Noonan syndrome with multiple lentigines

Last updated
Noonan syndrome with multiple lentigines (NSML)
Other namesLEOPARD syndrome, cardiocutaneous syndrome, Gorlin syndrome II, lentiginosis profusa syndrome, progressive cardiomyopathic lentiginosis, [1] : 550  Capute-Rimoin-Konigsmark-Esterly-Richardson syndrome, Moynahan syndrome
Leopardsyn1a.jpg
Three-quarter facial view, first-generation patient showing slight prognathism and low set ears
Specialty Medical genetics

Noonan syndrome with multiple lentigines (NSML) which is part of a group called Ras/MAPK pathway syndromes, [2] is a rare autosomal dominant, [3] 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, 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.

Contents

Noonan syndrome with multiple lentigines is caused by a different missense mutation of the same gene. Noonan syndrome is fairly common (1:1,000 to 1:2,500 live births), and neurofibromatosis 1 (which was once thought to be related to NSML) is also common (1:3500); however, no epidemiological data exists for NSML. [4]

Signs and symptoms

An alternative name of the condition, LEOPARD syndrome, is a mnemonic, originally coined in 1969, [5] 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. [6]

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.

Pathophysiology

NSML is inherited in an autosomal dominant fashion, although it can also arise due to spontaneous mutation. Autosomal Dominant Pedigree Chart.svg
NSML is inherited in an autosomal dominant fashion, although it can also arise due to spontaneous mutation.

In the two predominant mutations of NSML (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. [9] This interferes with growth factor and related signalling. While further research confirms this mechanism, [10] [11] 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. [12]

There are 5 identified allelic variants responsible for NSML. 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.

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. [13] 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: [13]

  1. For those with endocrine issues (low levels of thyrotropin [a pituitary hormone responsible for regulating thyroid hormones], follicle stimulating hormone) drug therapy is recommended.
  2. 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.
  3. 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.

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. [13]

Epidemiology

Various literature describes the syndrome as being "rare" [13] or "extremely rare". [14] There is no epidemiologic data available regarding how many individuals have the syndrome worldwide; however, there are approximately 200 cases described in medical literature. [15]

History

Zeisler and Becker first described a syndrome with multiple lentigines, hypertelorism, pectus carinatum (protruding breastbone) and prognathism (protrusion of lower jaw) in 1936. [16] Sporadic descriptions were added through the years. In 1962, cardiac abnormalities and short stature were first associated with the condition. [17] In 1966, three familial cases were added, a mother, her son and daughter. [18] Another case of mother to two separate children, with different paternity of the two children, was added in 1968. [19]

It was believed as late as 2002 [20] that Noonan Syndrome with Multiple Lentigines (NSML) was related to neurofibromatosis type I (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. [21]

See also

Related Research Articles

<span class="mw-page-title-main">Neurofibromatosis</span> Three genetic disorders involving benign tumors of the nervous system

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, each condition presents differently. Neurofibromatosis type I (NF1) is typically characterized by café au lait spots, neurofibromas, scoliosis, and headaches. Neurofibromatosis type II (NF2), on the other hand, may present with early-onset hearing loss, cataracts, tinnitus, difficulty walking or maintain balance, and muscle atrophy. The third type is called schwannomatosis and often presents in early adulthood with widespread pain, numbness, or tingling due to nerve compression.

<span class="mw-page-title-main">Noonan syndrome</span> Genetic condition involving facial, heart, blood and skeletal features

Noonan syndrome (NS) is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. Facial features include widely spaced eyes, light-colored eyes, low-set ears, a short neck, and a small lower jaw. Heart problems may include pulmonary valve stenosis. The breast bone may either protrude or be sunken, while the spine may be abnormally curved. Intelligence is often normal. Complications of NS can include leukemia.

<span class="mw-page-title-main">Andersen–Tawil syndrome</span> Rare autosomal dominant genetic disorder

Andersen–Tawil syndrome, also called Andersen syndrome and long QT syndrome 7, is a rare genetic disorder affecting several parts of the body. The three predominant features of Andersen–Tawil syndrome include disturbances of the electrical function of the heart characterised by an abnormality seen on an electrocardiogram and a tendency to abnormal heart rhythms, physical characteristics including low-set ears and a small lower jaw, and intermittent periods of muscle weakness known as hypokalaemic periodic paralysis.

<span class="mw-page-title-main">Neurofibromatosis type I</span> Type of neurofibromatosis disease

Neurofibromatosis type I (NF-1), or von Recklinghausen syndrome, is a complex multi-system human disorder caused by the mutation of neurofibromin 1 (NF-1), a gene on chromosome 17 that is responsible for production of a protein (neurofibromin) which is needed for normal function in many human cell types. NF-1 causes tumors along the nervous system which can grow anywhere on the body. NF-1 is one of the most common genetic disorders and is not limited to any person's race or sex. NF-1 is an autosomal dominant disorder, which means that mutation or deletion of one copy of the NF-1 gene is sufficient for the development of NF-1, although presentation varies widely and is often different even between relatives affected by NF-1.

<span class="mw-page-title-main">Neurofibroma</span> Benign nerve-sheath tumor in the peripheral nervous system

A neurofibroma is a benign nerve-sheath tumor in the peripheral nervous system. In 90% of cases, they are found as stand-alone tumors, while the remainder are found in persons with neurofibromatosis type I (NF1), an autosomal-dominant genetically inherited disease. They can result in a range of symptoms from physical disfiguration and pain to cognitive disability.

Phakomatoses, also known as neurocutaneous syndromes, are a group of multisystemic diseases that most prominently affect structures primarily derived from the ectoderm such as the central nervous system, skin and eyes. The majority of phakomatoses are single-gene disorders that may be inherited in an autosomal dominant, autosomal recessive or X-linked pattern. Presentations may vary dramatically between patients with the same particular syndrome due to mosaicism, variable expressivity, and penetrance.

<span class="mw-page-title-main">Costello syndrome</span> Medical condition

Costello syndrome, also called faciocutaneoskeletal syndrome or FCS syndrome, is a rare genetic disorder that affects many parts of the body. It is characterized by delayed development and intellectual disabilities, distinctive facial features, unusually flexible joints, and loose folds of extra skin, especially on the hands and feet. Heart abnormalities are common, including a very fast heartbeat (tachycardia), structural heart defects, and overgrowth of the heart muscle. Infants with Costello syndrome may be large at birth, but grow more slowly than other children and have difficulty feeding. Later in life, people with this condition have relatively short stature and many have reduced levels of growth hormones. It is a RASopathy.

<span class="mw-page-title-main">Carney complex</span> Medical condition

Carney complex and its subsets LAMB syndrome and NAME syndrome are autosomal dominant conditions comprising myxomas of the heart and skin, hyperpigmentation of the skin (lentiginosis), and endocrine overactivity. It is distinct from Carney's triad. Approximately 7% of all cardiac myxomas are associated with Carney complex.

<span class="mw-page-title-main">Loeys–Dietz syndrome</span> Medical condition

Loeys–Dietz syndrome (LDS) is an autosomal dominant genetic connective tissue disorder. It has features similar to Marfan syndrome and Ehlers–Danlos syndrome. The disorder is marked by aneurysms in the aorta, often in children, and the aorta may also undergo sudden dissection in the weakened layers of the wall of the aorta. Aneurysms and dissections also can occur in arteries other than the aorta. Because aneurysms in children tend to rupture early, children are at greater risk for dying if the syndrome is not identified. Surgery to repair aortic aneurysms is essential for treatment.

<span class="mw-page-title-main">Neurofibromin</span> Mammalian protein found in humans

Neurofibromin (NF-1) is a protein that is encoded in the human by the NF1 gene. NF1 is located on chromosome 17. Neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. NF1 has a high mutation rate and mutations can alter cellular growth control, and neural development, resulting in neurofibromatosis type 1. Symptoms of NF1 include disfiguring cutaneous neurofibromas (CNF), café au lait pigment spots, plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), pheochromocytoma, attention deficits, learning deficits and other cognitive disabilities.

<span class="mw-page-title-main">Axenfeld–Rieger syndrome</span> Medical condition

Axenfeld–Rieger syndrome is a rare autosomal dominant disorder, which affects the development of the teeth, eyes, and abdominal region.

<span class="mw-page-title-main">Craniofrontonasal dysplasia</span> Medical condition

Craniofrontonasal dysplasia is a very rare X-linked malformation syndrome caused by mutations in the ephrin-B1 gene (EFNB1). Phenotypic expression varies greatly amongst affected individuals, where females are more commonly and generally more severely affected than males. Common physical malformations are: craniosynostosis of the coronal suture(s), orbital hypertelorism, bifid nasal tip, dry frizzy curled hair, longitudinal ridging and/or splitting of the nails, and facial asymmetry.

Juvenile myelomonocytic leukemia (JMML) is a rare form of chronic leukemia that affects children, commonly those aged four and younger. The name JMML now encompasses all diagnoses formerly referred to as juvenile chronic myeloid leukemia (JCML), chronic myelomonocytic leukemia of infancy, and infantile monosomy 7 syndrome. The average age of patients at diagnosis is two (2) years old. The World Health Organization has included JMML as a subcategory of myelodysplastic and myeloproliferative disorders.

<span class="mw-page-title-main">Frontonasal dysplasia</span> Medical condition

Frontonasal dysplasia (FND) is a congenital malformation of the midface. For the diagnosis of FND, a patient should present at least two of the following characteristics: hypertelorism, a wide nasal root, vertical midline cleft of the nose and/or upper lip, cleft of the wings of the nose, malformed nasal tip, encephalocele or V-shaped hair pattern on the forehead. The cause of FND remains unknown. FND seems to be sporadic (random) and multiple environmental factors are suggested as possible causes for the syndrome. However, in some families multiple cases of FND were reported, which suggests a genetic cause of FND.

<span class="mw-page-title-main">Legius syndrome</span> Medical condition

Legius syndrome (LS) is an autosomal dominant condition characterized by cafe au lait spots. It was first described in 2007 and is often mistaken for neurofibromatosis type I. It is caused by mutations in the SPRED1 gene. It is also known as neurofibromatosis type 1-like syndrome.

<span class="mw-page-title-main">Goldberg–Shprintzen syndrome</span> Medical condition

Goldberg–Shprintzen is a very rare connective tissue condition associated with mutations in KIAA1279 gene which encodes KIF-binding protein (KBP), a protein that may interact with microtubules and actin filaments. KBP may play a key role in cytoskeleton formation and neurite growth.

The RASopathies are a group of developmental syndromes caused by germline mutations in genes belonging to the Ras/MAPK pathway. Common features include intellectual disability, congenital heart defects, skin abnormalities, and craniofacial abnormalities.

Fryns-Aftimos syndrome is a rare chromosomal condition and is associated with pachygyria, severe mental retardation, epilepsy and characteristic facial features. This syndrome is a malformation syndrome, characterized by numerous facial dysmorphias not limited to hypertelorism, iris or retinal coloboma, cleft lip, and congenital heart defects. This syndrome has been seen in 30 unrelated people. Characterized by a de novo mutation located on chromosome 7p22, there is typically no family history prior to onset. The severity of the disorder can be determined by the size of the deletion on 7p22, enveloping the ACTB gene and surrounding genes, which is consistent with a contiguous gene deletion syndrome. Confirming a diagnosis of Fryns-Aftimos syndrome typically consists of serial single-gene testing or multigene panel of genes of interest or exome sequencing.

Filippi syndrome, also known as Syndactyly Type I with Microcephaly and Mental Retardation, is a very rare autosomal recessive genetic disease. Only a very limited number of cases have been reported to date. Filippi Syndrome is associated with diverse symptoms of varying severity across affected individuals, for example malformation of digits, craniofacial abnormalities, intellectual disability, and growth retardation. The diagnosis of Filippi Syndrome can be done through clinical observation, radiography, and genetic testing. Filippi Syndrome cannot be cured directly as of 2022, hence the main focus of treatments is on tackling the symptoms observed on affected individuals. It was first reported in 1985.

<span class="mw-page-title-main">DiGeorge syndrome</span> Medical condition caused by chromosomal abnormality

DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent infections, developmental disability, intellectual disability and cleft palate. Associated conditions include kidney problems, schizophrenia, hearing loss and autoimmune disorders such as rheumatoid arthritis or Graves' disease.

References

  1. ↑ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. ISBN   0-7216-2921-0.
  2. ↑ Tidyman WE, Rauen KA (June 2009). "The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation". Current Opinion in Genetics & Development. 19 (3): 230–6. doi:10.1016/j.gde.2009.04.001. PMC   2743116 . PMID   19467855.
  3. ↑ Coppin BD, Temple IK (1997). "Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis)". Journal of Medical Genetics. 34 (7): 582–6. doi:10.1136/jmg.34.7.582. PMC   1051000 . PMID   9222968.
  4. ↑ Tullu MS, Muranjan MN, Kantharia VC, et al. (1 April 2000). "Neurofibromatosis-Noonan syndrome or LEOPARD Syndrome? A clinical dilemma". J Postgrad Med. 46 (2): 98–100. PMID   11013475.
  5. ↑ Gorlin RJ, Anderson RC, Blaw M (1969). "Multiple lentigenes syndrome". Am. J. Dis. Child. 117 (6): 652–62. doi:10.1001/archpedi.1969.02100030654006. PMID   5771505.
  6. ↑ Voron DA, Hatfield HH, Kalkhoff RK (1976). "Multiple lentigines syndrome. Case report and review of the literature". Am. J. Med. 60 (3): 447–56. doi:10.1016/0002-9343(76)90764-6. PMID   1258892.
  7. ↑ Yagubyan M, Panneton JM, Lindor NM, Conti E, Sarkozy A, Pizzuti A (April 2004). "LEOPARD syndrome: a new polyaneurysm association and an update on the molecular genetics of the disease". J. Vasc. Surg. 39 (4): 897–900. doi: 10.1016/j.jvs.2003.11.030 . PMID   15071461.
  8. ↑ Uçar C, Calýskan U, Martini S, Heinritz W (March 2006). "Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11 gene mutation positive)". J. Pediatr. Hematol. Oncol. 28 (3): 123–5. doi:10.1097/01.mph.0000199590.21797.0b. PMID   16679933. S2CID   21559684.
  9. ↑ Tartaglia M, Martinelli S, Stella L, et al. (2006). "Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease". American Journal of Human Genetics. 78 (2): 279–90. doi:10.1086/499925. PMC   1380235 . PMID   16358218.
  10. ↑ Hanna N, Montagner A, Lee WH, et al. (2006). "Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1". FEBS Lett. 580 (10): 2477–82. Bibcode:2006FEBSL.580.2477H. doi:10.1016/j.febslet.2006.03.088. PMID   16638574. S2CID   27676871.
  11. ↑ Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG (2006). "PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects". J. Biol. Chem. 281 (10): 6785–92. doi: 10.1074/jbc.M513068200 . PMID   16377799. Archived from the original on 2008-10-08. Retrieved 2008-01-20.
  12. ↑ Digilio MC, Sarkozy A, de Zorzi A, et al. (2006). "LEOPARD syndrome: clinical diagnosis in the first year of life". American Journal of Medical Genetics. 140 (7): 740–6. doi:10.1002/ajmg.a.31156. PMID   16523510. S2CID   19570040.
  13. 1 2 3 4 LEOPARD Syndrome at eMedicine
  14. ↑ "LEOPARD Syndrome". NORD — National Organization for Rare Disorders. Archived from the original on 2015-03-03. Retrieved 2014-09-01.
  15. ↑ "Noonan syndrome with multiple lentigines". U.S. National Library of Medicine.
  16. ↑ Zeisler EP, Becker SW (1936). "Generalized lentigo: its relation to systemic nonelevated nevi". Arch Dermatol Syphilol. 33: 109–125. doi:10.1001/archderm.1936.01470070112010.
  17. ↑ Moynahan EJ (1962). "Multiple symmetrical moles, with psychic and somatic infantilism and genital hypoplasia: first male case of a new syndrome". Proceedings of the Royal Society of Medicine. 55 (11): 959–960. doi:10.1177/003591576205501112. PMC   1896920 . PMID   19994192.
  18. ↑ Walther RJ, Polansky BJ, Grotis IA (1966). "Electrocardiographic abnormalities in a family with generalized lentigo". N. Engl. J. Med. 275 (22): 1220–5. doi:10.1056/NEJM196612012752203. PMID   5921856.
  19. ↑ Matthews NL (1968). "Lentigo and electrocardiographic changes". N. Engl. J. Med. 278 (14): 780–1. doi:10.1056/NEJM196804042781410. PMID   5638719.
  20. ↑ National Library of Medicine MeSH: C05.660.207.525
  21. ↑ Ahlbom BE, Dahl N, Zetterqvist P, Annerén G (1995). "Noonan syndrome with café-au-lait spots and multiple lentigines syndrome are not linked to the neurofibromatosis type 1 locus". Clin. Genet. 48 (2): 85–9. doi:10.1111/j.1399-0004.1995.tb04061.x. PMID   7586657. S2CID   31291484.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.