Proteus Syndrome: Description of Two Clinical Cases

Background. Proteus syndrome is extremely rare congenital multisystem disease with high variability in clinical manifestations. Its prevalence is unknown, there are less than 200 cases in the world literature. The syndrome is a classic example of somatic mosaicism, and all target drugs for its management are based on it. Clinical case description. This article describes two clinical cases with somatic variants of the nucleotide sequence in the AKT1 gene, mosaic form, revealed by the NGS method. Target drug (mTOR-inhibitors group) was assigned in one case. Conclusion. The description of the phenotypic features of patients with Proteus syndrome is crucial as this pathology is very rare. It is necessary to increase the awareness of clinicians about this disease to develop a plan for dynamic follow-up with consideration to life-threatening complications (malignant tumors and thrombembolia risk). Genetic verification of Proteus syndrome is mandatory nowadays as target therapy is actively developed and implemented, thus, revision of clinical guidelines is recommended.

1. Biesecker LG, Sapp JC. Proteus Syndrome. 2012 Aug 9 [updated 2023 May 25]. In: GeneReviews® [Internet]. Adam MP, Feldman J, Mirzaa GM, et al., eds. Seattle (WA): University of Washington, Seattle; 1993–2024.

2. Sapp JC, Hu L, Zhao J, et al. Quantifying survival in patients with Proteus syndrome. Genet Med. 2017;19(12):1376–1379. doi: https://doi.org/10.1038/gim.2017.65

3. Khaladkar SM, Jhala NA, Krishnani KS, Durgi EC. Proteus Syndrome: A Rare Congenital Disorder. Cureus. 2024;16(5):e60072. doi: https://doi.org/10.7759/cureus.60072

4. Sideris G, Nikolopoulos T, Sourla A, et al. Sinonasal Neuroendocrine Carcinoma in Adult Proteus Syndrome. Iran J Otorhinolaryngol. 2023;35(131):321–324. doi: https://doi.org/10.22038/IJORL.2023.73128.3472

5. Semyachkina AN, Novikov PV, Voinova VYu, et al. Proteus syndrome in children: diagnosis, treatment, prevention. Russian Bulletin of Perinatology and Pediatrics. 2007;52(1):45–9. (In Russ).

6. Ilyina HG, Eschova-Pavlova AA, Boyscha AS, et al. Severe Proteus syndrome in a newborn. Medical Genetics. 2009;8(7):39–41. (In Russ).

7. Elizarova TV, Zryachkin NI, Khmilevskaya SA, et al. Proteus syndrome in a child aged 14 years and 11 months. Almanac of Clinical Medicine. 2017;45(1):56–61. (In Russ). doi: https://doi.org/10.18786/2072-0505-2017-45-1-56-61

8. Kryuchkova TA. Klinicheskii sluchai sindroma Proteya u rebenka rannego vozrasta. Research Results in Biomedicine. 2019;5(3):15–23. (In Russ). doi: https://doi.org/10.18413/2658-6533-2019-5-3-0-3

9. Nikolaeva IE, Rayanova RR, Yakovleva LV. A case of myocardial hypertrophy in Proteus syndrome. Bashkortostan Medical Journal. 2020;15(5): 85–88. (In Russ)

10. Aleksandrov TI, Prokhorenko VM, Chorniy SI, Simonova EN. Treatment of a patient with local gigantism of the upper limb: Proteus syndrome (case report). Modern problems of science and education. 2022;(6-1). (In Russ). doi: https://doi.org/10.17513/spno.32228

11. Stozhkova IV, Pchelenok EV, Kosiakov SIa. Proteus syndrome in the practice of an otorhinolaryngologist: a clinical case. Russian Bulletin of Otorhinolaryngology. 2020;85(2):45–48. (In Russ). doi: https://doi.org/10.17116/otorino20208502145

12. Cohen MM Jr, Hayden PW. A newly recognized hamartomatous syndrome. Birth Defects Orig Artic Ser. 1979;15(5B):291–296.

13. Wiedemann HR, Burgio GR, Aldenhoff P, et al. The proteus syndrome. Partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies and possible accelerated growth and visceral affections. Eur J Pediatr. 1983;140(1):5–12. doi: https://doi.org/10.1007/BF00661895

14. The “Elephant Man,” Illustrated. South Med Rec. 1887; 17(5):191–193.

15. Tibbles JA, Cohen MM Jr. The Proteus syndrome: the Elephant Man diagnosed. Br Med J (Clin Res Ed). 1986;293(6548):683–685. doi:https://doi.org/10.1136/bmj.293.6548.683

16. Goodship J, Redfearn A, Milligan D, et al. Transmissionof Proteus syndrome from father to son? J Med Genet. 1991;28(11):781–785. doi: https://doi.org/10.1136/jmg.28.11.781

17. Cohen MM Jr. Proteus syndrome: clinical evidence for somatic mosaicism and selective review. Am J Med Genet. 1993;47(5): 645–652. doi: https://doi.org/10.1002/ajmg.1320470514

18. Zhou XP, Marsh DJ, Hampel H, et al. Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis. Hum Mol Genet. 2000;9(5): 765–768. doi: https://doi.org/10.1093/hmg/9.5.765

19. Waite KA, Eng C. Protean PTEN: Form and Function. Am J Hum Genet. 2002;70(4):829–844. doi: https://doi.org/10.1086/340026

20. Lindhurst MJ, Sapp JC, Teer JK, et al. A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome. N Engl J Med. 2011;365(7):611. doi: https://doi.org/10.1056/NEJMoa1104017

21. Buser A, Lindhurst MJ, Kondolf HC, et al. Allelic heterogeneity of Proteus syndrome. Cold Spring Harb Mol Case Stud. 2020;6(3):a005181. doi: https://doi.org/10.1101/mcs.a005181

22. Mundi PS, Sachdev J, McCourt C, Kalinsky K. AKT in Cancer: New Molecular Insights and Advances in Drug Development. Br J Clin Pharmacol. 2016;82(4):943–956. doi: https://doi.org/10.1111/bcp.13021

23. Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, et al. Pharmacodynamic Study of Miransertib in Individuals with Proteus Syndrome. Am J Hum Genet. 2019;104(3):484–491. doi: https:// doi.org/10.1016/j.ajhg.2019.01.015

24. Biesecker LG, Edwards M, O’Donnell S, et al. Clinical report: one year of treatment of Proteus syndrome with miransertib (ARQ 092). Cold Spring Harb Mol Case Stud. 2020;6(1):a004549. doi: https://doi.org/10.1101/mcs.a004549

25. Ours CA, Sapp JC, Hodges MB, et al. Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome. Cold Spring Harb Mol Case Stud. 2021;7(6):a006134. doi: https://doi.org/10.1101/mcs.a006134

26. Weibel L, Theiler M, Gnannt R, et al. Reduction of Disease Burden With Early Sirolimus Treatment in a Child With Proteus Syndrome. JAMA Dermatol. 2021;157(12):1514–1516. doi: https://doi.org/10.1001/jamadermatol.2021.4305

27. Nguyen D, Turner JT, Olsen C, et al. Cutaneous manifestations of proteus syndrome: correlations with general clinical severity. Arch Dermatol. 2004;140(8):947–953. doi: https://doi.org/10.1001/archderm.140.8.947

28. Sapp JC, Buser A, Burton-Akright J, et al. A dyadic genotypephenotype approach to diagnostic criteria for Proteus syndrome. Am J Med Genet C Semin Med Genet. 2019;181(4):565–570. doi: https://doi.org/10.1002/ajmg.c.31744

29. Sachdeva P, Minocha P, Jain R, et al. Proteus Syndrome with Neurological Manifestations: A Rare Presentation. J Pediatr Neurosci. 2017;12(1):109–111. doi: https://doi.org/10.4103/jpn.JPN_139_16

30. Gordon PL, Wilroy RS, Lasater OE, Cohen MM Jr. Neoplasms in Proteus syndrome. Am J Med Genet. 1995;57(1):74–78. doi: https://doi.org/10.1002/ajmg.1320570117

31. Slavotinek AM, Vacha SJ, Peters KF, Biesecker LG. Sudden death caused by pulmonary thromboembolism in Proteus syndrome. Clin Genet. 2000;58(5):386–389. doi: https://doi.org/10.1034/j.1399-0004.2000.580509.x

32. Mohammedbhai R, Hassan Miyan AM, Lacombe D. Neonatal Proteus syndrome? Am J Med Genet. 2002;112(2):228–230. doi: https://doi.org/10.1002/ajmg.10650

33. Ram S, Noor AR. Neonatal Proteus syndrome. Am J Med Genet. 1993;47(2):303. doi: https://doi.org/10.1002/ajmg.1320470233

34. Abell K, Tolusso L, Smith N, et al. Prenatal diagnosis of Proteus syndrome: Diagnosis of an AKT1 mutation from amniocytes. Birth Defects Res. 2020;112(19):1733–1737. doi: https://doi.org/10.1002/bdr2.1801