March 2024 Case Study

March 2024 Case Study

Authors: Cleo Whiting, BA¹, Emily Murphy, MD¹, Karl Saardi, MD¹

1. Department of Dermatology, George Washington University School of Medicine and Health Sciences

A 57-year-old female with a past medical history of hypertension presented with numerous pink to skin-colored, soft, mildly tender papules and nodules on the right posterior shoulder, upper arm, and forearm (figure 1A and 1B) that appeared 15 years ago. She also complained of several deeper and larger growths on the bilateral thighs and left hip that appeared a few years ago. A shave biopsy of one of the papules was performed (figure 2A and 2B, hematoxylin-eosin staining). Immunohistochemistry was positive for S100 and negative for smooth muscle actin. A buccal swab was obtained for sequencing of the NF1 gene and the results were negative for pathogenic mutations.

Based on the clinical presentation and biopsy findings, what risks should the patient be counseled about?

A.) None, reassurance only
B.) Risk of renal cell carcinoma
C.) Risk of malignant peripheral nerve sheath tumor
D.) Potential inheritance of condition by offspring
E.) B & D
F.) C & D

Correct Answer: F

Explanation/Literature review:

Given the segmental distribution of biopsy-confirmed neurofibromas and negative genetic testing, the patient was diagnosed with mosaic neurofibromatosis type 1 (NF1). Also referred to as segmental or localized NF1, this condition results from a post-zygotic pathogenic mutation in one copy of the NF1 gene.¹ Mosaic NF1 is a rare, heterogeneous disorder characterized by localized cutaneous or neural findings typical of generalized NF1, such as neurofibromas, intertriginous freckling, and multiple, large cafe-au-lait macules.² The affected NF1 gene encodes for the tumor suppressor protein neurofibromin, a GTPase-activating protein that regulates the RAS-MAPK pathway; biallelic loss of function of NF1 leads to the development of neurofibromas and other NF1-associated tumors.³

There are no specific guidelines for the management of mosaic NF1, although individuals with this condition may experience complications typical of generalized NF1, including the transformation of plexiform neurofibromas to malignant peripheral nerve sheath tumors (MPNSTs) (choice C), so reassurance alone is not appropriate (choice A).^2,4,5 Although rare, gonadal mosaicism is also possible and offspring of the individual can acquire generalized NF1 (choice D).⁵ The diagnostic criteria for mosaic NF1 have been recently re-established, and revealing NF1 mutations in affected skin, but not in seemingly unaffected tissues like saliva and blood, is one way to make the diagnosis.⁶

While individuals with mosaic NF1 have an increased risk of malignancy during their lifetime, renal cell carcinoma is associated with hereditary leiomyomatosis and renal cell cancer [HLRCC], also known as Reed syndrome,⁷ and neurofibromatosis type 2 (choice B, E).⁸ Characterized by cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma, HLRCC is caused by a pathogenic mutation in the fumarate hydratase gene and inherited in an autosomal dominant pattern with variable penetrance.⁷

References

1. Tinschert S, Naumann I, Stegmann E, et al. Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene. Eur J Hum Genet. 2000;8(6):455-459. doi:10.1038/sj.ejhg.5200493
2. Ruggieri M, Huson SM. The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology. 2001;56(11):1433-1443. doi:10.1212/wnl.56.11.1433
3. Maertens O, De Schepper S, Vandesompele J, et al. Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1. Am J Hum Genet. 2007;81(2):243-251. doi:10.1086/519562
4. Stewart DR, Korf BR, Nathanson KL, Stevenson DA, Yohay K. Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018;20(7):671-682. doi:10.1038/gim.2018.28
5. García-Romero MT, Parkin P, Lara-Corrales I. Mosaic Neurofibromatosis Type 1: A Systematic Review. Pediatr Dermatol. 2016;33(1):9-17. doi:10.1111/pde.12673
6. Legius E, Messiaen L, Wolkenstein P, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. 2021;23(8):1506-1513. doi:10.1038/s41436-021-01170-5
7. Scharnitz T, Nakamura M, Koeppe E, et al. The spectrum of clinical and genetic findings in hereditary leiomyomatosis and renal cell cancer (HLRCC) with relevance to patient outcomes: a retrospective study from a large academic tertiary referral center. Am J Cancer Res. 2023;13(1):236-244. Published 2023 Jan 15.
8. Paintal A, Tjota MY, Wang P, et al. NF2-mutated Renal Carcinomas Have Common Morphologic Features Which Overlap With Biphasic Hyalinizing Psammomatous Renal Cell Carcinoma: A Comprehensive Study of 14 Cases. Am J Surg Pathol. 2022;46(5):617-627. doi:10.1097/PAS.0000000000001846