Spectrum of Mutations in Noonan Syndrome and Their Correlation with Phenotypes

Lee, Beom Hee; Kim, Jae-Min; Jin, Hye Young; Kim, Gu-Hwan; Choi, Jin‐Ho; Yoo, Han‐Wook

doi:10.1016/j.jpeds.2011.05.024

Cited by 82 publications

(105 citation statements)

References 28 publications

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“…Gene defects in BRAF are responsible for 30-40% of cases of CFC. 11 We report a characteristic lymphatic phenotype associated with the Noonan and CFC spectrum of the RASopathies in a series of 11 cases. This is characterised by lower limb lymphoedema with genital oedema and lymphorrhoea (leakage of lymph or chyle from lymph blisters).…”

Section: Introductionmentioning

confidence: 92%

The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome

et al. 2015

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Section: Introductionmentioning

confidence: 92%

The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome

et al. 2015

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“…Activation of this pathway results in a number of overlapping syndromes, called 'rasopathies', including Noonan, LEOPARD, Costello, cardio-facio-cutaneous, and neurofibromatosis-Noonan syndrome, all characterized by postnatal growth failure of varying degree (156,157). Mutations in these genes can also cause short stature without obvious clinical features (158).…”

Section: Genetic Defects Of Intracellular Pathwaysmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

153

132

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The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T 3 /T 4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in w3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

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“…Neuropsychological functioning in individuals with NRAS, CBL, and RIT1 mutations is largely unknown. There is some evidence to suggest that individuals with KRAS and SHOC2 mutations may experience greater severity of neurological deficits and developmental delay compared to other children with a diagnosis of NS, with intellectual disability being relatively common (Lee et al 2011;Cesarini et al 2009;Alfieri et al 2014;Gripp et al 2013).…”

Section: Relationship Between Genotype and Neurocognitive Outcomesmentioning

confidence: 99%

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

Pierpont

2015

J Pediatr Neuropsychol

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Noonan syndrome (NS) is a relatively common genetic syndrome with variable features including short stature, congenital heart disease, distinctive facial characteristics, skeletal anomalies, and varying degrees of developmental delay. NS is caused by gene mutations in a cellular signaling pathway that is essential for typical growth and development. Research in the past few decades has revealed that individuals with NS have highly variable neurocognitive and behavioral outcomes. To a certain extent, variability in cognitive functioning depends on the particular gene where a mutation is found; additionally, factors related to medical severity and environmental effects contribute substantially to outcomes. This article contains a systematic review of research on neuropsychological features of NS, including cognition, motor development, language, memory, attention, visual perception, adaptive behavior, social skills, and mental health concerns. Given the wide variety of possible cognitive and behavioral complications associated with NS, it is recommended that clinical neuropsychological evaluation of cognitive, adaptive, and psychological domains of functioning should be standard of care for all individuals with NS. Suggested considerations for assessment of individuals with NS are provided. The paper concludes with recommendations for educational and therapeutic interventions, as well as suggestions for future research directions.

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Spectrum of Mutations in Noonan Syndrome and Their Correlation with Phenotypes

Cited by 82 publications

References 28 publications

The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome

The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

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