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Noonan syndrome with multiple lentigines (NSML) which is part of a group called Ras/
MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflamm ...
pathway syndromes, is a rare
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
, multisystem disease caused by a
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
in the
protein tyrosine phosphatase Protein tyrosine phosphatases (EC 3.1.3.48, systematic name protein-tyrosine-phosphate phosphohydrolase) are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins: : proteintyrosine phosphate + H2O = ...
, non-receptor type 11 gene (''
PTPN11 Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in hu ...
''). The disease is a complex of features, mostly involving the skin, skeletal and cardiovascular systems, which 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. Noonan syndrome with multiple
lentigines A lentigo () (plural lentigines, ) is a small pigmented spot on the skin with a clearly defined edge, surrounded by normal-appearing skin. It is a harmless (benign) hyperplasia of melanocytes which is linear in its spread. This means the hyperpl ...
is caused by a different
missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn alt ...
of the same gene. Noonan syndrome is fairly common (1:1,000 to 1:2,500 live births), and
neurofibromatosis 1 Neurofibromatosis type I (NF-1), or von Recklinghausen syndrome, is a complex multi-system neurocutaneous disorder caused by a subset of genetic mutations at the neurofibromin 1 (''NF1'') locus. Other conditions associated with mutation of the ...
(which was once thought to be related to NSML) is also common (1:3500); however, no
epidemiological Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and Risk factor (epidemiology), determinants of health and disease conditions in a defined population, and application of this knowledge to prevent dise ...
data exists for NSML.


Signs and symptoms

An alternative name of the condition, LEOPARD syndrome, is a
mnemonic A mnemonic device ( ), memory trick or memory device is any learning technique that aids information retention or retrieval in the human memory, often by associating the information with something that is easier to remember. It makes use of e ...
, 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 A lentigo () (plural lentigines, ) is a small pigmented spot on the skin with a clearly defined edge, surrounded by normal-appearing skin. It is a harmless (benign) hyperplasia of melanocytes which is linear in its spread. This means the hyperpl ...
that is reminiscent of the large cat. *
Lentigines A lentigo () (plural lentigines, ) is a small pigmented spot on the skin with a clearly defined edge, surrounded by normal-appearing skin. It is a harmless (benign) hyperplasia of melanocytes which is linear in its spread. This means the hyperpl ...
— Reddish-brown to dark brown
macules A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this sys ...
(surface skin
lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals. Types There is no de ...
) 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 ( buccal), or on the surface of the eye (
sclera The sclera, also known as the white of the eye or, in older literature, as the tunica albuginea oculi, is the opaque, fibrous, protective outer layer of the eye containing mainly collagen and some crucial elastic fiber. In the development of t ...
l). These have irregular borders and range in size from 1 mm in diameter to café-au-lait spots, several centimeters in diameter. Also, some areas of
vitiligo Vitiligo (, ) is a chronic autoimmune disorder that causes patches of skin to lose pigment or color. The cause of vitiligo is unknown, but it may be related to immune system changes, genetic factors, stress, or sun exposure, and susceptibili ...
-like
hypopigmentation Hypopigmentation is characterized specifically as an area of Human skin, skin becoming lighter than the baseline skin color, but not completely devoid of skin pigment, pigment. This is not to be confused with depigmentation, which is characterize ...
may be observed. *
Electrocardiographic Electrocardiography is the process of producing an electrocardiogram (ECG or EKG), a recording of the heart's electrical activity through repeated cardiac cycles. It is an electrogram of the heart which is a graph of voltage versus time of t ...
conduction Conductor or conduction may refer to: Biology and medicine * Bone conduction, the conduction of sound to the inner ear * Conduction aphasia, a language disorder Mathematics * Conductor (ring theory) * Conductor of an abelian variety * Condu ...
abnormalities: Generally observed on an electrocardiograph as a
bundle branch block A bundle branch block is a partial or complete interruption in the flow of electrical impulses in either of the bundle branches of the heart's electrical system. Anatomy and physiology The heart's electrical activity begins in the sinoatri ...
. *
Ocular An eye is a sensory organ that allows an organism to perceive visual information. It detects light and converts it into electro-chemical impulses in neurons (neurones). It is part of an organism's visual system. In higher organisms, the eye ...
hypertelorism Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition, the distance between the inner eye corners, a ...
: Wideset eyes, which lead to a similar facial resemblance between patients. Facial abnormalities are the second highest occurring symptom after the
lentigines A lentigo () (plural lentigines, ) is a small pigmented spot on the skin with a clearly defined edge, surrounded by normal-appearing skin. It is a harmless (benign) hyperplasia of melanocytes which is linear in its spread. This means the hyperpl ...
. Abnormalities also include: broad nasal root,
prognathism Prognathism is a positional relationship of the mandible 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 the case of ''mandibular'' prognathism (nev ...
(protruding lower jaw), or low-set, possibly rotated, ears. * Pulmonary stenosis: Narrowing of the
pulmonary artery A pulmonary artery is an artery in the pulmonary circulation that carries deoxygenated blood from the right side of the heart to the lungs. The largest pulmonary artery is the ''main pulmonary artery'' or ''pulmonary trunk'' from the heart, and ...
as it exits the
heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
. Other cardiac abnormalities may be present, including
aortic stenosis Aortic stenosis (AS or AoS) is the narrowing of the exit of the left ventricle of the heart (where the aorta begins), such that problems result. It may occur at the aortic valve as well as above and below this level. It typically gets worse o ...
, or
mitral valve prolapse Mitral valve prolapse (MVP) is a valvular heart disease characterized by the displacement of an abnormally thickened mitral valve leaflet into the atria of the heart, left atrium during Systole (medicine), systole. It is the primary form of myxom ...
. * Abnormal
genitalia A sex organ, also known as a reproductive organ, is a part of an organism that is involved in sexual reproduction. Sex organs constitute the primary sex characteristics of an organism. Sex organs are responsible for producing and transporting ...
: usually
cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is . It is the most common birth defect of the male genital tract. About 3% of full-term and 30% of premature infant boy ...
(retention of
testicles A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of androgens, primarily testosterone. The ...
in body) or monorchism (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. * Faltering growth: 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 Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is writte ...
: Sensorineural (nerve deafness). The presence of all of these hallmarks is not needed for a diagnosis. A clinical
diagnosis Diagnosis (: diagnoses) is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in a lot of different academic discipline, disciplines, with variations in the use of logic, analytics, and experience, to determine " ...
is considered made when, with
lentigines A lentigo () (plural lentigines, ) is a small pigmented spot on the skin with a clearly defined edge, surrounded by normal-appearing skin. It is a harmless (benign) hyperplasia of melanocytes which is linear in its spread. This means the hyperpl ...
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
hypopigmentation Hypopigmentation is characterized specifically as an area of Human skin, skin becoming lighter than the baseline skin color, but not completely devoid of skin pigment, pigment. This is not to be confused with depigmentation, which is characterize ...
, interdigital webbing, hyperelastic skin) *Mild
mental retardation Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
is observed in about 30% of those affected by the syndrome *
Nystagmus Nystagmus is a condition of involuntary (or voluntary, in some cases) Eye movement (sensory), eye movement. People can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in visual impairment, re ...
(involuntary eye movements),
seizures A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
, or
hyposmia Hyposmia, or microsmia, is a reduced ability to smell and to detect odors. A related condition is anosmia, in which no odors 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 An aneurysm is an outward bulging, likened to a bubble or balloon, caused by a localized, abnormal, weak spot on a blood vessel wall. Aneurysms may be a result of a hereditary condition or an acquired disease. Aneurysms can also be a nidus ( ...
that required surgical repairs. *In 2006, a NSML patient was reported with
acute myelogenous leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may includ ...
. Due to the rarity of the syndrome itself, it is hard to determine whether certain additional diseases are actually part 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. image:Leopardsyn2e.jpg, Hand of 37-year-old patient showing interdigital webbing Image:Leopardsyn2.jpg, 37-year-old patient (second generation), exhibiting hypertelorism, broad nasal root, slight ptosis Image:Leopardsyn2f.jpg, Thirty-seven-year-old patient demonstrating hyperelasticity Image:Leopardsyn3.jpg, 21-month-old, third generation patient, confirmed by genetic tests a
Y279C
exhibiting ocular hyperteliorism, cephalofacial similarity. Image:Leopardsyn2b.jpg,
Torso The torso or trunk is an anatomical terminology, anatomical term for the central part, or the core (anatomy), core, of the body (biology), body of many animals (including human beings), from which the head, neck, limb (anatomy), limbs, tail an ...
of thirty-seven-year-old, second-generation patient, exhibiting lentiginosis.


Pathophysiology

In the two predominant mutations of NSML
Y279C
an
T468M
the mutations cause a loss of catalytic activity of the SHP2 protein (the gene product of the ''
PTPN11 Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in hu ...
'' 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 NSML.


Diagnosis

The presence of the disease can be confirmed with a genetic test. In a study of 10 infants with clinical indications of NSML 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 NF1, following evaluation of the mother. There are 5 identified allelic variants responsible for NSML
Y279CT468MA461TG464A
an
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, refers to a point mutation in DNA in which a single (two ring) purine ( A or G) is changed for a (one ring) pyrimidine ( T or C), or vice versa. A transversion can be spontaneous, or it can be caused by ioniz ...
.


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. 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 thyrotropin pituitary hormone responsible for regulating thyroid hormones
follicle stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...
) 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
arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...
.


Prognosis

In itself, NSML 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.


Epidemiology

Various literature describes the syndrome as being "rare" or "extremely rare". There is no epidemiologic data available regarding how many individuals have the syndrome worldwide; however, there are approximately 200 cases described in medical literature.


History

Zeisler and Becker first described a syndrome with multiple
lentigines A lentigo () (plural lentigines, ) is a small pigmented spot on the skin with a clearly defined edge, surrounded by normal-appearing skin. It is a harmless (benign) hyperplasia of melanocytes which is linear in its spread. This means the hyperpl ...
,
hypertelorism Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition, the distance between the inner eye corners, a ...
,
pectus carinatum Pectus carinatum, also called pigeon chest or pidgon breast, is a malformation of the chest characterized by a protrusion of the Human sternum, sternum and ribs. It is distinct from the related malformation pectus excavatum. Pectus carinatum has ...
(protruding breastbone) and
prognathism Prognathism is a positional relationship of the mandible 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 the case of ''mandibular'' prognathism (nev ...
(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 Noonan Syndrome with Multiple Lentigines (NSML) was related to
neurofibromatosis type I Neurofibromatosis type I (NF-1), or von Recklinghausen syndrome, is a complex multi-system neurocutaneous disorder caused by a subset of genetic mutations at the neurofibromin 1 (''NF1'') locus. Other conditions associated with mutation of the ...
(von Recklinghausen syndrome). In fact, since both ICD9 and ICD10 lack a specific diagnosis code for NSML, 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.


See also

*
Neurofibromatosis Neurofibromatosis (NF) refers to a group of three distinct genetic conditions in which tumors grow in the nervous system. The tumors are non-cancerous (benign) and often involve the skin or surrounding bone. Although symptoms are often mild, e ...
* Noonan syndrome


References


External links

* * *
Dermnetnz


{{DEFAULTSORT:Noonan Syndrome with Multiple Lentigines Syndromes affecting the heart RASopathies Genodermatoses Melanocytic nevi and neoplasms Enzyme defects Neuro-cardio-facial-cutaneous syndromes Syndromes affecting hearing