LEOPARD syndrome: a variant of Noonan syndrome strongly associated with hypertrophic cardiomyopathy.
OBJECTIVE
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_002825.3T468M). 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.
Servicio de Pediatría, Hospital Virgen de la Salud, Toledo, Spain; Laboratorio de Genética Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. Electronic address: atcarcavilla@gmail.com.
Atilano
A
Carcavilla
Laboratorio de Genética Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
José L
JL
Santomé
Servicio de Pediatría, Hospital Severo Ochoa, Leganés, Madrid, Spain.
Isabel
I
Pinto
Servicio de Pediatría, Hospital Universitario 12 de Octubre, Madrid, Spain.
Jaime
J
Sánchez-Pozo
Unidad de Genética Médica, Servicio de Pediatría, Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain.
Encarna
E
Guillén-Navarro
Servicio de Pediatría, Hospital Universitario Ramón y Cajal, Madrid, Spain.
María
M
Martín-Frías
Instituto de Genética Médica y Molecular, Hospital Universitario La Paz, Madrid, Spain.
Pablo
P
Lapunzina
Laboratorio de Genética Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
Begoña
B
Ezquieta
D000293:Adolescent; D000328:Adult; D002312:Cardiomyopathy, Hypertrophic / Q000150:complications*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D044542:LEOPARD Syndrome / Q000145:classification / Q000150:complications* / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009634:Noonan Syndrome / Q000150:complications* / Q000175:diagnosis* / Q000235:genetics; D055815:Young Adult