Patient with confirmed leopard syndrome developing multiple myeloma

Abstract

LEOPARD syndrome, also known as Gorlin syndrome II, cardiocutaneous syndrome, lentiginosis profusa syndrome, Moynahan syndrome, was more recently coined as Noonan syndrome with multiple lentigines (NSML), inside the RASopathies. Historically, the acronym LEOPARD refers to the presence of distinctive clinical features such as: lentigines (L), electrocardiographic/conduction abnormalities (E), ocular hypertelorism (O), pulmonary stenosis (P), genital abnormalities (A), retardation of growth (R), and sensorineural deafness (D). This condition is identified in 85% of patients with phenotype hallmarks caused by presence a germline point mutation in PTPN11 gene. Association of melanoma to NSML seems to be rare: to our knowledge, two patients so far were reported in the literature. We herein present a patient diagnosed with LEOPARD syndrome, in whom molecular investigation confirmed the presence of the c.1403C>T mutation in exon 12 of the PTPN11 gene, who developed four superficial spreading melanomas and three atypical lentiginous hyperplasias. Three of the melanomas were achromic or hypochromic, three were in situ, and one had a Breslow index under 0.5 mm. Dermoscopic examination showed some characteristic white structures in most of the lesions, which were a signature pattern and a key for the diagnosis.

Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation

“…However, NS-ML clinically resembles NS, raising a long debated question why both GOF and LOF mutations of SHP2 result in similar clinical manifestations (Edouard et al, 2007;Zheng et al, 2009). Remarkably, both NS and NS-ML are predisposed to an elevated risk of malignancy (Cheng et al, 2013;Colmant et al, 2018;Laux et al, 2008;Liu et al, 2016;Tartaglia et al, 2004). These observations suggest that LOF mutations of SHP2 may, similarly as GOF mutations, also acquire capability to activate the RAS-MAPK signaling pathway.…”

Metastatic brain melanoma in a patient with Noonan syndrome with multiple lentigines

“…Cheng et al reported a 24-year-old female who developed a scalp melanoma and had a germline heterozygous PTPN11 missense mutation [8]. Colmant et al reported a 62-year-old male with NSML and a mutation in the PTPN11 gene who developed four superficial spreading melanomas (three were achromic or hypochromic) and three atypical lentiginous hyperplasias [1]. García-Gil et al reported a 44-year-old male with NSML confirmed by the genetic study of a mutation in heterozygosity in the PTPN11 gene who developed a melanoma at the dorsal level of the trunk [9].…”

“…LEOPARD syndrome (LS), currently termed Noonan syndrome with multiple lentigines ( NSML), is a complex, dysmorphogenetic, multisystemic disorder of autosomal dominant heredity and variable penetrance and expressivity [1,2]. Its prevalence remains unknown.…”

“…Gorlin et al [3] first introduced the acronym LEOPARD to describe the following manifestations: lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and deafness. The most common gene associated with NSML is PTPN11, identified in 50-85% of patients with NSML [4,1]. Other related mutations include the RAF1 (< 5%), BRAF, and MAP2K1 (< 1%) genes.…”

“…Other cutaneous manifestations include axillary freckling, café au lait macules, and localized hypopigmentation. Although it is unknown whether the pigmented lesions seen in NSML may progress to a malignancy [6], there are four reports of LS associated with a melanoma [1,[7][8][9].…”