LEOPARD Syndrome: Clinical Features and Gene Mutations

Abstract

The RAS/MAPK pathway proteins with germline mutations in their respective genes are associated with some disorders such as Noonan, LEOPARD (LS), neurofibromatosis type 1, Costello and cardio-facio-cutaneous syndromes. LEOPARD is an acronym, mnemonic for the major manifestations of this disorder, characterized by multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. Though it is not included in the acronym, hypertrophic cardiomyopathy is the most frequent cardiac anomaly observed, representing a potentially life-threatening problem in these patients. PTPN11, RAF1 and BRAF are the genes known to be associated with LS, identifying molecular genetic testing of the 3 gene mutations in about 95% of affected individuals. PTPN11 mutations are the most frequently found. Eleven different missense PTPN11 mutations (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro, and Gln510Glu/Pro) have been reported so far in LS, 2 of which (Tyr279Cys and Thr468Met) occur in about 65% of the cases. Here, we provide an overview of clinical aspects of this disorder, the molecular mechanisms underlying pathogenesis and major genotype-phenotype correlations.

Keywords: BRAF; Gene; LEOPARD; Mutation; PTPN11; RAF1; RAR/MAPK pathway.

Fig. 1

Schematic diagram showing the RAS-MAPK signal transduction pathway. Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. SHP2 is a ubiquitous protein-tyrosine phosphatase (PTP) which plays major biological functions in response to various growth factors, hormones or cytokines. Activation of SHP2 occurs upon interaction of phosphotyrosine residues from substrate or another protein with SH2 domains in these PTPs, promoting GRB2/SOS recruitment through direct binding to GRB2 (growth factor receptor-bound protein 2). GRB2 binds through its SH3 domains to the guanine nucleotide exchange factor (SOS), activating it. Activated SOS then promotes the removal of GDP from a member of the RAS subfamily (most notably HRAS or KRAS). RAS can then bind GTP and become active. Activated RAS activates the protein kinase activity of RAF1 kinase. RAF1 kinase phosphorylates and activates the MAPK/ERK kinases MEK1 and MEK2. MEK1 and MEK2 then phosphorylate and activate the ERK1 and ERK2 MAPKs. Activated ERKs translocate to the nucleus, where they phosphorylate and regulate various transcription factors leading to changes in gene expression. BRAF is also a member of the RAF kinase family of serine/threonine-specific protein kinases. BRAF is activated following GTP-bound RAS binding, and phosphorylates and activates the mitogen-activated protein kinase kinases (MEK1 and MEK2). Mitogen-activated protein kinase (MAPK) cascades are key signaling pathways involved in the regulation of normal cell proliferation, survival and differentiation. The syndromes and their mutated proteins are as indicated: red asterisk: LEOPARD syndrome; green asterisk: Noonan syndrome; blue asterisk: Cardio-facio-cutaneous syndrome (CFCS); brown asterisk: Costello syndrome (CS); violet asterisk: autoimmune lymphoproliferative syndrome.

Fig. 2

A Dysmorphic features showing hypertelorism, flat nasal bridge, mild palpebral ptosis, thick lips and low-set ears with diffuse lentiginosis in the upper part of the trunk and face. B The patient has hearing aids due to sensorineural deafness.

Fig. 3

A Numerous lentigines on the skin of the chest. B Lentigines and a large café-au-lait spot on the neck.

Fig. 4

Histology of a lentigo biopsy (hematoxylin-eosin stain; 4× original magnification) showing hyperpigmentation of the basal membrane, with increased numbers of melanocytes and slight acanthosis, diffuse lymphohistiocytic infiltrate with some scattered melanophages.

Fig. 5

A Four-chamber apical echocardiographic view showing an asymmetric HCM involving the interventricular septum (arrowhead). LV: left ventricle, RV: right ventricle, LA: left atrium, RA: right atrium. B Twelve-lead electrocardiogram showing high R waves in the right precordial leads with ST depression in relation to HCM and systolic ventricular overload.