Noonan syndrome with multiple lentigines

General Information (adopted from Orphanet):

Synonyms, Signs: LEOPARD syndrome
Familial multiple lentigines syndrome
Cardiomyopathic lentiginosis
Number of Symptoms 36
OrphanetNr: 500
OMIM Id: 151100
611554
613707
ICD-10: Q87.8
UMLs: C0175704
C2931424
MeSH: C537116
D044542
MedDRA: 10062901
Snomed: 111306001
403537000

Prevalence, inheritance and age of onset:

Prevalence: 200 cases - PMID: 24775816 [IBIS]
Inheritance: Autosomal dominant
- PMID: 24775816 [IBIS]
Age of onset: All ages
- PMID: 24775816 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Genetic hyperpigmentation of the skin
 -Rare genetic disease
Genetic multiple congenital anomalies/dysmorphic syndrome without intellectual deficit
 -Rare genetic disease
Hyperpigmentation of the skin
 -Rare skin disease
Malformation syndrome with hamartosis
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
Malformation syndrome with skin/mucosae involvement
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
Multiple congenital anomalies/dysmorphic syndrome without intellectual deficit
 -Rare developmental defect during embryogenesis
Noonan syndrome and Noonan-related syndrome
 -Rare cardiac disease
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
Palpebral lentiginosis
 -Rare eye disease
 -Rare genetic disease
Syndromic genetic deafness
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare otorhinolaryngologic disease

Comment:

LS shares many features with Noonan-Syndrome, which is characterized by an association with congenital heart disease, short stature, and craniofacial malformations but does not usually include multiple lentigines and deafness among its manifestations.

Symptom Information: Sort by abundance 

1
(HPO:0000316) Hypertelorism Very frequent [IBIS] 100%(n=8) 16523510 IBIS 644 / 7739
2
(HPO:0001712) Left ventricular hypertrophy 23239957 IBIS 76 / 7739
3
(HPO:0001667) Right ventricular hypertrophy 23239957 IBIS 23 / 7739
4
(HPO:0001639) Hypertrophic cardiomyopathy Frequent [IBIS] 63%(n=19) 24775816 IBIS 137 / 7739
5
(HPO:0001642) Pulmonic stenosis Occasional [IBIS] 32%(n=19) 24775816 IBIS 89 / 7739
6
(HPO:0011675) Arrhythmia Frequent [IBIS] 75% 18505544 IBIS 226 / 7739
7
(HPO:0001716) Wolff-Parkinson-White syndrome Rare [IBIS] 5%(n=19) 24775816 IBIS 21 / 7739
8
(HPO:0011710) Bundle branch block 23239957 IBIS 14 / 7739
9
(HPO:0001252) Muscular hypotonia Frequent [IBIS] 63%(n=8) 16523510 IBIS 990 / 7739
10
(HPO:0001328) Specific learning disability Occasional [IBIS] 30% 18505544 IBIS 114 / 7739
11
(HPO:0001263) Global developmental delay Frequent [IBIS] 79%(n=19) 24775816 IBIS 853 / 7739
12
(HPO:0000303) Mandibular prognathia Rare [IBIS] 18505544 IBIS 179 / 7739
13
(HPO:0003691) Scapular winging 23239957 IBIS 51 / 7739
14
(HPO:0000768) Pectus carinatum Rare [IBIS] 5%(n=19) 24775816 IBIS 136 / 7739
15
(HPO:0000767) Pectus excavatum Occasional [IBIS] 26%(n=19) 24775816 IBIS 244 / 7739
16
(HPO:0000914) Shield chest Rare [IBIS] 5%(n=19) 24775816 IBIS 14 / 7739
17
(HPO:0002650) Scoliosis Rare [IBIS] 18505544 IBIS 705 / 7739
18
(HPO:0005692) Joint hyperflexibility Rare [IBIS] 18505544 IBIS 20 / 7739
19
(HPO:0000598) Abnormality of the ear Frequent [IBIS] 87%(n=8) 16523510 IBIS 98 / 7739
20
(HPO:0000823) Delayed puberty 18505544 IBIS 65 / 7739
21
(HPO:0000047) Hypospadias Occasional [Orphanet] 18505544 IBIS 250 / 7739
22
(HPO:0008689) Bilateral cryptorchidism 18505544 IBIS 38 / 7739
23
(HPO:0003241) External genital hypoplasia 18505544 IBIS 25 / 7739
24
(HPO:0008724) Hypoplasia of the ovary 18505544 IBIS 6 / 7739
25
(HPO:0012471) Thick vermilion border 18505544 IBIS 115 / 7739
26
(HPO:0005280) Depressed nasal bridge Frequent [IBIS] 18505544 IBIS 381 / 7739
27
(HPO:0000407) Sensorineural hearing impairment Occasional [IBIS] 20% 18505544 IBIS 524 / 7739
28
(HPO:0005989) Redundant neck skin 18505544 IBIS 40 / 7739
29
(HPO:0000465) Webbed neck Frequent [Orphanet] 18505544 IBIS 81 / 7739
30
(HPO:0000957) Cafe-au-lait spot Frequent [IBIS] 50% 18505544 IBIS 84 / 7739
31
(HPO:0001003) Multiple lentigines Frequent [IBIS] 79%(n=19) 24775816 IBIS 11 / 7739
32
(HPO:0000974) Hyperextensible skin Very frequent [Orphanet] 23239957 IBIS 59 / 7739
33
(HPO:0100678) Premature skin wrinkling Occasional [Orphanet] 23239957 IBIS 25 / 7739
34
(HPO:0000077) Abnormality of the kidney Rare [IBIS] 18505544 IBIS 73 / 7739
35
(HPO:0001510) Growth delay Frequent [IBIS] 18505544 IBIS 295 / 7739
36
(HPO:0030680) Abnormality of cardiovascular system morphology Frequent [IBIS] 42% 18505544 IBIS 355 / 7739

Associated genes:

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference
BRAF rs387906661 pathogenic RCV000055896.1
BRAF rs387906661 pathogenic RCV000022681.29
BRAF rs397507466 pathogenic RCV000055897.1
PTPN11 rs121918456 pathogenic RCV000055889.1
PTPN11 rs121918456 pathogenic RCV000055890.4
PTPN11 rs121918457 pathogenic RCV000055884.5
PTPN11 rs121918468 pathogenic RCV000037612.2
PTPN11 rs121918468 pathogenic RCV000055882.3
PTPN11 rs121918469 pathogenic RCV000055883.5
PTPN11 rs121918470 pathogenic RCV000014272.25
PTPN11 rs397507541 pathogenic RCV000055885.1
PTPN11 rs397507542 pathogenic RCV000055886.1
PTPN11 rs397507548 pathogenic RCV000055887.1
PTPN11 rs397507549 pathogenic RCV000055888.2
RAF1 rs80338796 pathogenic RCV000020509.1
RAF1 rs80338796 pathogenic RCV000014986.21
RAF1 rs80338797 pathogenic RCV000020508.1
RAF1 rs80338797 pathogenic RCV000014989.26
RAF1 rs80338798 pathogenic RCV000020506.1
RAF1 rs80338799 pathogenic RCV000020507.1

Additional Information:

Diagnosis GeneReviews The diagnosis of LEOPARD syndrome (LS) is made on clinical grounds, by observation of key features....
Clinical Description GeneReviews Males are more likely than females to be affected with LEOPARD syndrome (LS) [Voron et al 1976], either as a result of bias of ascertainment or preferential survival of affected male fetuses, as proposed for Noonan syndrome (NS) [Tartaglia et al 2004a]....
Genotype-Phenotype Correlations GeneReviews No clear-cut genotype-phenotype correlations have been observed among the PTPN11 mutations causing LS....
Differential Diagnosis GeneReviews Turner syndrome, found only in females, is distinguished from LEOPARD syndrome (LS) by demonstration of an X-chromosome abnormality on cytogenetic studies. The characteristic facial features are also distinct, and in Turner syndrome renal anomalies are more common, developmental delay is much less frequently found, and left-sided heart defects are the rule. ...
Management GeneReviews To establish the extent of disease in an individual diagnosed with LEOPARD syndrome (LS), the following evaluations are recommended:...
Molecular genetics GeneReviews Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....