Symptomatic neurocutaneous melanosis: mild clinical onset in a teenager

Abstract

Neurocutaneous melanosis (NCM) is a rare disorder characterised by giant or multiple melanocytic nevi and meningeal melanosis or melanoma. Onset of neurological symptoms is typically in children younger than 2 years and can be rapidly fatal. We present the case of a 13-year-old adopted girl presenting with numerous congenital melanocytic nevi and a seizure. She had no significant previous neurological history. Electroencephalogram showed epileptiform discharges over the right frontal region. MRI of the brain showed T1 hyperintensity in the bilateral amygdala and anterior temporal lobes with corresponding hyperintensity on T2 and fluid attenuated inversion recovery. There was no hydrocephalus. Along with the history of nevi, these imaging findings were concerning for NCM. The patient is being managed with levetiracetam and trametinib and shows no further neurological decline at 1-year follow-up, providing prognostic hope in this case of NCM.

Background

Neurocutaneous melanosis (NCM) is a rare disorder characterised by melanocytic nevi and neurological dysfunction. It was first described in 1861 in a female with a giant congenital nevus and leptomeningeal melanosis.¹ Since then, additional cases have been reported in both children and adults. A diagnosis of NCM can be made in a patient with either the presence of a single ‘giant’ nevus or more than three nevi. In adults, a giant nevus is defined as being at least 20 cm in diameter, whereas in children, a giant nevus is at least 9 cm if on the head and at least 6 cm if on the trunk.² The nevi are most commonly located on the posterior or midline regions or the head and neck.³ These patients may have meningeal melanosis or meningeal melanoma as part of this condition. However, the diagnosis cannot be made if there is also cutaneous melanoma. This is because cutaneous melanoma can metastasize to the brain.⁴ The amygdala, pons and cerebellum are most commonly involved but melanosis can be seen anywhere in the central nervous system (CNS), including the spinal cord and cauda equina.⁵ On MRI, T1 hyperintensity, likely from melanin deposition, can be seen at these sites and is typically bilateral.⁶ However, there have been reports of patients with NCM who have no abnormalities noted on MRI but were found to have melanin deposits on histopathological examination. This suggests that normal imaging cannot fully rule out the presence of NCM.⁷

Common neurological complications of NCM are hydrocephalus, seizures, cranial nerve dysfunction and signs of spinal cord and root involvement.⁸ Two-thirds of children with NCM develop hydrocephalus, secondary to cerebrospinal fluid obstruction from thickening of the leptomeninges. This leads to symptoms of increased intracranial pressure, such as headache, nausea, diplopia and weakness.⁹ There is an association between Dandy-Walker malformation and NCM in infants, seen in 8%–10% of these cases. This can also be a result of hydrocephalus.^{10 11} Additionally, there have been rare reports of psychosis as the initial presenting symptom in one paediatric and one adult patient.^{12 13} However, not all patients fitting diagnostic criteria for NCM present with neurological deficits. Foster et al¹⁴ reported 10 of 46 patients with congenital melanocytic nevi had MRI findings consistent with meningeal melanosis. Of these, only one had a history of neurological symptoms and continued to decline. This suggests that patients with asymptomatic NCM have a better prognosis in comparison to those with symptomatic NCM, the latter of which is often fatal. Almost 50% of cases lead to fatality within 3 years of symptom onset.^{14 15} Patients with NCM are generally treated symptomatically, which can involve shunt placement for correction of hydrocephalus, or seizure control where applicable. These patients also benefit from close neuroradiological and developmental follow-up.^{16 17}

The development of more targeted therapies is underway but these, presently, remain experimental. There is evidence of involvement of the insulin-like growth factor-1 receptor pathway in the development of NCM, suggesting a possible drug target.¹⁸ Mutations in the neuroblastoma RAS viral oncogene (NRAS) have been specifically noted in cells comprising both congenital melanocytic nevi and melanocytic deposits in the brain.¹⁹ Patients with NCM who do harbour mutations in NRAS report no family history of this mutation, suggesting the role of somatic mosaicism in NCM pathophysiology.²⁰ Nevertheless, NCM is rare, and symptomatic NCM generally carries a poor prognosis. As there is no systematic study or formal guideline regarding the efficacy of management and treatment decisions, there arises a significant conundrum in regards to patient management.

Case presentation

A 13-year-old adopted, Chinese, right-handed girl had melanocytic nevi distributed diffusely on her face and body that were present since birth (see figure 1A–C). The largest extended across her back and flanks into her lumbosacral region, spanning over 50 cm in length. She also had a notably large nevus in the midline of her forehead, measuring 3.1 cm in diameter. Her nevi had been monitored by a dermatologist since early childhood. There was no notable progression of these nevi. The patient was excelling academically and an active golfer with no reported history of neurological concerns or emotional lability. She was admitted initially for a clinical seizure. Her mother said the patient was playing video games at home when she suddenly slumped over, became unresponsive to commands and became limp, and drooled. She remained in this state for a few minutes before she regained consciousness. She appeared unsteady on her feet and her mother noticed temporary right-sided facial droop. The patient also had difficulty following verbal commands and expressing herself. This entire episode lasted for 10 min, after which she was able to return to her baseline level of functioning. She denied any prodromal symptoms, and there was no bowel or bladder incontinence or tongue biting during this episode. She reported having decreased sleep the night prior. Her parents said that she had three episodes previously where she would blankly stare into space for a few minutes, without any degree of paralysis. Thus, these could already represent dyscognitive seizures.

Figure 1.

Images of the patient’s giant melanocytic nevi.

Investigations

An electroencephalogram was performed that showed infrequent epileptiform discharges over the right frontal region, indicating a low seizure threshold. The patient underwent an MRI of the brain that showed symmetric bilateral T1 hyperintensity in the amygdala and medial temporal lobes (figure 2A, B). There was no evidence of hydrocephalus, oedema, mass effect or pathological enhancement. No additional T1 hyperintensity was seen in the cerebellum or brainstem. There was corresponding hyperintensity on the T2 and fluid attenuated inversion recovery (FLAIR) sequences at these locations (figure 3). No appreciable loss of signal was seen on the gradient T2* sequence (figure 4). Along with the history of multiple congenital nevi, these unique findings in the temporal lobes were felt to be concerning for NCM.

Figure 2.

Precontrast (A) and postcontrast (B) T1-weighted magnetisation-prepared rapid gradient echo MRI sequences demonstrating hyperintensity in the bilateral amygdala (arrows), slightly greater on the right.

Figure 3.

Coronal T2 fluid attenuated inversion recovery MRI sequence showing corresponding hyperintensity in bilateral amygdala.

Figure 4.

Axial gradient T2*-weighted MRI sequence showing no apparent loss of signal in bilateral temporal lobes.

At follow-up 6 months after initial presentation, the patient continued to remain seizure-free. MRI at this time showed stable T1 hyperintensity in the medial temporal lobes. In order to improve detection of melanosis and haemorrhage, three-dimensional (3D) susceptibility weighted sequence (SWI) was added to the follow-up scan, and the examination was scheduled on a 3T scanner. No abnormal signal was seen on the 3D SWI done on this scan. As recommended by her oncologist, she underwent full thickness biopsy of three of her cutaneous lesions in order to confirm the presence of the BRAF V600E mutation, often implicated in melanoma. Three nevi were biopsied, located on her left proximal leg, left distal thigh and right lower back. There were no operative complications and the patient tolerated the procedure well. Pathology results of all three biopsies revealed compound nevi without atypia. Genetic analysis of the three samples was negative for the BRAF V600E mutation. Further analysis of the left leg and thigh samples was found to be positive for the NRAS Q61K mutation.

At 9 months from her initial presentation, the patient had a dyscognitive seizure, described as reduced responsiveness, slow gait and postictal fatigue.

Treatment

She was initially started on 22 mg/kg/day of levetiracetam daily, which helped effectively control her seizures. The patient also began taking oral trametinib 7 months after initial diagnosis, as preclinical and target modulation studies indicated the potential for activity by MEK (mitogen-activated protein kinase kinase) inhibitors in NRAS-activated NCM.¹⁸ At 9 months after diagnosis, when she had a breakthrough seizure-like episode, her dose of levetiracetam was increased to 32 mg/kg/day.

Outcome and follow-up

At 10-month follow-up, the patient reported no seizure recurrence. At this time, she had completed 10 weeks of trametinib therapy and 4 weeks of the increased levetiracetam dose. The nevus on her forehead had decreased in size from 3.1 cm in diameter to 2.7 cm and the borders of her largest nevus also appeared to be growing lighter. However, some of the other lesions were reportedly darker. Additionally, her parents noted that the patient had improved hand–eye coordination, having a greater ability to catch a ball if thrown at her.

She has shown no further clinical progression of her neurological symptoms at 1-year follow-up, continues to excel academically and is a member of her high school’s golf team. She is following closely with neurology, dermatology and oncology.

Discussion

A review of PubMed was conducted for cases of symptomatic NCM reported in teenagers aged 13–18 years. Reports not written in English or for which full-text English translations could not be located were excluded. Cases were reviewed in their entirety to ensure that the diagnosis of NCM was made in accordance with the criteria defined by Kadonaga and Frieden. The references and cases described in any previous systematic reviews that were identified through this search were reviewed in their entirety.

A total of 182 articles were found detailing NCM in a total of 230 patients. Of these cases, 196 occurred in paediatric patients and 34 in adults. Sixteen cases described new-onset neurological manifestations of NCM presenting in teenagers (table 1). Headache was the presenting symptom in eight cases,^21–28 while four presented with seizures.^{19 29–31} Only three patients (19%) presented with hydrocephalus.^{21 23 26} This is a smaller proportion than 5-year-old children or younger, of whom 74% have been reported to suffer from hydrocephalus at the time of symptom onset.¹⁵

Table 1.

Summary of findings for NCM studies in teenagers

Case	Sex	Age (in years)	Presenting symptoms	Affected CNS areas	Treatment	Outcome
Netherton21	M	17	Headache; hydrocephalus; diplopia; memory loss	Leptomeninges	Suboccipital craniectomy; high voltage roentgen therapy	Not available
Morris and Danta22	F	15	Headache; nuchal rigidity	Temporal lobe; choroid plexus; subarachnoid space	Mortality before intervention	Death in 1 month
Lamas et al29	M	13	Focal temporal lobe seizures	Temporal lobe; frontal lobe; cerebellum; optic chiasm; olfactory bulb; leptomeninges	Right parietal craniotomy	Local tumour recurrence in 4 months requiring re-operation. Death 2 months later, secondary to multiple episodes of subarachnoid haemorrhage
Kasantikul et al32	F	17	Right lower limb weakness	Thoracic spinal cord (T1–T8)	T1–T9 laminectomy	Not available
Salisbury and Rose30	F	13	Complex partial and generalised seizures	Cerebral cortex; basal ganglia	No intervention	Developed headache and nausea at the age of 26 years, prompting workup and NCM diagnosis. Death 6 months after
Barkovich et al33	Not available	15	Not available	Amygdala	Surgical excision	Not available
Marnet et al23	M	14	Headache; hydrocephalus; intracranial hypertension	Bulbomedullary junction	VP shunt; corticosteroids; chemotherapy	Death in 1 year
Rai et al34	F	16	Scalp swelling causing mechanical ptosis; comorbid tuberous sclerosis	Frontoparietal region	Surgical excision	Not available
D’Souza et al35	M	16	Symptoms of elevated intracranial pressure	Cerebellum; brainstem; parietooccipital region	Craniectomy	Not available
Furtado et al24	M	13	Headache; papilloedema; vomiting	Frontal lobe	Right parasagittal craniotomy; radiotherapy (36 Gy telecobalt-60 external beam); chemotherapy	Symptom recurrence in 3 months requiring exploratory operation. Death 2 months after
Kinsler et al19	Not available	18	Seizure; developmental delay	Parenchyma (unspecified)	Not available	Not available
Taylor et al31	F	14	Seizure	Amygdala	Right temporal lobectomy	Remission
Küsters-Vandevelde et al25	M	13	Headache; papilloedema; nausea; vomiting; vertigo; slurred speech; cerebellar dysfunction	Cerebellum	Cerebellar cyst drainage; binimetinib (MEK162 inhibitor)	Death due to neurogenic respiratory failure 5 days after starting binimetinib
Monica et al26	M	17	Headache; hydrocephalus; urinary incontinence; diplopia; abducens palsy	Posterior fossa; medulla	Radiotherapy (36 Gy total in 18 fractions)	Developed quadriplegia during radiotherapy
Thomas et al27	M	18	Headache; vomiting	Posterior fossa; cerebellum; cerebellopontine angle	Surgical excision	Local tumour recurrence in 20 months requiring re-operation. Death 5 months after
Schaff et al28	M	16	Headache; nausea; vomiting; photophobia; diplopia; tinnitus; lower extremity numbness	Spinal cord; cauda equina	VP shunt	Death in 3 months

Summary of 15 teenage cases of NCM identified through literature review.

CNS, central nervous system; F, Female; M, Male; MEK, mitogen-activated protein kinase; NCM, neurocutaneous melanosis; VP, ventriculoperitoneal.

The cerebellum and temporal lobe were most commonly involved in meningeal melanosis. One patient was positive for the same NRAS Q61K mutation found in our patient.²⁵ Treatments varied, with nine managed surgically,21 24 27 29 31–35 three receiving radiotherapy,^{21 24 26} two undergoing shunt placement^{23 28} and one managed with an MEK inhibitor.²⁵ Ten cases provided follow-up data and in five of these, deterioration led to mortality within 6 months.22 24 25 28 29 An additional patient suffered from quadriplegia as a result of radiotherapy.²⁶ Only one patient, managed via temporal lobectomy, achieved remission and resolution in neurological symptoms.³¹

It is rare for NCM to clinically present in teenagers. When onset of symptomatic NCM does occur in this age group, a review of previous cases suggests a poor prognosis. As the development of symptoms does entail negative outcomes, it is necessary for physicians to be vigilant when caring for patients with NCM. The characteristic radiological findings, namely the precontrast T1 hyperintensity, such as in the present case in the temporal lobes, can be subtle and potentially missed or misinterpreted. This may happen if a patient does not carry a dermatologic diagnosis or if a radiologist is unfamiliar with the imaging manifestation. It is necessary to be aware that, for patients with giant congenital nevi, these findings are significant and entail CNS melanosis. Interestingly, we also noted hyperintensity on T2 and FLAIR in the lesions with no loss of signal on gradient T2* or SWI sequences. This is in contrast to some reports that describe decreased signal on T2/FLAIR from the paramagnetic property of melanin.^{11 26}

While meningeal melanosis does not always indicate progression to neurological decline, it nevertheless does present a risk. For this reason, close monitoring, regular follow-up and early treatment is imperative for improving long-term outcomes for these young patients. As MRI can show progression of melanosis, regular imaging follow-up is necessary for patients with NCM. A greater extent of CNS involvement on imaging can correlate with the severity of symptoms, especially when meningeal involvement results in hydrocephalus.^{9 17} Our patient showed no progression of CNS melanosis at the 6-month imaging follow-up.

As demonstrated in our literature review of teenage cases, 50% were fatal within 6 months. Our patient is currently stable 1 year from her diagnosis. Additionally, aside from the patient described by Küsters-Vandevelde et al,²⁵ this patient is the only case reported in this age group to be managed with an MEK inhibitor. As our patient has completed over 10 weeks of trametinib therapy and demonstrated partial regression of her cutaneous lesions, this class of medications may play an important role in the management of NCM. She continues to be closely monitored by neurologists, dermatologists and oncologists. This case contributes to the current understanding of long-term outcomes in teenagers with symptomatic NCM. Patients with a history of multiple congenital melanocytic nevi who develop neurological sequelae as teenagers can be treated medically, thus avoiding functional impairment and preserving quality of life. Moreover, this case adds to the growing body of literature suggesting that onset of neurological symptoms in teenagers does not absolutely entail devastating clinical deterioration.

Patient’s perspective.

I am thankful to all the people, health professionals, who are there for me. I hope breakthroughs help others as well.

Learning points.

• Patients with giant congenital melanocytic nevi should undergo screening via MRI of the brain and the spinal cord.

• Precontrast T1 hyperintensity is a characteristic finding on MRI of the central nervous system and indicates meningeal melanosis in the appropriate clinical context.

• Neurological signs of neurocutaneous melanosis rarely present in teenagers and, when present, can be associated with variable prognosis. These patients require close neurological and radiological follow-up to monitor for signs of disease progression.

• The presented case is unique in that presenting neurological symptoms were relatively mild and easily controlled medically. No further decline has been noted at 1 year follow-up.