Leopard syndrome
Encyclopedia
LEOPARD syndrome - is part of a group called Ras/MAPK pathway syndromes - is a rare autosomal dominant, multisystem disease caused by a mutation
in the protein tyrosine phosphatase
, non-receptor type 11 gene (PTPN11
). The disease is a complex of features, mostly involving the skin, skeletal and cardiovascular systems, they may or may not be present in all patients. The nature of how the mutation causes each of the condition's symptoms is not well known, however research is ongoing. It is a RASopathy
.
Related to Noonan syndrome
, LEOPARD syndrome is caused by a different missense mutation
of the same gene. Noonan syndrome
is fairly common (1:1000 to 1:2500 live births), and neurofibromatosis 1
(which was once thought to be related to LEOPARD syndrome) is also common (1:3500), however no epidemiologic data exists for LEOPARD syndrome.
, originally coined in 1969, as the condition is characterized by some of the following seven conditions, the first letters of which spell LEOPARD, along with the characteristic "freckling" of the skin, caused by the lentigines
that is reminiscent of the large cat
.
The presence of all of these hallmarks is not needed for a diagnosis. A clinical diagnosis
is considered made when, with lentigines
present there are 2 other symptoms observed, such as ECG abnormalities and ocular hypertelorism, or without lentigines, 3 of the above conditions are present, with a first-degree relative (i.e. parent, child, sibling) with a clinical diagnosis.
Due to the rarity of the syndrome itself, it is hard to determine whether certain additional diseases are actually a threat of the syndrome. With a base population of possibly less than one thousand individuals, one or two outlying cases can skew the statistical population very quickly.
, following evaluation of the mother.
There are 5 identified allelic variant
s responsible for LEOPARD syndrome. Y279C, T468M, A461T, G464A, and Q510P which seems to be a unique familial mutation, in that all other variants are caused by transition errors, rather than transversion
.
In the two predominant mutations of LEOPARD syndrome (Y279C and T468M) the mutations cause a loss of catalytic activity of the SHP2 protein (the gene product of the PTPN11
gene), which is a previously unrecognized behavior for this class of mutations. This interferes with growth factor and related signalling. While further research confirms this mechanism, additional research is needed to determine how this relates to all of the observed effects of LEOPARD syndrome.
It is recommended that those with the syndrome who are capable of having children seek genetic counseling before deciding to have children. As the syndrome presents frequently as a forme fruste (incomplete, or unusual form) variant, an examination of all family members must be undertaken. As an autosomal dominant trait there is a fifty percent chance with each child, that they will also be born with the syndrome. This does not take into account the possibility of the gene mutating, on its own, in a child of a LEOPARD syndrome patient who does not inherit the gene from the affected parent. Although fully penetrant, since the syndrome has variable expressivity, one generation may have a mild expression of the syndrome, while the next may be profoundly affected.
Once a decision to have children is made, and the couple conceives, the fetus is monitored during the pregnancy for cardiac evaluation. If a gross cardiac malformation is found, parents receive counseling on continuing with the pregnancy.
Other management is routine care as symptoms present:
, hypertelorism
, pectus carinatum
(protruding breastbone) and prognathism
(protrusion of lower jaw) in 1936. Sporadic descriptions were added through the years. In 1962, cardiac abnormalities and short stature were first associated with the condition. In 1966, three familial cases were added, a mother, her son and daughter. Another case of mother to two separate children, with different paternity of the two children, was added in 1968.
It was believed as late as 2002 that LEOPARD syndrome was related to neurofibromatosis type I
(von Recklinghausen syndrome). In fact, since both ICD9 and ICD10 lack a specific diagnosis code for LEOPARD syndrome, the diagnosis code for NF1
is still sometimes used for diagnostic purposes, although it has been shown that the gene is not linked to the NF1
locus.
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in the protein tyrosine phosphatase
Protein tyrosine phosphatase
Protein tyrosine phosphatases are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins. Protein tyrosine phosphorylation is a common post-translational modification that can create novel recognition motifs for protein interactions and cellular...
, non-receptor type 11 gene (PTPN11
PTPN11
Tyrosine-protein phosphatase non-receptor type 11 also known as protein-tyrosine phosphatase 1D or protein-tyrosine phosphatase 2C is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase Shp2.PTPN11 is a member of the protein tyrosine phosphatase ...
). The disease is a complex of features, mostly involving the skin, skeletal and cardiovascular systems, they may or may not be present in all patients. The nature of how the mutation causes each of the condition's symptoms is not well known, however research is ongoing. It is a RASopathy
RASopathy
The RASopathies are developmental syndromes caused by germline mutations in genes that alter the Ras subfamily and Mitogen-activated protein kinase that control Signal transduction, including:*Capillary malformation-AV malformation syndrome...
.
Related to Noonan syndrome
Noonan syndrome
Noonan Syndrome is a relatively common autosomal dominant congenital disorder considered to be a type of dwarfism, that affects both males and females equally. It used to be referred to as the male version of Turner's syndrome ; however, the genetic causes of Noonan syndrome and Turner syndrome...
, LEOPARD syndrome is caused by a different missense mutation
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...
of the same gene. Noonan syndrome
Noonan syndrome
Noonan Syndrome is a relatively common autosomal dominant congenital disorder considered to be a type of dwarfism, that affects both males and females equally. It used to be referred to as the male version of Turner's syndrome ; however, the genetic causes of Noonan syndrome and Turner syndrome...
is fairly common (1:1000 to 1:2500 live births), and neurofibromatosis 1
Neurofibromatosis type I
Neurofibromatosis type I , formerly known as von Recklinghausen disease after the researcher who first documented the disorder, is a human genetic disorder. It is possibly the most common inherited disorder caused by a single gene...
(which was once thought to be related to LEOPARD syndrome) is also common (1:3500), however no epidemiologic data exists for LEOPARD syndrome.
Signs and symptoms
The name of the condition is a mnemonicMnemonic
A mnemonic , or mnemonic device, is any learning technique that aids memory. To improve long term memory, mnemonic systems are used to make memorization easier. Commonly encountered mnemonics are often verbal, such as a very short poem or a special word used to help a person remember something,...
, originally coined in 1969, as the condition is characterized by some of the following seven conditions, the first letters of which spell LEOPARD, along with the characteristic "freckling" of the skin, caused by the lentigines
Lentigo
A lentigo is a small pigmented spot on the skin with a clearly-defined edge, surrounded by normal-appearing skin. It is a harmless hyperplasia of melanocytes which is linear in its spread. This means the hyperplasia of melanocytes is restricted to the cell layer directly above the basement...
that is reminiscent of the large cat
Leopard
The leopard , Panthera pardus, is a member of the Felidae family and the smallest of the four "big cats" in the genus Panthera, the other three being the tiger, lion, and jaguar. The leopard was once distributed across eastern and southern Asia and Africa, from Siberia to South Africa, but its...
.
- LentiginesLentigoA lentigo is a small pigmented spot on the skin with a clearly-defined edge, surrounded by normal-appearing skin. It is a harmless hyperplasia of melanocytes which is linear in its spread. This means the hyperplasia of melanocytes is restricted to the cell layer directly above the basement...
- Reddish-brown to dark brown macules (surface skin lesionLesionA lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...
) generally occurring in a high number (10,000+) over a large portion of the skin, at times higher than 80% coverage. These can even appear inside the mouth (buccalCheekCheeks constitute the area of the face below the eyes and between the nose and the left or right ear. They may also be referred to as jowls. "Buccal" means relating to the cheek. In humans, the region is innervated by the buccal nerve...
), or on the surface of the eye (scleraScleraThe sclera , also known as the white or white of the eye, is the opaque , fibrous, protective, outer layer of the eye containing collagen and elastic fiber. In the development of the embryo, the sclera is derived from the neural crest...
l). These have irregular borders and range in size from 1 mm in diameter to café-au-lait spots, several centimetres in diameter. Also, some areas of vitiligoVitiligoVitiligo is a condition that causes depigmentation of sections of skin. It occurs when melanocytes, the cells responsible for skin pigmentation, die or are unable to function. The cause of vitiligo is unknown, but research suggests that it may arise from autoimmune, genetic, oxidative stress,...
-like hypopigmentationHypopigmentationHypopigmentation is the loss of skin color. It is caused by melanocyte or melanin depletion, or a decrease in the amino acid tyrosine, which is used by melanocytes to make melanin.-Treatments:...
may be observed. - Electrocardiographic conduction abnormalities: Generally observed on an electrocardiograph as a bundle branch blockBundle branch blockA bundle branch block refers to a defect of the heart's electrical conduction system.-Anatomy and physiology:The heart's electrical activity begins in the sinoatrial node , which is situated on the upper right atrium. The impulse travels next through the left and right atria and summates at the...
. - OcularHuman eyeThe human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
hypertelorismHypertelorismHypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits . In this condition the distance between the inner eye corners as well as the distance between the pupils is greater than normal...
: Wideset eyes, which lead to a similar facial resemblance between patients. Facial abnormalities are the second highest occurring symptom after the lentiginesLentigoA lentigo is a small pigmented spot on the skin with a clearly-defined edge, surrounded by normal-appearing skin. It is a harmless hyperplasia of melanocytes which is linear in its spread. This means the hyperplasia of melanocytes is restricted to the cell layer directly above the basement...
. Abnormalities also include: broad nasal root, prognathismPrognathismPrognathism is a term used to describe the positional relationship of the mandible and/or maxilla to the skeletal base where either of the jaws protrudes beyond a predetermined imaginary line in the coronal plane of the skull. In general dentistry, oral and maxillofacial surgery and orthodontics...
(protruding lower jaw), or low-set, possibly rotated, ears. - Pulmonary stenosis: Narrowing of the pulmonary arteryPulmonary arteryThe pulmonary arteries carry deoxygenated blood from the heart to the lungs. They are the only arteries that carry deoxygenated blood....
as it exits the heartHeartThe heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
. Other cardiac abnormalities may be present, including aortic stenosis, or mitral valve prolapseMitral valve prolapseMitral valve prolapse is a valvular heart disease characterized by the displacement of an abnormally thickened mitral valve leaflet into the left atrium during systole. There are various types of MVP, broadly classified as classic and nonclassic. In its nonclassic form, MVP carries a low risk of...
. - Abnormal genitalia: (usually cryptorchidismCryptorchidismCryptorchidism is the absence of one or both testes from the scrotum. It is the most common birth defect regarding male genitalia. In unique cases, cryptorchidism can develop later in life, often as late as young adulthood. About 3% of full-term and 30% of premature infant boys are born with at...
(retention of testicles in body) or monorchismMonorchism-Causes:This can be due to:* One testicle not descending into the scrotum during normal embryonic or fetal development , also known as: undescended testis or cryptorchidism. In this case the testis is within the abdominal cavity, somewhere along the normal route of descent — most commonly,...
(single testicle). In female patients, this presents as missing or single ovaries, much harder by nature to detect. Ultrasound imaging is performed at regular intervals, from the age of 1 year, to determine if ovaries are present. - Retarded growthFailure to thriveFailure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....
: Slow, or stunted growth. Most newborns with this syndrome are of normal birth weight and length, but will often slow within the first year. - Deafness: SensorineuralSensorineural hearing lossSensorineural hearing loss is a type of hearing loss in which the root cause lies in the vestibulocochlear nerve , the inner ear, or central processing centers of the brain....
(nerve deafness).
The presence of all of these hallmarks is not needed for a diagnosis. A clinical diagnosis
Diagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...
is considered made when, with lentigines
Lentigo
A lentigo is a small pigmented spot on the skin with a clearly-defined edge, surrounded by normal-appearing skin. It is a harmless hyperplasia of melanocytes which is linear in its spread. This means the hyperplasia of melanocytes is restricted to the cell layer directly above the basement...
present there are 2 other symptoms observed, such as ECG abnormalities and ocular hypertelorism, or without lentigines, 3 of the above conditions are present, with a first-degree relative (i.e. parent, child, sibling) with a clinical diagnosis.
- additional dermatologic abnormalities (axillary freckling, localized hypopigmentationHypopigmentationHypopigmentation is the loss of skin color. It is caused by melanocyte or melanin depletion, or a decrease in the amino acid tyrosine, which is used by melanocytes to make melanin.-Treatments:...
, interdigital webbingInterdigital webbingInterdigital webbing is the presence of membranes of skin between the digits. Normally in mammals, webbing is present in the embryo but resorbed later in development, but in various mammal species it occasionally persists in adulthood...
, hyperelastic skin) - Mild mental retardation is observed in about 30% of those affected with the syndrome
- Nystagmus (involuntary eye movements), seizures, or hyposmiaHyposmiaHyposmia is a reduced ability to smell and to detect odours. A related condition is anosmia, in which no odours can be detected. Some of the causes of olfaction problems are allergies, nasal polyps, viral infections and head trauma...
(reduced ability to smell) has been documented in a few patients - In 2004, a patient was reported with recurrent upper extremity aneurysms that required surgical repairs.
- In 2006, a LEOPARD syndrome patient was reported with acute myelogenous leukemiaLeukemiaLeukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
.
Due to the rarity of the syndrome itself, it is hard to determine whether certain additional diseases are actually a threat of the syndrome. With a base population of possibly less than one thousand individuals, one or two outlying cases can skew the statistical population very quickly.
Diagnosis
The presence of the disease can be confirmed with a genetic test. In a study of 10 infants with clinical indications of LEOPARD syndrome prior to their first birthday, 8 (80%) patients were confirmed to have the suspected mutation. An additional patient, with the suspected mutation was subsequently found to have NF1Neurofibromatosis type I
Neurofibromatosis type I , formerly known as von Recklinghausen disease after the researcher who first documented the disorder, is a human genetic disorder. It is possibly the most common inherited disorder caused by a single gene...
, following evaluation of the mother.
There are 5 identified allelic variant
Genetic diversity
Genetic diversity, the level of biodiversity, refers to the total number of genetic characteristics in the genetic makeup of a species. It is distinguished from genetic variability, which describes the tendency of genetic characteristics to vary....
s responsible for LEOPARD syndrome. Y279C, T468M, A461T, G464A, and Q510P which seems to be a unique familial mutation, in that all other variants are caused by transition errors, rather than transversion
Transversion
In molecular biology, transversion refers to the substitution of a purine for a pyrimidine or vice versa. It can only be reverted by a spontaneous reversion. Because this type of mutation changes the chemical structure dramatically, the consequences of this change tend to be more drastic than those...
.
Pathophysiology
PTPN11
Tyrosine-protein phosphatase non-receptor type 11 also known as protein-tyrosine phosphatase 1D or protein-tyrosine phosphatase 2C is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase Shp2.PTPN11 is a member of the protein tyrosine phosphatase ...
gene), which is a previously unrecognized behavior for this class of mutations. This interferes with growth factor and related signalling. While further research confirms this mechanism, additional research is needed to determine how this relates to all of the observed effects of LEOPARD syndrome.
Prognosis
In itself, LEOPARD syndrome is not a life threatening diagnosis, most people diagnosed with the condition live normal lives. Obstructive cardiomyopathy and other pathologic findings involving the cardiovascular system may be a cause of death in those whose cardiac deformities are profound.Treatment
It is suggested that, once diagnosed, individuals be routinely followed by a cardiologist, endocrinologist, dermatologist, and other appropriate specialties as symptoms present.It is recommended that those with the syndrome who are capable of having children seek genetic counseling before deciding to have children. As the syndrome presents frequently as a forme fruste (incomplete, or unusual form) variant, an examination of all family members must be undertaken. As an autosomal dominant trait there is a fifty percent chance with each child, that they will also be born with the syndrome. This does not take into account the possibility of the gene mutating, on its own, in a child of a LEOPARD syndrome patient who does not inherit the gene from the affected parent. Although fully penetrant, since the syndrome has variable expressivity, one generation may have a mild expression of the syndrome, while the next may be profoundly affected.
Once a decision to have children is made, and the couple conceives, the fetus is monitored during the pregnancy for cardiac evaluation. If a gross cardiac malformation is found, parents receive counseling on continuing with the pregnancy.
Other management is routine care as symptoms present:
- For those with endocrine issues (low levels of thyrotopin [a pituitary hormone responsible for regulating thyroid hormones], follicle stimulating hormone) drug therapy is recommended.
- For those who are disturbed by the appearance of lentigines, cryosurgery may be beneficial. Due to the large number of lentigines this may prove time consuming. An alternative treatment with tretinoin or hydroquinone creams may help.
- Drug therapies for those with cardiac abnormalities, as those abnormalities become severe enough to warrant the use of these therapies. ECG's are mandatory prior to any surgical interventions, due to possible arrythmia.
Epidemiology
Various literature describes it as being "rare" or "extremely rare". There is no epidemiologic data available, regarding how many in the world population suffer from the syndrome, however there are slightly over 100 cases described in medical literature.History
Zeisler and Becker first described a syndrome with multiple lentiginesLentigo
A lentigo is a small pigmented spot on the skin with a clearly-defined edge, surrounded by normal-appearing skin. It is a harmless hyperplasia of melanocytes which is linear in its spread. This means the hyperplasia of melanocytes is restricted to the cell layer directly above the basement...
, hypertelorism
Hypertelorism
Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits . In this condition the distance between the inner eye corners as well as the distance between the pupils is greater than normal...
, pectus carinatum
Pectus carinatum
Pectus carinatum, , also called pigeon chest, is a deformity of the chest characterized by a protrusion of the sternum and ribs. It is the opposite of pectus excavatum.-Causes:...
(protruding breastbone) and prognathism
Prognathism
Prognathism is a term used to describe the positional relationship of the mandible and/or maxilla to the skeletal base where either of the jaws protrudes beyond a predetermined imaginary line in the coronal plane of the skull. In general dentistry, oral and maxillofacial surgery and orthodontics...
(protrusion of lower jaw) in 1936. Sporadic descriptions were added through the years. In 1962, cardiac abnormalities and short stature were first associated with the condition. In 1966, three familial cases were added, a mother, her son and daughter. Another case of mother to two separate children, with different paternity of the two children, was added in 1968.
It was believed as late as 2002 that LEOPARD syndrome was related to neurofibromatosis type I
Neurofibromatosis type I
Neurofibromatosis type I , formerly known as von Recklinghausen disease after the researcher who first documented the disorder, is a human genetic disorder. It is possibly the most common inherited disorder caused by a single gene...
(von Recklinghausen syndrome). In fact, since both ICD9 and ICD10 lack a specific diagnosis code for LEOPARD syndrome, the diagnosis code for NF1
Neurofibromatosis type I
Neurofibromatosis type I , formerly known as von Recklinghausen disease after the researcher who first documented the disorder, is a human genetic disorder. It is possibly the most common inherited disorder caused by a single gene...
is still sometimes used for diagnostic purposes, although it has been shown that the gene is not linked to the NF1
Neurofibromatosis type I
Neurofibromatosis type I , formerly known as von Recklinghausen disease after the researcher who first documented the disorder, is a human genetic disorder. It is possibly the most common inherited disorder caused by a single gene...
locus.