Phenotypic variability associated with the invariant <i>SHOC2</i> c.4A&gt;G (p.Ser2Gly) missense mutation

Baldassarre, Giuseppina; Mussa, Alessandro; Banaudi, Elena; Rossi, Cesare; Tartaglia, Marco; Silengo, Margherita; Ferrero, Giovanni Battista

doi:10.1002/ajmg.a.36697

Cited by 24 publications

(26 citation statements)

References 30 publications

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“…Generalized hyperpigmentation was noted in 15%, almost always in adult patients, and it appeared highly specific to PTPN11 ‐NSML in our study as it was always absent in other NS genotypes. These results were consistent with previous studies, except for SOS1 ‐NS and SHOC2 ‐NS, for which hyperpigmentation was noted for an average of 49% and 68% of cases, respectively . Our strict definition of generalized hyperpigmentation excluded localized or partial forms of hyperpigmentation, and the inclusion of patients with an ethnic origin conferring a familial medium or dark skin colour could explain these results.…”

Section: Discussionsupporting

confidence: 92%

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Bessis

Miquel

Bourrat³

et al. 2019

Br J Dermatol

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Summary Background Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. Objectives To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype–genotype correlations with or without the presence of PTPN11 mutations. Methods We performed a large 4‐year, prospective, multicentric, collaborative dermatological and genetic study. Results Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11‐NS, 34 patients with PTPN11‐NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11‐NS, present in 53·8% of patients. Multiple lentigines and café‐au‐lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. Conclusions The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

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Section: Discussionsupporting

confidence: 92%

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Bessis

Miquel

Bourrat³

et al. 2019

Br J Dermatol

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“…One started GH treatment (Patient 1), but no growth data after treatment initiation were available at the time of this report. Ocular abnormalities occurred in three individuals reported here, these are common in patients with NS‐LAH [Baldassarre et al, ]. Relative or absolute macrocephaly with mildly enlarged ventricles and arachnoid spaces are seen in NS‐LAH [Gripp et al, ] and were present in all patients reported here.…”

Section: Discussionmentioning

confidence: 69%

“…These characteristics are suggestive of loose anagen hair, an abnormality resulting from abnormal root sheaths. Loose anagen hair is seen in most individuals with a recurrent point mutation in SHOC2 resulting in Noonan syndrome with loose anagen hair (NS‐LAH) [Cordeddu et al, ; Gripp et al, ; Baldassarre et al, ], in Costello syndrome due to the HRAS p.G13C mutation [Gripp et al, ] and rarely in cardio‐facio‐cutaneous syndrome [Wong Ramsey et al, ]. Short stature, often due to growth hormone deficiency, is common in NS‐LAH.…”

Section: Discussionmentioning

confidence: 99%

A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair

Gripp

Aldinger²,

Bennett

et al. 2016

American J of Med Genetics Pt A

112

114

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Noonan syndrome is a rasopathy caused by mutations in multiple genes encoding components of the RAS/MAPK pathway. Despite its variable phenotype, limited genotype-phenotype correlations exist. Noonan syndrome with loose anagen hair (NS-LAH) is characterized by its distinctive hair anomalies, developmental differences and structural brain abnormalities and is caused by a single recurrent missense SHOC2 mutation. SHOC2 forms a complex with protein phosphatase 1 (PP1C). Protein phosphatases counterbalance kinases and control activation of signaling proteins, such as the mitogen activated protein kinases of the RAS/MAPK pathway. Here we report four patients with de novo missense mutations in protein phosphatase 1 catalytic subunit beta (PPP1CB), sharing a recognizable phenotype. Three individuals had the recurrent PPP1CB c.146G>C, p.Pro49Arg mutation, the fourth had a c.166G>C, p.Ala56Pro change. All had relative or absolute macrocephaly, low-set and posteriorly angulated ears and developmental delay. Slow growing and/or sparse hair and/or an unruly hair texture was present in all. Three individuals had feeding difficulties requiring feeding tubes. One of two males had cryptorchidism, another had pectus excavatum. Short stature was present in three. A female with the recurrent mutation had a Dandy-Walker malformation and optic nerve hypoplasia. Mild ventriculomegaly occurred in all, cerebellar tonsillar ectopia was seen in two and progressed to Chiari 1 malformation in one individual. Based on the combination of phenotypic findings and PPP1CB’s effect on RAF dephosphorylation within the RAS/MAPK pathway, this novel condition can be considered a rasopathy, most similar to NS-LAH. Collectively, these mutations meet the standardized criteria for pathogenicity.

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“…20,59 In following case reports on individuals with the SHOC2 p.S2G mutation, phenotypic variability was noted. 60 Costello syndrome is a rare RASopathy that is characterized by distinctive facial features, including full lips, a large mouth and a full nasal tip; soft skin with deep palmer and planter creases, failure to thrive, mild to severe intellectual disability and increased risk of malignant tumors are also characteristics of these patients. Germline activating mutations in HRAS (G12S in~80% of Costello syndrome patients) have been identified in individuals with Costello syndrome.…”

Section: Rasa1mentioning

confidence: 99%

Recent advances in RASopathies

et al. 2015

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RASopathies or RAS/mitogen-activated protein kinase (MAPK) syndromes are a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the RAS/MAPK signaling pathway. These disorders include neurofibromatosis type I, Legius syndrome, Noonan syndrome, Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome), Costello syndrome, cardiofaciocutaneous (CFC) syndrome, Noonan-like syndrome, hereditary gingival fibromatosis and capillary malformation-arteriovenous malformation. Recently, novel gene variants, including RIT1, RRAS, RASA2, A2ML1, SOS2 and LZTR1, have been shown to be associated with RASopathies, further expanding the disease entity. Although further analysis will be needed, these findings will help to better elucidate an understanding of the pathogenesis of these disorders and will aid in the development of potential therapeutic approaches. In this review, we summarize the novel genes that have been reported to be associated with RASopathies and highlight the cardiovascular abnormalities that may arise in affected individuals.

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Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation

Cited by 24 publications

References 30 publications

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair

Recent advances in RASopathies

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