Original article
LEOPARD Syndrome: A Variant of Noonan Syndrome Strongly Associated With Hypertrophic CardiomyopathySíndrome LEOPARD: una variante del síndrome de Noonan con fuerte asociación a miocardiopatía hipertrófica

https://doi.org/10.1016/j.rec.2012.09.015Get rights and content

Abstract

Introduction and objectives

LEOPARD syndrome is an autosomal dominant condition related to Noonan syndrome, although it occurs less frequently. The aim of this study was to characterize the clinical and molecular features of a large series of LEOPARD syndrome patients.

Methods

We collected clinical data from 19 patients in 10 hospitals. Bidirectional sequencing analysis of PTPN11, RAF1, and BRAF focused on exons carrying recurrent mutations.

Results

After facial dysmorphism, structural heart defects (88%) were the most common feature described. Hypertrophic cardiomyopathy (71%) was diagnosed more often than pulmonary valve stenosis (35%). Multiple lentigines or café au lait spots were found in 84% of the series, and deafness was diagnosed in 3 patients. Mutations in PTPN11 were identified in 16 (84%) patients (10 patients had the recurrent LEOPARD syndrome mutation, p.Thr468Met) (NP_002825.3T468 M). Two other patients had a mutation in RAF, and 1 patient had a mutation in BRAF. When compared with other neurocardiofaciocutaneous syndromes, LEOPARD syndrome patients showed a higher prevalence of hypertrophic cardiomyopathy and cutaneous abnormalities, and a lower prevalence of pulmonary valve stenosis and short stature.

Conclusions

LEOPARD syndrome patients display distinctive features apart from multiple lentigines, such as a higher prevalence of hypertrophic cardiomyopathy and lower prevalence of short stature. Given its clinical implications, active search for hypertrophic cardiomyopathy is warranted in Noonan syndrome spectrum patients, especially in LEOPARD syndrome patients.

Resumen

Introducción y objetivos

El síndrome LEOPARD es una enfermedad autosómica dominante relacionada con el síndrome de Noonan, aunque menos conocida. El objetivo del presente estudio es describir las características clínicas y moleculares de una serie amplia de pacientes con síndrome LEOPARD.

Métodos

Se obtuvieron datos clínicos de 19 pacientes procedentes de 10 hospitales. Se estudiaron los genes PTPN11, RAF1 y BRAF mediante secuenciación bidireccional de los exones más recurrentes.

Resultados

Tras las dismorfias faciales, la principal característica descrita es la cardiopatía congénita (88%). La más frecuente es la miocardiopatía hipertrófica (71%), por delante de la estenosis pulmonar (35%). Se describió lentiginosis múltiple o manchas café con leche en un 84% y sordera en 3 pacientes; 16 pacientes (84%) portaban mutación en PTPN11 (en 10 de ellos, la mutación recurrente en el síndrome LEOPARD, p.Thr468Met) (NP_002825.3). En otros 2 pacientes se identificó mutación en RAF1 y 1 solo en BRAF. En comparación con otros síndromes neurocardiofaciocutáneos, los pacientes con LEOPARD tienen mayor prevalencia de miocardiopatía hipertrófica y lesiones cutáneas y menor prevalencia de estenosis pulmonar y talla baja.

Conclusiones

El síndrome LEOPARD presenta algunas características distintivas además de la lentiginosis múltiple, como son la mayor frecuencia de miocardiopatia hipertrófica y menor prevalencia de talla baja. Dadas las potenciales implicaciones clínicas de la miocardiopatía hipertrófica, se debe buscar activamente en los pacientes del espectro clínico del síndrome de Noonan, y muy especialmente en aquellos con síndrome LEOPARD.

Section snippets

INTRODUCTION

LEOPARD syndrome (LS), or Noonan syndrome (NS) with multiple lentigines (OMIM 151100), is an autosomal dominant disorder characterized by multiple lentigines or café au lait spots, electrocardiographic abnormalities, ocular hypertelorism, pulmonary valve stenosis or hypertrophic cardiomyopathy, genital abnormalities, constitutional growth delay, and deafness.1 LS shares many features with NS (OMIM 163950), which is characterized by an association with congenital heart disease, short stature,

Clinical Evaluation

Patients were evaluated by clinical geneticists and pediatric cardiologists or endocrinologists involved in a Spanish multicenter study of genotype-phenotype relationships, and were diagnosed with LS using the criteria described by Voron et al.12 Blood samples or patient DNA were sent to our center from participating hospitals by the attending clinicians, who had previously obtained informed consent from patients. An initial clinical evaluation based on the preanalytical questionnaire described

RESULTS

The study included 19 patients (13 men, 6 women; age at diagnosis, 11 months to 49 years; mean age, 7.4 years). Cases were referred from 9 hospitals in 5 Spanish regions and 1 hospital in Belgrade (Serbia). Five patients were identified as familial cases (families A and B; 26% of cases; 95% confidence interval [95%CI], 9.1%-51.2%), and the rest were considered sporadic. Table 1 summarizes the phenotypic and molecular findings. Of the total, 15 met Voron's clinical criteria and 4 were considered

DISCUSSION

As some authors have suggested, a classification of cardiomyopathies that takes into account their underlying molecular characteristics could contribute to more appropriate management.19 In the case of hypertrophic cardiomyopathy, the relevance of both NS and LS should be borne in mind.20 This is particularly true when, from a cardiological perspective, the accompanying phenotype can vary from fatal cases to completely asymptomatic patients. Only a high level of suspicion will allow the

CONCLUSIONS

Pulmonary valve stenosis and particularly hypertrophic cardiomyopathy are cardiological findings which may provide the key to identifying the syndrome. Given the potential clinical implications of hypertrophic cardiomyopathy, patients within the clinical spectrum of NS and particularly those with LS should be actively evaluated for this disease. The criteria originally described by Voron et al. in 1976 are still helpful in classifying these patients in terms of diagnosis. Nevertheless, the

FUNDING

Fondo de Investigaciones Sanitarias (PI 06/1179).

CONFLICTS OF INTEREST

None declared.

Acknowledgements

The authors would like to thank the patients and their families for collaborating on the study as well as the clinicians who could not be included as authors. They include Drs. López-Siguero (Hospital Carlos Haya, Málaga), Barrio, and García-Sagredo (Hospital Ramón y Cajal, Madrid), Kuburovic (Mother and Child Healthcare Institute, Serbia), Gracia (Hospital Universitario La Paz, Madrid), Gener Querol (Hospital Universitario de Cruces, Barakaldo, Vizcaya), González-Meneses (Hospital Virgen del

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