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Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia(NSLL)

MedGen UID:
462153
Concept ID:
C3150803
Disease or Syndrome
Synonyms: CBL MUTATION-ASSOCIATED SYNDROME; CBL SYNDROME; NOONAN SYNDROME-LIKE DISORDER WITHOUT JUVENILE MYELOMONOCYTIC LEUKEMIA; NSLL
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): CBL (11q23.3)
OMIM®: 613563

Definition

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 anomalies. There is extensive phenotypic heterogeneity and variable expressivity (summary by Martinelli et al., 2010). Patients with heterozygous germline CBL mutations have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia (JMML; 607785), as also seen in patients with Noonan syndrome (summary by Niemeyer et al., 2010). [from OMIM]

Clinical features

Aortic valve stenosis
MedGen UID:
1621
Concept ID:
C0003507
Disease or Syndrome
A pathological constriction that can occur above (supravalvular stenosis), below (subvalvular stenosis), or at the AORTIC VALVE. It is characterized by restricted outflow from the LEFT VENTRICLE into the AORTA.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
Drooping of the upper lid due to deficient development or paralysis of the levator palpebrae muscle.
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (145410), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Mitral regurgitation
MedGen UID:
7670
Concept ID:
C0026266
Finding
An abnormality of the mitral valve characterized by insufficiency or incompetence of the mitral valve resulting in retrograde leaking of blood through the mitral valve upon ventricular contraction.
Joint laxity
MedGen UID:
39439
Concept ID:
C0086437
Pathologic Function
Lack of stability of a joint.
Bicuspid aortic valve
MedGen UID:
57436
Concept ID:
C0149630
Congenital Abnormality
A congenital anomaly in which the aortic valve has two leaflets. It is associated with mutations in the NOTCH1 gene or the SMAD6 gene, encoding neurogenic locus notch homolog protein 1 and mothers against decapentaplegic homolog 6, respectively. It is a clinically heterogeneous condition, with a high incidence of aortic valve and ascending aortic complications requiring surgery.
Macrotia
MedGen UID:
488785
Concept ID:
C0152421
Congenital Abnormality
Median longitudinal ear length greater than two standard deviations above the mean and median ear width greater than two standard deviations above the mean (objective); or, apparent increase in length and width of the pinna (subjective).
Cubitus valgus
MedGen UID:
490152
Concept ID:
C0158465
Acquired Abnormality
Abnormal positioning in which the elbows are turned out.
Webbed neck
MedGen UID:
113154
Concept ID:
C0221217
Congenital Abnormality
A congenital, usually bilateral, thick web-like fold of skin that extends from the acromion to the mastoid process. This deformity is associated with Turner Syndrome and Noonan Syndrome.
Cafe-au-lait spot
MedGen UID:
113157
Concept ID:
C0221263
Finding
A light brown, sharply demarcated skin patch. It is a manifestation of neurofibromatosis type 1 and McCune-Albright syndrome.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
A skeletal deformity characterized by an unusually prominent forehead. Causes include acromegaly, Hurler syndrome, Silver-Russell syndrome, and thalassemia major.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Juvenile myelomonocytic leukemia
MedGen UID:
138109
Concept ID:
C0349639
Neoplastic Process
Juvenile myelomonocytic leukemia is an aggressive pediatric myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD) characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny (Loh et al., 2009). JMML constitutes approximately 30% of childhood cases of myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999). Although JMML is a progressive and often rapidly fatal disease without hematopoietic stem cell transplantation (HSCT), some patients have been shown to have a prolonged and stable clinical course without HSCT (Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a similar disorder with later onset. Both JMML and CMML have a high frequency of mutations affecting the RAS signaling pathway and show hypersensitivity to stimulation with GM-CSF, which causes STAT5 (601511) hyperphosphorylation (Loh et al., 2009). Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due to somatic mutations in the PTPN11 (176876), KRAS (190070), and NRAS (164790) genes. Additionally, both germline and somatic mutations in the CBL gene have been found in patients with JMML, indicating a frequency of 10 to 15% of JMML patients overall (Loh et al., 2009). Somatic disruptions of the GRAF gene (ARHGAP26; 605370) have also been found in patients with JMML. About 10 to 15% of JMML cases arise in children with neurofibromatosis type I (NF1; 162200) due to germline mutations in the NF1 gene (613113). In addition, patients with Noonan syndrome (NS1, 163950; NS3, 609942) or Noonan syndrome-like disorder (NSLL; 613563) due to germline mutations in the PTPN11, KRAS2, and CBL genes, respectively, also have an increased risk of developing JMML. Genetic Heterogeneity of Chronic Myelomonocytic Leukemia Somatic mutations in the CBL, ASXL1 (612990), TET2 (612839), and SF3B1 (605590) genes have been found in patients with CMML.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Fine hair
MedGen UID:
98401
Concept ID:
C0423867
Finding
Hair that is fine or thin to the touch.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Wide intermamillary distance
MedGen UID:
473489
Concept ID:
C1827524
Finding
A larger than usual distance between the left and right nipple.
Triangular face
MedGen UID:
324383
Concept ID:
C1835884
Finding
Facial contour, as viewed from the front, triangular in shape, with breadth at the temples and tapering to a narrow chin.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Thick vermilion border
MedGen UID:
332232
Concept ID:
C1836543
Finding
Increased width of the skin of vermilion border region of upper lip.
Sparse hair
MedGen UID:
332942
Concept ID:
C1837770
Finding
Reduced density of hairs.
Deep philtrum
MedGen UID:
374311
Concept ID:
C1839797
Finding
Accentuated, prominent philtral ridges giving rise to an exaggerated groove in the midline between the nasal base and upper vermillion border.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The ability of a joint to move beyond its normal range of motion.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Long philtrum
MedGen UID:
351278
Concept ID:
C1865014
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.
Pectus excavatum
MedGen UID:
781174
Concept ID:
C2051831
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.

Recent clinical studies

Etiology

Coe RR, McKinnon ML, Tarailo-Graovac M, Ross CJ, Wasserman WW, Friedman JM, Rogers PC, van Karnebeek CDM
Eur J Med Genet 2017 Jul;60(7):374-379. Epub 2017 Apr 13 doi: 10.1016/j.ejmg.2017.04.009. PMID: 28414188
Muraoka M, Okuma C, Kanamitsu K, Ishida H, Kanazawa Y, Washio K, Seki M, Kato M, Takita J, Sato Y, Ogawa S, Tsukahara H, Oda M, Shimada A
J Hum Genet 2016 Jun;61(6):523-6. Epub 2016 Feb 25 doi: 10.1038/jhg.2016.8. PMID: 26911351

Diagnosis

Coe RR, McKinnon ML, Tarailo-Graovac M, Ross CJ, Wasserman WW, Friedman JM, Rogers PC, van Karnebeek CDM
Eur J Med Genet 2017 Jul;60(7):374-379. Epub 2017 Apr 13 doi: 10.1016/j.ejmg.2017.04.009. PMID: 28414188
Muraoka M, Okuma C, Kanamitsu K, Ishida H, Kanazawa Y, Washio K, Seki M, Kato M, Takita J, Sato Y, Ogawa S, Tsukahara H, Oda M, Shimada A
J Hum Genet 2016 Jun;61(6):523-6. Epub 2016 Feb 25 doi: 10.1038/jhg.2016.8. PMID: 26911351

Therapy

Muraoka M, Okuma C, Kanamitsu K, Ishida H, Kanazawa Y, Washio K, Seki M, Kato M, Takita J, Sato Y, Ogawa S, Tsukahara H, Oda M, Shimada A
J Hum Genet 2016 Jun;61(6):523-6. Epub 2016 Feb 25 doi: 10.1038/jhg.2016.8. PMID: 26911351

Prognosis

Muraoka M, Okuma C, Kanamitsu K, Ishida H, Kanazawa Y, Washio K, Seki M, Kato M, Takita J, Sato Y, Ogawa S, Tsukahara H, Oda M, Shimada A
J Hum Genet 2016 Jun;61(6):523-6. Epub 2016 Feb 25 doi: 10.1038/jhg.2016.8. PMID: 26911351

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