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LEOPARD syndrome

This is part of Rare diseases.

Diagnosis: LEOPARD syndrome

Synonyms: Noonan syndrome with muliple lentigines, Cardiocutaneous syndrome

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Publication date: 2012-08-21
Version: 1.0

ICD 10 code

Q87.8W

The disease

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. Separate information on Noonan syndrome and cardiofaciocutaneous syndrome can be found in the Rare Disease Database of the Swedish National Board of Health and Welfare.

Occurrence

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. The number of affected individuals in Sweden is unknown.

Cause

Both LEOPARD syndrome and the other RASopathies are caused by a mutation in one of the genes expressing (coding for) proteins in a signal transduction pathway named RAS-MAPK. This signalling pathway is important in cell signalling, an essential process by which cells communicate with each other and respond to external stimuli, including growth factors. RASopathies are named after the affected signalling pathway (RAS-MAPK). The cause of LEOPARD syndrome is a mutation in one of the genes PTPN11 (12q24.1), RAF1 (3p25), or BRAF (7q34). Approximately 90 per cent of all individuals with LEOPARD syndrome have a PTPN11 mutation. In the remaining 10 per cent, a RAF1 mutation is most common. In a small number of cases the underlying genetic cause is still unknown.

PTPN11, RAF1, and BRAF are important components in the RAS-MAKP signalling pathway, and a mutation in one of these genes can also cause Noonan syndrome. In LEOPARD syndrome PTPN11 mutations seem to inactivate protein function, while it is activated in Noonan syndrome. This suggests that different mechanisms underlie the two related syndromes.

Figure: Outline of the RAS-MAKP signalling pathway. Syndromes caused by mutations in genes controlling the production of signalling proteins.

Heredity

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.

Figure: Autosomal dominant inheritance

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.

Symptoms

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.

Development

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 hyperflexible 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. 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.

Hearing

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.

Vision

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

Skin

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.

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 tumours.

Diagnosis

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.

Treatment/interventions

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 regularly 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.

Practical advice

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National and regional resources in Sweden

Diagnostics is carried out at departments of clinical genetics at Sweden’s university hospitals.

Paediatric cardiac operations are carried out at The Queen Silvia Children’s Hospital in Gothenburg and at Skåne University Hospital in Lund. Sweden’s regional hospitals have paediatric cardiology units.

There are paediatric neurology departments at Swedish county and regional hospitals.

Resource personnel

Professor Göran Annerén, Department of Clinical Genetics, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 59 42, fax: +46 18 611 40 25, email: goran.anneren@igp.uu.se.

Clinical Molecular Geneticist, Professor Marie-Louise Bondeson, Department of Clinical Genetics, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 59 39, fax: +46 18 611 40 25, email: marielouise.bondeson@igp.uu.se.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations

The Swedish Noonan Association, Box 54, SE-431 21 Mölndal, Sweden. Email: info@noonanforeningen.se, www.noonanforeningen.se.

Rare Diseases Sweden, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 764 49 99, fax: +46 8 546 404 94, email: info@sallsyntadiagnoser.se, www.sallsyntadiagnoser.se
Rare Diseases Sweden is a federation of rare disease organizations, serving the interests of people with rare disorders.

FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities, Gävlegatan 18 C, Box 6436, SE-113 82 Stockholm, Sweden. Tel: +46 8 508 866 00, fax: +46 8 508 866 66, email: fub@fub.se, www.fub.se.

Courses, exchanges of experience for personnel

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Research and development (R&D)

Research on LEOPARD syndrome is ongoing in Europe and the US. In Sweden, research on the RASopathies is performed at the Department of Clinical Genetics at Uppsala University Hospital. Clinical trials are taking place in the US to establish whether chemotherapy can alleviate some of the symptoms of RASopathies.

Information material

An information leaflet on LEOPARD syndrome summarising the information in this database text is available free of charge from the Publications Department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2011-11-26). Address: SE-106 30 Stockholm, Sweden. Fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se, or tel: +46 75 247 38 80. Postage will be charged for bulk orders.

Literature

Digilio MC, Sarkozy A, DeZorsi A, Pacileo G, Limingelli G, Mingarelli R et al. LEOPARD syndrome: clinical diagnosis in the first year of life. Am J Med Genet A 2006; 140: 740-746.

Gorlin Rj, Anderson RC, Blaw M. Multiple lentigines syndrome. Am J Dis Child 1969; 17: 652-662.

Kratz CP, Rapisuwon S, Reed H, Hasle H, Rosenberg PS. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndrome. Am J Med Genet C 2011; 157: 83-89.

Limongelli G, Pacileo G, Marino B, Digilio MC, Sarcozy A, Elliot P et al. Prevalence and significance of cardiovascular abnormalities in patients with LEOPARD syndrome. Am J Cardiol 2007; 100: 736-741.

Marin TM, Keith K, Davies B, Conner DA, Guha P, Kalaitzidis D et al. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest 2011; 1: 1026-1043.

Sarkozy A, Digilio MC, Dallapiccola B. Leopard syndrome. Orphanet J Rare Dis 2008; 3: 13. Review.

Tartaglia, M, Gelb B, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab 2011; 25: 161-179.

Zeisler EP. Generalized Lentigo: Its relation to systemic nonelevated nevi. Arch Dermato Syph 1936; 33: 109-125.

Database references

OMIM (Online Medelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: LEOPARD syndrome

GeneReviews (University of Washington)
www.genetests.org (find GeneReviews, then Titles)
Search: LEOPARD syndrome

Genetics Home Reference (US National Library of Medicine)
http://ghr.nlm.nih.gov/condition/leopard-syndrome/show/print

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Marie-Louise Bondeson, Uppsala University Hospital, Sweden.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Publication date: 2012-08-21
Version: 1.0
Publication date of the Swedish version: 2011-12-30

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.