Clinical characteristics and imaging analysis of Proteus syndrome: a case description

Proteus syndrome is an extremely rare and complex disorder caused by somatic mutations in the AKT serine/threonine kinase 1 (AKT1) gene. It is clinically characterized by progressive, asymmetric tissue overgrowth with high heterogeneity and often leads to diagnostic challenges and frequent misdiagnosis. With an estimated incidence of less than 1 in 1,000,000 (1), the condition derives its name from the Greek sea god Proteus, reflecting its variable and changing morphology (2,3). This report describes a case of an adolescent patient with typical Proteus syndrome as confirmed through genetic testing. A multimodal diagnostic approach for Proteus syndrome, including clinical, imaging, and molecular testing, is discussed in detail, along with the related management strategies, which may serve as a reference for the comprehensive the diagnosis and treatment of the condition.

Case presentation

A 14-year-old male adolescent presented with bilateral scrotal swelling that exhibited positional variation and had persisted for more than 1 year. There was no symptomatic improvement with previous conservative management. Six years prior, he underwent resection of a left foot mass, with postoperative pathology confirming a cavernous hemangioma. The patient exhibited multiple dysplastic skeletal changes, including scattered bony protuberances on the scalp without depression and with normal hair distribution, significant spinal scoliosis, and discrepant hand lengths. Multiple fingers showed irregular, tumor-like bony enlargements, resulting in impaired fist closure. Examination of the left inguinal-scrotal region revealed a palpable mass measuring approximately 2 cm × 3 cm × 3 cm in size. The mass was well-demarcated, firm, nonreducible, and nontender; the transillumination test was negative, and there was no overlying skin erythema or edema.

Radiographic evaluation revealed elongation of the bilateral femora, tibiae, fibulae, humeri, ulnae, radii, and hand bones. The distal ulnae were shortened, with localized bony hyperplasia noted at the proximal radii. Osseous demineralization and narrowed interphalangeal joint spaces were observed in both hands. The fourth left proximal phalanx and the fourth right phalanx demonstrated bony overgrowth with irregular, mass-like, high-density shadows exhibiting expansile features. Spinal scoliosis with vertebral rotation was present, alongside osteoma-like protrusions arising from the right humeral head and right femoral neck. Pelvic imaging identified a small ischial ramus and swelling of the right pubic symphysis (Figure 1). Chest computed tomography (CT) demonstrated pulmonary emphysematous changes and inflammatory infiltrates in both lungs. Contrast-enhanced CT revealed tortuosity and dilation of the right subclavian, axillary, splenic, left renal, and portal veins. Full-spine CT scans indicated thoracic asymmetry, thinning of the bilateral ribs, and spinal scoliosis. Head CT showed localized thickening and protrusion of the calvarial plate, accompanied by widening of the left frontal sinus (Figure 2).

Figure 1 Radiographic manifestations of skeletal abnormalities. (A,B) Images of both hands showing osseous structural anomalies and digit length discrepancy, with soft-tissue masses (white arrows) involving multiple digits. (C,D) Anteroposterior whole-spine radiographs obtained at age 10 years old (C) and age 14 years old (D) revealing progressive worsening of spinal curvature, consistent with disease progression (increase in Cobb angle).

Figure 2 CT findings. (A) Chest CT showing multiple pulmonary cysts (white arrow), emphysematous changes, and interstitial inflammatory infiltrates (red arrow). (B) Abdominal CT indicating marked dilation of the renal vein (white arrow). (C,D) Cranial CT showing focal thickening of the frontal and left temporal bones involving the lamina interna. CT, computed tomography.

Magnetic resonance imaging (MRI) indicated increased fat content within the pelvic bones. The internal and external iliac arteries and their distal branches were tortuous and dilated. Atrophy of the anterior abdominal wall and gluteal muscles was noted, with multiple serpiginous, dilated vascular structures present within the soft tissue compartments (Figure 3).

Figure 3 MRI findings. (A,B) Pelvic MRI showing pelvic asymmetry, reduced subcutaneous adipose tissue (red arrow), and scrotal enlargement (white arrow). (C,D) Axial images indicating fat deposition within the bilateral iliac bones and sacrum (red arrow), along with abnormally dilated vascular structures in the pelvic cavity (white arrow). MRI, magnetic resonance imaging.

Genetic testing was performed on DNA extracted from multiple affected tissues, including the left scrotal skin, left epididymal mass, and skin/mass from the bilateral ring fingers. Whole-exome sequencing identified a somatic mosaic variant in AKT1 (c.49G>A, p.Glu17Lys) in these specimens, with a variant allele frequency (VAF) of 11/135 (Figure 4A). In contrast, sequencing of peripheral blood-derived DNA was negative for this variant (0/214 reads) (Figure 4B).

Figure 4 IGV visualization of whole-exome sequencing data from peripheral blood and multiple tissues of the patient and parents. (A) Multitissue sequencing results from the affected child, demonstrating the specific read counts and sequence alignment at the variant locus. (B) Peripheral blood-derived sequencing results from the child and both parents, confirming the absence of the variant in parental samples and supporting its somatic mosaic origin. IGV, Integrative Genomics Viewer.

The AKT1:c.49G>A variant has been classified as pathogenic based on the following criteria from the American College of Medical Genetics and Genomics (ACMG) guidelines: PS2, de novo occurrence (confirmed via parental testing); PS3, well-established functional evidence from in vivo and in vitro studies demonstrating its pathogenic role; PS4, significant enrichment of the variant in affected individuals compared to controls; and PM2 supporting, absence in population databases (1000 Genomes Project Consortium, Exome Sequencing Project, and Exome Aggregation Consortium). The clinical presentation, imaging features, and molecular findings were considered, and the patient was diagnosed with Proteus syndrome.

All procedures in this study were performed in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was provided by the patient’s legal guardians for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Proteus syndrome is a rare congenital hamartomatous disorder caused by somatic activating mutations in the AKT1 gene, a key regulator within the signaling pathway that controls cellular growth, proliferation, and apoptosis. These mutations result in constitutive activation of the AKT1 protein, leading to dysregulated cell growth and excessive tissue proliferation. The condition is characterized by multifocal tissue overgrowth involving all three germ layers (1). We report a case with comprehensive, genetically confirmed Proteus syndrome data with complete records and long-term follow-up, which is relatively rare in the existing literature. Multitissue variant allele fraction analysis indicated that the patent had a Proteus syndrome subtype characterized by a specific aggressive phenotypic combination.

Biesecker et al. (4) proposed specific diagnostic criteria for Proteus syndrome, which can be divided into general and specific criteria. The general criteria include mosaic distribution of lesions, sporadic occurrence, and slow disease progression. The specific criteria are further subdivided into categories A to C. Category A is characterized by the presence of cerebriform connective tissue nevi, which are considered pathological hallmarks. Category B involves disproportionate overgrowth of musculoskeletal or visceral tissues, accompanied by epidermal nevi, as well as specific tumors such as ovarian cystadenomas and monomorphic adenomas of the parotid gland, with onset required before the age of 30 years. Category C encompasses abnormalities in adipose tissue, vascular malformations, bullous pulmonary degeneration, and facial dysmorphism. A diagnosis of Proteus syndrome requires meeting all general criteria, along with either two category B criteria, three category C criteria, or all category A criteria. Our case meets all general criteria and one category B criterion (asymmetric musculoskeletal overgrowth) and three category C criteria (abnormal adipose tissue, vascular malformations, and bullous pulmonary degeneration), indicating a clinical diagnosis of Proteus syndrome (4).

Genetic testing provides definitive molecular confirmation of the disorder. The pathogenic AKT1 mutation VAF detected in our case was 8.15% (11/135 reads), a level consistent with the typical somatic mosaicism of Proteus syndrome. This finding aligns with the range of mosaic allele frequencies (10–33%) reported in clinical studies of AKT1-related overgrowth disorders (5,6). As a classic mosaic overgrowth syndrome, Proteus syndrome is driven by postzygotic AKT1 mutations (c.49G>A, p.Glu17Lys variant) that arise during early embryonic development, resulting in mosaic layers that exhibit significant inter- and intratissue variation in affected individuals. The AKT1 mosaic VAF in Proteus syndrome lesions ranges from approximately 1% to 30%, with lower VAFs commonly found in mildly affected tissues and higher VAFs (≥15%) in severely overgrown or malformed tissues (7,8). The observed VAF of 8.15% falls within this established range, further confirmed the patient’s somatic mutation. In genetic testing, due to a desire to detect variants as quickly as possible, sample pooling was performed. Ideally, separate testing would be conducted, but this was not feasible due to sample volume limitations. This represents a limitation of the genetic testing in this case. For similar patients in the future, we will perform separate sample testing to improve the accuracy of the results.

A hallmark of Proteus syndrome is the progressive nature of its clinical manifestations. In individuals with Proteus syndrome, disease progression can be defined as a no-uniform, unpredictable multisystem evolution, characterized at its core by mosaic growth dysregulation caused by somatic AKT1 gene mutations. The clonal expansion of mutated cells directly drives progressive abnormalities in affected tissues. Clinical manifestations are multisystemic, progressive, and heterogeneous, meaning that the skeletal system (asymmetric overgrowth and deformities), soft tissues (lipomas and fibromas), skin (epidermal nevi), and vascular system (malformations and dilation) can be involved independently or simultaneously. Growth patterns vary significantly both between and within individuals, often presenting as irreversible, accelerated overgrowth or structural destruction (such as rapidly worsening scoliosis) following relatively stable periods. Disease progression ultimately manifests as the emergence or worsening of secondary complications, including joint dysfunction, cardiopulmonary impairment due to spinal deformities, vascular complications (thrombosis and embolism), and increased tumor risk. Specific physiological stages (such as puberty) often become significant periods of accelerated progression, when hormonal changes may promote the clonal advantage of mutated cells, leading to previously subtle or latent phenotypes becoming widespread and severe in a short time. In our case, the rapid progression of scoliosis observed on imaging, alongside the simultaneous emergence of cystic air spaces in the lungs (emphysematous changes), exemplified the typical pattern of multisystem, progressive structural destruction. The patient also exhibited the characteristic progressive evolution, with clinical manifestations including asymmetrical limb overgrowth, hand deformities with digital enlargement, cranial hyperostosis, multiple facial exostoses, scoliosis, and scrotal swelling. Symptom onset occurred in early childhood and further manifested during adolescence, which was followed by a progressive disease course (9-11). The patient had a prior history of resection for a dorsal foot vascular tumor, after which progressive skeletal overgrowth deformities developed. Imaging studies revealed distinctive features, including limb length discrepancy, bilateral hand bone hyperplasia and enlargement, significant scoliosis, emphysematous changes in the lungs, and excessive deposition of osseous and subcutaneous adipose tissue. These constituted a progressive evolution, with documented worsening of scoliosis and skeletal deformities. Comparative analysis of full-spine X-rays taken 4 years apart confirmed progressive worsening of spinal curvature, specifically an increase in the Cobb angle of scoliosis, increased rotation of some vertebrae, narrowing of intervertebral spaces, and increased irregularity of vertebral margins as compared to previous findings. Furthermore, generalized vascular dilation was observed throughout the body. Although the patient presented with scrotal swelling, this was attributed to venous and lymphatic anomalies leading to scrotal effusion. In male patients with Proteus syndrome, the incidence of paratesticular tumors can reach 19%, and these tumors exhibit a unique histological spectrum and molecular basis. Matoso et al. conducted a retrospective analysis on 12 molecularly confirmed cases and found that these tumors often originate from Müllerian epithelial differentiation commonly test positive for PAX8, WT1, and hormone receptors and almost invariably harbor the AKT1 c.49G>A activating mutation. Notably, half of the patients experienced recurrence or developed new contralateral lesions, indicating that close, long-term follow-up is necessary even when the initial pathology is benign (12). MRI revealed abnormal signal intensities within the nervous system, intraosseous fat deposition, and alterations in skeletal muscle and soft tissues. Chest CT more clearly delineated emphysematous changes and pulmonary cysts. In a study, quantifying chest CT findings in patients with Proteus syndrome, Ours et al. (13). confirmed that associated lung disease is progressive, with cystic lesion evolution correlating with the overall rate of disease progression (14). Thus, imaging examinations play a crucial role in the diagnosis, longitudinal assessment, and management of Proteus syndrome.

Proteus syndrome exhibits a broad phenotypic spectrum, necessitating differential diagnosis from several other overgrowth and hamartomatous disorders, including PTEN hamartoma tumor syndrome (PHTS), CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies syndrome) syndrome, Klippel-Trénaunay syndrome (KTS), and neurofibromatosis (NF). PHTS is a highly heterogeneous autosomal dominant disorder characterized by systemic involvement. In contrast, Proteus syndrome demonstrates a mosaic pattern of involvement, typically of only certain regions of the body. Pediatric PHTS commonly manifests developmental delay, intellectual disability, autism spectrum disorder, and macrocephaly and is associated with an elevated lifetime risk of malignant transformation. Due to its nonspecific and variable early manifestations, PHTS is frequently misdiagnosed in childhood, with many patients receiving a definitive diagnosis only after developing multiple tumors in adulthood (15,16). CLOVES syndrome is an overgrowth disorder caused by somatic gain-of-function mutations in the PIK3CA gene, which plays a critical role in regulating cellular proliferation. Its principal manifestations comprise congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal abnormalities such as scoliosis. Distinct from Proteus syndrome, which is driven by AKT1 mutations, CLOVES syndrome results from PIK3CA activation. Clinically, this is reflected in the early presentation of many abnormalities during the neonatal period. Although certain features may evolve over time, a significant proportion of manifestations are already present at birth. Surgical intervention involving the hands or feet in patients with CLOVES syndrome may trigger accelerated osseous overgrowth, mimicking the hyperostotic features observed in Proteus syndrome (16). A highly characteristic finding in CLOVES syndrome is the presence of a broad, midline lipomatous mass in the thoracoabdominal region, frequently associated with specific spinal anomalies. This feature serves as a critical discriminator in the differential diagnosis of Proteus syndrome. KTS is a rare congenital disorder caused by somatic mutations in the PIK3CA gene. It is classically characterized by a triad of capillary malformations, venous and/or lymphatic anomalies, and limb overgrowth. Typical clinical manifestations include cutaneous capillary malformations (port-wine stains), venous malformations, and soft-tissue and bony hypertrophy. In contrast to Proteus syndrome, which frequently involves truncal skeletal deformities, KTS often has no significant axial involvement (17). NF is an autosomal dominant disorder categorized into type 1 (NF1) and type 2 (NF2) based on distinct phenotypes and genetic etiology. NF1 is characterized by the development of neurofibromas, extensive cutaneous involvement, and a range of systemic complications. In contrast, NF2 is defined by the presence of schwannomas, particularly bilateral vestibular schwannomas, with milder cutaneous manifestations and predominant involvement of the nervous system and eyes. Patients with NF1 are at increased risk of developing both low- and high-grade gliomas. Cutaneous café-au-lait macules are often the initial clinical sign. Additional diagnostic features include axillary or inguinal freckling, melanocytic iris hamartomas (Lisch nodules), spinal scoliosis, sphenoid wing dysplasia, congenital tibial dysplasia, and localized osseous defects. These multisystem manifestations necessitate differentiation from the skeletal and cutaneous abnormalities observed in Proteus syndrome. NF2 primarily manifests with bilateral vestibular schwannomas and is frequently associated with other benign tumors such as meningiomas, retinal hamartomas, and various peripheral nerve sheath tumors (18). The neoplastic manifestations observed in this case of Proteus syndrome necessitate careful differential diagnosis.

Although the imaging evaluation in this patient was comprehensive, a limitation of this study is the absence of Sanger sequencing for independent validation of the identified variant. However, it is worth noting that technological advancements have established whole-exome sequencing as a methodology capable of providing conclusive genetic evidence. The genetic analysis in this case was performed on pooled tissue samples rather than on individually segregated anatomical specimens. This approach, while precluding the precise determination of the mosaic distribution across distinct lesions, was adopted as a cost-effective and time-efficient diagnostic strategy. Future studies with optimized resources may benefit from analyzing separate tissue samples to precisely delineate the spatial pattern of somatic mosaicism.

The treatment strategy for this case primarily centered on symptom control, with the core emphasis on suppressing pathological bone overgrowth. Treatment decisions and management measures for the patient were as follows:

• Treatment decision
  • Symptomatic and supportive care as the main approach: there is currently no curative therapy available. For this case, the primary goal was to control rapidly progressing complications.
  • Surgical intervention: surgical excision was performed for the scrotal mass and finger masses in both hands. For progressive and potentially disabling scoliosis, an orthopedic evaluation was initiated; however, due to the child’s poor cardiopulmonary function, staged spinal fusion surgery could not be conducted. Mainly, symptomatic and supportive treatments were provided to protect cardiopulmonary function.
  • Prevention of complications: for extensive vascular abnormalities, regular monitoring and anticoagulation prophylaxis were implemented to reduce the risk of deep vein thrombosis and pulmonary embolism.
• Long-term management plan
  • Multidisciplinary team follow-up: a fixed follow-up schedule (every 3–6 months was established.
  • Imaging surveillance plan: an individualized imaging surveillance schedule was developed, including annual whole-spine X-rays, low-dose chest CT (for monitoring emphysema), and targeted vascular ultrasound.
  • Functional and quality-of-life assessment: regular pulmonary function tests, pain assessments, and activities of daily living evaluations were conducted at our pediatric hospital to comprehensively evaluate disease burden and treatment response.
  • Genetic counseling and family support: detailed genetic counseling has been provided to the patient and family, and connections have been made with patient support organizations.

In summary, despite the rarity and phenotypic heterogeneity of Proteus syndrome, adherence to established diagnostic criteria and systematic differentiation from related overgrowth syndromes can facilitate accurate diagnosis. The diagnostic process relies primarily on comprehensive clinical evaluation and characteristic imaging findings, with confirmatory genetic testing serving as a definitive adjunct.

Acknowledgments

None.

Footnote

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2431/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was provided by the patient’s legal guardians for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Rostagni OM, Early CL, Hodges MB, Obasohan JO, Sapp JC, Livinski AA, Biesecker LG, Ours CA. Tumour spectrum in AKT1-related Proteus syndrome: a systematic review of clinical reports and series. J Med Genet 2025;62:74-81. [Crossref] [PubMed]
2. Klimeczek-Chrapusta MK, Kachnic M, Chrapusta A. Proteus Syndrome: Case Report and Updated Literature Review. Arch Plast Surg 2024;51:423-31. [Crossref] [PubMed]
3. Cohen MM Jr. Proteus syndrome review: molecular, clinical, and pathologic features. Clin Genet 2014;85:111-9. [Crossref] [PubMed]
4. Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr, Viljoen DL, Cohen MM Jr. Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet 1999;84:389-95. [Crossref] [PubMed]
5. Tian W, Huang Y, Sun L, Guo Y, Zhao S, Lin M, et al. Phenotypic and genetic spectrum of isolated macrodactyly: somatic mosaicism of PIK3CA and AKT1 oncogenic variants. Orphanet J Rare Dis 2020;15:288. [Crossref] [PubMed]
6. Lindhurst MJ, Brinster LR, Kondolf HC, Shwetar JJ, Yourick MR, Shiferaw H, Keppler-Noreuil KM, Elliot G, Rivas C, Garrett L, Gomez-Rodriguez J, Sebire NJ, Hewitt SM, Schwartzberg PL, Biesecker LG. A mouse model of Proteus syndrome. Hum Mol Genet 2019;28:2920-36. [Crossref] [PubMed]
7. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 2011;365:611-9. [Crossref] [PubMed]
8. Cytrynbaum C, Choufani S, Weksberg R. Epigenetic signatures in overgrowth syndromes: Translational opportunities. Am J Med Genet C Semin Med Genet 2019;181:491-501. [Crossref] [PubMed]
9. Mirmomen SM, Arai AE, Turkbey EB, Bradley AJ, Sapp JC, Biesecker LG, Sirajuddin A. Cardiothoracic imaging findings of Proteus syndrome. Sci Rep 2021;11:6577. [Crossref] [PubMed]
10. Khaladkar SM, Jhala NA, Krishnani KS, Durgi EC. Proteus Syndrome: A Rare Congenital Disorder. Cureus 2024;16:e60072. [Crossref] [PubMed]
11. Biesecker LG, Sapp JC. Proteus Syndrome. In: Adam MP, Feldman J, Mirzaa GM, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; August 9, 2012.
12. Matoso A, Vang R, Xing D, Killian JK, Meltzer PS, Keppler-Noreuil KM, Redick C, Biesecker LG, Ours CA. Characterizing Paratesticular Neoplasms in Proteus Syndrome. Am J Surg Pathol 2026;50:326-37. [Crossref] [PubMed]
13. Ours CA, Buser A, Hodges MB, Chen MY, Sapp JC, Gochuico BR, Biesecker LG. Quantification of Proteus syndrome-associated lung disease. Orphanet J Rare Dis 2024;19:44. [Crossref] [PubMed]
14. Macken WL, Tischkowitz M, Lachlan KL. PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature. Am J Med Genet C Semin Med Genet 2019;181:591-610. [Crossref] [PubMed]
15. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet 2008;16:1289-300. [Crossref] [PubMed]
16. Kanji A, Cobben J, Laguda B. CLOVES Syndrome. JAMA Dermatol 2023;159:659-60. [Crossref] [PubMed]
17. Turner VL, Kearns C, Wattamwar K, McKenney AS. Klippel-Trenaunay Syndrome. Radiographics 2022;42:E167-8. [Crossref] [PubMed]
18. Farschtschi S, Mautner VF, McLean ACL, Schulz A, Friedrich RE, Rosahl SK. The Neurofibromatoses. Dtsch Arztebl Int 2020;117:354-60. [Crossref] [PubMed]