Leopard Syndrome

Author: hirad akberi
Date: 31/01/2014



LEOPARD syndrome is a rare genetic disorder that affects multiple organs. LEOPARD is an acronym for the initial letters of characteristic symptoms: Lentigines (dark-brown skin spots similar to freckles), ECG conduction abnormalities, Ocular hypertelorism (widely space eyes), Pulmonary stenosis (a narrowing of the pulmonary valve), Abnormal genitalia, Retardation of growth leading to short stature, and Deafness or hearing loss owing to inner ear defects. Many other symptoms may present, and there are significant differences between individuals. Common symptoms include a thickening of the ventricular walls of the heart (hypertrophic cardiomyopathy), bone abnormalities, and behavioural disorders. Owing to the many similarities with Noonan syndrome, it has been suggested that the name of the condition should be changed to Noonan syndrome with multiple lentigines.

LEOPARD syndrome was first reported in 1936 by Zeisler and Becker. They described a 24-year-old woman who had increasing numbers of lentigines through her childhood years. She also had chest abnormalities (funnel chest, pectus carinatum), hypertelorism, and protruding lower jaw (mandibular prognathism). A few decades later, the American geneticist Robert James Gorlin described the disorder and named it LEOPARD syndrome.

This syndrome belongs to a group of related disorders, denoted RASopathies, or the RAS-MAPKsyndromes (Ras/mitogen-activated protein kinase). Every syndrome of the RASopathies presents with some unique clinical features but may also share some characteristics. This creates problems in making individual diagnoses. RASopathies may be caused by many different mutations in various genes, but sometimes a mutation in one and the same gene may result in separate syndromes. This complicates the diagnosis of syndromes within this group.

Other syndromes included in the group of RASopathies are Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome, neurofibromatosis type 1 and NF1-like (Legius) syndrome.
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LEOPARD syndrome is a rare condition, but the exact prevalence is currently unknown. Among the RASopathies, LEOPARD syndrome is probably the second most prevalent, following Noonan syndrome.


LS may be sporadic or inherited as an autosomal dominant fully penetrant trait. In approximately 85% of the patients with a definite diagnosis of LS, a missense mutation is found in the PTPN11 gene, located on chromosome 12q24.1. The PTPN11 gene encodes for the SRC homology 2 (SH2) domain-containing PTPase (SHP2) protein, characterised by two tandemly arranged SH2 (N-SH2 and C-SH2) domains and one protein tyrosine phosphatase (PTP) domain. SHP2 functions as a cytoplasmic signaling transducer downstream of multiple receptors for growth factors, cytokines and hormones, with a particular role through the RAS-mitogen activated protein kinase (MAPK) pathway. To the best of our knowledge, 11 different missense PTPN11 mutations, in exon 7, 12 and 13 (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro, and Gln510Glu/Gly), have been reported so far, two of which (Tyr279Cys and Thr468Met) occur in about 65% of the cases ( LEOPARD syndrome caused by Tyr279Cys mutation in the PTPN gene ). Germinal mutations in the PTPN11 gene are also responsible for about 40–50% of Noonan (NS) and Noonan-like/Multiple Giant Cell lesions syndrome cases. Known changes appear to be exclusive for NS or LS, leading to specific genotype-phenotype correlations between these two disorders. Among patients with PTPN11 mutations, an association between exon 7 and 12 mutations and HCM, and between exon 8 mutations and PVS, has been established ( grouping of multiple lentigenes/LEOPARD and Noonan syndromes on the PTPN11 gene ). LS patients without PTPN11 mutations show a higher prevalence of ECG abnormalities and left ventricle hypertrophy. Analyses of the natural history of HCM in LS patients with different genotypes indicate that patients without PTPN11 mutations show a higher frequency of family history of sudden death, increased left atrial dimensions, bradyarrhythmias and other adverse arrhythmic and nonarrhythmic events. Mutations affecting exon 13 in the PTPN11 gene are often associated with an important cardiac phenotype, characterised by rapidly progressive severe biventricular obstructive HCM, often with prenatal onset, and with serious cardiac complications during follow-up (heart failure, septal myectomy, and sudden death). Analysis of personal cohorts of LS patients indicate that mutation of the Thr468 residue is less frequently associated with short stature, compared to mutation of the Tyr279 residue (26% vs. 47%), in which also deafness is more common (24% vs. 9%). This data confirm a previous observation of less adverse effects of the Thr468Met mutation on body growth and cardiac development, with lower prevalence of PVS in these patients.

Although LS and NS are clinically overlapping conditions, nosological splitting is well supported by distinct functional effects of the disease causing mutation: gain of function in NS and reduced protein tyrosine phosphatase activity in LS, suggestive of a dominant-negative effect.

Genetic heterogeneity was supported by linkage analysis, and recently confirmed by the identification of RAF1 gene mutations in two out of six PTPN11 mutation negative LS patients. RAF1 protein is one of the three mammalian RAF isoforms (ARAF, BRAF and CRAF or RAF1), threonine-serine protein kinases with nonredundant developmental functions, acting downstream of RAS. RAF1 gene mutations are also responsible for a subset of NS, 75% of which develop HCM. The two LS subjects carrying the Leu613Val and Ser257Leu changes disclosed a full blown LS phenotype, with multiple lentigines, CLS, HCM and delayed puberty. Pandit et al. investigated the functional effect of different RAF1 mutants, including the Leu613Val change, and showed that those associated with HCM had increased kinase activity and enhanced ERK activation. These data reinforce the role of increased RAS signalling in cardiomyocyte hypertrophy pathogenesis and suggest that LS pathogenesis should not be simply related to a reduced RAS signal transduction.

About 5% of LS patients of the reported series do not have PTPN11 or RAF1 mutations. Analysis of additional genes encoding for member or the RAS pathway will likely expand the LS genetic heterogeneity.

Distinct missense PTPN11 gene mutations occur as somatic events in myeloid or lymphoid malignancies. Both the spectrum and the distribution of these PTPN11 mutations are different from those documented in LS and related disorders.
Leopard syndrome
The RASopathies


The inheritance pattern of LEOPARD syndrome is autosomal dominant. This means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disease and do not pass it down.

The syndrome may also be caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. However, the new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children.


As the name of the condition reveals, multiple organs may be affected, for example the skin, heart, ears and genitals, although there is considerable variation among individuals. The facial appearance of children with LEOPARD syndrome may resemble that of individuals with Noonan syndrome or Neurofibromatosis type 1- Noonan syndrome (NFNS). It can be difficult to make a diagnosis in early childhood as many of the characteristic symptoms present later.


Birth length is normal and weight is normal or above average. Low muscle tone (hypotonia) is common, and may cause delays in motor development. Mild learning disability is sometimes associated with the syndrome, but severe intellectual disability is rare.

Bone development and growth

The growth and maturity of the skeleton may be delayed, which results in the child being shorter than others of the same age. There is no data available on the average final height in adults with LEOPARD syndrome. Chest wall deformities (funnel chest or keeled chest) are common, and are usually detected in newborns. Some children also have abnormal curvature of the spine (scoliosis or kyphosis). Other, less common, skeletal anomalies include a protruding lower jaw (mandibular prognathia) and prominent shoulder blades. Some children have hyper flexible joints.

The heart

Many individuals with LEOPARD syndrome have cardiac anomalies, which may be present at birth or develop during early childhood. Heart defects including abnormal transmission of the electrical impulses that coordinate the contractions of the heart (atrioventricular, AV block) are most common, varying in severity from benign to life threatening ( Cardiovascular abnormalities in patient with LEOPARD syndrome ). Thickened ventricular walls (hypertrophic cardiomyopathy) are also common. The condition may be congenital but usually develops in childhood, before the onset of lentigines. In some cases cardiomyopathy is discovered when lentigines first appear. The condition may also progresses at this point in time.

Other cardiac abnormalities include narrowing of the pulmonary artery valve (pulmonary stenosis). In most cases, the condition tends to be mild and is usually asymptomatic. If symptoms develop, they often do so later in childhood. It is possible to have both pulmonary stenosis and hypertrophic cardiomyopathy.

it is important to be aware that anaesthesia is associated with a risk for children with hypertrophic cardiomyopathy or abnormal heart rate.
A variant of Noonan syndrome associated with hypertrophic cardiomyopathy


Approximately 20 per cent of individuals with the syndrome have hearing loss (sensorineural hearing loss), ranging from mild to severe. The condition is caused by damaged or absent nerve cells in the cochlea or in the auditory nerve. In most cases hearing loss is discovered in newborns or in infants, but sometimes the condition develops later in life.


Some children with the syndrome squint, which may result in delayed visual development. Vision usually improves with age.


The skin of newborns with the syndrome may be loose and hyperelastic. A characteristic feature of the syndrome is the abundant presence of lentigines, which are black or dark brown skin spots. These spots are 1-5 mm in size, and look like dark freckles. Lentigines may be present at birth but more commonly appear around the ages of 4-5, and may increase in number until the child reaches puberty. Many people with the syndrome have thousands of spots, which may appear anywhere on the body, but mostly on the neck and trunk. There are also a few individuals with the syndrome who do not have lentigines.

Approximately half of all individuals with the syndrome also have larger, lighter brown skin spots (café-au-lait spots), which usually develop in the first few months of the child’s life. The café-au-lait spots are usually present before lentigines develop.

In adults, the skin may age prematurely.

Neurological abnormalities

Hypotonia is common in the newborn and can result in delayed psychomotor development. Mild learning difficulties are reported in about 30% of the cases, while mental retardation is rare.


Haematological complications, such as myelodysplasia, acute myelogenous leukaemia and neuroblastoma, have been described in a few patients. Malignant melanoma was diagnosed in a patient with a germline PTPN11 and a somatic BRAF mutation. Bilateral choristomas have been reported in a 5-year-old girl.

Other symptoms

The syndrome is associated with characteristic facial features, including thick lips, a broad forehead, and widely spaced eyes (hypertelorism). The eyes often slant downwards, and drooping eyelids (ptosis) are common. The ears are low set and rotated inwards, and the cartilaginous outer rim of the ear is thickened. The neck may be short, with surplus skin and a low hairline. The characteristic appearance associated with the syndrome becomes less distinct over the years.

Urogenital abnormalities sometimes occur. The testes of affected males often remain in the abdominal cavity (cryptorchidism). In some, the urinary opening is on the underside of the penis, and the penis is sometimes underdeveloped. In affected females the ovaries may in rare cases be underdeveloped or absent. The production of sex hormones may be impaired in both girls and boys, which in some cases leads to delayed puberty.

A rare congenital anomaly known as horseshoe kidney may also occur, meaning that the two lower ends of the kidneys have fused in the shape of a horseshoe. Normally the condition does not cause any symptoms, and is usually only discovered in association with surgery carried out for other problems.

There are reports of a few individuals with LEOPARD syndrome who developed leukaemia or other malignant tumors.
Leopard syndrome symptoms


The diagnosis LEOPARD syndrome is based on a clinical examination and confirmed by DNA-based testing. In most cases it is possible to identify PTPN11, RAF, and BRAF1 mutations in a DNA analysis.

When it is not possible to establish a mutation in one of these genes, the diagnosis should be re-considered. In such cases other syndromes within the RAS-MAPK group of diseases should be considered as alternative diagnoses, for example Noonan syndrome or Neurofibromatosis type 1-Noonan syndrome.

At the time of diagnosis the family should be offered genetic counselling. Carrier diagnostics as well as prenatal diagnostics is possible if the underlying mutation has been identified in the family.


Currently, there is no cure for LEOPARD syndrome, but early intervention is important to alleviate symptoms and prevent complications. As many organ systems can be affected, treatment should be directed toward the specific needs of each individual and his or her family.

Cardiac anomalies are usually diagnosed by ultrasound examinations and ECG. Sometimes further examinations are called for, and different X-ray techniques or electrophysiological methods can be used. The type and severity of the disorder determine the treatment. As a rule, mild, asymptomatic forms of heart arrhythmias require no treatment. Treatment for heart anomalies such as severe heart arrhythmias, thickening of the heart muscle, and narrowing of the pulmonary artery valve may include medication, and in rare cases surgical intervention. Sometimes a pacemaker is required. In rare cases the valve of the pulmonary artery is severely constricted, and may require a balloon angioplasty procedure or an operation. In a balloon angioplasty a catheter is passed into the body through a blood vessel in the groin and is placed in the constricted valve. The balloon is then inflated so that the constricted area is widened.

Cardiac function must be monitored as the condition may change, especially when lentigines first appear.

Urogenital malformations are detected in ultrasound examinations or X-rays. Early surgical intervention is required if the testicles have not descended into the scrotum. In some cases deficiencies in certain hormones (gonadotropins) cause delayed puberty and impaired fertility. Hormonal levels should therefore be monitored, and hormonal treatment is sometimes needed.

Hearing should be evaluated on a regular basis for early detection of hearing loss. Impaired hearing can sometimes be improved with hearing aids or by surgically inserting a cochlear implant (CI). Auditory habiliation is important.

Some children with LEOPARD syndrome require early contact with a habilitation team. These are made up of professionals with special expertise in how disability affects everyday life, health and development. Support and treatment take place within the medical, educational, psychological, social and technical fields. Visual and auditory habilitation are also included. Interventions may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. They also include information about support offered by the local authority. The measures focus on existing needs, may vary over time and occur in collaboration with individuals close to the child.


LS is caused by heterozygous missense mutations in autosomal genes. Familial cases are commonly reported, and prevalence of transmitting mothers might be related to reduced male fertility. Genetic counselling should include:

  • revision of a three generation family tree, with specific enquiries for skin and cardiac anomalies, short stature and learning difficulties;
  • revision of pregnancy and developmental history and schooling;
  • examination of growth parameters, facial dysmorphisms, skin, skeleton, joints, heart and external genitalia;
  • complete clinical and cardiological examination of parents, inclusive of echocardiogram and ECG, if possible;
  • revision of natural history of the condition, its manifestation and clinical variability, occurrence and recurrence risks, and the eventual recommendation for clinical and molecular investigations to confirm the diagnosis;
  • management and follow-up, inclusive of available treatments and interventions.

If one of the parents is affected, a 50% recurrence risk is appropriate. Germinal mutations and autosomal recessive inheritance have not been reported so far. Accordingly, in case of identified de novo mutation in sporadic patients, the recurrence risk for siblings is marginal. Molecular investigation should take into account the PTPN11 gene screening first, and then the RAF1 gene screening in PTPN11-negative individuals.


The LS phenotype is extremely heterogeneous, ranging from adults with mild facial features and multiple lentigines, to patients with severe HCM, mental retardation, deafness and additional defects. Genotype-phenotype correlation analysis and functional studies are providing answers to these questions. In early childhood and before the appearance of lentigines, diagnosis of LS is sometimes difficult because of the overlap with NS and NFNS. In these patients, a mutation-based diagnosis is recommended.

Presence of patients without PTPN11 and RAF1 mutations further expand genetic heterogeneity of LS and points towards other genes likely involved in the same RAS-MAPK pathway.

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