The Term “Dermal Hyperneury” Hits a Nerve

By Warren R. Heymann, MD
Dec. 21, 2017

 

I was intrigued by the title “Dermal hyperneury and multiple sclerotic fibromas in multiple endocrine neoplasia type 2A spectrum” by Alegría-Landa et al. (1) [Please see the addendum for the definition of the multiple endocrine neoplasia (MEN) syndromes.]

I am familiar with “neural hypertrophy” or “neural hyperplasia” that has been described in prurigo nodularis (2) and chondrodermatitis nodularis helicis chronica (3), respectively, but what is “dermal hyperneury”?
 
Dermal hyperneury has been defined as the presence of increased and hypertrophic myelinated and nonmyelinated nerve fibers in the dermis. Cutaneous nerve hyperplasia is rare and can be seen in lesional skin in localized or multifocal forms. It may also have syndromic associations. (4) The term has also been used to describe the profusely sprouting peripheral nerve fascicles in a blue nevus-like neurocristic hamartoma. (5)

Watson et al presented the case of a 75 year-old woman with a 4 year history of a pruritic rash, unresponsive to potent topical steroids and phototherapy. These lesions were initially considered to be insect bites that appeared after a vacation — she was certain that subsequent lesions were not bites. The lesions were described as tumid papules and nodules. Histologically, neural hypertrophy associated with a superficial and deep perineural and perivascular chronic inflammatory infiltrate of lymphocytes, with occasional plasma cells and eosinophils, was observed. Infectious etiologies were ruled out, and the diagnosis of dermal hyperneury was rendered. (6) This presentation differs from other reports of dermal hyperneury because of the ample inflammation noted with the neural changes.
 
Winkelmann and Carney studied the normal skin of seven patients with multiple endocrine neoplasia type 2B (MEN 2B) and demonstrated abnormalities of the cutaneous nerves that were comparable to changes in the mucosa, gastrointestinal tract, and eye. They found an increase in masses of mixed (myelinated and nonmyelinated) nerves. Electron microscopy showed axonal organelles, mild degeneration of the axons, and numerous axons unassociated with Schwann cells. The authors stated: “Generally, the nerve fascicles were uniformly larger than normal dermal nerve from the same level, but some showed abrupt changes in diameter, and some also showed mild internal disorganization, as in a neuroma.” (7)

Schaffer et al described a 5-year-old boy with macrocephaly, prominent corneal nerves, and progressive development of approximately 15, 2 to 6 mm, painful, dome-shaped, translucent pink to skin-colored papules on the vermilion portion of the upper lip, fingers, palms, and shins. Histologic evaluation demonstrated dermal proliferation of well-demarcated nerve bundles associated with abundant mucin and surrounded by a distinct perineural sheath, findings diagnostic of a nonencapsulated neuroma. Genetic analysis revealed a novel heterozygous germline nonsense mutation in PTEN, predicted to result in a truncated PTEN protein. Apparently this was the first report of multiple neuromas as the sole mucocutaneous manifestation of a PTEN hamartoma-tumor syndrome (PHTS, including Cowden, Bannayan-Riley-Ruvalcaba, and Proteus-like syndromes). The authors concluded that along with MEN 2B, PHTS should be considered in the differential diagnosis of multiple mucocutaneous neuromas, particularly those involving extrafacial sites. (8)
 
Alegría-Landa studied a kindred of 11 individuals with the familial medullary thyroid carcinoma variant of MEN 2B syndrome demonstrating a moderate risk RET p.Val804Met (protein valine at residue 804 replace by methionine) genetic mutation. Two family members had “dermal hyperneury” lesions characteristically seen in MEN 2B; 1 family member also showed multiple sclerotic fibromas, a cutaneous manifestation previously described in PHTS, but not in MEN 2A syndrome. The authors concluded that the PTEN hamartoma-tumor and multiple endocrine neoplasia type 2 syndromes show considerable overlap in the signaling pathways regulated by PTEN and RET genes, respectively, which may explain the clinical overlap between the 2 syndromes. (1)

These outstanding articles by Schaffer et al and Alegría-Landa et al beautifully demonstrate how genetic molecular pathways overlap, affirming the limitations of diagnosing syndromes based solely on phenotypic expression.

My difficulty, however, remains with the term “dermal hyperneury.” Both patients’ lesions in Alegría-Landa et al (mother and daughter), were described as “slightly tender, hyperpigmented, 3-to-5 mm diameter papules on the trunk and forearms. The lesions showed a linear configuration along the lines of skin tension.” Based on the figure presented, these truncal papules are distinct lesions.

As a clinician and dermatopathologist, I appreciate the concept of a “spectrum of disease” or disorders that may present as a “forme fruste”. In my estimation, the term “dermal hyperneury” obfuscates rather than clarifies. Even if there are slight variations in their clinical or histologic presentations, it is hard to fathom that the “nonencapsulated neuromas” of Schaffer et al are significantly distinct from the “dermal hyperneury” of  Alegría-Landa et al. Regardless, both are clearly differentiated from the other cases of “dermal hyperneury” that are non-syndromal or inflammatory.
 
I am willing to add “dermal hyperneury” to my vocabulary if I can be convinced that it is a reproducible, well-defined entity. For now, I will continue with my current lexicon of “neural hyperplasia/hypertrophy” and “neuroma.”

1. Alegría-Landa V, et al. Dermal hyperneury and multiple sclerotic fibromas in multiple endocrine neoplasia type 2A spectrum. JAMA Dermatol 2017; 153: 1298-1301.
2. Lee MR, Shumack S. Prurigo nodularis: A review. Australas J Dermatol 2005; 46: 211-20.
3. Cribier B, et al. Neural hyperplasia in chondrodermatitis nodularis chronica helicis. J Am Acad Dermatol 2006; 55: 844-8.
4. Ieremia E, et al. The spectrum of dermal hyperneury. Report of six cases. Br J Dermatol 2014; 171 (Suppl): 90.
5. Karamitopoulou-Diamantis E, et al. Cutaneous neurocristic hamartoma with blue-naevus-like features and plexiform dermal hyperneury. Histopathology 2006; 49: 326-8.
6. Watson N, et al. Dermal hyperneury: A rare but increasingly recognized entity. Clin Exp Dermatol 2017; 42: 200-19.
7. Winkelmann RK, Carney JA. Cutaneous neuropathology in multiple endocrine neoplasia, type 2b. J Invest Dermatol 1982; 79: 307-12.
8. Schaffer JV, et al. Mucocutaneous neuromas: A underrecognized manifestation of PTEN hamartoma-tumor syndrome. Arch Dermatol 2006; 142: 625-32.


Addendum (from Stratakis CA. Hereditary syndromes predisposing to endocrine tumors and their skin manifestations. Rev Endocr Metab Disord 2016; 381-8)

MEN type 1 is an autosomal dominant disorder with variable penetrance characterized by tumors of the parathyroids, anterior pituitary, pancreas, other locations of the gastrointestinal tract, and other tissues. The MEN1 gene codes for the protein menin and is located on chromosome 11q13.

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