiting growth of Proteus syndrome patient cells compared to mTOR inhibition

Oral manifestations of proteus syndrome: case report

Proteus Syndrome: Manifestations of Systemic Deformities.

49: Palmar connective tissue nevi in Proteus syndrome: A longitudinal report of seven individuals

281 Pregnancy in patients with proteus syndrome and Klippel-Trenaunay Syndrome: a retrospective cohort study using epic cosmos

AKT1-related Proteus syndrome is an ultra-rare mosaic overgrowth disorder with tumour predisposition. We conducted a systematic review to determine the range and characteristics of these tumours. A systematic review was...