Objectives: The aim of this study was to evaluate the response to recombinant human growth hormone (rhGH) treatment in patients with Noonan syndrome (NS). Materials and Methods: Forty-two patients (35 PTPN11+) were treated with rhGH, and 17 were followed-up until adult height. The outcomes were changes in growth velocity (GV) and height standard deviation scores (SDS) for normal (height-CDC SDS) and Noonan standards (height-NS SDS). Results: The pretreatment chronological age was 10.3 ± 3.5 years. Height-CDC SDS and height-NS SDS were –3.1 ± 0.7 and –0.5 ± 0.6, respectively. PTPN11+ patients had a better growth response than PTPN11– patients. GV SDS increased from –1.2 ± 1.8 to 3.1 ± 2.8 after the first year of therapy in PTPN11+ patients, and from –1.9 ± 2.6 to –0.1 ± 2.6 in PTPN11– patients. The gain in height-CDC SDS during the first year was higher in PTPN11+ than PTPN11– (0.6 ± 0.4 vs. 0.1 ± 0.2, p = 0.008). Similarly, the gain was observed in height-NS SDS (0.6 ± 0.3 vs. 0.2 ± 0.2, respectively, p < 0.001). Among the patients that reached adult height (n = 17), AH-CDC SDS and AH-NS SDS were –2.1 ± 0.7 and 0.7 ± 0.8, respectively. The total increase in height SDS was 1.3 ± 0.7 and 1.5 ± 0.6 for normal and NS standards, respectively. Conclusions: This study supports the advantage of rhGH therapy on adult height in PTPN11+ patients. In comparison, PTPN11– patients showed a poor response to rhGH. However, this PTPN11– group was small, preventing an adequate comparison among different genotypes and no guarantee of response to therapy in genes besides PTPN11.
OBJECTIVENon-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.PATIENTSWe 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.DESIGNMutational 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.RESULTSThe 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.CONCLUSIONSOur 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.
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.
Ao longo da vida, encontramo-nos com pessoas muito especiais. Assim posso definir todos da Unidade de Endocrinologia, que não só colegas de trabalho transformaram-se em grandes amigos. Gostaria de agradecer cada um pelos momentos divididos que jamais serão esquecidos. Em primeiro lugar, a Deus por transmitir seu amor ágape, sempre iluminando meu caminho e permitindo que eu complete mais um ciclo na minha vida. Aos meus pais, Ailton Paulo de Moraes e Vani Buscarilli de Moraes, a vocês não bastaria apenas um muito-obrigada. O que dizer de vocês, pessoas que me ensinaram tudo que sei, ensinaram-me a viver. Que me ampararam nas horas em que mais precisava, sabendo dizer, na dose certa, uma palavra amiga quando precisava de consolo, uma dura quando precisava de correção, sempre com sabedoria e justiça. A figura de vocês representa todo amor, respeito e consideração que possa existir. Sua honestidade e força são exemplo de vida e me dão o rumo do caminho que vou seguir. Queria poder retribuir, um dia, todo carinho e atenção que me deram. Ensinaram a andar e estavam lá, quando precisava para amparar minha queda. Ensinaram-me a falar e estavam lá para corrigir minhas palavras, a escrever e estavam lá para orientar meus primeiros rabiscos. Ensinaram-me a viver e tenho certeza de que posso contar com vocês em qualquer fase da minha vida, nos bons e maus momentos, sempre com dedicação e prontidão. Espero poder, um dia, representar para meus filhos tudo aquilo que representam para mim, pois cultivo por vocês os sentimentos mais puros e verdadeiros que podem existir: o amor, o carinho, o respeito, e acima de tudo a admiração. Agradeço todos os dias por poder compartilhar da companhia e convívio com vocês e, principalmente, por poder me orgulhar de ter vocês, pai e mãe, como também meus amigos, e por fazer parte de uma família, que cultiva os melhores sentimentos que existem: a paz, a compreensão e o respeito mútuo. Obrigada por tudo. Obrigada por serem pais maravilhosos. Obrigada por guiarem meus passos e por incentivarem, a cada dia, meus sonhos e objetivos. Obrigada pela oportunidade de me fazerem alguém, para que eu possa retribuir, ao menos, um pouco de tudo que recebi de vocês. Ao meu querido irmão, Wesley Buscarilli de Moraes e minha cunhada Cibele Ceconni por todo apoio, amor e carinho e prontidão sempre quando precisei. Vocês são exemplos para mim. Amo vocês. Ao meu noivo, Rafael Bueno Texeira pelo apoio imensurável e compreensão na minha ausência. Por todo amor e cuidado por mim. Sempre ao meu lado, me fazendo acreditar que posso mais que imagino. Minha vida mudou quando encontrei você. Obrigada, por um dia ter cruzado meu caminho e nunca mais ter largado minha mão. Te amo!. À todos da minha família, tios (as) por todo carinho e apoio. A Dra. Debora Bertola, minha gratidão, admiração e respeito pela oportunidade da orientação e de desenvolver este trabalho. Muito obrigada pelo privilégio de ser sua orientanda. Ao Dr. Alexsander Jorge, minha gratidão pela atenção sincera e disponível, sempre com muita paciência, trans...
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