CLINICAL REPORT: A 7-year-old boy presented with unexplained splenomegaly, attention deficit hyperactivity disorder, mild learning difficulties, easy bruising, mild thrombocytopenia, and subtle dysmorphic features. [eunetworkadultadhd.com]

A literature review revealed seven cases of Noonan syndrome presenting GCT, none of which were associated with JMML. [pubmed.ncbi.nlm.nih.gov]

Hypertrophic cardiomyopathy (obstructive or nonobstructive type) is present in up to 30% of patients and can present at birth or in infancy or childhood. [misc.medscape.com]

Acronym NSLL Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. [uniprot.org]

Both twins presented with somatic aberrations of chromosome 7 and mutations in PTPN11. [clinmedjournals.org]

• Short Stature

  […] neck ; Short stature ; Sparse hair ; Thick vermilion border ; Triangular face ; Webbed neck ; Wide intermamillary distance Associated Genes CBL (Withdrawn symbols: CBL2, RNF55, c-Cbl ) Mouse Orthologs Cbl (Withdrawn symbols: 4732447J05Rik, Cbl-2, cbl [mousephenotype.org]

  References Medication Summary Growth hormone may be used to treat short stature associated with Noonan syndrome. [misc.medscape.com]

  Almost 50% to 70% of people with Noonan Syndrome have short stature, according to NIH. Zaria was born with short stature. S he is estimated to be 4’6 ” at full grown heigh t. [scijourner.org]

  stature, skin and genital abnormalities, and mental retardation. [mysciencework.com]

  By adulthood about 1/3 of people with NS have normal height, but short stature remains more common. [flipper.diff.org]

• Developmental Delay

  Clinical features are highly variable, including facial dysmorphism, short neck, developmental delay, hyperextensible joints and thorax abnormalities with widely spaced nipples. [uniprot.org]

  Epicanthus ; Fine hair ; Frontal bossing ; Generalized hypotonia ; Global developmental delay ; Hypertelorism ; Joint hypermobility ; Joint laxity ; Juvenile myelomonocytic leukemia ; Long philtrum ; Low-set ears ; Lymphedema ; Macrotia ; Mitral regurgitation [mousephenotype.org]

  delay, postnatal growth retardation, and autoimmune phenomena. [rasopathiesnet.org]

  The investigators suggested that the improvement in performance IQ in individuals with Noonan syndrome points to a developmental delay in executive functioning that is outgrown in adulthood. [misc.medscape.com]

  Sotos and Weaver Syndromes Sotos syndrome is caused by heterozygous germline mutations in NSD1 and is characterized by a distinctive facial appearance, height and head circumference >97th percentile, advanced bone age, and developmental delay ( 46, 47 [clincancerres.aacrjournals.org]

• Developmental Disorder

  Noonan syndrome-like disorder is a developmental disorder resembling Noonan syndrome (NS1; 163950) and characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, and ectodermal and musculoskeletal [ncbi.nlm.nih.gov]

  In this book, internationally recognized experts review the most important advances regarding the group of human developmental disorders caused by constitutive dysregulation of the Ras-MAPK signalling pathway, including Noonan, cardiofaciocutaneous, LEOPARD [books.google.de]

  RASopathies are a class of developmental disorders caused by germline mutations in genes that encode for components or regulators of the Ras/ mitogen-activated protein kinase (MAPK) pathway. [radiopaedia.org]

  Mutations in PTPN11 cause Noonan syndrome (NS), a developmental disorder characterized by facial dysmorphisms, short stature, skeletal and haematological defects, and cardiovascular abnormalities. [structure.bmc.lu.se]

  Sara Ekvall Maria Wilbe Jovanna Dahlgren Eric Legius Arie van Haeringen Otto Westphal Göran Annerén Marie-Louise Bondeson Open Access Case report First Online: 14 October 2015 Abstract Background Noonan syndrome (NS), a heterogeneous developmental disorder [link.springer.com]

• Swelling

  Finally, there can be l ymphatic problems such as lymphedema in which there’s a buildup of lymph fluid in the feet resulting in swelling. [scijourner.org]

  […] collected cancer cells have fevers from infections have easy bruising or bleeding because the bone marrow doesn't make enough platelets (cells that help clotting) have bone and joint pain because the bone marrow is full of abnormal cells have belly pain and swelling [kidshealth.org]

  Your child may have swelling in the lymph nodes under the arms, in the groin, chest and in the neck. Leukemia cells may collect in the nodes, causing swelling. [danafarberbostonchildrens.org]

  Avoid secondhand smoke People with Noonan syndrome should watch closely for general signs or symptoms that could signal cancer: Unexplained weight loss Loss of appetite Pain in abdomen Blood in the stool or changes in bowel habits Aches, pains, lumps or swelling [stjude.org]

  Articulation difficulties Poor tongue control Limbs/extremities [ edit ] Bluntly ended fingers Extra padding on fingers and toes Edema of the back of hands and tops of feet Cubitus valgus (Wide carrying angle of the elbows) Skin [ edit ] Lymphedema (lymph swelling [en.wikipedia.org]

• Pulmonary Valve Stenosis

  valve stenosis (heart valve disorder in which blood does not flow through the heart properly) Hypertrophic cardiomyopathy (thickening of the heart muscle) Atrial septal defect (abnormal hole between the two sides of the heart) Blood clotting (coagulation [stjude.org]

  The diagnosis of Noonan syndrome is often made on clinical grounds, based on the presence of specific features, including: Short stature (less than the third percentile) Congenital heart defect Pulmonary valve stenosis (a heart valve disorder in which [chop.edu]

  valve stenosis is most common), abnormalities in the lymphatic system (e.g. lymphedematous legs and probably also the cause of the neck webbing), and mild mental retardation. [familialcancerdatabase.nl]

  valve stenosis. [1] The breast bone may be either protruding or be sunk while the spine may be abnormally curved. [1] Intelligence is often normal. [1] Complications of NS may include leukemia. [1] A number of genetic mutations can result in Noonan syndrome [en.wikipedia.org]

  The most common forms of congenital heart disease associated with this disorder include: - Pulmonary valve stenosis: often associated with a thickened and dysplastic valve. [flipper.diff.org]

• Cough

  Typical signs of JMML include: pallor (appearing pale), fever, infection, skin bleeding, and cough. Most children with JMML have an enlarged spleen and liver, which can lead to a distended abdomen. Many patients also have big lymph nodes. [jmmlfoundation.org]

  Physical findings include: Skin: eczema, xanthoma, cafe-au-lait spots, macular-papular rash Lymphadenopathy Hepatosplenomegaly Bleeding Respiratory symptoms: chronic tachypnea, cough, wheezing Fever, infection. [78stepshealth.us]

  […] category of myelodysplastic and myeloproliferative disorders. [1] Symptoms [ edit ] The following symptoms are typical ones which lead to testing for JMML, though children with JMML may exhibit any combination of them: pallor, fever, infection, bleeding, cough [en.wikipedia.org]

  Your child may have had several viral or bacterial infections over the past few weeks, and may show symptoms of an infection such as fever, runny nose and cough. Bone and joint pain. Your child may experience pain in his bones and joints. [danafarberbostonchildrens.org]

  Pallor, fatigue, weakness, fevers, and a dry cough are common symptoms of JMML. Pallor is specifically described as an abnormal paleness of the skin. [rarediseases.org]

• Vomiting

  After two months of chemo, more vomit that you could possibly imagine, and countless blood tests, Ezra’s JMML was in remission. BLOG: Researcher Targets Childhood Cancer With a Virus > Ezra and his family joining the fun at their local St. [stbaldricks.org]

  These problems include gastroesophageal reflux (severe heartburn), aspiration (inhaling food particles), vomiting and oral aversion (unwillingness to put things into the mouth). [stjude.org]

  However, people with CFC syndrome tend to have: Unique facial features (overall, a broad, long face with features that are sometimes described as “coarse”) More severe feeding problems (such as gastroesophageal reflux, aspiration, vomiting, and oral aversion [chop.edu]

  Gastrointestinal tract [ edit ] Failure to thrive from infancy to puberty (75%) Decreased appetite Digestive problems Frequent or forceful vomiting Swallowing difficulties Intestinal malrotation Need for a feeding tube Low gut motility Gastroparesis [en.wikipedia.org]

  Affected infants may also have feeding difficulties (poor sucking function, prolonged feeding time, recurrent vomiting and reflux), which typically get better by age 1 or 2. [flipper.diff.org]

• Nausea

  Anemia occurs when there are low levels of circulating red blood cells and may be associated with pallor, fatigue, nausea and lightheadedness. [rarediseases.org]

• Hepatomegaly

  […] with JMML may exhibit any combination of them: pallor, fever, infection, bleeding, cough, poor weight gain, a maculopapular rash (discolored but not raised, or small and raised but not containing pus), lymphadenopathy (enlarged lymph nodes), moderate hepatomegaly [en.wikipedia.org]

• Heart Disease

  She studied 833 patients at the congenital heart disease clinic, looking for other congenital abnormalities, and in 1963 presented a paper: "Associated non-cardiac malformations in children with congenital heart disease". [24] This described 9 children [en.wikipedia.org]

  […] distinct condition with a unique phenotype, due to common mechanisms of Ras/MAPK pathway dysregulation, there are clinical commonalities, many of which may evident as early as in the first year of life, including 1-5 : craniofacial dysmorphia congenital heart [radiopaedia.org]

  Congenital heart diseases in children with Noonan syndrome: an expanded cardiac spectrum with high prevalence of atrioventricular canal. J Pediatr 1999 ; 135 : 703 –6. [jmg.bmj.com]

  […] scrotum, granular cell tumor of the seminoma testicular Sertoli-Leydig cell tumor Wilms' tumor (nephroblastoma) Non-tumor features café au lait spots cubitus valgus developmental delay/mental deficiency/mental retardation ears, low-set epicanthal folds heart [familialcancerdatabase.nl]

• Pterygium Colli

  Last updated: 05 Jul 2013 Name: Noonan syndrome Synonym: Male Turner syndrome, Pterygium Colli syndrome, incl. [familialcancerdatabase.nl]

• Low Set Ears

  The facial features consist of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Some patients manifest cardiac defects. [uniprot.org]

  Depressed nasal bridge ; Downslanted palpebral fissures ; Epicanthus ; Fine hair ; Frontal bossing ; Generalized hypotonia ; Global developmental delay ; Hypertelorism ; Joint hypermobility ; Joint laxity ; Juvenile myelomonocytic leukemia ; Long philtrum ; Low-set [mousephenotype.org]

  She also has curly hair, low-set ears that are rotated backwards, a short neck, pointed chin, Valvular Pulmonary Stenosis, a hole in her heart and widely spaced eyes that are a blueish-gray tint. [scijourner.org]

  […] of the eye) Ptosis (drooping of the eyelids) Proptosis (bulging eyes) Refractive visual errors Strabismus (inward or outward turning of the eyes) Nystagmus (jerking movement of the eyes) Nose [ edit ] Small, upturned nose Ears and hearing [ edit ] Low-set [en.wikipedia.org]

  The eyes may have epicanthal folds (skin folds of the upper eyelid that partially cover the inner corners of the eyes) and thick or droopy eyelids Low-set ears that are rotated backward or are unusually fleshy Broad neck or webbed neck Short stature [stjude.org]

• Hypertelorism

  The facial features consist of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Some patients manifest cardiac defects. [uniprot.org]

  […] myelomonocytic leukemia Clinical features : Imported from Human Phenotype Ontology (HPO) Abnormality of blood and blood-forming tissues Juvenile myelomonocytic leukemia Abnormality of head or neck Downslanted palpebral fissures Epicanthus Frontal bossing Hypertelorism [familydiagnosis.com]

  Chylothorax ; Cryptorchidism ; Cubitus valgus ; Deep philtrum ; Delayed speech and language development ; Depressed nasal bridge ; Downslanted palpebral fissures ; Epicanthus ; Fine hair ; Frontal bossing ; Generalized hypotonia ; Global developmental delay ; Hypertelorism [mousephenotype.org]

  Noonan produced a paper entitled "Hypertelorism with Turner Phenotype" in 1968, [25] and in 1971 at the Symposium of Cardiovascular defects, the name 'Noonan syndrome' became officially recognized. [en.wikipedia.org]

  At the age of 62 years, he has the following features of NS (Fig. 2a – c ): slight macrocephaly (61 cm, +2 SDS), bilateral ptosis, hypertelorism and down-slanting palpebral fissures. He also has curly hair and lentigines on his back. [link.springer.com]

• Short Neck

  Clinical features are highly variable, including facial dysmorphism, short neck, developmental delay, hyperextensible joints and thorax abnormalities with widely spaced nipples. [uniprot.org]

  neck ; Short stature ; Sparse hair ; Thick vermilion border ; Triangular face ; Webbed neck ; Wide intermamillary distance Associated Genes CBL (Withdrawn symbols: CBL2, RNF55, c-Cbl ) Mouse Orthologs Cbl (Withdrawn symbols: 4732447J05Rik, Cbl-2, cbl [mousephenotype.org]

  Excess skin on the back of the neck Low hairline at the nape of the neck High hairline at the front of the head Large head Triangular face shape Broad forehead Short neck, webbed neck Eyes [ edit ] Hypertelorism (widely set eyes) (95%) Epicanthal folds [en.wikipedia.org]

  She also has curly hair, low-set ears that are rotated backwards, a short neck, pointed chin, Valvular Pulmonary Stenosis, a hole in her heart and widely spaced eyes that are a blueish-gray tint. [scijourner.org]

  neck/webbed neck -low hairline at the nape of the neck Nevertheless, the phenotypical expression is highly variable and these facial features may change with age. [flipper.diff.org]

• Cryptorchidism

  MUTATION-ASSOCIATED SYNDROME, CBL SYNDROME Classification cardiac, cardiac malformation, developmental, genetic, neoplastic, neurological Phenotypes Aortic valve stenosis ; Autosomal dominant inheritance ; Bicuspid aortic valve ; Cafe-au-lait spot ; Chylothorax ; Cryptorchidism [mousephenotype.org]

  Besides JMML predisposition, germline CBL mutation defines a new dominant genetic condition with a markedly variable phenotype combining dysmorphic features, hyperpigmented skin lesions, cryptorchidism, cardiopathy, neurological lesions, developmental [rasopathiesnet.org]

  Cryptorchidism adversely affects male fertility. Men with Noonan syndrome are however likely to be fertile if they have normally descended testes. [flipper.diff.org]

  The most characteristic features of this syndrome are craniofacial dysmorphy, short stature, cardiovascular defects, bone and skeletal defects, as well as delayed puberty and cryptorchidism in males. [news-medical.net]

  […] hole between the two sides of the heart) Blood clotting (coagulation) defects Unusual shape of the chest, such as superior pectus carinatum (protruding chest) or inferior pectus excavatum (sunken chest) Low-set nipples Undescended testicles in males (cryptorchidism [stjude.org]

Moreover, before any patient with Noonan syndrome can undergo a surgical procedure, a full hematologic workup must be performed. If full phenotypic expression is not apparent, karyotyping may be necessary. [misc.medscape.com]

There is no recommendation for tumor surveillance at this time, but clinical vigilance and workup of potential tumor-related symptoms, especially for NBL, are suggested ( 61, 65 ). [clincancerres.aacrjournals.org]

[…] pallor, fever and skin rash, peripheral blood monocyte counts >1x109/L, bone marrow blast counts < 20% and the absence of BCR-ABL1 rearrangements are usually indicative of JMML [2], yet diagnosis can be established with certainty only after laboratory workup [clinmedjournals.org]

Clinical Testing and Workup A complete blood count (CBC) can be taken to evaluate the size, number, and maturity of blood cells. In JMML, the CBC frequently reveals high levels of white blood cells and low levels of red blood cells and platelets. [rarediseases.org]

See also the following treatment articles: Treatments for Noonan syndrome Treatments for Juvenile myelomonocytic leukemia Causes See also causal information: Causes of Noonan syndrome Causes of Juvenile myelomonocytic leukemia Similar Topic Articles [familydiagnosis.com]

Despite advances in treatment, JMML remains difficult to cure. Without treatment, the five-year survival rate is dismal (about 5%). [danafarberbostonchildrens.org]

Treatment Chemotherapy (the use of drugs to kill cancer cells) may be used to temporarily control JMML. However, effective treatment of JMML usually requires a stem cell (bone marrow) transplant. [rchsd.org]

The COG JMML study includes splenectomy as a standard component of treatment for all clinically stable patients. [en.wikipedia.org]

What conventional treatment approaches are employed in JMML? One unresolved question in JMML is the role of pretransplant chemotherapy. [hematology.org]

Prognosis [ edit ] Prognosis refers to how well a patient is expected to respond to treatment based on their individual characteristics at time of diagnosis. [en.wikipedia.org]

Detailed discussion of the specific treatment and prognosis of each RASopathy can be found in the individual articles (see above). Related Radiopaedia articles Promoted articles (advertising) [radiopaedia.org]

Prognosis Adverse factors include: Age at diagnosis: 2 years or more High fetal hemoglobin level at diagnosis Platelet count below 33,000/mm3 at diagnosis (considered to be the strongest indicator of prognosis). [78stepshealth.us]

Subclonal mutations in SETBP1 confer a poor prognosis in juvenile myelomonocytic leukemia. Blood. 2015;125:516-524. Cseh A, Niemeyer CM, Yoshimi A, et al. [hematology.org]

At the beginning, the prognosis looked good. We remember optimistic words from doctors like, “He looks great! This all will probably clear up on its own.” [stbaldricks.org]

Publication type, MeSH terms Publication type Review MeSH terms Humans Leukemia, Myelomonocytic, Chronic/classification* Leukemia, Myelomonocytic, Chronic/diagnosis Leukemia, Myelomonocytic, Chronic/drug therapy Leukemia, Myelomonocytic, Chronic/etiology [ncbi.nlm.nih.gov]

RIT1 represents a minor etiology for NS, explaining about 3% of cases. [nature.com]

Epidemiological studies from Denmark and British Columbia show a JMML incidence of 1.2 cases per million children per year. A lower incidence of 0.6 cases per million children per year has been reported in the United Kingdom. [jmmlfoundation.org]

Juvenile Myelomonocytic Leukemia Last Updated on Tue, 20 Sep 2016 | Bone Marrow Epidemiology Incidence: 1.2 per million children per year Median age at diagnosis: 1.8 years; 35% below 1 year of age, and only 4% above 5 years of age Male:female ratio of [78stepshealth.us]

EPIDEMIOLOGY Noonan syndrome is characterized by marked variable expressivity, which makes it difficult to identify mildly affected individuals. The overall incidence is believed to be between 1/1000 and 1/2500 live births. [flipper.diff.org]

References Epidemiology Frequency United States The incidence of Noonan syndrome is estimated to be 1 case per 1000 to 1 case per 2500 live births. International The incidence of Noonan syndrome appears to be consistent worldwide. [misc.medscape.com]

The final chapter covers the critical area of treatment including prospects emerging from an improved understanding of the pathophysiology of these disorders. [books.google.de]

Skeletal, neurologic, genitourinary, lymphatic, eye, and skin findings may be present to varying degrees. [1, 2] References Pathophysiology The pathophysiology of Noonan syndrome is not fully understood but is associated with mutations in genes that are [misc.medscape.com]

The first clue to this pathophysiology was the identification of gain-of-function mutations in the PTPN11 gene (OMIM 176876) in 40% of NS patients. 6 Several other genes involved in the RAS/MAPK cascade were later found to explain smaller subgroups of [nature.com]

It’s important to understand that there’s nothing you could have done or avoided doing that would have prevented your child’s cancer from developing. [danafarberbostonchildrens.org]

After bone marrow transplant, reducing ongoing immunosuppressive therapy has worked successfully to reverse the course of a bone marrow with a dropping donor percentage [ clarification needed ] and to prevent a relapse. [en.wikipedia.org]

For example, antibiotics may be given to help prevent or fight infections. Investigational Therapies Targeted therapies are being studied for the treatment of children with JMML. [rarediseases.org]

Finally, cancer prevention strategies remain an objective for future research. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. Received March 3, 2017. Revision received April 24, 2017. [clincancerres.aacrjournals.org]

References Deterrence/Prevention If a causative mutation is found in patients, parental studies should be offered in order to distinguish familial cases from sporadic ones. [misc.medscape.com]