Malformación de Arnold-Chiari en el síndrome de Noonan y otros síndromes de la vía RAS/MAPK / Arnold-Chiari malformation in Noonan syndrome and other syndromes of the RAS/MAPK pathway

Introducción. El síndrome de Noonan (SN) y otros síndromes con fenotipo similar, como LEOPARD, cardiofaciocutáneo, Costello y Legius, están asociados a mutaciones en genes incluidos en la vía RAS/MAPK (rasopatías), una importante vía de señalización relacionada con la proliferación celular. El descenso de las amígdalas cerebelares dentro del canal medular cervical, conocido como malformación de Arnold-Chiari (MAC), se ha descrito en pacientes afectos de SN, lo que ha llevado a sugerir que la MAC podría formar parte del espectro fenotípico del SN. Presentamos dos casos con SN y MAC. Casos clínicos. Caso 1: mujer de 29 años con fenotipo de Noonan. Fue intervenida a los 9 años de estenosis valvular pulmonar. A los 27 años, presentó MAC sintomática que precisó descompresión quirúrgica. Presentaba mutación c.922A>G (N308D) en el gen PTPN perteneciente a la vía RAS/MAPK. Caso 2: niña de 10 años con fenotipo de Noonan y MAC asintomática detectada en resonancia magnética cerebral. Era portadora de la mutación c.923A>G (N308S) en el gen PTPN11. Conclusiones. Hemos encontrado en la bibliografía seis pacientes con esta asociación, cuatro con fenotipo Noonan y dos con LEOPARD. Nuestros dos pacientes aportan evidencia suplementaria a la hipótesis de que la MAC formaría parte del espectro fenotípico del SN. El escaso número de pacientes publicados con esta asociación no permite extraer recomendaciones sobre el momento y la frecuencia de estudio de neuroimagen; no obstante, una exploración neurológica cuidadosa debería incluirse en la guía anticipatoria de salud en los síndromes de la vía RAS/MAPK (AU)

Introduction. Noonan syndrome (NS) and other syndromes with a similar phenotype, such as LEOPARD, cardiofaciocutaneous, Costello and Legius, are associated to mutations in genes included in the RAS/MAPK pathway (RASopathies), which is an important signalling pathway related to cell proliferation. Tonsillar descent into the upper cervical spinal canal, known as Arnold-Chiari malformation (ACM), has been reported in patients with NS and this has led some researchers to suggest that ACM could be part of the phenotypic spectrum of NS. We report two cases of NS and ACM. Case reports. Case 1: 29-year-old female with Noonan phenotype who underwent surgery at the age of nine years due to pulmonary valve stenosis. At the age of 27, she presented symptomatic ACM that required surgical decompression. She presented the c.922A>G (N308D) mutation in the gene PTPN that belongs to the RAS/MAPK pathway. Case 2: a 10-yearold female with Noonan phenotype and asymptomatic ACM detected in magnetic resonance imaging of the brain. She was a carrier of the c.923A>G (N308S) mutation in gene PTPN11. Conclusions. Six patients with this association have been found in the literature, four with the Noonan phenotype and two with LEOPARD. Our two patients provide supplementary evidence that backs up the hypothesis by which ACM would be part of the phenotypic spectrum of NS. The small number of reported cases of patients with this association does not allow us to draw up recommendations about when and how often neuroimaging studies should be performed; a careful neurological examination, however, should be included in the anticipatory health guidelines in syndromes involving the RAS/MAPK pathway (AU)

[Arnold-Chiari malformation in Noonan syndrome and other syndromes of the RAS/MAPK pathway]. / Malformacion de Arnold-Chiari en el sindrome de Noonan y otros sindromes de la via RAS/MAPK.

INTRODUCTION: Noonan syndrome (NS) and other syndromes with a similar phenotype, such as LEOPARD, cardiofaciocutaneous, Costello and Legius, are associated to mutations in genes included in the RAS/MAPK pathway (RASopathies), which is an important signalling pathway related to cell proliferation. Tonsillar descent into the upper cervical spinal canal, known as Arnold-Chiari malformation (ACM), has been reported in patients with NS and this has led some researchers to suggest that ACM could be part of the phenotypic spectrum of NS. We report two cases of NS and ACM. CASE REPORTS: Case 1: 29-year-old female with Noonan phenotype who underwent surgery at the age of nine years due to pulmonary valve stenosis. At the age of 27, she presented symptomatic ACM that required surgical decompression. She presented the c.922A>G (N308D) mutation in the gene PTPN that belongs to the RAS/MAPK pathway. Case 2: a 10-year-old female with Noonan phenotype and asymptomatic ACM detected in magnetic resonance imaging of the brain. She was a carrier of the c.923A>G (N308S) mutation in gene PTPN11. CONCLUSIONS: Six patients with this association have been found in the literature, four with the Noonan phenotype and two with LEOPARD. Our two patients provide supplementary evidence that backs up the hypothesis by which ACM would be part of the phenotypic spectrum of NS. The small number of reported cases of patients with this association does not allow us to draw up recommendations about when and how often neuroimaging studies should be performed; a careful neurological examination, however, should be included in the anticipatory health guidelines in syndromes involving the RAS/MAPK pathway.

TITLE: Malformacion de Arnold-Chiari en el sindrome de Noonan y otros sindromes de la via RAS/MAPK.Introduccion. El sindrome de Noonan (SN) y otros sindromes con fenotipo similar, como LEOPARD, cardiofaciocutaneo, Costello y Legius, estan asociados a mutaciones en genes incluidos en la via RAS/MAPK (rasopatias), una importante via de señalizacion relacionada con la proliferacion celular. El descenso de las amigdalas cerebelares dentro del canal medular cervical, conocido como malformacion de Arnold-Chiari (MAC), se ha descrito en pacientes afectos de SN, lo que ha llevado a sugerir que la MAC podria formar parte del espectro fenotipico del SN. Presentamos dos casos con SN y MAC. Casos clinicos. Caso 1: mujer de 29 años con fenotipo de Noonan. Fue intervenida a los 9 años de estenosis valvular pulmonar. A los 27 años, presento MAC sintomatica que preciso descompresion quirurgica. Presentaba mutacion c.922A>G (N308D) en el gen PTPN perteneciente a la via RAS/MAPK. Caso 2: niña de 10 años con fenotipo de Noonan y MAC asintomatica detectada en resonancia magnetica cerebral. Era portadora de la mutacion c.923A>G (N308S) en el gen PTPN11. Conclusiones. Hemos encontrado en la bibliografia seis pacientes con esta asociacion, cuatro con fenotipo Noonan y dos con LEOPARD. Nuestros dos pacientes aportan evidencia suplementaria a la hipotesis de que la MAC formaria parte del espectro fenotipico del SN. El escaso numero de pacientes publicados con esta asociacion no permite extraer recomendaciones sobre el momento y la frecuencia de estudio de neuroimagen; no obstante, una exploracion neurologica cuidadosa deberia incluirse en la guia anticipatoria de salud en los sindromes de la via RAS/MAPK.

Papel de la atención primaria ante el cáncer hereditario / The role of primary care in hereditary cancer

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Evaluation of clinical diagnosis criteria of familial ligand defective apoB 100 and lipoprotein phenotype comparison between LDL receptor gene mutations affecting ligand-binding domain and the R3500Q mutation of the apoB gene in patients from a South European population.

Familial hypercholesterolemia (FH) and familial defective apoB 100 (FDB) are characterized by increased plasma low-density lipoprotein cholesterol (LDLc) levels and risk of coronary heart disease (CHD). FDB is clinically indistinguishable from FH. The aims of this study were to evaluate clinical diagnosis criteria for FDB and to compare the lipoprotein phenotype between carriers of LDL receptor (LDLR) gene mutations that affect the ligand-binding domain and subjects with the R3500Q mutation in apoB gene. We studied 213 subjects (113 probands) with FH and 19 heterozygous FDB subjects. Genetic diagnosis was determined by following a protocol based on Southern blot and polymerase chain reaction-single strand conformation polymorphism (SSCP) analysis. Thirty FH carriers of LDLR gene missense mutations that affect ligand-binding domain were matched by age, gender, and body mass index to the 19 FDB subjects (R3500Q mutation). Lipoprotein phenotype comparison was conducted between the 2 groups. FH patients showed plasma total and LDL cholesterol levels significantly higher than those in FDB patients. Three FDB showed plasma total and LDLc values in the normal range. Using the 1999 clinical Med-Ped criteria for diagnosis of genetic hypercholesterolemia, no FDB subjects had a confirmed diagnosis; it was probable in 36% of the subjects, it was possible in 32% of the subjects, and it could be excluded in the remaining 32% of the subjects. We conclude that the FDB lipoprotein phenotype was significantly less severe than that observed in FH carriers of LDLR gene missense ligand-binding domain mutations. Clinical Med-Ped diagnosis criteria tend to under-diagnose FDB.

El médico de familia y sus competencias en genética clínica / Family doctors and their responsibilities in clinical genetics

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[Clinical and biochemical characteristics of familial ligand-defective apo B-100 in a South European population]. / Estudio del defecto familiar de unión de la apolipoproteína B100 en una población mediterránea.

BACKGROUND AND OBJECTIVE: To compare the lipoprotein phenotype between FDB and heterozygous familial hypercholesterolemia (FH); to study the prevalence and possible founder effect of familial ligand-defective apo B100 (FDB) in a Mediterranean population, and to analyze the clinical and biochemical characteristics of FDB patients. SUBJECTS AND METHOD: We studied 19 heterozygous FDB subjects (8 males) from 12 related families, carriers of the R3500Q mutation on the apo B gene, and 57 heterozygous FH (24 males) genetically characterized, randomly selected from a total of 213 FH. The genetic diagnosis was established with Southern blot analysis, PCR-SSCP analysis and automatic sequencing. In all subjects, plasma lipids and apolipoprotein levels were determined with standard procedures. RESULTS: We demonstrated a founder effect for the R3500Q mutation in a geographically isolated rural area from our community. The prevalence of FDB in this area is high: 4/350. Heterozygous FDB subjects showed a statistical significantly lower prevalence of xanthomas and coronary heart disease, plasma concentrations of total and LDL cholesterol, HDL cholesterol, apo B and apo A-I values than heterozygous FH subjects. CONCLUSIONS: A founder effect for the R3500Q mutation was found in a rural population with a high prevalence of FDB. In our population, FDB patients showed a mild clinical expression and lipoprotein phenotype compared with FH patients.

Influence of LDL receptor gene mutations and the R3500Q mutation of the apoB gene on lipoprotein phenotype of familial hypercholesterolemic patients from a South European population.

Few data are available on genotype-phenotype interactions among familial hypercholesterolemia (FH) patients in South European populations and there are no data about the influence of R3500Q mutation on lipoprotein phenotype compared to low-density lipoprotein receptor (LDLR) mutations. The objective of the study is to analyze the influence of mutations in the LDLR and apolipoprotein B (apoB) genes on lipoprotein phenotype among subjects clinically diagnosed of FH living in East Spain. In all, 113 FH index patients and 100 affected relatives were studied. Genetic diagnosis was carried out following a protocol based on Southern blot and PCR-SSCP analysis. A total of 118 FH subjects could be classified into three groups according to the type of LDLR mutations (null mutations, missense mutations affecting the ligand binding 3-5 repeat, and missense mutations outside this domain). In addition, the lipoprotein phenotype of these FH groups was compared with 19 heterozygous subjects with familial ligand-defective apoB (FDB), due to R3500Q mutation. FH patients carrying missense mutations affecting the ligand binding repeat 3-5 showed total and LDL cholesterol levels significantly higher than FH patients with missense mutations in other LDLR domains or FDB patients. FH subjects carrying null mutations showed lower high-density lipoprotein cholesterol plasma values compared to FH carrying missense mutations. FDB subjects showed the lowest total and LDL cholesterol plasma values. In conclusion, the type of LDLR gene mutation and R3500Q mutation influences the lipoprotein phenotype of FH population from East Spain.

Identificación y caracterización del primer español con defecto homocigoto familiar de unión de la apolipoproteína B / Identification and characterization of the first Spanish familial ligand-defective apolipoprotein B homozygote

FUNDAMENTO: El defecto familiar de unión de la apolipoproteína B-100 (DFB) es una enfermedad hereditaria autosómica dominante debida a mutaciones localizadas en el gen de la apolipoproteína B-100, clínicamente indistinguible de la hipercolesterolemia familiar. Describimos el primer homocigoto español para el DFB. MÉTODOS: Estudiamos por técnica de PCR-SSCP la mutación R3500Q en los familiares de primer y segundo grado de la familia con DFB previamente descrita por nuestro grupo. Además, analizamos la actividad del receptor de LDL en un ensayo con LDL conjugada con oro coloidal. RESULTADOS: El paciente presenta en ambos alelos la mutación R3500Q causante de DFB. El estudio de la actividad del receptor de LDL es normal, lo que descarta que se trate de una hipercolesterolemia familiar. El grado de hipercolesterolemia es menor del esperado tratándose de un homocigoto (colesterol total, 415, y cLDL, 352 mg/dl), y presenta una buena respuesta terapéutica a estatinas y resinas (descensos de hasta un 42 por ciento para el colesterol total y de un 51 por ciento para el cLDL). CONCLUSIONES: Hemos detectado y caracterizado el primer homocigoto español para el DFB (mutación R3500Q), que presenta valores moderadamente elevados de colesterol total y cLDL a pesar de su situación de homocigosis. Estos datos demuestran que el fenotipo lipoproteico de los homocigotos DFB es diferente de la situación de homocigosis para la hipercolesterolemia familiar (AU)