Noonan syndrome-like disorder with juvenile myelomonocytic leukemia

General Information (adopted from Orphanet):

Synonyms, Signs: CBL MUTATION-ASSOCIATED SYNDROME
CBL SYNDROME
NSLL
Noonan syndrome-like disorder with JMML
Number of Symptoms 100
OrphanetNr: 363972
OMIM Id: 613563
ICD-10: Q87.1
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: No data available.
Inheritance: Autosomal dominant
20543203 [IBIS]
Age of onset: Neonatal
25358541 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Noonan syndrome and Noonan-related syndrome
 -Rare cardiac disease
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
Polymalformative genetic syndrome with increased risk of developing cancer
 -Rare genetic disease
 -Rare oncologic disease

Comment:

Noonan syndrome-like disorder with juvenile myelomonocytic leukemia (NSLL) belongs to the group of RASopathies characterized by abnormalities in the RAS-MAPK signaling pathway, which is known to play a major role in lymphangiogenesis. NSLL is caused by heterozygous germline mutations in the Casitas B-cell lymphoma (CBL) gene. (PMID:25358541)

Symptom Information: Sort by abundance 

1
 (HPO:0011968) Feeding difficulties 25358541 IBIS 240 / 7739
2
 (HPO:0008872) Feeding difficulties in infancy 25358541 IBIS 153 / 7739
3
 (HPO:0001892) Abnormal bleeding 25358541 IBIS 85 / 7739
4
 (HPO:0000421) Epistaxis 25358541 IBIS 85 / 7739
5
 (HPO:0000978) Bruising susceptibility 25358541 IBIS 123 / 7739
6
 (HPO:0000316) Hypertelorism 25358541 IBIS 644 / 7739
7
 (HPO:0000483) Astigmatism 25358541 IBIS 67 / 7739
8
 (HPO:0000486) Strabismus 25358541 IBIS 576 / 7739
9
 (HPO:0000565) Esotropia 25358541 IBIS 58 / 7739
10
 (HPO:0000540) Hypermetropia 25358541 IBIS 99 / 7739
11
 (HPO:0000508) Ptosis 25358541 IBIS 459 / 7739
12
 (HPO:0001488) Bilateral ptosis 25358541 IBIS 42 / 7739
13
 (HPO:0006521) Pulmonary lymphangiectasia 25358541 IBIS 6 / 7739
14
 (HPO:0002202) Pleural effusion Occasional [IBIS] 27% (n=11) 25358541 IBIS 22 / 7739
15
 (HPO:0010310) Chylothorax rare [HPO:skoehler] 25358541 IBIS 6 / 7739
16
 (HPO:0002098) Respiratory distress 25358541 IBIS 75 / 7739
17
 (HPO:0004322) Short stature Frequent [IBIS] rare [HPO:skoehler] 36% (n=28) 25358541 IBIS 1232 / 7739
18
 (HPO:0001531) Failure to thrive in infancy 25358541 IBIS 26 / 7739
19
 (HPO:0012311) Monocytosis 25358541 IBIS 10 / 7739
20
 (HPO:0001631) Atria septal defect 25358541 IBIS 274 / 7739
21
 (HPO:0001650) Aortic valve stenosis 20619386 IBIS 49 / 7739
22
 (HPO:0001647) Bicuspid aortic valve 20619386 IBIS 34 / 7739
23
 (HPO:0001638) Cardiomyopathy Rare [IBIS] 7% (n=28) 25358541 IBIS 192 / 7739
24
 (HPO:0001642) Pulmonic stenosis 25358541 IBIS 89 / 7739
25
 (HPO:0000822) Hypertension Occasional [IBIS] 14% (n=28) 25358541 IBIS 224 / 7739
26
 (HPO:0012201) Reduced prothrombin activity 25358541 IBIS 4 / 7739
27
 (HPO:0008321) Reduced factor X activity 25358541 IBIS 4 / 7739
28
 (HPO:0011858) Reduced factor IX activity 25358541 IBIS 7 / 7739
29
 (HPO:0004841) Reduced factor XII activity 25358541 IBIS 4 / 7739
30
 (HPO:0004840) Hypochromic microcytic anemia 25358541 IBIS 15 / 7739
31
 (HPO:0000297) Facial hypotonia 25358541 IBIS 8 / 7739
32
 (HPO:0000969) Edema 25358541 IBIS 117 / 7739
33
 (HPO:0001004) Lymphedema rare [HPO:skoehler] 25358541 IBIS 62 / 7739
34
 (HPO:0012209) Juvenile myelomonocytic leukemia Frequent [IBIS] 75% (n=28) 25358541 IBIS 3 / 7739
35
 (HPO:0003199) Decreased muscle mass 25358541 IBIS 27 / 7739
36
 (HPO:0003198) Myopathy 25358541 IBIS 151 / 7739
37
 (HPO:0001252) Muscular hypotonia 25358541 IBIS 990 / 7739
38
 (HPO:0000473) Torticollis 25358541 IBIS 42 / 7739
39
 (HPO:0001263) Global developmental delay Frequent [IBIS] 25358541 IBIS 853 / 7739
40
 (HPO:0001270) Motor delay Frequent [IBIS] 25358541 IBIS 322 / 7739
41
 (HPO:0000750) Delayed speech and language development Frequent [IBIS] 25358541 IBIS 197 / 7739
42
 (HPO:0001288) Gait disturbance 25358541 IBIS 318 / 7739
43
 (HPO:0001561) Polyhydramnios rare [HPO:skoehler] 25358541 IBIS 191 / 7739
44
 (HPO:0001212) Prominent fingertip pads 25358541 IBIS 12 / 7739
45
 (HPO:0009623) Proximal placement of thumb 25358541 IBIS 50 / 7739
46
 (HPO:0001837) Broad toe 25358541 IBIS 13 / 7739
47
 (HPO:0001760) Abnormality of the foot 25358541 IBIS 96 / 7739
48
 (HPO:0001385) Hip dysplasia 25358541 IBIS 242 / 7739
49
 (HPO:0007598) Bilateral single transverse palmar creases 25358541 IBIS 13 / 7739
50
 (HPO:0002967) Cubitus valgus 20619386 IBIS 49 / 7739
51
 (HPO:0002007) Frontal bossing 20694012 IBIS 366 / 7739
52
 (HPO:0000348) High forehead 25358541 IBIS 157 / 7739
53
 (HPO:0000256) Macrocephaly 25358541 IBIS 298 / 7739
54
 (HPO:0000252) Microcephaly Occasional [IBIS] 18% (n=11) 25358541 IBIS 832 / 7739
55
 (HPO:0011220) Prominent forehead 25358541 IBIS 137 / 7739
56
 (HPO:0000765) Abnormality of the thorax Frequent [IBIS] 64% (n=11) 25358541 IBIS 64 / 7739
57
 (HPO:0000768) Pectus carinatum 25358541 IBIS 136 / 7739
58
 (HPO:0000767) Pectus excavatum 25358541 IBIS 244 / 7739
59
 (HPO:0000470) Short neck 20619386 IBIS 345 / 7739
60
 (HPO:0001382) Joint hypermobility 20619386 IBIS 231 / 7739
61
 (HPO:0001388) Joint laxity 20619386 IBIS 117 / 7739
62
 (HPO:0008070) Sparse hair 25358541 IBIS 94 / 7739
63
 (HPO:0000534) Abnormality of the eyebrow 25358541 IBIS 39 / 7739
64
 (HPO:0002162) Low posterior hairline 25358541 IBIS 88 / 7739
65
 (HPO:0002020) Gastroesophageal reflux 25358541 IBIS 101 / 7739
66
 (HPO:0001081) Cholelithiasis 25358541 IBIS 36 / 7739
67
 (HPO:0001433) Hepatosplenomegaly 25358541 IBIS 78 / 7739
68
 (HPO:0001743) Abnormality of the spleen 25358541 IBIS 37 / 7739
69
 (HPO:0001744) Splenomegaly 25358541 IBIS 337 / 7739
70
 (HPO:0001541) Ascites 25358541 IBIS 94 / 7739
71
 (HPO:0000023) Inguinal hernia 25358541 IBIS 181 / 7739
72
 (HPO:0000028) Cryptorchidism Frequent [IBIS] 33% (n=12) 25358541 IBIS 347 / 7739
73
 (HPO:0000034) Hydrocele testis 25358541 IBIS 18 / 7739
74
 (HPO:0001999) Abnormal facial shape Very frequent [IBIS] 100% (n=11) 25358541 IBIS 169 / 7739
75
 (HPO:0000494) Downslanted palpebral fissures 25358541 IBIS 328 / 7739
76
 (HPO:0000325) Triangular face 20543203 IBIS 91 / 7739
77
 (HPO:0012471) Thick vermilion border 20543203 IBIS 115 / 7739
78
 (HPO:0002002) Deep philtrum 20543203 IBIS 42 / 7739
79
 (HPO:0000343) Long philtrum 20619386 IBIS 262 / 7739
80
 (HPO:0005280) Depressed nasal bridge 20694012 IBIS 381 / 7739
81
 (HPO:0000286) Epicanthus 25358541 IBIS 371 / 7739
82
 (HPO:0000465) Webbed neck 20619386 IBIS 81 / 7739
83
 (HPO:0000369) Low-set ears 25358541 IBIS 372 / 7739
84
 (HPO:0000368) Low-set, posteriorly rotated ears 25358541 IBIS 38 / 7739
85
 (HPO:0000358) Posteriorly rotated ears 20619386 IBIS 163 / 7739
86
 (HPO:0000957) Cafe-au-lait spot Occasional [IBIS] 29% (n=28) 25358541 IBIS 84 / 7739
87
 (HPO:0000953) Hyperpigmentation of the skin 25358541 IBIS 75 / 7739
88
 (HPO:0000961) Cyanosis 25358541 IBIS 60 / 7739
89
 (HPO:0001873) Thrombocytopenia 25358541 IBIS 224 / 7739
90
 (HPO:0001789) Hydrops fetalis 25358541 IBIS 63 / 7739
91
 (HPO:0030680) Abnormality of cardiovascular system morphology Frequent [IBIS] 64% (n=11) 25358541 IBIS 355 / 7739
92
 (HPO:0045026) Abnormality of the mediastinum 25358541 IBIS 6 / 7739
93
 (HPO:0012703) Abnormality of the subarachnoid space 25358541 IBIS 1 / 7739
94
 (HPO:0007036) Hypoplasia of olfactory tract 25358541 IBIS 2 / 7739
95
 (HPO:0012758) Neurodevelopmental delay Frequent [IBIS] 25358541 IBIS 949 / 7739
96
 (MedDRA:10022840) Intraventricular haemorrhage 25358541 IBIS 1 / 7739
97
 (MedDRA:10066239) Mediastinal shift 25358541 IBIS 1 / 7739
98
 (MedDRA:10057471) Spleen palpable 25358541 IBIS 2 / 7739
99
 (OMIM) Hypoplasia of the optic chiasm 25358541 IBIS 2 / 7739
100
 (OMIM) Pes planovalgus 25358541 IBIS 2 / 7739

Associated genes:

CBL;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference
CBL rs267606706 pathogenic RCV000014822.24
CBL rs387906664 pathogenic RCV000022698.21
CBL rs387906665 pathogenic RCV000022699.21
CBL rs387906666 pathogenic RCV000022700.25

Additional Information:

Description: (OMIM) 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 ...
Clinical Description OMIM Martinelli et al. (2010) reported 4 unrelated probands, including 1 who met the diagnostic criteria for NS and 3 who had a phenotype reminiscent of Noonan syndrome, but without fulfilling the complete diagnostic criteria. Clinical features were highly ...
Molecular genetics OMIM Martinelli et al. (2010) identified 4 different heterozygous mutations in the CBL gene (165360.0001-165360.0004) in 4 unrelated probands with a Noonan syndrome-like disorder. Two of the mutations were de novo, and 2 were inherited from an affected father. ...