Zespół noonana
Etiologia i przyczyny

Zespół Noonana to genetyczne zaburzenie pleomorficzne, występujące z częstością 1:1000 do 1:2500 żywych urodzeń, będące jedną z najczęstszych przyczyn wrodzonych wad serca dziedziczonych autosomalnie dominująco. Patogeneza opiera się na mutacjach genów kodujących białka szlaku sygnałowego RAS/MAPK, prowadzących do konstytutywnej aktywacji tego szlaku, co zaburza regulację wzrostu i proliferacji komórek. Najczęstsze mutacje dotyczą genów PTPN11 (ok. 50% przypadków), SOS1 (10-20%), RAF1 (5-17%), RIT1 (ok. 5%) oraz KRAS (2-5%). Mutacje w genie PTPN11 wiążą się z klasycznym fenotypem i zwężeniem zastawki płucnej, RAF1 z kardiomiopatią przerostową, a KRAS z cięższymi formami zespołu. Diagnostyka genetyczna potwierdza rozpoznanie w 70-80% przypadków, wykorzystując panele genowe oraz sekwencjonowanie eksomu lub genomu. W około 15-20% przypadków mutacje nie są wykrywane, co sugeruje istnienie nieznanych genów zaangażowanych w patogenezę.

  1. Przyczyny zespołu Noonana
    1. Podłoże molekularne
    2. Geny związane z zespołem Noonana
    3. Model dziedziczenia
  2. Korelacje genotyp-fenotyp w zespole Noonana
    1. Specyfika kliniczna w zależności od mutacji
    2. Zespół Noonana a inne RASopatie
  3. Mechanizmy patofizjologiczne
    1. Zaburzenia szlaku RAS/MAPK
    2. Zaburzenia wzrostu w zespole Noonana
  4. Diagnostyka genetyczna
    1. Metody diagnostyczne
    2. Znaczenie diagnostyki genetycznej
  5. Czynniki ryzyka i wnioski
    1. Kolejne rozdziały

Przyczyny zespołu Noonana

Zespół Noonana jest zaburzeniem genetycznym o charakterze pleomorficznym, które występuje z częstością od 1 na 1000 do 1 na 2500 żywych urodzeń. Jest jedną z najczęstszych przyczyn wrodzonych wad serca dziedziczonych w sposób niekromosomowy.123

Podłoże molekularne

Zespół Noonana należy do grupy zaburzeń określanych jako RASopatie, które charakteryzują się mutacjami w genach kodujących białka szlaku sygnałowego RAS/MAPK (Ras/mitogen-activated protein kinase). Szlak ten odgrywa kluczową rolę w regulacji różnicowania komórek, ich wzrostu, proliferacji i starzenia się.123

Mutacje związane z zespołem Noonana prowadzą do nadmiernej aktywacji (gain-of-function) tego szlaku sygnałowego. W przypadku tego zespołu białka szlaku RAS/MAPK pozostają aktywne przez dłuższy czas niż normalnie, zamiast być włączane i wyłączane w odpowiedzi na określone sygnały komórkowe. Ta przedłużona aktywacja zaburza regulację wzrostu i podziału komórek, prowadząc do charakterystycznych cech i objawów zespołu Noonana.123

Geny związane z zespołem Noonana

Zidentyfikowano wiele genów, których mutacje mogą być przyczyną zespołu Noonana. Najczęściej występujące to:

  • PTPN11 (na chromosomie 12q24) – mutacje w tym genie występują u około 50% pacjentów z zespołem Noonana. Gen ten koduje nieznajdującą się na receptorze białkową fosfatazę tyrozynową SHP-2, która uczestniczy w wielu wewnątrzkomórkowych kaskadach sygnałowych.123
  • SOS1 – mutacje w tym genie odpowiadają za około 10-20% przypadków. Jest to specyficzny dla RAS czynnik wymiany nukleotydów guaninowych, który katalizuje uwalnianie GDP z RAS.123
  • RAF1 – mutacje w tym genie występują w około 5-17% przypadków.12
  • RIT1 – mutacje odpowiadają za około 5% przypadków.12
  • KRAS – mutacje występują w około 2-5% przypadków i zwykle wiążą się z łagodniejszymi efektami aktywującymi.12

Rzadziej spotykane są mutacje w genach: NRAS, BRAF, MAP2K1 (MEK1), MEK2, MRAS, RASA2, RRAS2, SOS2, LZTR1 i innych.123

Warto zauważyć, że u około 15-20% pacjentów z klinicznym rozpoznaniem zespołu Noonana nie zidentyfikowano mutacji w żadnym ze znanych genów, co sugeruje, że mogą istnieć dodatkowe, jeszcze nieodkryte geny zaangażowane w patogenezę tego zespołu.123

Model dziedziczenia

Zespół Noonana najczęściej dziedziczy się w sposób autosomalny dominujący. Oznacza to, że do wystąpienia zespołu wystarczy mutacja w jednej kopii genu, a osoba z taką mutacją ma 50% szans na przekazanie jej potomstwu.123

W zależności od badań, u około 30-75% pacjentów zespół Noonana jest dziedziczony od jednego z rodziców. Często rodzic będący nosicielem zmutowanego genu może nie mieć widocznych objawów zespołu lub objawy te mogą być bardzo łagodne, co sprawia, że stan pozostaje niezdiagnozowany.123

Pozostałe przypadki (około 25-70%) stanowią mutacje de novo, które powstają spontanicznie i występują po raz pierwszy u danej osoby, bez historii rodzinnej zespołu. W takich przypadkach szansa, że rodzice będą mieli kolejne dziecko z zespołem Noonana, jest bardzo mała (poniżej 1%).123

Warto wspomnieć, że mutacje w genie LZTR1 mogą powodować zarówno autosomalną dominującą, jak i autosomalną recesywną postać zespołu Noonana, co ma istotne znaczenie dla oszacowania ryzyka wystąpienia zespołu w przyszłych ciążach w rodzinie.123

Korelacje genotyp-fenotyp w zespole Noonana

W zespole Noonana zaobserwowano pewne korelacje między określonymi mutacjami genetycznymi a prezentacją kliniczną pacjentów. Badania wykazały, że osoby z zespołem Noonana posiadające różne warianty genetyczne mogą wykazywać nieco odmienne spektrum objawów lub różną ich nasilenie.12

Specyfika kliniczna w zależności od mutacji

  • PTPN11 – mutacje w tym genie są związane z klasycznym fenotypem zespołu Noonana. Pacjenci częściej mają zwężenie zastawki płucnej i charakterystyczne cechy dysmorficzne.1
  • SOS1 – pacjenci z mutacjami tego genu zwykle mają lepsze funkcje poznawcze niż osoby z mutacjami PTPN11. Często wykazują normalny wzrost, ale mogą mieć bardziej wyraźne cechy ektodermalne (jak anomalie skórne).12
  • RAF1 – mutacje w tym genie są silnie związane z kardiomiopatią przerostową i opóźnieniem rozwojowym.1
  • KRAS – mutacje tego genu często powodują cięższe lub atypowe formy zespołu Noonana.1

Badanie przeprowadzone przez Meier i wsp. wykazało, że u osób z kardiomiopatią związaną z zespołem Noonana występuje znaczna nadekspresja genu FGF10 w tkance mięśnia lewej komory serca. Dowody sugerują, że zwiększona ekspresja tego genu może napędzać produkcję kardiomiocytów lewej komory w kardiomiopatii związanej z zespołem Noonana.1

Zespół Noonana a inne RASopatie

Zespół Noonana wykazuje wiele podobieństw fenotypowych z innymi zaburzeniami genetycznymi określanymi jako RASopatie, które również wynikają z mutacji zarodkowych w szlaku RAS/MAPK:123

  • Zespół LEOPARD (zespół Noonana z lentiginami)
  • Zespół sercowo-twarzowo-skórny (CFC)
  • Zespół Costello
  • Neurofibromatoza typu 1 (NF1)

Wszystkie te zaburzenia charakteryzują się wysoką częstością występowania pewnej formy wrodzonej choroby serca i wspólnymi mutacjami w szlaku RAS-MAPK. Niektórzy badacze zaproponowali termin „zespoły neuro-sercowo-twarzowo-skórne” dla wszystkich tych zaburzeń, podkreślając ich wspólne cechy i wspólne podłoże molekularne.12

Mechanizmy patofizjologiczne

Na poziomie komórkowym i molekularnym, patofizjologia zespołu Noonana wiąże się z nieprawidłową regulacją szlaku sygnałowego RAS/MAPK, który odgrywa kluczową rolę w wielu procesach komórkowych.12

Zaburzenia szlaku RAS/MAPK

Szlak RAS/MAPK jest kluczowy dla prawidłowego różnicowania komórek, ich wzrostu i podziału. Mutacje związane z zespołem Noonana prowadzą do konstytutywnej aktywacji białek tego szlaku, co oznacza, że są one stale aktywne, zamiast być włączane i wyłączane w odpowiedzi na określone sygnały.12

Przykładowo, mutacje w genie PTPN11 prowadzą do zwiększonej aktywności białka SHP-2, co powoduje nadmierną aktywację szlaku RAS/MAPK. Podobnie, mutacje w innych genach (SOS1, RAF1, RIT1, itp.) również prowadzą do wzmożonej sygnalizacji przez ten szlak, chociaż poprzez różne mechanizmy.12

Ta nadmierna aktywacja zaburza precyzyjną regulację wzrostu i podziału komórek, co przekłada się na różnorodne objawy zespołu Noonana, takie jak wady serca, zaburzenia wzrostu czy charakterystyczne cechy dysmorficzne.12

Zaburzenia wzrostu w zespole Noonana

Jednym z głównych objawów zespołu Noonana jest niskorosłość. Badania sugerują, że może to być związane z częściową niewrażliwością na hormon wzrostu (GH) na poziomie postreceptorowym i/lub wpływem na aktywację szlaku RAS/MAPK.1

Dane z modeli mysich z zespołem Noonana dostarczają dowodów, że opóźnienie wzrostu, przynajmniej w przypadkach związanych z określonym wariantem genu Ptpn11, może wynikać z częściowej niewrażliwości na GH i/lub wpływu na aktywację RAS/MAPK.1

Mutacje w genie PTPN11 mogą powodować łagodną formę oporności na GH i niedobór IGF-1, prawdopodobnie ze względu na zakłócenie sygnalizacji JAK2-STAT5b receptora GH.1

Diagnostyka genetyczna

Diagnostyka genetyczna odgrywa kluczową rolę w potwierdzeniu rozpoznania zespołu Noonana oraz ma istotne implikacje dla poradnictwa genetycznego i prowadzenia pacjenta.1

Metody diagnostyczne

Badania genetyczne mogą potwierdzić diagnozę zespołu Noonana w około 70-80% przypadków. W pozostałych przypadkach przyczyna pozostaje nieznana, co może wynikać z obecności mutacji w jeszcze niezidentyfikowanych genach.12

W diagnostyce genetycznej zespołu Noonana stosuje się różne metody:

  • Ukierunkowane badania molekularne genów związanych z zespołem Noonana (panel genów)
  • Sekwencjonowanie całego eksomu (WES) lub całego genomu (WGS) w przypadkach, gdy początkowe testy genetyczne nie wykryją mutacji. Te kompleksowe techniki sekwencjonowania mogą analizować cały eksom lub genom w celu identyfikacji rzadkich lub nowych mutacji.1

Ważne jest, aby podkreślić, że osoby z zespołem Noonana mają prawidłowe badania chromosomalne. Zmiany zachodzą na poziomie pojedynczych genów, a nie całych chromosomów.1

Znaczenie diagnostyki genetycznej

Identyfikacja konkretnej mutacji genetycznej u pacjenta z zespołem Noonana ma kilka istotnych konsekwencji:

  • Potwierdza kliniczne rozpoznanie
  • Pomaga w poradnictwie genetycznym – rodzice mogą być poinformowani o ryzyku przekazania mutacji przyszłemu potomstwu
  • Może pomóc w przewidywaniu pewnych aspektów przebiegu klinicznego, biorąc pod uwagę znane korelacje genotyp-fenotyp
  • W przypadku mutacji de novo, rodzice mogą być zapewnieni o niskim ryzyku (poniżej 1%) posiadania kolejnego dziecka z zespołem Noonana12

Wczesna i dokładna diagnoza zespołu Noonana jest ważna, ponieważ ma wpływ na indywidualne postępowanie z pacjentem i rokowanie.1

Czynniki ryzyka i wnioski

Głównym czynnikiem ryzyka rozwoju zespołu Noonana jest posiadanie rodzica z tym zespołem. W takim przypadku ryzyko przekazania zmutowanego genu i wystąpienia zespołu Noonana u dziecka wynosi 50% przy każdej ciąży.12

Zespół Noonana został również powiązany z zaawansowanym wiekiem ojca, co może zwiększać ryzyko spontanicznych mutacji.12

Nie ma dowodów sugerujących, że wada genetyczna powodująca zespół Noonana jest wywoływana przez czynniki środowiskowe, takie jak dieta czy ekspozycja na promieniowanie.12

Zespół Noonana charakteryzuje się nieznacznym zwiększeniem ryzyka określonych nowotworów, w tym białaczki. Badania przeprowadzone przez Jongmans i wsp. wykazały podwyższone ryzyko nowotworów u pacjentów z zespołem Noonana.1

Pomimo rosnących badań medycznych, wiedza o zespole Noonana wśród pracowników służby zdrowia pozostaje często ograniczona, co może prowadzić do trudności w dostępie do odpowiedniej opieki. Rzadkie choroby genetyczne są często pomijane ze względu na przekonanie, że dotyczą one tylko niewielkiej części populacji.12

W przypadku zespołu Noonana głównym źródłem chorobowości i śmiertelności jest obecność i typ wrodzonej wady serca.1

Kolejne rozdziały

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  1. 11.04.2026
  2. www.leksykon.com.pl

Materiały źródłowe

  • #1 Noonan Syndrome – StatPearls – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK532269/
    Noonan syndrome is a pleomorphic autosomal dominant inherited disease. Thus, parents with Noonan syndrome have a 50% chance of passing the mutation on to their children. Noonan syndrome has been associated with advanced paternal age. Noonan Syndrome can also occur via de novo mutation or sporadic mutation. The mutated genes are involved in the RAS/MAPK cell signaling pathway. […] The RAS/MAPK pathway mutation in Noonan syndrome classifies Noonan syndrome as RASopathy. RASopathies are genetic syndromes that involve germline mutations in the Ras/mitogen-activated protein kinase (MAPK) pathway. The most common mutation in Noonan syndrome occurs in the PTPN11 gene. A smaller portion of mutations occurs in SOS1, RAF1, and RIT1. Mutations in PTPN11 can be inherited, autosomal dominant, or occur de novo through sporadic mutation. The mutations involved in Noonan syndrome are considered a gain of function mutation, causing inappropriate prolongation of the RAS/MAPK signaling. The prolongation of the RAS/MAPK pathway gives way to the pleomorphic characteristics found in Noonan syndrome.
  • #1 Noonan syndrome and RASopathies: Clinical features, diagnosis and management
    https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2019.16.1.1
    The germ-line mutations enhancing the function of the RAS-MAPK pathway components are underlying molecular mechanism for the development of NS and NS-related disorders. […] Since the consequences of genetic defect of these genes are the gain of function in the rat sarcoma viral oncogene (RAS) /mitogen-activated protein kinase (MAPK) pathway, Noonan syndrome and its related disorders (LEOPARD, CFC, CSs, and neurofibromatosis type I) are named as RASopathies. […] The PTPN11 (4050%), SOS1 (1020%), RAF1 (317%), and RIT1 (59%) mutations are common in NS patients. […] As of 2019, more than 20 genes (PTPN11, SOS1, RAF1, SHOC2, BRAF, KRAS, NRAS, HRAS, MEK1, MEK2, CBL, SOS2, RIT, RRAS, RASA2, SPRY1, LZTR1, MAP3K8, MYST4, A2ML1, RRAS2) were known to cause NS and its related disorders. […] The mutation spectrum of CS and NSML are unique, mostly found in HRAS and PTPN11 genes respectively. […] The frequently detected upstream defects of this pathway are gain-of-function mutations of PTPN11, leading to a mild form of GH resistance and IGF-1 deficiency, presumably due to interference with the JAK2-STAT 5b signaling of the GH receptor.
  • #1 Noonan Syndrome Clinical Presentation: History, Physical, Causes
    https://emedicine.medscape.com/article/947504-clinical
    Sporadic and autosomal dominant cases have been identified. Female patients with Noonan syndrome have normal pubertal development and fertility, while fertility in males with undescended testes may be decreased. For this reason, the mother is more frequently the transmitting parent in familial cases. […] Causative gene mutations in Noonan syndrome include the following: PTPN11 mutations – Account for approximately 50% of clinically recognized cases, SOS1 mutations – Account for approximately 13% of cases, RAF1 mutations – Account for 5-17% of cases, RIT1 mutations – Account for 5% of cases, KRAS, NRAS, BRAF, MAP2K1, MRAS, RASA2, RRAS2, SOS2, and LZATR1 mutations. […] Cases due to SOS1 mutations are generally associated with better cognitive function than those associated with PTPN11 mutations.
  • #1 Azthena logo with the word Azthena
    https://www.news-medical.net/health/Noonan-Syndrome-Causes.aspx
    Mutations in SOS1, which is a RAS-specific guanine nucleotide exchange factor that catalyzes the release of GDP from RAS, occur in approximately 10% of the patients. […] A mutation in the RAF1 gene (a member of a small family of serine-threonine kinases) accounts for between 5-10% of cases. […] Defects in the KRAS proto-oncogene account for approximately 2% of cases and generally confer milder gain-of-function effects. […] Other aforementioned genes are very rarely implicated in the disease, and it is estimated that no specific genetic mutation can be found in 20% of all cases of Noonan syndrome.
  • #1 Noonan syndrome – Wikipedia
    https://en.wikipedia.org/wiki/Noonan_syndrome
    About 15-20% of NS cases remain genetically undiagnosed. […] The fact that an affected parent is not always identified for children with NS suggests several possibilities: […] NS is heterogeneous, comprising more than one similar condition of differing causes, and some of these may not be inherited. […] A high proportion of cases may represent new, sporadic mutations.
  • #1
    https://www.nhs.uk/conditions/noonan-syndrome/causes/
    Noonan syndrome is caused by a faulty gene, which is usually inherited from one of the child’s parents. […] There’s no evidence to suggest the genetic fault is caused by environmental factors, such as diet or exposure to radiation. […] Faults in at least 8 different genes have been linked to Noonan syndrome. […] In around 30-75% of cases, Noonan syndrome is inherited in what’s known as an autosomal dominant pattern. […] In the remaining cases, the condition is caused by a new genetic fault that isn’t inherited from either parent.
  • #1
    https://www.nhs.uk/conditions/noonan-syndrome/
    Noonan syndrome is caused by a fault in one of several genes. At least 8 different faulty genes have been linked to the condition so far. […] In some cases, the faulty gene associated with Noonan syndrome is inherited from one of the child’s parents. The parent with the faulty gene may or may not have obvious features of the condition themselves. Only one parent needs to carry the fault to pass it on and each child they have has a 50% chance of being born with the condition. […] In other cases, the condition is caused by a new genetic fault that isn’t inherited from either parent. In these cases, the chance of the parents having another child with Noonan syndrome is very small.
  • #1 Noonan Syndrome – GeneReviews® – NCBI Bookshelf
    https://www.ncbi.nlm.nih.gov/books/NBK1124/
    Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. […] The diagnosis of Noonan is established in a proband with suggestive findings and a heterozygous pathogenic variant in BRAF, KRAS, MAP2K1, MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS2, SOS1, or SOS2 or either a heterozygous variant or biallelic pathogenic variants in LZTR1 identified by molecular genetic testing. […] NS is most often inherited in an autosomal dominant manner. While many individuals with autosomal dominant NS have a de novo pathogenic variant, an affected parent is recognized in 30%-75% of families. […] NS caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner. […] The genes implicated in Noonan syndrome are part of or interact with the Ras/MAPK pathway. […] Noonan syndrome pathogenic variants usually enhance signal flow through this pathway.
  • #1 Noonan Syndrome Clinical Presentation: History, Physical, Causes
    https://emedicine.medscape.com/article/947504-clinical
    Correlations have been demonstrated between patient phenotype in Noonan syndrome and mutations in specific genes. A study by Lee et al found that patients with Noonan syndrome who had SOS1 mutations tended to have normal stature, while RAF1 mutations appeared to be associated with hypertrophic cardiomyopathy and developmental delay. […] A study by Meier et al found that in individuals with childhood-onset cardiomyopathy associated with Noonan syndrome, cell cycle pathways in left ventricular myocardial tissue demonstrated significant upregulation, including in genes in charge of mitotic processes. Importantly, the expression of FGF10 was found to be greatly elevated; according to the investigators, evidence suggests that left ventricular cardiomyocyte production in Noonan syndrome-associated cardiomyopathy is being driven by increased expression of this gene.
  • #1 About Noonan Syndrome
    https://www.genome.gov/Genetic-Disorders/Noonan-Syndrome
    Noonan syndrome is caused by changes in one of several autosomal dominant genes. A person who has Noonan syndrome may have inherited an altered (mutated) gene from one of his or her parents, or the gene change may be a new change due to an error carried by the egg or sperm or occurring at conception. Alterations in four genes – PTPN11, SOS1, RAF1 and KRAS – have been identified to date. […] Individuals who have Noonan syndrome have normal chromosome studies. Four genes – PTPN11, SOS1, RADF1and KRAS – are the only genes that are known to be associated with Noonan syndrome. Approximately 50 percent of individuals with Noonan syndrome have mutations in the PTPN11 gene. Twenty percent of those with Noonan Syndrome have mutations in the SOS1. Mutations in the RAF1 gene account for between 10 and 15 percent of Noonan syndrome cases. About 5 percent of people with Noonan syndrome have mutations in the KRAS gene and usually have a more severe or atypical form of the disorder. The cause of Noonan syndrome in the remaining 10 to 15 percent of people with this disorder is not yet known.
  • #1 Noonan Syndrome—Historical Awareness and Genetic Issues | [current-page:pager]touchENDOCRINOLOGY
    https://touchendocrinology.com/thyroid/journal-articles/noonan-syndrome-historical-awareness-and-genetic-issues/
    In 1994, Jamieson et al. performed a linkage analysis on two multigenerational families and mapped the gene for Noonan syndrome to the distal part of chromosome 12q (12q22-qter). […] In 2001, Tartaglia et al found a mutation in the PTPN11 gene on chromosome 12 that was present in approximately 50% of patients with Noonan syndrome. […] Mutations in three additional genes have been identified in Noonan syndrome in the past three years: KRAS, SOS1, and RAF1. […] It is now clear that Noonan syndrome shares many phenotypic similarities with other disorders such as LEOPARD syndrome, cardio-facio-cutaneous (CFC) syndrome, Costello syndrome, and neurofibromatosis type 1 (NF1), all of which have a high incidence of some form of congenital heart disease and share germline mutations in the RAS-MAPK pathway.
  • #1 Noonan Syndrome—Historical Awareness and Genetic Issues | [current-page:pager]touchENDOCRINOLOGY
    https://touchendocrinology.com/thyroid/journal-articles/noonan-syndrome-historical-awareness-and-genetic-issues/
    The shared phenotypic features have led some researchers to suggest an umbrella term of neuro-cardio-facio-cutaneous syndromes for all of these disorders. […] The phenotypic similarities and disturbances of the RAS-MAPK pathway among these aptly named neuro-cardio-facio-cutaneous syndromes are indicative of this pathway’s important role in development.
  • #1 Noonan syndrome: MedlinePlus GeneticsLock
    https://medlineplus.gov/genetics/condition/noonan-syndrome/
    Noonan syndrome is a condition that affects many areas of the body. […] Mutations in multiple genes can cause Noonan syndrome. Mutations in the PTPN11 gene cause about half of all cases. […] The PTPN11, SOS1, RAF1, and RIT1 genes all provide instructions for making proteins that are important in the RAS/MAPK cell signaling pathway, which is needed for cell division and growth (proliferation), the process by which cells mature to carry out specific functions (differentiation), and cell movement (migration). […] Many of the mutations in the genes associated with Noonan syndrome cause the resulting protein to be turned on (active) longer than normal, rather than promptly switching on and off in response to cell signals. This prolonged activation alters normal RAS/MAPK signaling, which disrupts the regulation of cell growth and division, leading to the characteristic features of Noonan syndrome. […] Rarely, Noonan syndrome is associated with genes that are not involved in the RAS/MAPK cell signaling pathway. Researchers are working to determine how mutations in these genes can lead to the signs and symptoms of Noonan syndrome.
  • #1 Noonan syndrome | Orphanet Journal of Rare Diseases | Full Text
    https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-2-4
    NS may occur on a sporadic basis or in a pattern consistent with autosomal dominant inheritance with a predominance of maternal transmission. […] In approximately 50% of the patients with definite NS, a missense mutation is found in the PTPN11 gene on chromosome 12. PTPN11 encodes the non-receptor protein tyrosine phosphatase SHP-2. This enzyme is involved in a wide variety of intracellular signal cascades downstream of receptors for growth factors, cytokines and hormones, and is required in several developmental processes. The mutations associated with NS result in a gain of function of SHP-2. […] Heterogeneous gain-of-function mutations in PTPN11 are found in almost half of the patients with clinically definite NS. These mutations are found in 59% of the familial cases and in 37% of the sporadic cases. Most of the mutations are recurrent and cluster in exons 3, 8 and 13. […] Recently activating mutations in the KRAS gene, which is associated with the Ras pathway, were found as the causative dominant mutations in a few cases with NS. These findings establish hyperactive Ras as a cause of developmental abnormalities seen in NS.
  • #1 Frontiers | Etiology and Treatment of Growth Delay in Noonan Syndrome
    https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.691240/full
    Noonan syndrome is characterized by multiple phenotypic features, including growth retardation, which represents the main cause of consultation to the clinician. […] Several studies regarding the function of the somatotrophic axis in patients with Noonan syndrome and data from murine models, suggest that partial GH insensitivity at a post-receptor level, as well as possible derangements in the RAS/MAPK pathway, are the most likely causes for the growth failure in these patients. […] All of these conditions, including Noonan syndrome, are known as RASopathies, since their common molecular etiology are gain of function pathogenic variants of different components of the Ras/mitogen-activated protein kinase (MAPK) signaling pathway. […] Data from murine NS models provide evidence that the growth retardation in NS, at least in those cases associated with a specific Ptpn11 variant, may be due either to partial GH insensitivity at a post-receptor level, and/or to an effect on RAS/MAPK activation. […] Despite the recent description of new genes associated with Noonan syndrome, and the availability of several murine models with pathogenic variants of the RAS/MAPK pathway, the molecular pathophysiology for the growth delay observed in these patients has not been elucidated.
  • #1 Noonan Syndrome | AAFP
    https://www.aafp.org/pubs/afp/issues/2014/0101/p37.html
    Noonan syndrome is a common genetic disorder that causes multiple congenital abnormalities and a large number of potential health conditions. […] Familial recurrence is consistent with an autosomal dominant mode of inheritance, but most cases are due to de novo mutations. […] Molecular genetic testing can confirm diagnosis in 70% of cases and has important implications for genetic counseling and management. […] Noonan syndrome is caused by mutations in the RAS/mitogen-activated protein kinase (MAPK) pathway, which is essential for cell cycle differentiation, growth, and senescence. […] Approximately one-half of the known mutations are in the protein tyrosine phosphatase non-receptor, type 11 (PTPN 11) gene. […] Most cases are sporadic. In familial cases, autosomal dominant inheritance is confirmed.
  • #1 Noonan Syndrome (Leopard Syndrome): Causes & Outlook
    https://my.clevelandclinic.org/health/diseases/17926-noonan-syndrome
    Noonan syndrome occurs most often due to changes (mutations) in certain genes that help your bodys tissues grow and develop. These mutated genes produce proteins that are active longer than they should be. They interfere with proper cell growth and division. […] Noonan syndrome may be: Inherited: One parent passes the condition to a child. […] Spontaneous mutation: It develops without any family history. […] Genetic testing can find an abnormality in almost 80% of people with Noonan syndrome. For the rest, researchers dont know the exact cause.
  • #1 Noonan Syndrome: Exploring Karyotypes and Genetic Causes
    https://3billion.io/blog/noonan-syndrome-and-karyotype-genetic-code
    Noonan Syndrome does not have a specific karyotype associated with it. Instead, it is primarily caused by mutations in various specific genes, such as PTPN11, SOS1, RAF1, and others. […] These mutations occur in specific genes on certain chromosomes and are responsible for the characteristic features and health issues associated with Noonan Syndrome. […] While karyotype testing can provide valuable information, it may not identify the specific genetic mutations responsible for Noonan Syndrome. To pinpoint the exact genetic cause, more targeted genetic testing is necessary. […] The diagnosis of Noonan Syndrome typically involves a combination of genetic testing and clinical evaluation. […] In some cases, whole exome sequencing (WES) or whole genome sequencing (WGS) may be used if initial genetic tests do not identify a mutation. These comprehensive sequencing techniques can analyze the entire exome or genome to identify rare or novel mutations.
  • #1 About Noonan Syndrome
    https://www.genome.gov/Genetic-Disorders/Noonan-Syndrome
    Noonan syndrome is inherited in families in an autosomal dominant pattern. This means that a person who has Noonan syndrome has one copy of an altered gene that causes the disorder. In about one-third to two-thirds of families one of the parents also has Noonan syndrome. The parent who has Noonan syndrome has a 1 in 2 (50 percent) chance to pass on the altered gene to a child who will be affected; and a 1 in 2 (50 percent) chance to pass on the normal version of the gene to a child who will not have Noonan syndrome. In many individuals who have Noonan syndrome, the altered gene happens for the first time in them, and neither of the parents has Noonan syndrome. This is called a de novo mutation. The chance for these parents to have another child with Noonan syndrome is very small (less than 1 percent).
  • #1 Noonan syndrome: improving recognition and diagnosis | Archives of Disease in Childhood
    https://adc.bmj.com/content/107/12/1073
    Noonan syndrome (NS) is a mostly dominantly inherited disorder affecting 1:1000 to 1:2500 live births. […] NS is caused primarily by gain-of-function (activating) mutations in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway, which is essential for cell cycle differentiation, growth and senescence. […] Genes implicated in NS include PTPN11 (in about half of patients with NS), SOS1, RAF1, RIT1, KRAS, NRAS, BRAF, LZTR1, SOS2 and others. […] The causative mutations remain unidentified in 10%20% of patients, and de novo mutations account for a majority of NS cases. […] Genetic heterogeneity partly explains the observed phenotypical variability, and a number of clinically relevant genotypephenotype correlations have been identified. […] Early, accurate diagnosis of NS is important because it has an impact on individual management and prognosis. […] The NS phenotype varies from oligosymptomatic adults without significant medical issues to severely affected neonates with life-threatening heart disease or lymphatic issues.
  • #1 Noonan syndrome: Causes, symptoms, and management
    https://www.medicalnewstoday.com/articles/179200
    Noonan syndrome is caused by an abnormality or mutation in one of several genes. […] The faulty gene associated with Noonan syndrome can be inherited from a parent. Approximately 50 percent of people with the condition have an affected parent. The parent carrying the genetic abnormality may or may not have any obvious features of the disorder. […] A new mutation that randomly occurs in children without any genetic predisposition. […] Having a parent with Noonan syndrome is the greatest risk factor for development of the condition. The risk of passing the defective gene from parent to child is 50 percent for each pregnancy.
  • #1 Noonan Syndrome: Practice Essentials, Pathophysiology, Epidemiology
    https://emedicine.medscape.com/article/947504-overview
    Noonan syndrome is a genetic disorder that prevents normal development of various parts of the body. […] The pathophysiology of Noonan syndrome is not fully understood but is associated with mutations in genes that are part of the RAS/RAF/MEK/ERK signal transduction pathway, an important regulator of cell growth. Approximately 50% of patients have gene mutations in PTPN11, with SOS1 and RAF1 mutations identified in another 13% and 5-17% of patients, respectively. […] A study by Barg et al indicated that platelet dysfunction and plasma coagulation factor deficiencies contribute to bleeding diathesis in Noonan syndrome. […] The primary source of morbidity and mortality in patients with Noonan syndrome depends on the presence and type of congenital heart disease. […] Noonan syndrome is also characterized by a slight increase in the risk for certain cancers. […] A study by Jongmans et al also demonstrated an elevated cancer risk in patients with Noonan syndrome.
  • #1 Families living with Noonan Syndrome call for more social support and medical awareness | Media Centre | Loughborough University
    https://www.lboro.ac.uk/media-centre/press-releases/2024/february/noonan-syndrome-awareness-report-families-impact/
    Noonan Syndrome, though classed as a rare genetic condition, is estimated to affect between 1 in 2000 to 1 in 2500 births in the UK, causing diverse health issues. […] One of the key survey findings is that there is a lack of awareness of the rare genetic condition even among medical professionals, which can lead to difficulties in accessing care. […] Despite increasing medical research, very often medical professionals involved in families care don’t know much about Noonan Syndrome, if anything at all, she said. […] Noonan Syndrome can be inherited (a 50:50 chance) if one or both parents carry an altered gene. It can also occur de novo (through spontaneous mutation of the gene), in which case the child can be the first in the family to have the syndrome. […] The couple discovered at 26 weeks pregnant, after a prenatal screening test, that one of their twins, Matilda, had Noonan Syndrome.
  • #2 Noonan syndrome | Orphanet Journal of Rare Diseases | Full Text
    https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-2-4
    NS may occur on a sporadic basis or in a pattern consistent with autosomal dominant inheritance with a predominance of maternal transmission. […] In approximately 50% of the patients with definite NS, a missense mutation is found in the PTPN11 gene on chromosome 12. PTPN11 encodes the non-receptor protein tyrosine phosphatase SHP-2. This enzyme is involved in a wide variety of intracellular signal cascades downstream of receptors for growth factors, cytokines and hormones, and is required in several developmental processes. The mutations associated with NS result in a gain of function of SHP-2. […] Heterogeneous gain-of-function mutations in PTPN11 are found in almost half of the patients with clinically definite NS. These mutations are found in 59% of the familial cases and in 37% of the sporadic cases. Most of the mutations are recurrent and cluster in exons 3, 8 and 13. […] Recently activating mutations in the KRAS gene, which is associated with the Ras pathway, were found as the causative dominant mutations in a few cases with NS. These findings establish hyperactive Ras as a cause of developmental abnormalities seen in NS.
  • #2 Noonan syndrome: MedlinePlus GeneticsLock
    https://medlineplus.gov/genetics/condition/noonan-syndrome/
    Noonan syndrome is a condition that affects many areas of the body. […] Mutations in multiple genes can cause Noonan syndrome. Mutations in the PTPN11 gene cause about half of all cases. […] The PTPN11, SOS1, RAF1, and RIT1 genes all provide instructions for making proteins that are important in the RAS/MAPK cell signaling pathway, which is needed for cell division and growth (proliferation), the process by which cells mature to carry out specific functions (differentiation), and cell movement (migration). […] Many of the mutations in the genes associated with Noonan syndrome cause the resulting protein to be turned on (active) longer than normal, rather than promptly switching on and off in response to cell signals. This prolonged activation alters normal RAS/MAPK signaling, which disrupts the regulation of cell growth and division, leading to the characteristic features of Noonan syndrome. […] Rarely, Noonan syndrome is associated with genes that are not involved in the RAS/MAPK cell signaling pathway. Researchers are working to determine how mutations in these genes can lead to the signs and symptoms of Noonan syndrome.
  • #2 About Noonan Syndrome
    https://www.genome.gov/Genetic-Disorders/Noonan-Syndrome
    Noonan syndrome is caused by changes in one of several autosomal dominant genes. A person who has Noonan syndrome may have inherited an altered (mutated) gene from one of his or her parents, or the gene change may be a new change due to an error carried by the egg or sperm or occurring at conception. Alterations in four genes – PTPN11, SOS1, RAF1 and KRAS – have been identified to date. […] Individuals who have Noonan syndrome have normal chromosome studies. Four genes – PTPN11, SOS1, RADF1and KRAS – are the only genes that are known to be associated with Noonan syndrome. Approximately 50 percent of individuals with Noonan syndrome have mutations in the PTPN11 gene. Twenty percent of those with Noonan Syndrome have mutations in the SOS1. Mutations in the RAF1 gene account for between 10 and 15 percent of Noonan syndrome cases. About 5 percent of people with Noonan syndrome have mutations in the KRAS gene and usually have a more severe or atypical form of the disorder. The cause of Noonan syndrome in the remaining 10 to 15 percent of people with this disorder is not yet known.
  • #2 Azthena logo with the word Azthena
    https://www.news-medical.net/health/Noonan-Syndrome-Causes.aspx
    Mutations in SOS1, which is a RAS-specific guanine nucleotide exchange factor that catalyzes the release of GDP from RAS, occur in approximately 10% of the patients. […] A mutation in the RAF1 gene (a member of a small family of serine-threonine kinases) accounts for between 5-10% of cases. […] Defects in the KRAS proto-oncogene account for approximately 2% of cases and generally confer milder gain-of-function effects. […] Other aforementioned genes are very rarely implicated in the disease, and it is estimated that no specific genetic mutation can be found in 20% of all cases of Noonan syndrome.
  • #2 Noonan Syndrome | Children’s Hospital Colorado
    https://www.childrenscolorado.org/conditions-and-advice/conditions-and-symptoms/conditions/noonan-syndrome/
    Noonan syndrome is a genetic disorder that affects the whole body, including the heart, blood vessels, skeletal system, eyes, ears and brain. […] Noonan syndrome is genetic and the only way to develop the condition is to be born with the gene change that causes the disease. Children with Noonan syndrome could have inherited the gene from a parent or it could be a gene new in them. […] More than 50% of Noonan syndrome cases in children happen when there’s a family history of the disease. Sometimes a parent may not even know that they have the disease. The remainder of children with Noonan syndrome have no family history. When a genetic change is new in a person, we call it de novo. […] Neither family-related Noonan syndrome nor spontaneous Noonan syndrome is preventable, but the symptoms of Noonan syndrome are very treatable.
  • #2 Noonan Syndrome Clinical Presentation: History, Physical, Causes
    https://emedicine.medscape.com/article/947504-clinical
    Sporadic and autosomal dominant cases have been identified. Female patients with Noonan syndrome have normal pubertal development and fertility, while fertility in males with undescended testes may be decreased. For this reason, the mother is more frequently the transmitting parent in familial cases. […] Causative gene mutations in Noonan syndrome include the following: PTPN11 mutations – Account for approximately 50% of clinically recognized cases, SOS1 mutations – Account for approximately 13% of cases, RAF1 mutations – Account for 5-17% of cases, RIT1 mutations – Account for 5% of cases, KRAS, NRAS, BRAF, MAP2K1, MRAS, RASA2, RRAS2, SOS2, and LZATR1 mutations. […] Cases due to SOS1 mutations are generally associated with better cognitive function than those associated with PTPN11 mutations.
  • #2 FAQs • Genetics & RASopathies • Noonan Syndrome Association
    https://www.noonansyndrome.org.uk/faqs/genetics-rasopathies/
    SOS1 is the second most common causative gene, with variants occurring in 16-20% of individuals without PTPN11 variants. […] Mutations in other genes RAF1, RIT1, KRAS, NRAS, BRAF, MAP2K1, RRAS, RASA2, SOS2, LZTR1 are less common causes. […] In about 5-10% of cases, the genetic cause of Noonan syndrome is still not known.
  • #2 Noonan syndrome – Symptoms and causes – Mayo Clinic
    https://www.mayoclinic.org/diseases-conditions/noonan-syndrome/symptoms-causes/syc-20354422
    Noonan syndrome is a genetic condition that stops typical development in various parts of the body. […] A changed gene causes Noonan syndrome. A child inherits a copy of an affected gene from a parent. This is called dominant inheritance. The condition also can occur as a spontaneous change. This means there’s no family history involved. […] A change in one or more genes can cause Noonan syndrome. Changes in these genes produce proteins that are always active. Because these genes play a role in how tissues form in the body, this constant activation of proteins disrupts the typical process of cell growth and division. […] The gene changes that cause Noonan syndrome can be: Inherited. Children who have one parent with Noonan syndrome who carries the changed gene have a 50% chance of developing the condition. This is called an autosomal dominant inheritance pattern. […] Random. Noonan syndrome can develop in a child because of a new changed gene meaning the child did not inherit that gene from a parent. This is known as a de novo genetic condition. […] In some cases, the cause of Noonan syndrome is not known.
  • #2
    https://www.nhs.uk/conditions/noonan-syndrome/
    Noonan syndrome is caused by a fault in one of several genes. At least 8 different faulty genes have been linked to the condition so far. […] In some cases, the faulty gene associated with Noonan syndrome is inherited from one of the child’s parents. The parent with the faulty gene may or may not have obvious features of the condition themselves. Only one parent needs to carry the fault to pass it on and each child they have has a 50% chance of being born with the condition. […] In other cases, the condition is caused by a new genetic fault that isn’t inherited from either parent. In these cases, the chance of the parents having another child with Noonan syndrome is very small.
  • #2 About Noonan Syndrome
    https://www.genome.gov/Genetic-Disorders/Noonan-Syndrome
    Noonan syndrome is inherited in families in an autosomal dominant pattern. This means that a person who has Noonan syndrome has one copy of an altered gene that causes the disorder. In about one-third to two-thirds of families one of the parents also has Noonan syndrome. The parent who has Noonan syndrome has a 1 in 2 (50 percent) chance to pass on the altered gene to a child who will be affected; and a 1 in 2 (50 percent) chance to pass on the normal version of the gene to a child who will not have Noonan syndrome. In many individuals who have Noonan syndrome, the altered gene happens for the first time in them, and neither of the parents has Noonan syndrome. This is called a de novo mutation. The chance for these parents to have another child with Noonan syndrome is very small (less than 1 percent).
  • #2
    https://www.omim.org/entry/163950
    Autosomal recessive forms of Noonan syndrome include NS2 (605275), caused by mutation in the LZTR1 gene (600574), and NS14 (619745), caused by mutation in the SPRED2 gene (609292). […] Mutations in the neurofibromin gene (NF1; 613113), which is the site of mutations causing classic neurofibromatosis type I (NF1; 162200), have been found in neurofibromatosis-Noonan syndrome (NFNS; 601321). […] Noonan syndrome is inherited in an autosomal dominant pattern (Tartaglia et al., 2010).
  • #2 Noonan syndrome: improving recognition and diagnosis | Archives of Disease in Childhood
    https://adc.bmj.com/content/107/12/1073
    Noonan syndrome (NS) is a mostly dominantly inherited disorder affecting 1:1000 to 1:2500 live births. […] NS is caused primarily by gain-of-function (activating) mutations in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway, which is essential for cell cycle differentiation, growth and senescence. […] Genes implicated in NS include PTPN11 (in about half of patients with NS), SOS1, RAF1, RIT1, KRAS, NRAS, BRAF, LZTR1, SOS2 and others. […] The causative mutations remain unidentified in 10%20% of patients, and de novo mutations account for a majority of NS cases. […] Genetic heterogeneity partly explains the observed phenotypical variability, and a number of clinically relevant genotypephenotype correlations have been identified. […] Early, accurate diagnosis of NS is important because it has an impact on individual management and prognosis. […] The NS phenotype varies from oligosymptomatic adults without significant medical issues to severely affected neonates with life-threatening heart disease or lymphatic issues.
  • #2 Noonan Syndrome Clinical Presentation: History, Physical, Causes
    https://emedicine.medscape.com/article/947504-clinical
    Correlations have been demonstrated between patient phenotype in Noonan syndrome and mutations in specific genes. A study by Lee et al found that patients with Noonan syndrome who had SOS1 mutations tended to have normal stature, while RAF1 mutations appeared to be associated with hypertrophic cardiomyopathy and developmental delay. […] A study by Meier et al found that in individuals with childhood-onset cardiomyopathy associated with Noonan syndrome, cell cycle pathways in left ventricular myocardial tissue demonstrated significant upregulation, including in genes in charge of mitotic processes. Importantly, the expression of FGF10 was found to be greatly elevated; according to the investigators, evidence suggests that left ventricular cardiomyocyte production in Noonan syndrome-associated cardiomyopathy is being driven by increased expression of this gene.
  • #2 Noonan Syndrome—Historical Awareness and Genetic Issues | [current-page:pager]touchENDOCRINOLOGY
    https://touchendocrinology.com/thyroid/journal-articles/noonan-syndrome-historical-awareness-and-genetic-issues/
    The shared phenotypic features have led some researchers to suggest an umbrella term of neuro-cardio-facio-cutaneous syndromes for all of these disorders. […] The phenotypic similarities and disturbances of the RAS-MAPK pathway among these aptly named neuro-cardio-facio-cutaneous syndromes are indicative of this pathway’s important role in development.
  • #2 Noonan syndrome and RASopathies: Clinical features, diagnosis and management
    https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2019.16.1.1
    Noonan syndrome (NS) and NS-related disorders (cardio-facio-cutaneous syndrome, Costello syndrome, NS with multiple lentigines, or LEOPARD [lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensory neural deafness] syndrome) are collectively named as RASopathies. […] During past decades, molecular etiologies of RASopathies have been growingly discovered. The functional perturbations of the RAS-mitogen-activated protein kinase pathway are resulted from the mutation of more than 20 genes (PTPN11, SOS1, RAF1, SHOC2, BRAF, KRAS, NRAS, HRAS, MEK1, MEK2, CBL, SOS2, RIT, RRAS, RASA2, SPRY1, LZTR1, MAP3K8, MYST4, A2ML1, RRAS2). […] The molecular pathogenesis behind RASopathies is now increasingly understood. It is commonly resulted from gain of function of the RAS-MAPK signaling pathway.
  • #2 Noonan Syndrome | AAFP
    https://www.aafp.org/pubs/afp/issues/2014/0101/p37.html
    Noonan syndrome is a common genetic disorder that causes multiple congenital abnormalities and a large number of potential health conditions. […] Familial recurrence is consistent with an autosomal dominant mode of inheritance, but most cases are due to de novo mutations. […] Molecular genetic testing can confirm diagnosis in 70% of cases and has important implications for genetic counseling and management. […] Noonan syndrome is caused by mutations in the RAS/mitogen-activated protein kinase (MAPK) pathway, which is essential for cell cycle differentiation, growth, and senescence. […] Approximately one-half of the known mutations are in the protein tyrosine phosphatase non-receptor, type 11 (PTPN 11) gene. […] Most cases are sporadic. In familial cases, autosomal dominant inheritance is confirmed.
  • #2 Noonan Syndrome | Children’s Hospital of Philadelphia
    https://www.chop.edu/conditions-diseases/noonan-syndrome
    Noonan syndrome is caused by alterations (also known as mutations) at specific areas within a person’s genetic information. […] Noonan syndrome is caused by mutations in one of several different genes, including PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF or MEK1. Together mutations in these genes account for 70-75 percent of Noonan syndrome cases. […] Noonan syndrome is an autosomal dominant condition, which means that alterations involving only one of the two copies of a Noonan syndrome-associated gene are sufficient to cause the disorder. The cause of Noonan syndrome in the remaining 25-30 percent of people with the disorder is unknown. […] Noonan syndrome-associated mutations cause the resulting proteins to be continuously active, instead of switching on and off in response to specific external cues. This disrupts the normal pattern of signals that control cell growth and division, and leads to the characteristic features of Noonan syndrome and the increased risk for developing benign or malignant tumors.
  • #2 Azthena logo with the word Azthena
    https://www.news-medical.net/health/Noonan-Syndrome-Causes.aspx
    Noonan syndrome has a genetic background with the autosomal dominant pattern of inheritance. […] It belongs to the group of the RAS-opathies, which means that this condition arises as a result of mutations in the genes encoding proteins of RAS/MAPK signaling pathway responsible for cell proliferation and differentiation. […] All the genes that have a role in Noonan syndrome encode proteins integral to this pathway, and mutations causing the disease usually enhance signal flow through this pathway. […] At least eight genes that are pivotal for the RASMAPK signaling pathway cause Noonan syndrome or closely related conditions (PTPN11, SOS1, RAF1, KRAS, NRAS, SHOC2, BRAF and CBL). […] Missense, gain-of-function mutations in the PTPN11 gene, which encodes the Src homology 2 (SH2) that contains protein tyrosine phosphatase SHP-2, account for approximately 50% of all cases of Noonan syndrome.
  • #2 Noonan syndrome | Beacon Health System
    https://www.beaconhealthsystem.org/library/diseases-and-conditions/noonan-syndrome/
    A changed gene causes Noonan syndrome. A child inherits a copy of an affected gene from a parent. This is called dominant inheritance. The condition also can occur as a spontaneous change. This means there’s no family history involved. […] A change in one or more genes can cause Noonan syndrome. Changes in these genes produce proteins that are always active. Because these genes play a role in how tissues form in the body, this constant activation of proteins disrupts the typical process of cell growth and division. […] The gene changes that cause Noonan syndrome can be: Inherited. Children who have one parent with Noonan syndrome who carries the changed gene have a 50% chance of developing the condition. This is called an autosomal dominant inheritance pattern. […] Random. Noonan syndrome can develop in a child because of a new changed gene meaning the child did not inherit that gene from a parent. This is known as a de novo genetic condition. […] In some cases, the cause of Noonan syndrome is not known.
  • #2 Noonan Syndrome | Children’s Hospital of Philadelphia
    https://www.chop.edu/conditions-diseases/noonan-syndrome
    Approximately 30-75 percent of patients inherit a mutation in one of the genes associated with Noonan syndrome from a parent who also has Noonan syndrome. In the remaining patients, there is no family history of Noonan syndrome. In these individuals, Noonan syndrome likely results from occurrence of a „new mutation” in one copy of a Noonan syndrome-associated gene. […] Mutations in the PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, or MEK1 genes are identified in 70-75 percent of people with Noonan syndrome. However, it is important to remember that not all patients with Noonan syndrome carry a detectable alteration in one of these genes. There are likely to be additional, undiscovered genes that play a role in the development of Noonan syndrome for the remaining 25-30 percent of patients.
  • #2 Noonan syndrome and congenital heart conditions
    https://www.aboutkidshealth.ca/noonan-syndrome-and-congenital-heart-conditions
    Noonan syndrome is a genetic condition. […] In 60% of cases, Noonan syndrome is caused by a genetic change (variant) which occurs for the first time in the child. However, it can also be inherited from a parent. […] Noonan syndrome is caused by one of several genes that play a key role in the normal functioning of cells. At least 12 genes have currently been associated with Noonan syndrome. […] In most cases (60%), Noonan syndrome is caused by a genetic change (variant) that occurs for the first time (de novo) in the child. […] Noonan syndrome can also be inherited from a parent. Most cases of inherited Noonan syndrome are inherited in an autosomal dominant manner. This means that if a parent has Noonan syndrome, there is a 50% chance in each pregnancy to have a child with Noonan syndrome. […] When the genetic change occurs de novo in the child, there is a less than 1% chance for the parents to have another child with Noonan syndrome.
  • #2 Noonan Syndrome: Symptoms, Diagnosis, Treatment, and More
    https://www.healthline.com/health/childrens-health/noonan-syndrome
    Noonan syndrome is a genetic condition that affects around 1 in every 1,0002,500 people. […] Noonan syndrome may result from any of eight different gene mutations and can be inherited from a parent who carries an affected gene (referred to as autosomal dominant inheritance). However, it may also be spontaneous, meaning it can happen at random without any family history. […] There are eight gene mutations that can be linked to the syndrome. These mutations in these five genes are most associated with the disorder: PTPN11, SOS1, RIT1, RAF1, KRAS. […] About 30 to 75 percent of people with Noonan syndrome inherit it from a parent who carries a gene mutation. This means that the parent with the gene mutation also actually has Noonan syndrome, too, but their symptoms may be so mild that they’ve never been diagnosed or may have been misdiagnosed. […] For other people with Noonan syndrome, the genetic mutation happens randomly. […] As far as what causes Noonan syndrome to begin with, scientists aren’t so sure. There’s currently no research to suggest that it’s caused by exposure to radiation, diet, or any other environmental factors.
  • #2 Noonan Syndrome: What Physicians Need to Know
    https://www.medscape.org/viewarticle/563459
    Noonan syndrome is one of the most common nonchromosomal syndromes seen in children with congenital heart disease. […] The syndrome can not only be inherited as an autosomal dominant disorder with variable expression, but also is frequently sporadic. […] NS is an autosomal dominant (AD) disorder with complete penetrance and variable expressivity. […] When a child has been diagnosed with NS, about half of the time it is inherited from a parent and half of the time it is sporadic — and the child is the first in the family to have the disorder. Sporadic mutations have been associated with advanced paternal age. […] It was not until the discovery of the PTPN11 gene in 2001 that the molecular genetic causes of NS began to be uncovered. […] Since 2001, 3 additional genes have been found to cause NS — KRAS, SOS1, and RAF — all components of this pathway and all mutations that lead to increased RAS signaling. […] Causative NS genes are all important regulators of this pathway. Pathogenic mutations are gain-of-function and lead to increased Ras signaling. […] One third of cases of NS are not explained by a PTPN11, KRAS, SOS1, or RAF1 mutation. This remains an active area of research.
  • #2 Families living with Noonan Syndrome call for more social support and medical awareness | Media Centre | Loughborough University
    https://www.lboro.ac.uk/media-centre/press-releases/2024/february/noonan-syndrome-awareness-report-families-impact/
    They say the lack of awareness among medical professionals has been challenging, especially at the point of diagnosis. […] Andrea worries her daughter and other people with the same gene mutation will never get a diagnosis as she believes there is a hesitancy to fund studies into rare genetic diseases. […] She says rare genetic conditions are often overlooked due to the perception that they only affect a small portion of the population.
  • #3 Noonan syndrome: improving recognition and diagnosis | Archives of Disease in Childhood
    https://adc.bmj.com/content/107/12/1073
    Noonan syndrome (NS) is a mostly dominantly inherited disorder affecting 1:1000 to 1:2500 live births. […] NS is caused primarily by gain-of-function (activating) mutations in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway, which is essential for cell cycle differentiation, growth and senescence. […] Genes implicated in NS include PTPN11 (in about half of patients with NS), SOS1, RAF1, RIT1, KRAS, NRAS, BRAF, LZTR1, SOS2 and others. […] The causative mutations remain unidentified in 10%20% of patients, and de novo mutations account for a majority of NS cases. […] Genetic heterogeneity partly explains the observed phenotypical variability, and a number of clinically relevant genotypephenotype correlations have been identified. […] Early, accurate diagnosis of NS is important because it has an impact on individual management and prognosis. […] The NS phenotype varies from oligosymptomatic adults without significant medical issues to severely affected neonates with life-threatening heart disease or lymphatic issues.
  • #3 Azthena logo with the word Azthena
    https://www.news-medical.net/health/Noonan-Syndrome-Causes.aspx
    Noonan syndrome has a genetic background with the autosomal dominant pattern of inheritance. […] It belongs to the group of the RAS-opathies, which means that this condition arises as a result of mutations in the genes encoding proteins of RAS/MAPK signaling pathway responsible for cell proliferation and differentiation. […] All the genes that have a role in Noonan syndrome encode proteins integral to this pathway, and mutations causing the disease usually enhance signal flow through this pathway. […] At least eight genes that are pivotal for the RASMAPK signaling pathway cause Noonan syndrome or closely related conditions (PTPN11, SOS1, RAF1, KRAS, NRAS, SHOC2, BRAF and CBL). […] Missense, gain-of-function mutations in the PTPN11 gene, which encodes the Src homology 2 (SH2) that contains protein tyrosine phosphatase SHP-2, account for approximately 50% of all cases of Noonan syndrome.
  • #3 Noonan Syndrome | Children’s Hospital of Philadelphia
    https://www.chop.edu/conditions-diseases/noonan-syndrome
    Noonan syndrome is caused by alterations (also known as mutations) at specific areas within a person’s genetic information. […] Noonan syndrome is caused by mutations in one of several different genes, including PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF or MEK1. Together mutations in these genes account for 70-75 percent of Noonan syndrome cases. […] Noonan syndrome is an autosomal dominant condition, which means that alterations involving only one of the two copies of a Noonan syndrome-associated gene are sufficient to cause the disorder. The cause of Noonan syndrome in the remaining 25-30 percent of people with the disorder is unknown. […] Noonan syndrome-associated mutations cause the resulting proteins to be continuously active, instead of switching on and off in response to specific external cues. This disrupts the normal pattern of signals that control cell growth and division, and leads to the characteristic features of Noonan syndrome and the increased risk for developing benign or malignant tumors.
  • #3 FAQs • Genetics & RASopathies • Noonan Syndrome Association
    https://www.noonansyndrome.org.uk/faqs/genetics-rasopathies/
    Noonan Syndrome is a genetic disorder a change in a gene causes disruption in one of the pathways that guides the development and growth of the body. […] Noonan syndrome is caused by a fault in one of several genes. The commonest gene involved is called PTPN11 but there have now been around 15 genes discovered which may cause Noonan syndrome or a related disorder. […] In 2001, this link was narrowed down to a genetic change a mutation in the PTPN11 gene on chromosome 12, present in about half of patients with Noonan syndrome. […] The most common genetic cause of Noonan syndrome is a mutation in a gene called PTPN11. This was discovered in 2001 and, since then, other genes have been linked to the condition. […] A mutation in PTPN11 occurs in about 50% of people with Noonan syndrome.
  • #3 FAQs • Genetics & RASopathies • Noonan Syndrome Association
    https://www.noonansyndrome.org.uk/faqs/genetics-rasopathies/
    SOS1 is the second most common causative gene, with variants occurring in 16-20% of individuals without PTPN11 variants. […] Mutations in other genes RAF1, RIT1, KRAS, NRAS, BRAF, MAP2K1, RRAS, RASA2, SOS2, LZTR1 are less common causes. […] In about 5-10% of cases, the genetic cause of Noonan syndrome is still not known.
  • #3 Orphanet: Noonan syndrome
    https://www.orpha.net/en/disease/detail/648
    NS is caused by mutations in PTPN11(12q24.13) seen in 50% of cases, SOS1(2p22.1) in 15%, RAF1(3p25.2), RIT1(1q22) and LZTR1(22q11.21), and less commonly in other genes associated with the RAS/MAPK signaling pathway. […] The clinical spectrum of NS may differ slightly between causative genes, and some forms have been described as ”Noonan like” (NS-like disorder with juvenile myelomonocytic leukemia and NS-like disorder with loose anagen hair).
  • #3 NOONAN SYNDROME
    https://medicover-genetics.com/product/noonan-syndrome/
    Noonan syndrome is an autosomal dominant inherited disorder with a broad, variable spectrum of symptoms, including facial dysmorphia, short stature, chest deformities and heart defects. It belongs to a group of cardiovascular conditions known as RASopathies, and in 50% of cases is due to pathogenic variants in the PTPN11 gene. […] The PTPN11 gene, which codes for a cytoplasmic protein tyrosine phosphatase (SHP-2), is the gene mainly affected in Noonan syndrome. Pathogenic variants in the PTPN11 gene, which almost exclusively lead to amino acid exchanges, are the molecular cause in about 50% of all Noonan patients investigated so far. […] Pathogenic variants have currently been identified in several other genes, including the RASERK-MAP kinase signal transduction in Noonan syndrome. Mutations in the SOS1 (Son of Sevenless) gene were detected in up to 15% of Noonan patients who did not have a mutation in the PTPN11 gene. Pathogenic variants in the RAF1 gene could be identified in about 8% of Noonan patients. […] In about 25% of all patients with Noonan syndrome, no causative variant can be detected in the genes that are currently known.
  • #3 Noonan syndrome: Causes, symptoms, and management
    https://www.medicalnewstoday.com/articles/179200
    Noonan syndrome is caused by an abnormality or mutation in one of several genes. […] The faulty gene associated with Noonan syndrome can be inherited from a parent. Approximately 50 percent of people with the condition have an affected parent. The parent carrying the genetic abnormality may or may not have any obvious features of the disorder. […] A new mutation that randomly occurs in children without any genetic predisposition. […] Having a parent with Noonan syndrome is the greatest risk factor for development of the condition. The risk of passing the defective gene from parent to child is 50 percent for each pregnancy.
  • #3 Noonan Syndrome: Symptoms, Diagnosis, Treatment, and More
    https://www.healthline.com/health/childrens-health/noonan-syndrome
    Noonan syndrome is a genetic condition that affects around 1 in every 1,0002,500 people. […] Noonan syndrome may result from any of eight different gene mutations and can be inherited from a parent who carries an affected gene (referred to as autosomal dominant inheritance). However, it may also be spontaneous, meaning it can happen at random without any family history. […] There are eight gene mutations that can be linked to the syndrome. These mutations in these five genes are most associated with the disorder: PTPN11, SOS1, RIT1, RAF1, KRAS. […] About 30 to 75 percent of people with Noonan syndrome inherit it from a parent who carries a gene mutation. This means that the parent with the gene mutation also actually has Noonan syndrome, too, but their symptoms may be so mild that they’ve never been diagnosed or may have been misdiagnosed. […] For other people with Noonan syndrome, the genetic mutation happens randomly. […] As far as what causes Noonan syndrome to begin with, scientists aren’t so sure. There’s currently no research to suggest that it’s caused by exposure to radiation, diet, or any other environmental factors.
  • #3 Noonan syndrome – UpToDate
    https://www.uptodate.com/contents/noonan-syndrome
    Noonan syndrome (NS) is a common autosomal-dominant condition that is associated with short stature and congenital heart disease (CHD), most often pulmonic stenosis. […] NS is nearly always an autosomal-dominant condition, and two-thirds of patients are the first affected person in their family due to a de novo pathogenic variant. […] Approximately 50 percent of patients have a pathogenic variant in protein tyrosine phosphatase, nonreceptor type 11 (PTPN11), with clustering of variants in specific codons. […] The genetic basis in the remainder of patients is usually a pathogenic variant in one of many other genes encoding a protein of the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway. […] Approximately 10 percent of patients tested do not have an identifiable pathogenic variant in any of the known genes, suggesting that additional genes may be involved.
  • #3 Noonan syndrome – UpToDate
    https://www.uptodate.com/contents/noonan-syndrome/print
    Noonan syndrome (NS) is a common autosomal-dominant condition that is associated with short stature and congenital heart disease (CHD), most often pulmonic stenosis. […] NS is nearly always an autosomal-dominant condition, and two-thirds of patients are the first affected person in their family due to a de novo pathogenic variant. […] Approximately 50 percent of patients have a pathogenic variant in protein tyrosine phosphatase, nonreceptor type 11 (PTPN11), with clustering of variants in specific codons. […] The genetic basis in the remainder of patients is usually a pathogenic variant in one of many other genes encoding a protein of the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway. […] Pathogenic variants in leucine zipper-like transcription regulator 1 (LZTR1) may underpin approximately 10 percent of NS, and these may show either autosomal-dominant or autosomal-recessive inheritance, with consequent implications for recurrence risk in future pregnancies in the family. […] Approximately 10 percent of patients tested do not have an identifiable pathogenic variant in any of the known genes, suggesting that additional genes may be involved.
  • #3 Noonan Syndrome | Symptoms, Diagnosis & Treatment
    https://www.cincinnatichildrens.org/health/n/noonan-syndrome
    Noonan syndrome is a genetic condition with an incidence of 1 in 1,000 to 1 in 2,500 live births. […] Currently, around 60-70% of patients have an identifiable mutation in one of several genes that are known to cause Noonan syndrome. […] Noonan syndrome is an autosomal dominant condition. This means a change in only one copy of a gene known to cause the condition is enough to cause the observed features. […] Noonan syndrome is part of a group of related disorders caused by changes in genes linked with the Ras / MAPK pathway. […] Genetic syndromes caused by changes in genes of the Ras / MAPK pathway are referred to as RASopathies. Conditions in this group include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome and neurofibromatosis, among others.

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