Paula and Bobby
Parents of Lillie
What is LEOPARD syndrome?
LEOPARD syndrome is a rare genetic condition. The main symptoms of the syndrome affect the skin, heart, inner ear and genitalia.
It belongs to a group of diseases known as RASopathies. The body’s RAS pathway is responsible for its growth and development. RASopathies, like LEOPARD syndrome, are caused by gene changes that affect and impair these pathways in some way.
What gene changes cause LEOPARD syndrome?
There are three types of the syndrome, each caused by a specific gene change.
Type 1: caused by mutations in the PTPN11 gene.
Type 2: caused by mutations in the RAF1 gene.
Type 3: caused by mutations in the BRAF gene.
Mutations in the MAP2K1 gene are responsible for some of the cases of the syndrome.
It is inherited in an autosomal dominant pattern, or as the result of a de novo mutation.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.
In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
What are the main symptoms of LEOPARD syndrome?
The name of the syndrome is an acronym for the main symptoms of the condition.
Lentigines: dark spots on the skin
Electrocardiographic conduction defects: issues with the electrical activity of the heart
Ocular hypertelorism: widely spaced eyes
Pulmonary stenosis: outflow of blow from the right ventricle of the heart is restricted or affected
Abnormalities of genitalia
Reatrded growth: a short stature
Deafness: caused by inner ear abnormalities
How does someone get tested for LEOPARD syndrome?
The initial testing for LEOPARD syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing
Medical information on 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.
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