RESUMEN
Noonan syndrome (NS) and NS related disorders (NRD) are frequent monogenic diseases. Pathogenic variants in PTPN11 are observed in approximately 50% of these NS patients. Several pleiotropic phenotypes have previously been described in this condition. This study aimed at characterizing glucose and lipid profiles in patients with NS/NRD. We assessed fasting blood glucose, insulin, cholesterol (total and fractions), and triglyceride (TG) levels in 112 prepubertal children and 73 adults. Additionally, an oral glucose tolerance test (OGTT) was performed in 40 children and 54 adults. Data were analyzed between age groups according to the presence (+) or absence (-) of PTPN11 mutation. Prepubertal patients with NS/NRD were also compared with a control group. Despite the lean phenotype of children with NS/NRD, they presented an increased frequency of low HDL-cholesterol (63% in PTPN11+, 59% in PTPN11- and 16% in control, p < .001) and high TG levels (29% in PTPN11+, 18% in PTPN11- and 2.3% in control). PTPN11+ patients had a higher median HOMA-IR (1.0, ranged from 0.3 to 3.2) in comparison with PTPN11- (0.6; 0.2 to 4.4) and controls (0.6; 0.4 to 1.4, p = .027). Impaired glucose tolerance was observed in 19% (10:54) of lean adults with NS/NRD assessed by OGTT. Moreover, women with PTPN11 mutations had lower HDL-cholesterol levels than those without. Our results suggest that children and young adult patients with NS/NRD have an unfavorable metabolic profile characterized by low HDL, a tendency of elevated TGs, and glucose metabolism impairment despite a lean phenotype.
Asunto(s)
Metaboloma , Síndrome de Noonan/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Adolescente , Adulto , Anciano , Estudios Transversales , Femenino , Estudios de Seguimiento , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Síndrome de Noonan/genética , Síndrome de Noonan/metabolismo , Fenotipo , Pronóstico , Adulto JovenRESUMEN
OBJECTIVE: Non-pituitary tumors have been reported in a subset of patients harboring germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. However, no detailed investigations of non-pituitary tumors of AIP-mutated patients have been reported so far. PATIENTS: We examined a MEN1- and p53-negative mother-daughter pair with acromegaly due to somatotropinoma. Subsequently, the mother developed a large virilizing adrenocortical carcinoma and a grade II B-cell non-Hodgkin's lymphoma. DESIGN: Mutational analysis was performed by automated sequencing. Loss-of-heterozygosity (LOH) analysis was carried out by sequencing and microsatellite analysis. AIP expression was assessed through quantitative PCR (qPCR) and immunohistochemistry. RESULTS: The functional inactivating mutation c.241C>T (R81X), which blocks the AIP protein from interacting with phosphodiesterase 4A (PDE4A), was identified in the heterozygous state in the leukocyte DNA of both patients. Analyzing the tumoral DNA revealed that the AIP wild-type allele was lost in the daughter's somatotropinoma and the mother's adrenocortical carcinoma. Both tumors displayed low AIP protein expression levels. Low AIP gene expression was confirmed by qPCR in the adrenocortical carcinoma. No evidence of LOH was observed in the DNA sample from the mother's B-cell lymphoma, and this tumor displayed normal AIP immunostaining. CONCLUSIONS: Our study presents the first molecular analysis of non-pituitary tumors in AIP-mutated patients. The finding of AIP inactivation in the adrenocortical tumor suggests that further investigation of the potential role of this recently identified tumor suppressor gene in non-pituitary tumors, mainly in those tumors in which the cAMP and the 11q13 locus are implicated, is likely to be worthwhile.
Asunto(s)
Acromegalia/genética , Adenoma/genética , Carcinoma Corticosuprarrenal/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Hipofisarias/genética , Adenoma/metabolismo , Adolescente , Adulto , Femenino , Expresión Génica , Genes p53 , Mutación de Línea Germinal , Humanos , Pérdida de Heterocigocidad/genética , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasias Hipofisarias/metabolismo , Reacción en Cadena de la PolimerasaRESUMEN
The objective of this paper was to evaluate the applicability of the method developed by Caldas to measure the vertebral bone age of Brazilians suffering from Down syndrome. A database comprised of 57 case records of individuals with this syndrome, both male and female, with ages ranging between 5 and 18 years, was used for this purpose. These records had lateral cephalometric radiographs and radiographs of hand and wrist, all of which had been obtained on the same date. There were 48 other records of individuals who did not suffer from Down syndrome. The Tanner and Whitehouse (TW3) method was used to perform the hand and wrist radiographs for obtaining bone age. The Caldas method was employed on the lateral cephalometric radiographs in order to obtain the vertebral bone age. From the information acquired on bone age, vertebral bone age and chronological age, it could be concluded that there is a statistically significant difference between the three ages for both the male and the female control group and for the female Down syndrome group. Therefore, this method was employed only on male Down syndrome individuals. Based on the results, a formula was developed to obtain the bone age for Down syndrome individuals (AU).
O objetivo deste trabalho foi avaliar a aplicabilidade do método desenvolvido por Caldas para medir a idade óssea vertebral em brasileiros, quando empregado em indivíduos portadores da síndrome de Down. Foram estudados 57 prontuários de indivíduos com síndrome de Down, de ambos os sexos, com idades variando entre 5 e 18 anos. Esses prontuários continham radiografias cefalométricas laterais e radiografias de mão e punho, obtidas no mesmo dia, e também foram avaliados 48 prontuários de indivíduos não portadores de síndrome de Down. Para as radiografias de mão e punho, o método de Tanner e Whitehouse (TW3) foi usado para que pudéssemos obter a idade óssea. O método de Caldas foi empregado nas radiografias cefalométricas laterais, e assim obtivemos a idade óssea vertebral. A partir das informações sobre a idade óssea, idade óssea vertebral e idade cronológica, foi verificada uma diferença estatisticamente significativa entre as três faixas etárias para ambos os sexos do grupo controle e grupo com síndrome de Down do sexo feminino. Portanto, este método foi aplicável apenas em indivíduos do sexo masculino portadores da síndrome de Down. Com base nos resultados, uma fórmula para obtenção da idade óssea de indivíduos com síndrome de Down foi desenvolvida (AU).
Asunto(s)
Humanos , Masculino , Femenino , Preescolar , Niño , Adolescente , Radiología/instrumentación , Desarrollo Óseo , Vértebras Cervicales , Síndrome de Down , Registros MédicosRESUMEN
OBJECTIVE: Non-pituitary tumors have been reported in a subset of patients harboring germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. However, no detailed investigations of non-pituitary tumors of AIP-mutated patients have been reported so far. PATIENTS: We examined a MEN1- and p53-negative mother-daughter pair with acromegaly due to somatotropinoma. Subsequently, the mother developed a large virilizing adrenocortical carcinoma and a grade II B-cell non-Hodgkin's lymphoma. DESIGN: Mutational analysis was performed by automated sequencing. Loss-of-heterozygosity (LOH) analysis was carried out by sequencing and microsatellite analysis. AIP expression was assessed through quantitative PCR (qPCR) and immunohistochemistry. RESULTS: The functional inactivating mutation c.241C>T (R81X), which blocks the AIP protein from interacting with phosphodiesterase 4A (PDE4A), was identified in the heterozygous state in the leukocyte DNA of both patients. Analyzing the tumoral DNA revealed that the AIP wild-type allele was lost in the daughter's somatotropinoma and the mother's adrenocortical carcinoma. Both tumors displayed low AIP protein expression levels. Low AIP gene expression was confirmed by qPCR in the adrenocortical carcinoma. No evidence of LOH was observed in the DNA sample from the mother's B-cell lymphoma, and this tumor displayed normal AIP immunostaining. CONCLUSIONS: Our study presents the first molecular analysis of non-pituitary tumors in AIP-mutated patients. The finding of AIP inactivation in the adrenocortical tumor suggests that further investigation of the potential role of this recently identified tumor suppressor gene in non-pituitary tumors, mainly in those tumors in which the cAMP and the 11q13 locus are implicated, is likely to be worthwhile.
Asunto(s)
Adolescente , Adulto , Femenino , Humanos , Acromegalia/genética , Adenoma/genética , Carcinoma Corticosuprarrenal/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Hipofisarias/genética , Adenoma , Expresión Génica , Mutación de Línea Germinal , Pérdida de Heterocigocidad/genética , Neoplasia Endocrina Múltiple Tipo 1/genética , Reacción en Cadena de la Polimerasa , Neoplasias HipofisariasRESUMEN
Bone exostosis has long been described in the literature, appearing in most cases as a torus palatinus or mandibularis. These two variations are relatively common and affect approximately 30% of the world's population. Incidence is even higher when human skulls are examined post mortem, indicating that in some cases the exostosis is small and cannot be seen under the soft tissue. Removal of an exostosis is usually associated with the construction of a prothesis, but in rare cases such as the present, the lesion enlarges enough to affect speech and feeding. Few studies have reported the removal of such a large exostosis, and all were conducted in a hospital environment. In this case, complete removal was successfully conducted in an ambulatory clinic under local anesthesia.