Giant congenital nevi are melanocytic proliferations of the skin that may be complicated by melanoma, neurocutaneous melanocytosis, pain, pruritus, and disfigurement. Current treatment options include surgical resection and medical management of associated symptoms. There is limited efficacy in these modalities. No effective pharmacologic treatments are available for the treatment of these lesions. We present the case of a 7-year-old girl with a giant congenital melanocytic nevus that had an AKAP9-BRAF fusion and was treated with trametinib, which resulted in rapid resolution of the patient’s lifelong, intractable pain and pruritus as well as dramatic improvement in the extent of her nevus.

Congenital melanocytic nevi (CMNs) are melanocytic proliferations that typically present in the skin at birth or shortly thereafter and are classified primarily on the basis of size. Giant congenital melanocytic nevi (GCMNs) are defined as those CMNs that are predicted to be ≥40 cm in diameter by adulthood and that may be complicated by melanoma, neurocutaneous melanocytosis, severe pain and pruritus, hypohidrosis, xerosis, cosmetic disfigurement, and social isolation. There is an estimated incidence of ∼1 in 20 000 to 500 000 live births.1,2 

GCMNs are caused by somatic mosaicism in melanocytic precursors. NRAS mutations can be found in 80% to 95% of GCMNs and result in the activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways, which ultimately increases the proliferation and survival of melanocytes.3BRAF-activating mutations (single-nucleotide variants and fusions) that activate the MAPK pathway have also been reported.4,5 

Traditional treatments of GCMNs have relied on serial surgical resection with skin grafting or tissue expansion and advancement. However, this is of limited use in large lesions and in those that impinge on vital structures. The presence of activation of the MAPK pathway has led to the suggestion that targeting MAP/ERK kinase (MEK), which is a downstream target of this pathway, may be a viable treatment option.6 No successful attempts at this therapy have been reported thus far, and GCMNs continue to be difficult to manage.

A 6-week-old African American girl presented with a dark brown nevus that covered the majority of the back and extended onto the flanks, right abdomen, buttocks, thighs, and suprapubic area. There were scattered satellite nevi on the scalp, face, extremities, and buttocks, with multiple hyperpigmented nail bands. Over the next several years, she developed significant, disfiguring thickening of the nevus, predominantly over her back and abdomen (Fig 1 A–C). She developed intractable, sleep- and behavior-altering pruritus that was only minimally responsive to topical steroids and systemic antihistamines, topiramate, gabapentin, pregabalin, and clonidine. MRI at age 6 years revealed numerous T1-hyperintense foci in the brain that were consistent with neurocutaneous melanocytosis, but the results of her neurologic examination were normal, and she had no history of seizures (Fig 2). There was marked thickening of the dermis with invasion of the nevus through the subcutaneous tissue and into the fascia and musculature in the trunk and pelvis (Fig 3 A–C).

FIGURE 1

Clinical images of the patient over time reveal a GCMN with progressive growth and thickening. A, The patient at age 8 months. B, The patient at age 4 years. C, The patient at age 6 years. D, Six months after the initiation of treatment with trametinib at age 7 years, there is marked improvement with a decrease in thickness, rugosity, and nodularity.

FIGURE 1

Clinical images of the patient over time reveal a GCMN with progressive growth and thickening. A, The patient at age 8 months. B, The patient at age 4 years. C, The patient at age 6 years. D, Six months after the initiation of treatment with trametinib at age 7 years, there is marked improvement with a decrease in thickness, rugosity, and nodularity.

Close modal
FIGURE 2

A, Sagittal T1-weighted image of the brain with T1 shortening in the mesial temporal lobe (marked by the arrow). B, Coronal T1-weighted image of the brain with T1 shortening in the mesial temporal lobe (marked by the arrow).

FIGURE 2

A, Sagittal T1-weighted image of the brain with T1 shortening in the mesial temporal lobe (marked by the arrow). B, Coronal T1-weighted image of the brain with T1 shortening in the mesial temporal lobe (marked by the arrow).

Close modal
FIGURE 3

A, Abdominal MRI reveals dermal thickening and latissimus dorsi enhancement (marked by the arrow). The arrowhead indicates the uninvolved anterior abdominal wall. B, Pelvic images reveal enlargement and enhancement of the inguinal lymph nodes (marked by the arrow) and marked dermal thickening (marked by the double arrow). C, Posterior dermis measuring 29 mm before treatment. D, Abdominal MRI reveals that the dermal thickening and latissimus dorsi enhancement (marked by the arrow) are significantly improved after treatment. The arrowhead indicates the uninvolved anterior abdominal wall. E, Pelvic images reveal that the enlargement and enhancement of the inguinal lymph nodes (marked by the arrow) and marked dermal thickening (marked by the double arrow) are significantly improved after treatment. F, Posterior dermis measuring 14 mm after treatment.

FIGURE 3

A, Abdominal MRI reveals dermal thickening and latissimus dorsi enhancement (marked by the arrow). The arrowhead indicates the uninvolved anterior abdominal wall. B, Pelvic images reveal enlargement and enhancement of the inguinal lymph nodes (marked by the arrow) and marked dermal thickening (marked by the double arrow). C, Posterior dermis measuring 29 mm before treatment. D, Abdominal MRI reveals that the dermal thickening and latissimus dorsi enhancement (marked by the arrow) are significantly improved after treatment. The arrowhead indicates the uninvolved anterior abdominal wall. E, Pelvic images reveal that the enlargement and enhancement of the inguinal lymph nodes (marked by the arrow) and marked dermal thickening (marked by the double arrow) are significantly improved after treatment. F, Posterior dermis measuring 14 mm after treatment.

Close modal

Surgical management consisted of incisional biopsies of suspicious lesions (including areas of infiltrating enhancement based on the MRI and enlarged inguinal lymph nodes, all of which were benign) as well as debulking procedures. However, these procedures provided no relief of her symptoms, and the decision was made to forgo any further surgical intervention. Histologic evaluation of excision specimens revealed melanocytic proliferation with sheets of melanocytes within the dermis that extended into the subcutis. There was normal maturation with smaller nests and melanocytes in deeper portions of the lesion, in which cells were slightly elongated and pigmentation was denser. No mitotic activity was identified (Fig 4). The results of immunohistochemical staining for BRAF V600E mutation were negative, and direct sequencing of involved tissue revealed no activating single-nucleotide mutations in NRAS, BRAF, or PIK3CA.

FIGURE 4

A, Histologic analysis of a biopsy specimen that was taken before treatment with trametinib reveals a deeply infiltrative intradermal proliferation of melanocytes, with relatively uniform nuclei and moderate amounts of pale-staining to lightly pigmented cytoplasm. B, No mitotic figures were identified within the lesion. C, Small, mature melanocytes are present at the deep border of this 4-cm-thick excisional biopsy, which is just superficial to fascia. There is a conspicuous absence of subcutaneous adipose tissue, which has been replaced by nevus.

FIGURE 4

A, Histologic analysis of a biopsy specimen that was taken before treatment with trametinib reveals a deeply infiltrative intradermal proliferation of melanocytes, with relatively uniform nuclei and moderate amounts of pale-staining to lightly pigmented cytoplasm. B, No mitotic figures were identified within the lesion. C, Small, mature melanocytes are present at the deep border of this 4-cm-thick excisional biopsy, which is just superficial to fascia. There is a conspicuous absence of subcutaneous adipose tissue, which has been replaced by nevus.

Close modal

Because BRAF-activating fusions have been previously reported in GCMNs, the residual biopsy material was also tested in an extended sequencing panel for additional activating mutations, including fusions. This additional testing revealed an AKAP9-BRAF fusion. Fusions with similar break points in BRAF have been reported as being constitutively active and oncogenic, which hyperactivates the MAPK pathway.7 

At 7 years of age and on the basis of the AKAP9-BRAF fusion, the patient was started on trametinib, an oral MEK inhibitor, at a dose of 0.5 mg daily. Within a month of starting the medication, she was weaned off hydroxyzine, cetirizine, naproxen, pregabalin, and clonidine. Her pain and pruritus resolved completely. She had no additional complaints of insomnia. Repeat MRI was completed 6 months into therapy and revealed decreased thickening of the dermis and near resolution of muscular invasion (Fig 3 D–F). By this time, she had a dramatic improvement in the size, texture, and thickness of her lesions (Fig 1D). Eleven months into therapy, her clinical findings and symptoms continued to improve.

Activating mutations in NRAS occur in 80% to 95% of GCMNs.3BRAF V600E mutations have also been identified in a smaller percentage of patients (∼8%) and lead to activation of the MAPK pathway, with minimal activation of PI3K.4 The activation of these signaling pathways leads to melanocyte growth, proliferation, survival, and transformation.1 Although inhibition of the MAPK pathway has been targeted in the treatment of numerous malignancies (including melanoma), no reports of its successful use in the treatment of benign cellular proliferations, such as complex GCMNs and neurocutaneous melanocytosis, have been reported to date.1,6,8 

Initial sequencing evaluation for single-nucleotide mutations in 25 genes (including NRAS and BRAF) revealed no mutations in biopsy samples from our patient. However, fusion analysis revealed an AKAP9-BRAF fusion that has not previously been reported in CMNs. AKAP9-BRAF fusion produces a kinase that lacks the regulatory domains of BRAF, which results in constitutive activation in a RAS-independent manner and exhibits transforming activity similar to that of BRAF V600E point mutation.5,7,9 Existing data suggest that such BRAF-activating alterations may confer sensitivity to MEK inhibition.10 

Trametinib is a MEK inhibitor that is well tolerated in pediatric patients.11 Given her extreme symptoms and lack of improvement with surgical intervention, our patient was started on this therapy and has tolerated it well without any detectable toxicity to date. She had an excellent initial response in symptoms with remarkable continued improvement in her skin findings. Importantly, she has had a dramatic improvement in her quality of life as described subjectively by her family. Her previous anxiety, pain, and insomnia are now resolved.

Our findings reveal that patients with BRAF-mutated giant congenital nevi and symptomatic neurocutaneous melanocytosis may benefit from therapy that is targeted at the MAPK pathway. Although this represents a small proportion of patients with GCMNs, it suggests that combination therapy that is used to target the PI3K and MAPK pathways may be effective in the majority of patients whose nevi harbor NRAS mutations. Additional studies will be required to determine the rates of disease- and treatment-related complications in these patients. Malignant transformation in large CMNs and GCMNs occurs in 2% to 3% of patients, and it remains to be seen whether inhibition of the PI3K and MAPK pathways affects this rate of transformation.2,12,13 

Dr Mir initiated the testing that led to the described treatment and drafted the manuscript; Drs Agim, Kane, and Josephs collected data and critically reviewed the manuscript; Dr Park performed genetic testing for the patient described in this study and critically reviewed the manuscript; Dr Ludwig initiated therapy, coinitiated the submission of this manuscript, and performed the first critical review of the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

     
  • CMN

    congenital melanocytic nevus

  •  
  • GCMN

    giant congenital melanocytic nevus

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MEK

    MAP/ERK kinase

  •  
  • PI3K

    phosphatidylinositol 3-kinase

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.