Phacomatosis Pigmentokeratotica: Case Study

Background. Phacomatosis pigmentokeratotica (PPK) is an orphan genodermatosis from the epidermal nevus syndrome group. This disease is caused by somatic mosaicism predominantly in the HRAS gene. Pathognomonic PPK sign is combination of congenital linear nevus sebaceus of Jadassohn and speckled lentiginous nevus. Second one may debut much later. In some cases, there are signs of nervous system damages, skeletal disorders, visual impairments. Case description. Description of a patient with PPK and novel for this disease mosaic variant G469A in the BRAF gene is presented. Clinical picture included typical signs of the syndrome and immunological disorders unusual for patients with PPK. Possible genotype-phenotype correlations were analyzed based on 16 previously published observations of genetically verified PPK. Conclusion. The syndrome rarity, its course variability, and patients genetic testing features determine the difficulties in PPK diagnosis. The disease should be considered not only in terms of dermatological signs, but also regarding comorbid disorders. The dynamic follow-up should include consultations of pediatric oncologist, neurologist, ophthalmologist, endocrinologist, orthopedist, cardiologist, and immunologist.

1. Hill VA, Felix RH, Mortimer PS, Harper JI. Phacomatosis pigmentokeratotica. J R Soc Med. 2003;96(1):30–31. doi: https://doi.org/10.1177/014107680309600109

2. Torchia D, Happle R. Phacomatosis spilosebacea: A new name for a distinctive binary genodermatosis. J Am Acad Dermatol. 2023;89(4):764–773. doi: https://doi.org/10.1016/j.jaad.2020.12.082

3. Gamayunov BN, Korotkiy NG, Baranova EE. Phacomatosis pigmentokeratotica or the Schimmelpenning-Feuerstein-Mims syndrome? Clin Case Rep. 2016;4(6):564–567. doi: https://doi.org/10.1002/ccr3.570

4. Happle R, Hoffmann R, Restano L, et al. Phacomatosis pigmentokeratotica: a melanocytic-epidermal twin nevus syndrome. Am J Med Genet. 1996;65(4):363–365. doi: https://doi.org/10.1002/(SICI)1096-8628(19961111)65:43.0.CO;2-R

5. Wauschkuhn J, Rohde B. Systematized sebaceous, pigmented and epithelial nevi with eurologic symptoms. Neuroectodermal Feuerstein Mims syndrome. Hautarzt. 1971;22(1):10–13.

6. Goldberg LH, Collins SAB, Siege1 DM. The epidermal nevus syndrome: Case report and review. Pediatr Dermatol. 1987;4(1): 27–33. doi: https://doi.org/10.1111/j.1525-1470.1987.tb00749.x

7. Stein KM, Shmunes E, Thew M. Neurofibromatosis presenting as the epidermal nevus syndrome. Arch Dermatol. 1972;105(2):229–232.

8. Brufau C, Moran M, Armijo M. Naevus sur naevus: A propos de 7 observations, trois associees a d‘autres dysplasies, et une a un melanome malin invasif. Ann Dermatol Venereal. 1986;113(5):409–418.

9. Sugarman GI, Reed WB. Two unusual neurocutaneous disorders with facial cutaneous signs. Arch Neural. 1969;21(3):242–247. doi: https://doi.org/10.1001/archneur.1969.00480150032003

10. Aschinberg LC, Solomon LM, Zeis PM, et al. Vitamin D-resistant rickets associated with epidermal nevus syndrome: Demonstration of a phosphaturic substance in the dermal lesions. J Pediatr. 1977;91(1):56–60. doi: https://doi.org/10.1016/s0022- 3476(77)80444-7

11. Goldblum JR, Headington JT. Hypophosphatemic vitamin D-resistant rickets and multiple spindle and epithelioid nevi associated with linear nevus sebaceus syndrome. J Am Acad Dermatol. 1993;29(1):109–111. doi: https://doi.org/10.1016/s0190-9622(08)81813-0

12. Gruson LM, Orlow SJ, Schaffer JV. Phacomatosis pigmentokeratotica associated with hemihypertrophy and a rhabdomyosarcoma of the abdominal wall. J Am Acad Dermatol. 2006;55(2 Suppl):S16–S20. doi: https://doi.org/10.1016/j.jaad.2005.08.045

13. Prieto-Barrios M, Llamas-Martin R, Velasco-Tamariz V, et al. Phacomatosis pigmentokeratotica: a case of HRAS mosaicism causing rhabdomyosarcoma. Br J Dermatol. 2018;179(5): 1163–1167. doi: https://doi.org/10.1111/bjd.16435

14. Jacobelli S, Leclerc-Mercier S, Salomon R, et al. Phacomatosis pigmentokeratotica with nephroblastoma and juvenile hypertension. Acta Derm Venereol. 2010;90(3):279–282. doi: https://doi.org/10.2340/00015555-0824

15. Bouthors J, Vantyghem MC, Manouvrier-Hanu S, et al. Phacomatosis pigmentokeratotica associated with hypophosphataemic rickets, pheochromocytoma and multiple basal cell carcinomas. Br J Dermatol. 2006;155(1):225–226. doi: https://doi.org/10.1111/j.1365-2133.2006.07313.x

16. Vidaurri-de la Cruz H, Tamayo-Sánchez L, Durán-McKinster C, et al. Epidermal nevus syndromes: clinical findings in 35 patients. Pediatr Dermatol. 2004;21(4):432–439. doi: https://doi.org/10.1111/j.0736-8046.2004.21402.x

17. Garcıa de Jalon A, Azua-Romeo J, Trivez MA, et al. Epidermal naevus syndrome (Solomon’s syndrome) associated with bladder cancer in a 20-year-old female. Scand J Urol Nephrol. 2004;38(1): 85–87. doi: https://doi.org/10.1080/00365590310017316

18. Martínez-Menchón T, Mahiques Santos L, Vilata Corell JJ, et al. Phacomatosis pigmentokeratotica: a 20-year follow-up with malignant degeneration of both nevus components. Pediatr Dermatol. 2005;22(1):44–47. doi: https://doi.org/10.1111/j.1525-1470.2005.22110.x

19. Groesser L, Herschberger E, Sagrera A, et al. Phacomatosis pigmentokeratotica is caused by a postzygotic HRAS mutation in a pluri potent progenitor cell. J Invest Dermatol. 2013;133(8): 1998–2003. doi: https://doi.org/10.1038/jid.2013.24

20. Ayala D, Ramón MD, Martín JM, Jordá E. Atypical Phacomatosis Pigmentokeratotica as the Expression of a Mosaic RASopathy With the BRAF Glu586Lys Mutation. Actas Dermosifiliogr. 2016;107(4): 344–346. doi: https://doi.org/10.1016/j.ad.2015.07.017

21. Kuentz P, Mignot C, St-Onge J, et al. Postzygotic BRAF p.Lys601Asn Mutation in Phacomatosis Pigmentokeratotica with Woolly Hair Nevus and Focal Cortical Dysplasia. J Invest Dermatol. 2016;136(5):1060–1062. doi: https://doi.org/10.1016/j.jid.2016.01.015

22. Om A, Cathey SS, Gathings RM, et al. Phacomatosis Pigmentokeratotica: A Mosaic RASopathy with Malignant Potential. Pediatr Dermatol. 2017;34(3):352–355. doi: https://doi.org/10.1111/pde.13119

23. Li JY, Berger MF, Marghoob A, et al. Combined melanocytic and sweat gland neoplasm: cell subsets harbor an identical HRAS mutation in phacomatosis pigmentokeratotica. J Cutan Pathol. 2014;41(8):663–671. doi: https://doi.org/10.1111/cup.12339

24. Martin RJ, Arefi M, Splitt M, et al. Phacomatosis pigmentokeratotica and precocious puberty associated with HRAS mutation. Br J Dermatol. 2018;178(1):289–291. doi: https://doi.org/10.1111/bjd.15643

25. Huang L, Zhang J, Chen F, et al. The first case of Chinese phacomatosis pigmentokeratotica diagnosed by a missense HRAS mosaicism. J Dermatol. 2022;49(9):921–924. doi: https://doi.org/10.1111/1346-8138.16434

26. Wiedemeyer K, Hartschuh W. Trichoblastomas with Merkel cell proliferation in nevi sebacei in Schimmelpenning-Feuerstein-Mims syndrome — histological differentiation between trichoblastomas and basal cell carcinomas. J Dtsch Dermatol Ges. 2009;7(7): 612–615. doi: https://doi.org/10.1111/j.1610-0387.2009.07036.x

27. Torrelo A, Zambrano A. What syndrome is this. Phakomatosis pigmen tokeratotica (Happle). Pediatr Dermatol. 1998;15(4):321–323. doi: https://doi.org/10.1046/j.1525-1470.1998.1998015321.x

28. Chantorn R, Shwayder T. Phacomatosis pigmentokeratotica: a further case without extracutaneous anomalies and review of the condition. Pediatr Dermatol. 2011;28(6):715–719. doi: https://doi.org/10.1111/j.1525-1470.2011.01655.x

29. Wollenberg A, Butnaru C, Oppel T. Phacomatosis pigmentokeratotica (Happle) in a 23-year-old man. Acta Derm Venereol. 2002;82(1):55–57. doi: https://doi.org/10.1080/000155502753600911

30. Kubo A, Yamada D. Phakomatosis Pigmentokeratotica. N Engl J Med. 2019;381(15):1458. doi: https://doi.org/10.1056/NEJMicm1817155

31. Cranwell WC, Walsh M, Winship I. Phacomatosis pigmentokeratotica: Postzygotic HRAS mutation with malignant degeneration of the sebaceous naevus. Australas J Dermatol. 2019;60(3):e245–e246. doi: https://doi.org/10.1111/ajd.13007

32. Jennings L, Cummins R, Murphy GM, et al. HRAS mutation in phacomatosis pigmentokeratotica without extracutaneous disease. Clin Exp Dermatol. 2017;42(7):791–792. doi: https://doi.org/10.1111/ced.12961

33. Hayani K, Giehl K, Kumbrink J, et al. Gene Mutation Mapping in a Fatal Case of Phacomatosis Pigmentokeratotica Happle. Acta Derm Venereol. 2020;100(15):adv00241. doi: https://doi.org/10.2340/00015555-3599

34. Amayiri N, Al-Hussaini M, Maraqa B, et al. Next-generation sequencing for pediatric CNS tumors: does it add value in a middle-income country setup? Front Oncol. 2024;14:1329024. doi: https://doi.org/10.3389/fonc.2024.1329024

35. Julius K, Kromer C, Schnabel V, et al. Response of metastatic acral melanoma with exon 11 BRAF G469A mutation to BRAF/MEK inhibition. J Dtsch Dermatol Ges. 2022;20(4):528–530. doi: https://doi.org/10.1111/ddg.14737

36. Dagogo-Jack I. Durable Response to Dabrafenib Combined With Trametinib in a Patient With NSCLC Harboring a BRAF G469A Mutation. J Thorac Oncol. 2020;15(10):e174–e176. doi: https://doi.org/10.1016/j.jtho.2020.07.007

37. Di Majo BE, Leoni C, Cartisano E, et al. Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort. Front Immunol. 2025;16:1598896. doi: https://doi.org/10.3389/fimmu.2025.1598896

38. Belysheva TS, Zelenova EE, Semenova NA, et al. Proteus Syndrome: Description of Two Clinical Cases. Voprosy sovremennoi pediatrii — Current Pediatrics. 2024;23(5):343–349. (In Russ). doi: https://doi.org/10.15690/vsp.v23i5.2797

39. Lena CP, Kondo RN, Nicolacópulos T. Do you know this syndrome? Schimmelpenning-Feuerstein-Mims syndrome. An Bras Dermatol. 2019;94(2):227–229. doi: https://doi.org/10.1590/abd1806-4841.20197661

40. Ramspacher J, Carmignac V, Vabres P, Mazereeuw-Hautier J. Becker’s Naevus Syndrome with Breast Aplasia Due to Postzygotic Mutation of ACTB. Acta Derm Venereol. 2022;102:adv00806. doi: https://doi.org/10.2340/actadv.v102.1141.