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Case Reports
. 2023 Aug 24:10:1225667.
doi: 10.3389/fcvm.2023.1225667. eCollection 2023.

Case report: Distinctive cardiac features and phenotypic characteristics of Noonan syndrome with multiple lentigines among three generations in one family

Chon-Hou Chan #  1 , Man-Fong Chu #  2 , U-Po Lam  2 , Toi-Meng Mok  2 , Weng-Chio Tam  2 , Brian Tomlinson  3 , Ricardo Coelho  1 , Màrio Évora  2
Affiliations
Case Reports

Case report: Distinctive cardiac features and phenotypic characteristics of Noonan syndrome with multiple lentigines among three generations in one family

Chon-Hou Chan et al. Front Cardiovasc Med. .

Abstract

Noonan syndrome with multiple lentigines (NSML, formerly known as LEOPARD syndrome) is a variant of Noonan syndrome which is an autosomal dominant disorder. Most cases of NSML are secondary to mutations of the protein-tyrosine phosphatase nonreceptor type 11 (PTPN11). Hypertrophic cardiomyopathy (HCM) remains the most frequent and serious cardiac abnormality in this inherited syndrome, and it may lead to sudden cardiac death related to HCM-associated outflow obstruction and fatal arrhythmia. Beyond cardiac involvement, NSML may present with multiple lentigines, ocular hypertelorism, genital anomalies, short stature and deafness. Herein, we report three patients with NSML among three generations in one family, all presenting with multiple lentigines, HCM and other distinctive clinical and molecular features, including facial dysmorphism, deafness, family history of sudden death and PTPN11 mutations. This case series highlights the importance of early echocardiography examinations for patients with NSML. Careful family screening and genetic counselling are also necessary, especially in patients with diffuse lentigines or a history of sudden death among family members. We also discuss the distinctive cardiac features and phenotypic characteristics at different stages of NSML, including childhood, adulthood and elderhood.

Keywords: Noonan syndrome with multiple lentigines; echocardiography; hypertrophic cardiomyopathy; inherited disorder; sudden cardiac death.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
A Diffuse black to brownish lentigines seen mainly on the face of the proband (individual II-3). Ocular hypertelorism (asterisk), ptosis (arrowhead) and thick lips were remarkable. (B) Multiple lentigines over the anterior trunk and limbs varied in shape and size, and with diameters ranging from to 5 mm. (C) A café au lait macule (arrowhead) was seen on his mid-back. (D) Low set ears and retrognathism (arrowhead) were revealed. Echocardiography demonstrated (E) eccentric left ventricular hypertrophy (septal wall thickness: 22 mm, arrowhead), (F) without left ventricle outflow tract obstruction. (G,H) Cardiac magnetic resonance imaging showed hypertrophic segments over septal and apical walls (arrowhead).
Figure 2
Figure 2
Pedigree of the proband (II-3, arrowhead). The black-filled squares and circle indicated the individuals with clinical evidence of NSML. Both proband (II-3), proband's mother (I-8), elder brother (II-2) and son (III-2) presented with multiple lentigines and facial dysmorphism. Clinical features of NSML were labelled with relevant symbols in the pedigree. Same heterozygous missense mutation of PTPN11 was confirmed in proband (II-3) and proband's son (III-2). Two unaffected family members (I-7 and III-1) showed no clinical evidence of NSML. Individual II-2 died at the age of 32 due to sudden cardiac death.
Figure 3
Figure 3
(A) The proband's son (individual III-2) presented with diffuse lentigines over the face, thick lips and ocular hypertelorism. (B) Low set ears and (C) Diffuse lentigines over the trunk and pectus excavatum (arrowhead) were also revealed. Echocardiography showed (D) septal wall hypertrophy without intra-cavity or left ventricle outflow tract obstruction. (E) Secundum atrial septal defect (cross-mark) (defect size about 7 mm, shunting from left to right). (F) Narrowing color-flow at the right pulmonary artery, indicating right pulmonary artery stenosis.
Figure 4
Figure 4
(A) The proband's mother (individual I-8) presented with ocular hypertelorism and diffuse black to brownish facial lentigines. (B) Numerous lentigines on her back, varying in size and shape. (C) Close-up of back lentigines with diameters ranging from 1 mm to 5 mm. Echocardiography revealed (D) significant septal wall hypertrophy (septal wall thickness: 26 mm, cross-mark). (E) Apical aneurysm formation was revealed with midventricular obstruction. (F) Pulsed wave Doppler showed mid-cavity pressure gradient was around 17 mmHg.
See this image and copyright information in PMC

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