ORPHA: 500; DO: 0080550;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q34 | LEOPARD syndrome 3 | 613707 | Autosomal dominant | 3 | BRAF | 164757 |
A number sign (#) is used with this entry because of evidence that LEOPARD syndrome-3 (LPRD3) is caused by heterozygous mutation in the BRAF gene (164757) on chromosome 7q34.
For a phenotypic description and a discussion of genetic heterogeneity of LEOPARD syndrome, see 151100.
Sarkozy et al. (2009) reported a patient with LEOPARD syndrome who had poor growth, craniofacial anomalies, short and webbed neck, mitral and aortic valve dysplasia, cognitive deficits, neonatal hypotonia, sensorineural deafness, and seizures. Other features included thoracic defects, delayed puberty, reduced bone density, and fibrous cystic lesions of the pelvis. The skin showed hyperkeratosis, cafe-au-lait spots, multiple nevi, and dark colored lentigines that were spread on the whole body including the palms and soles.
Koudova et al. (2009) reported a 17-year-old Czech boy with LEOPARD syndrome. He was diagnosed with tetralogy of Fallot shortly after birth and was also found to have cardiac conduction defects. From age 5 years, he developed multiple pigmented skin lesions and showed growth retardation, delayed puberty, and delayed bone age. Notable facial features included hypertelorism, depressed nasal bridge, and low-set and posteriorly rotated ears. He also had curly hair and mild unilateral sensorineural hearing loss. Psychomotor development was normal. Koudova et al. (2009) noted the phenotypic similarities to cardiofaciocutaneous syndrome-1 (CFC1; 115150).
The heterozygous mutations in the BRAF gene that were identified in patients with LEOPARD syndrome-3 by Sarkozy et al. (2009) and Koudova et al. (2009) occurred de novo.
In 1 (17%) of 6 unrelated patients with a clinical diagnosis of LEOPARD syndrome, Sarkozy et al. (2009) identified a heterozygous de novo mutation in the BRAF gene (T241P; 164757.0024). The same mutation had previously been identified by Schulz et al. (2008) in 2 patients with CFC1, indicating the overlapping nature of the 2 disorders.
In a 17-year-old Czech boy with LPRD3, Koudova et al. (2009) identified a de novo heterozygous missense mutation in the BRAF gene (L245F; 164757.0027). Functional studies of the variant were not performed.
Koudova, M., Seemanova, E., Zenker, M. Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence. Europ. J. Med. Genet. 52: 337-340, 2009. [PubMed: 19416762] [Full Text: https://doi.org/10.1016/j.ejmg.2009.04.006]
Sarkozy, A., Carta, C., Moretti, S., Zampino, G., Digilio, M. C., Pantaleoni, F., Scioletti, A. P., Esposito, G., Cordeddu, V., Lepri, F., Petrangeli, V., Dentici, M. L., and 15 others. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum. Mutat. 30: 695-702, 2009. [PubMed: 19206169] [Full Text: https://doi.org/10.1002/humu.20955]
Schulz, A. L., Albrecht, B., Arici, C., van der Burgt, I., Buske, A., Gillessen-Kaesbach, G., Heller, R., Horn, D., Hubner, C. A., Korenke, G. C., Konig, R., Kress, W., and 15 others. Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome Clin. Genet. 73: 62-70, 2008. [PubMed: 18042262] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00931.x]