SHORT COMMUNICATION

Melanoma and LEOPARD Syndrome: Understanding the Role of PTPN11 Mutations in Melanomagenesis

Rodolfo David PALACIOS-DIAZ¹, Mónica POZUELO-RUIZ¹, Blanca de UNAMUNO-BUSTOS^1,3, Margarita LLAVADOR-ROS² and Rafael BOTELLA-ESTRADA^1,3

¹Dermatology Department and ²Pathology Department, Hospital Universitari i Politècnic La Fe, 106 Fernando Abril Martorell Avenue, ES-46026 Valencia and ³Dermatology, Instituto de Investigación Sanitaria La Fe, Valencia, Spain. E-mail: blancaunamuno@yahoo.es

 

 

INTRODUCTION

“RASopathies” is an umbrella term that includes multisystemic disorders with overlapping clinical features. They develop due to a genetic variation in components or modulators of RAS-MAPK signalling cascade (1). Skin involvement comprises a wide heterogeneous spectrum of cutaneous features including pigmentation anomalies (1, 2). Propensity to non-cutaneous malignancy and reports of cutaneous melanoma have drawn attention to the role of these germline mutations in melanomagenesis.

CASE REPORT

A 53-year-old woman presented to the Dermatology department of Hospital Universitari i Politècnic La Fe, Valencia, with a pigmented macule that had grown steadily to a maximum diameter of 40 mm on her right leg. Dermoscopic examination showed an atypical pigment network and dotted-whitish areas suggesting regression (Fig. 1A). Histopathological examination confirmed the diagnosis of melanoma in situ with a radial lentiginous growth pattern (Fig. 1B). Direct sequencing of melanoma tissue showed a BRAF and NRAS wild type. In addition, physical examination showed multiple lentigines predominantly in the head and neck, upper trunk, and proximal upper extremities (Fig. 1C). The patient had short stature, hypertelorism, low-set ears, exaggerated Cupid’s bow and bilateral lymphedema. Pertinent personal history included Bricker’s ureteroileostomy due to neurogenic bladder after spina bifida surgery, pulmonary valve stenosis and puberty delay. Exome sequencing (Custom NGS SureSelect panel, Illumina, San Diego, California) revealed a heterozygous variant c.1403C > T (p.Thr468Met) in exon 12 of PTPN11, compatible with Noonan syndrome with multiple lentigines (NSML). After 5 years of follow-up, the patient has not had any other atypical lesions.

Fig. 1. (A) Pigmented macule with atypical pigment network and dotted-whitish areas in the patient’s right leg (dermoscopic image in the lower right corner). (B) Melanoma in situ with a radial lentiginous growth pattern (haematoxylin and eosin (H&E); 40×). (C) The patient had also multiple lentigines predominantly on the upper trunk and proximal upper extremities.

DISCUSSION

NSML is a rare autosomal dominant inherited disorder, and it has been linked to mutations in PTPN11 (90%) and, more rarely, to mutations in RAF1 and BRAF (2). The most frequent PTPN11 missense mutations cause p.Thr468Met and p.Thr279Cys variants in 82% of patients in a case series (3). Mutations in PTPN11 in NSML affect the catalytic domain of SHP-2, resulting in decreased phosphatase activity (4).

Common clinical features are grouped in the formerly used “LEOPARD” acronym (multiple lentigines (ML), electrocardiogram (ECG) conduction abnormalities, ocular hypertelorism, pulmonary valve stenosis, genitourinary anomalies, growth retardation, and sensorineural deafness) (1, 2). ML are the most common pigmentary disorder in NSML, and they are present in 94% of NSML patients over the age of 1 year (3). ML have high specificity and increase in number in puberty and adulthood (2, 3). SHP-2 mutation causes an abnormal enhanced synthesis of melanosomes in melanocytes, which might be involved in the pathogenesis of ML (4). Furthermore, mutants of SHP-2 may also result in enhancement of migration and prevention of apoptosis of melanocytes (4).

Malignancy associated with NSML include leukaemia, cerebellar medulloblastoma, neuroblastoma and unilateral choristoma (5). Apart from the current case, only 4 other cases of melanoma in patients with NSML have been reported in the literature (6–9) (Table I). The patients had the most frequent germline PTPN11 mutations: p.Thr468Met (40%; 2/5) and p.Tyr279Cys (40%; 2/5). All cases displayed an incomplete clinical “LEOPARD” acronym phenotype. Melanomas were on the back (40%; 2/5), lower extremities (60%; 3/5) and scalp (20%, 1/5). One patient (20%) had multiple primary melanomas without CDKN2A mutation (8). Except for a scalp melanoma of 5 mm, most of the melanomas were thin (< 1 mm). One patient had an additional BRAF mutation (6). The authors hypothesized that a BRAF mutation on skin with a germline mutated PTPN11 might severely affect MAPK signalling, resulting in the development of melanoma (6). The remaining melanomas did not have, or were not reported to have, NRAS, HRAS or BRAF mutations (7–9).

Table I. Summary of the reports of melanoma in patients with Noonan syndrome with multiple lentigines

Number	Authors	Year	Sex	Age, years	Germline mutation	Clinical phenotype	Histopathological characteristics	Melanoma genes studied
1	Seishima M et al. (6)	2007	F	60	Thr468Pro (PTPN11)	L,cardiac abnormality, R	Heel: BI 0.9 mm	BRAF Val600Glu
2	Cheng Y et al. (7)	2013	F	24	Tyr279Cys (PTPN11)	L,E,O,R,D *	Scalp: SSM, BI 5 mm, no associated nevus	BRAF, NRAS & HRAS wt
3	Colmant C et al. (8)	2018	M	62	Thr468Met (PTPN11)	L,E,A	MPM: 1. Foot: SSM, BI 0.42 mm, associated nevus. 2,3 & 4. Back: LM	CDKN2A wt
4	García-Gil M et al. (9)	2020	M	44	Tyr279Cys (PTPN11)	L,E,P,D	Back: SSM, BI 0.15 mm	–
5	Palacios-Diaz RD et al.	2023	F	53	Thr468Met (PTPN11)	L,O,P,A,R	Leg: MIS	BRAF & NRAS wt
F: female; M: male; L: lentigines; E: electrocardiogram abnormalities; O: ocular hypertelorism; P: pulmonary valve stenosis; R: growth retardation; D: sensorineural deafness; BI: Breslow index; MIS: melanoma in situ; MPM: multiple primary melanomas; LM: lentigo maligna; SSM: superficial spreading melanoma; wt: wild type.
*The patient had regurgitation of the tricuspid valve, but it was not specified pulmonary stenosis.

Beside its phosphatase activity, SPH-2 might function as a tumour suppressor protein (7). Mutations in SHP-2 induce activation of Akt/mTOR and STAT3 pathway, which plays an important role in melanoma tumorigenesis (4, 7). Moreover, development of two primary melanomas within a naevus spilus with a mosaic p.(Thr468Met) variant and heterozygous deletions involving PTPN11 has been reported in 8 of 345 melanomas (10). These authors found a significant activation of the MAPK pathway, but not of the PI3K-protein kinase B-mTOR pathway, in generated cell lines with p.(Ala461Thr) and p.(Thr468Met) variants (10). Although more studies are needed to elucidate the role of NSML germline-PTPN11 mutations in melanomagenesis, we believe that the risk of developing melanoma should encourage a close clinical and digital follow-up of patients with NSML.

ACKNOWLEDGEMENTS

The patient in this manuscript has given written informed consent to publication of their case details. The authors accept and agree with the United Nations’s Declaration of Human Rights.

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