LEOPARD Syndrome: A Variant of Noonan Syndrome Strongly Associated With Hypertrophic Cardiomyopathy

Carcavilla, Atilano; Santomé, José L.; Pinto, Isabel; Sánchez-Pozo, Jaime; Guillén-Navarro, Encarna; Martín-Frías, Maria; Lapunzina, Pablo; Ezquieta, Begoña

doi:10.1016/j.rec.2012.09.015

Cited by 24 publications

(29 citation statements)

References 33 publications

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“…Specific PTPN11 missense mutations are now found in about 95% of cases . Dark‐brown ML are the diagnostic clue and our results confirm their high frequency in 94% of patients with PTPN11 ‐NSML over the age of 1 year . In our study, diffuse ML (> 100) on the cephalic extremity appeared to increase in adulthood and were consistently associated with PTPN11 mutations, discriminating this phenotype from all other NS cutaneous phenotypes.…”

Section: Discussionsupporting

confidence: 84%

“…Some of the previously reported cases of RAF1 ‐NSML were possibly associated with MMN rather than ML, and in three observations were documented with images; the relatively low density and sparse distribution of the pigmented lesions seems to support this hypothesis. However, MMN were not reported in a series of PTPN11 ‐NSML and were present in only 6% of cases in our study. These findings might justify including MMN, and not only ML, in the spectrum of pigmented lesions of NSML and suggest that, in a context of suspicion of NSML, the presence of MMN may be a marker of RAF1 mutation.…”

Section: Discussionmentioning

confidence: 70%

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Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Bessis

Miquel

Bourrat³

et al. 2019

Br J Dermatol

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Summary Background Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. Objectives To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype–genotype correlations with or without the presence of PTPN11 mutations. Methods We performed a large 4‐year, prospective, multicentric, collaborative dermatological and genetic study. Results Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11‐NS, 34 patients with PTPN11‐NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11‐NS, present in 53·8% of patients. Multiple lentigines and café‐au‐lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. Conclusions The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 70%

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Bessis

Miquel

Bourrat³

et al. 2019

Br J Dermatol

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“…22 Noonan syndrome with Multiple Lentigenes (formerly known as LEOPARD syndrome) is similar to NS, is caused by loss of function mutations inthe PTPN11 gene and has a high frequency (>70%) of associated HCM. 23 Additional manifestations of this rare syndrome include multiple lentigines and sensorineural deafness. 24 …”

Section: Monogenic Causes Of Heart Failure In Cardiomyopathy and Chdmentioning

confidence: 99%

Heart Failure in Congenital Heart Disease

Fahed

Roberts

Mital

et al. 2014

Heart Failure Clinics

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Heart failure (HF) is a common cause of morbidity and mortality in congenital heart disease (CHD), with rising prevalence due to improved interventional and surgical treatment options and outcomes. The interplay between genetic factors and acquired postnatal factors in CHD might play a major role in the progression to HF. In this review, we propose three putative routes which lead to HF in CHD: rare monogenic entities that cause both CHD and HF, severe CHD lesions in which acquired hemodynamic effects of CHD or surgery result in HF, and most commonly a combined effect of complex genetics in overlapping pathways and acquired stressors caused by the primary lesion. Novel sequencing technologies have allowed a better understanding of the genomic architecture of HF and CHD with multiple overlapping pathways and hypothesized mechanisms through which pathway deficiencies that led to CHD can increase the risk of progression to HF. Through next-generation sequencing technologies and drug screening using patient-specific induced pluripotent stem cells, the coming years hold a tremendous promise of better understanding this confluence and yielding effective therapeutics.

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“…1 Th e prevalence of this rare syndrome is not known precisely, though a minimum of 200 patients have been reported. 2,3 LS is the result of diff erent missense-mutations in one of 3 genes -PTPN11 = 90%, RAF1 <5%, BRAF <5%. 1 Cardiac abnormalities found in patients with LS include electrocardiographic abnormalities and anatomical malformations, hypertrophic cardiomyopathy (HCM) being currently described as the most frequent abnormality (in up to 80% of cases).…”

Section: Introductionmentioning

confidence: 99%

Biventricular Hypertrophic Cardiomyopathy in a Child with LEOPARD Syndrome: a Case Report

Blesneac

Șuteu

Bănescu

et al. 2017

Journal of Interdisciplinary Medicine

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Background:LEOPARD syndrome is a complex dysmorphogenetic disorder of inconstant penetrance and various morphologic expressions. The syndrome is an autosomal dominant disease that features multiple lentigines, electrocardiographic changes, eye hypertelorism, pulmonary valve stenosis or hypertrophic cardiomyopathy, genital malformations, and a delayed constitutional growth hearing loss, which can be associated with rapidly progressive severe biventricular obstructive hypertrophic cardiomyopathy. No epidemiologic data are available on the real incidence of LEOPARD syndrome; however, this seems to be a rare disease, being often underdiagnosed, as many of its features are mild.Case presentation:We report the case of a 10-year-old female pediatric patient, diagnosed with obstructive hypertrophic cardiomyopathy at the age of 3 months, and recently diagnosed with LEOPARD syndrome. The patient first presented for a cardiologic examination at the age of 3 months, due to a murmur. She presented failure to thrive and psychomotor retardation, and was diagnosed with biventricular obstructive hypertrophic cardiomyopathy for which she had received high-dose beta-blocker therapy. At the age of 7 years she underwent a biventricular myectomy for relief of outflow tract obstruction, completed with another myectomy after 2 years due to progressive increase of pressure gradient in the left ventricular outflow tract. Prior to the second surgical intervention, multiple lentigines appeared on her skin, and genetic testing revealed the presence of LEOPARD syndrome.Conclusion:LEOPARD syndrome is a rare disease, which can be very difficult to diagnose, especially based on features other than lentigines. Cardiac involvement in LEOPARD syndrome can be progressive and requires multiple medical and surgical interventions.

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LEOPARD Syndrome: A Variant of Noonan Syndrome Strongly Associated With Hypertrophic Cardiomyopathy

Cited by 24 publications

References 33 publications

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Heart Failure in Congenital Heart Disease

Biventricular Hypertrophic Cardiomyopathy in a Child with LEOPARD Syndrome: a Case Report

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