Síndrome de Noonan: actualización genética, clínica y de opciones terapéuticas

Carcavilla, Atilano; Suarez-Ortega, Larisa; Sánchez, Amparo Rodríguez; González‐Casado, Isabel; Ramón-Krauel, Marta; Labarta, José Ignacio; González, Sofı́a Quinteiro; Galán, Isolina Riaño; Zubicaray, Begoña Ezquieta; López-Siguero, Juan Pedro

doi:10.1016/j.anpedi.2020.04.008

Cited by 20 publications

(17 citation statements)

References 37 publications

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“…Its prevalence is estimated as 1 in 1000 to 2500 live births ( 3 , 4 ). NS is a heterogeneous condition, with variable phenotypic expression and severity ( 5 ). Clinical diagnosis is based on clinical criteria and a scoring system that includes the typical facial characteristics, typical heart defect, and short stature ( 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

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Differences in severity of cardiovascular anomalies in children with Noonan syndrome based on the causative gene

Shehade-Awwad¹,

Yeshayahu²,

Pinhas‐Hamiel³

et al. 2022

Front. Pediatr.

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BackgroundNoonan syndrome (NS) is a genetic syndrome, characterized by various dysmorphic features, cardiac anomalies, short stature, and developmental delay. NS is a leading cause of cardiovascular anomalies. The syndrome results from dysregulation in the RAS-MAPK pathway and is related to the RASopathy family syndromes. Pathogenic variants in more than 20 related genes have been identified in association with NS, and several genotype-phenotype correlations were suggested. The specific severity of the same cardiovascular anomalies has not been described as linked to a specific causative gene.MethodsFor this retrospective, single-center study, data retrieved from medical charts of a multidisciplinary NS clinic included genetic diagnosis, cardiac malformations, the need for intervention, demographics, and prenatal diagnosis. We analyzed molecular genetics and the severity of cardiac malformations.ResultsThe cohort comprised 74 children with NS. Consistent with previous studies, pathogenic variants in PTPN11 were the most common (62%). Cardiovascular anomalies presented in 57%; pulmonary stenosis (PS) was the most common (about 79% of anomalies). In children with pathogenic variants in PTPN11, PS tended to be more severe and required intervention in 53%, compared to 25% of children with PS and a variant in other genes.ConclusionThis first Israeli cohort of NS showed similar rates of cardiac malformations and genetic breakdown as previously published. Variants in PTPN11 were prone to a higher risk for severe PS that requires intervention. This finding may assist in genetic counseling and cardiac treatment decisions, and stresses the importance of genetic in addition to clinical diagnosis of NS.

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Section: Introductionmentioning

confidence: 99%

“…More than 20 other genes related to NS have been discovered ( 13 ). Despite advances in genetic testing, many patients are diagnosed clinically without molecular testing to identify the causative variant ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Differences in severity of cardiovascular anomalies in children with Noonan syndrome based on the causative gene

Shehade-Awwad¹,

Yeshayahu²,

Pinhas‐Hamiel³

et al. 2022

Front. Pediatr.

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“…The US Food and Drug Administration approved the treatment of NS patients with rhGH in 2007, and recently the European Medicine Agency (EMA) approved it too. In several other countries, such as Brazil, Israel, The Philippines, South Korea and Switzerland, rhGH is also licensed for this indication (43).…”

Section: Growth Hormone Treatment For Noonan Syndromementioning

confidence: 99%

“…Data are expressed as means; 1 according to Tanner; 2 according to Noonan reference [Adapted fromDahlgren (57) and Cascavilla et al(43)]. …”

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confidence: 99%

Etiology and Treatment of Growth Delay in Noonan Syndrome

2021

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Noonan syndrome is characterized by multiple phenotypic features, including growth retardation, which represents the main cause of consultation to the clinician. Longitudinal growth during childhood and adolescence depends on several factors, among them an intact somatotrophic axis, which is characterized by an adequate growth hormone (GH) secretion by the pituitary, subsequent binding to its receptor, proper function of the post-receptor signaling pathway for this hormone (JAK-STAT5b and RAS/MAPK), and ultimately by the production of its main effector, insulin like growth factor 1 (IGF-1). Several studies regarding the function of the somatotrophic axis in patients with Noonan syndrome and data from murine models, suggest that partial GH insensitivity at a post-receptor level, as well as possible derangements in the RAS/MAPK pathway, are the most likely causes for the growth failure in these patients. Treatment with recombinant human growth hormone (rhGH) has been used extensively to promote linear growth in these patients. Numerous treatment protocols have been employed so far, but the published studies are quite heterogeneous regarding patient selection, length of treatment, and dose of rhGH utilized, so the true benefit of GH therapy is somewhat difficult to establish. This review will discuss the possible etiologies for the growth delay, as well as the outcomes following rhGH treatment in patients with Noonan syndrome.

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“…Rasopathies are a group of phenotypically overlapping conditions that include Noonan, Noonan with multiple lentigines, Noonan with loose anagen hair, Costello, Cardio-facio-cutaneous, and Neurofibromatosis-Noonan syndromes. They are caused mainly by gainof-function germline pathogenic variants in genes involved in the regulation of the RAS/MAPK signaling pathway (Carcavilla et al, 2020). Noonan syndrome with loose anagen hair (NS-LAH) is clinically characterized by prominent forehead, macrocephaly, growth hormone deficiency, sparse, loose and slow-growing anagen hair, hyperpigmented skin with eczema or ichthyosis, mild psychomotor delays, hypernasal voices, and attention deficit hyperactivity disorder (Cordeddu et al, 2009;Mazzanti et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Noonan syndrome with loose anagen hair with variants in the PPP1CB gene: First familial case reported

Huckstadt

Chinton

Gomez

et al. 2021

American J of Med Genetics Pt A

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Rasopathies are a group of phenotypically overlapping conditions that include Noonan, Noonan with multiple lentigines, Noonan with loose anagen hair, Costello, Cardio‐facio‐cutaneous, and Neurofibromatosis‐Noonan syndromes. Noonan syndrome with loose anagen hair (NS‐LAH) is clinically characterized by prominent forehead, macrocephaly, growth hormone deficiency, sparse, loose and slow‐growing anagen hair, hyperpigmented skin with eczema or ichthyosis, mild psychomotor delays, hypernasal voices, and attention deficit hyperactivity disorder. Variants in SHOC2 are responsible for the majority of the cases. Gripp et al. identified four unrelated individuals with similar phenotype to NS‐LAH with pathogenic variants in PPP1CB. In this study, we present one family and one patient with NS‐LAH and variants in PPP1CB. The first patient belongs to a family with a likely pathogenic variant, c.545T>A (p.Met182Lys), the first family published so far with a variant in this gene. The second patient harbors a de novo pathogenic variant, c.146C>G (p.Pro49Arg). This study presents two additional patients with this rare syndrome in order to increase the clinical characterization of the syndrome and provide more evidence of the pathogenicity of the c.545T>A (p.Met182Lys) variant in PPP1CB, a gene recently associated with NS‐LAH.

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Síndrome de Noonan: actualización genética, clínica y de opciones terapéuticas

Cited by 20 publications

References 37 publications

Differences in severity of cardiovascular anomalies in children with Noonan syndrome based on the causative gene

Differences in severity of cardiovascular anomalies in children with Noonan syndrome based on the causative gene

Etiology and Treatment of Growth Delay in Noonan Syndrome

Noonan syndrome with loose anagen hair with variants in the PPP1CB gene: First familial case reported

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