LEOPARD syndrome

¿Que es LEOPARD syndrome?

LEOPARD syndromees una condición genética rara. El principal síntomas del síndrome afectan la piel, el corazón, el oído interno y los genitales.

Pertenece a un grupo de enfermedades conocidas como RASopatías. La vía RAS del cuerpo es responsable de su crecimiento y desarrollo. RASopatías, como LEOPARD syndrome, son causados por cambios genéticos que afectan y deterioran estas vías de alguna manera.

¿Qué causan los cambios genéticos LEOPARD syndrome?

Hay tres tipos de síndrome, cada uno causado por un cambio genético específico.

Tipo 1: causado por mutaciones en el gen PTPN11.
Tipo 2: causado por mutaciones en el gen RAF1.
Tipo 3: causado por mutaciones en el gen BRAF.

Las mutaciones en el gen MAP2K1 son responsables de algunos de los casos del síndrome.

Se hereda con un patrón autosómico dominante o como resultado de una mutación de novo.

En algunos casos, un síndrome genético puede ser el resultado de una mutación de novo y el primer caso en una familia. En este caso, se trata de una nueva mutación genética que se produce durante el proceso reproductivo.

En el caso de la herencia autosómica dominante, solo uno de los padres es el portador de la mutación genética y tiene un 50% de posibilidades de transmitirla a cada uno de sus hijos. Los síndromes heredados en una herencia autosómica dominante son causados por una sola copia de la mutación genética.

¿Cuales son los principales síntomas de LEOPARD syndrome?

El nombre del síndrome es un acrónimo de los principales síntomas de la afección.

Lentigos: manchas oscuras en la piel.
Defectos de conducción electrocardiográfica: problemas con la actividad eléctrica del corazón
Hipertelorismo ocular: ojos muy espaciados
Estenosis pulmonar: el flujo de salida del golpe del ventrículo derecho del corazón está restringido o afectado.
Anomalías de los genitales
Crecimiento retenido: una estatura baja
Sordera: causada por anomalías del oído interno



¿Cómo se hace la prueba a alguien? LEOPARD syndrome?

La prueba inicial para LEOPARD syndrome puede comenzar con la detección del análisis facial, a través de la FDNA Telehealth plataforma de telegenética, que puede identificar los marcadores clave de la síndrome y describa la necesidad de realizar más pruebas. Seguirá una consulta con un asesor genético y luego con un genetista.

Sobre la base de esta consulta clínica con un genetista, se compartirán las diferentes opciones para las pruebas genéticas y se buscará el consentimiento para realizar más pruebas.

Información médica sobre LEOPARD syndrome

The acronym LEOPARD stands for Lentigines (multiple), Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth and Deafness (sensorineural) (Gorlin et al., 1969). The lentigines are small (less than 5mm) dark brown spots, concentrated on the face and upper trunk. They develop at an earlier age than freckles, and unlike the latter do not increase in number on exposure to the sun. Do note the rapid growth of the lentigines in 2 patients reported by Kalev et al., (2010). Cardiac abnormalities include mild pulmonary stenosis, subaortic stenosis, or other abnormalities. There is widening of the QRS complex with bundle branch block, abnormal P-waves and prolongation of the P-R interval. Genital abnormalities include hypogenitalism and hypospadias. Height is usually below the 25th centile, but is not severely affected. Sensorineural deafness is variable, ranging from normal to severe. There is also an association with granular cell schwannomas. Coppin and Temple (1997) provide a good review. Sarkozy et al., (2004) reviewed 30 patients with mutations: 86% had multiple lentigenes, 90% were facially dysmorphic, 71% had cardiac involvement and 25% had sensorineural deafness. These authors state that the diagnosis should not be ruled out in young people without lentigines, but who have a hypertrophic cardiomyopathy (or pulmonary stenosis) and sensorineural deafness. In a further study of those with a mutation, Digilio et al., (2006) suggest that the diagnosis can be made in the first year of life in those with a hypertrophic cardiomyopathy, cafe-au-lait spots, hypertelorism, ptosis, down-slanting palpebral fissures and dysmorphic ears. Noonan's-NF would need to be excluded. Autosomal dominant isolated lentigines occur; this has been mapped at 4q21.1-q22.3 (Xing et al., 2005).
Multiple dot cortical lens opacities have been reported in patients in their third decade. There may also be patchy defects in the retinal pigment epithelium. A mother and her monozygotic twin offspring were reported by Rudolph et al., (2001) with variable expression of chorioretinal colobomata. The patient reported by Choiet al., (2003) had a congenital corneal tumour (choristoma) in both eyes. Leukemia has been associated with the condition (Laux et al., 2008) as has a patient with a scalp melanoma (Cheng et al., 2013)
Edman Ahlbom et al., (1995) excluded linkage to the NF1 gene in a small dominant family. On the other hand Wu et al., (1996) found an NF1 gene mutation in a 32-year-old woman thought to have some features of the condition. She had a valvular aortic stenosis and mitral insufficiency, mild mental handicap, lentignes, cafe-au-lait spots, hypertelorism but no neurofibromas. Schepis et al., (1998) reported a possible case with ichthyosis, however this case was unusual as there were apparently no heart abnormalities and the boy also had axillary freckling, two cafe au lait spots, and a neurofibroma.
Legius et al., (2002) reported a father and daughter and an unrelated patient with features of the condition who had a Ty279Cys mutation in the PTN11 gene. Digilio et al., (2002) studied nine cases with LEOPARD syndrome and two cases with Noonan syndrome who had multiple cafe au lait spots and found one of two specific mutations in the PTPN11 gene in two of these cases. The mutations were Ty279Cys and Thr468Met.
Sarkozy et al., (2003) looked for PTPN11 gene mutations in 71 patients with Noonan syndrome and 13 with multiple lentigenes or LEOPARD syndrome. Fourteen different PTPN11 mutations were detected in 23 patients with Noonan syndrome and 11 with lentigenes or LEOPARD syndrome. Pulmonary valve stenosis, most commonly seen in Noonan syndrome, was related to an exon 8 mutation hot spot, while hypertrophic cardiomyopathy, predominant in patients with lentigenes or LEOPARD syndrome, was associated with mutations in exon 7 and 12. Atrial septal defects were related to exon 3 mutations, while atrioventricular canal defects and mitral valve anomalies were found in association with different exon mutations. Those with Gln510Glu mutations might have a rapidly progressive obstructive cardiomyopathy (Digilio et al., 2006).
Pacheco et al., (2002) excluded linkage to the PTPN11 gene in a large dominant family segregating for isolated multiple lentigines without other abnormalities. Two single cases with lentigines and nothing else were reported by Chong et al., (2004. A large family with dominantly inheritance of lentigines was reported by Pacheco et al., (2004). The condition showed linkage to 6q. Mutations in PTPN11 were reported by Yoshida et al., (2004). PTPN11encodes SHP-2, which is involved in a number of cytokine and growth factor initiated signal transduction processes. SHP-2 has 2 domains, one at the N-terminus and the other a phosphatase domain (PTP) at he C terminus. It is in the PTP domain that the LEOPARD syndrome mutations occur (Keren et al., 2004). One of the Keren et al., (2004) patients developed acute myeloid leukaemia. In their series of children with cancer, Merks et al., (2005) reported on a molecularly proven patient with a neuroblastoma. A medulloblastoma has also been reported (Rankin et al., 2013). Two families without mutations, were reported by Kalidas et al., (2005). Two patients reported by Digilio et al., (2006) and 1 by Takahashi et al., (2005) all with a Gln510Glu mutation, had a rapidly progressive obstructive, hypertrophic cardiomyopathy.
Note the patient reported by Koudava et al., (2009) with a BRAF mutation. The condition is well reviewed by Martinez-Quintana and Rodriguez-Gonzales (2012).
A mutation in MAP2K1 was found by Nishi et al., (2015) in a patient with Noonan features and multiple lentigines, but without a cardiac lesion.
Plexiform neuromas, dumbbell spinal tumours were reported in 3 families with PTPN11 mutations (Conboy et al., 2016)
Zhang et al. (2016) described three Chinese boys with multiple lentiginous phenotypes. The authors reported novel heterozygous missense and frameshift mutations in SASH1 and a missense mutation in PTPN11 in three respective patients. Patient 1 had multiple freckle-like lesions that began to appear over his entire body at the age of three years. Multiple lentigines intermixed with scattered hypopigmented spots were noted on the trunk and face, and mild dyschromatosis was observed in elbow joints and dorsal area of hands and feet. The boy’s mother, maternal grandmother and maternal aunt had similar lentiginous phenotype. Patient 2 was a 15-year-old boy. His whole skin surface was relatively white, and multiple lentigines were noted on the face, trunk, extremities and mucous membranes. Patient 3 was an 11-year-old boy with several café au-lait spots (CALSs) and freckles over the trunk and face since he was two years old. He also had dysmorphic craniofacial features, ocular hypertelorism, bone anomalies and lack of mucocutaneous hyperpigmentation of the lips. He also had a surgical history of pectus excavatum.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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