Primary cutaneous malignant melanoma in Rett syndrome: Report of a case with nuclear features resembling herpes simplex virus cytopathic effects—a hitherto unrecognized morphological variant

Rett syndrome (RTT) is a progressive neurological disorder, affecting females with mutations in the X‐linked gene methyl‐CpG‐binding protein 2 (MECP2). While MECP2 has been implicated in cancers of the breast, colon, and prostrate, cancer in patients with RTT is rare. We present a case of malignant melanoma in a patient with RTT, which additionally, displayed hitherto undescribed nuclear features, resembling herpes simplex virus cytopathic effects.


| INTRODUCTION
Methyl-CpG-binding protein (MECP2) is an X-chromosome-linked gene. Since its discovery over two decades ago, it has been implicated in pathological conditions linked with Rett syndrome (RTT) 1 and other disorders including autism, neonatal encephalopathy, and X-linked retardation. 2 Cancers in patients with RTT have been occasionally documented, 3 and mutations in MECP2 gene are thought to be associated with breast, colon, and prostate cancers. 2 We describe herein a patient with RTT who presented with a subungual melanoma. The nuclear features of the melanoma, resembling herpes simplex virus (HSV) inclusions, were unusual and have not been described in melanomas previously.  F I G U R E 3 Higher power view reveals the highly unusual nuclear morphology (hematoxylin-eosin ×400) F I G U R E 5 S100 highlighting the malignant melanocytes (×200) F I G U R E 6 Herpes simplex virus (HSV) immunostain is negative (×100) analysis was negative for BRAF or NRAS mutations. Her staging computed tomography imaging did not reveal any metastatic focus.

| CASE REPORT
Following the surgery, the patient was followed up every 3 months for 3 years. During this period, her caretakers were asked to examine her axilla on a regular basis, as physical examination was deemed to be difficult during her follow-up visits. Unfortunately, 3 years postsurgery, the patient developed multiple subcutaneous deposits of metastatic melanoma in the breast, back, left axilla, and left lower abdominal wall. Due to her severe autism, she was not considered to be a candidate for systemic therapy and is currently managed conservatively.

| DISCUSSION
We describe a rare case of malignant melanoma in a patient with RTT. Initially described by Andreas Rett, an Austrian pediatric neurologist in 1966, 4 RTT is a progressive neurodevelopmental disorder, caused by mutations in the X-linked gene MECP2, a ubiquitously expressed transcriptional regulator. 5 It is one of the most common causes of mental retardation in females. 1 There are limited options for treatment and most of these are based around symptom relief. 5

Malignancy in patients with
RTT is documented in rare case reports, 3 although recent studies have described an additional role for MECP2 during carcinogenesis. 6,7 As far as we are aware, melanoma in RTT has never been reported previously.
Interestingly, our case also showed a previously undescribed morphological variant, with nuclear features resembling HSV cytopathic effects.
It is well known that malignant melanoma has various histopathological morphologies, some more common than others. [8][9][10][11] Our case adds to these morphological variants, where the tumor nuclei display ground glass appearance with chromatin margination, nuclear molding and multinucleation-features that are usually associated with HSV cytopathic effects in keratinocytes. The cause for this highly unusual morphology is unclear, but in the context of the patient's clinical background, one is inclined to propose that the presence of mutations in MECP2 may have played a role. The exact mechanism is uncertain, but as MECP2 is considered as a predicted epigenetic regulator, it is possible that the unusual nuclear changes may have arisen from defects in the epigenetic mechanisms resulting from MECP2 mutations. As more cancer cases are reported in patients with RTT, further studies highlighting the role of MECP2 gene in the etiology of malignancies in these patients may illuminate the molecular basis of this highly unusual morphology.

ACKNOWLEDGMENT
Open Access funding provided by Qatar National Library.

CONFLICT OF INTEREST
The authors declare no potential conflict of interest.