RESUMO
OBJECTIVE: To assess the growth promoting effect of a recombinant growth hormone (rGH) treatment protocol adjusted on insulin-like growth factor 1 (IGF-1) dosing in children affected by the most severe forms of FGFR3 N540K-mutated hypochondroplasia. STUDY DESIGN: Midterm results of an open-label, single-center, nonrandomized, 2003-2020 pilot trial to final stature, including 6 children (mean age, 2.6 ± 0.7 years; mean height SDS, -3.0 ± 0.5) with the N540K mutation of FGFR3 gene who received an rGH dosage titrated to an IGF-1 level close to 1.5 SDS of the normal range. rGH therapy was interrupted 1 day per week, 1 month per year, and 6 months every 2 years. RESULTS: The mean height SDS increased by 1.9 during the 6.1 ± 0.9-year study period, reaching -0.8 to -1.3 at age 8.7 ± 1 years. The mean±SDS baseline IGF-1 value was -1.6 ± 0.5 before rGH treatment and 1.4±0.3 during the last year of observation. The average cumulative rGH dose was 0.075 ± 0.018 mg/kg/day (range, 0.059-0.100 mg/kg/day). Trunk/leg disproportion was improved. CONCLUSION: IGF-1-dosing rGH treatment durably improves growth and reduces body disproportion in children with severe forms of hypochondroplasia.
Assuntos
Nanismo/tratamento farmacológico , Nanismo/genética , Hormônio do Crescimento Humano/administração & dosagem , Fator de Crescimento Insulin-Like I/metabolismo , Osteocondrodisplasias/tratamento farmacológico , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Estatura/efeitos dos fármacos , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , França , Humanos , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Masculino , Mutação , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Projetos Piloto , Doenças Raras , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Medição de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
CONTEXT: Among the genomic loci harboring potential candidate genes for prostatic cancer (PCa) is the 2q31-33 chromosomal region that harbors the gene encoding phosphodiesterase 11A (PDE11A). In addition, the combined cancer genome expression metaanalysis datasets included PDE11A among the top 1% down-regulated genes in PCa. OBJECTIVE: In the present study, we screened 50 unrelated PCa patients of Brazilian descent for PDE11A coding defects. DESIGN: The study consisted of PDE11A sequencing, in vitro functional assays, and immunostaining analysis. RESULTS: We identified eight different sequence alterations in 15 patients (30%): one stop-codon and seven missense mutations. Three of the variants (R202C, Y658C, and E840K) were novel, and the remaining five (Y727C, R804H, R867G, M878V, and R307X) have been associated with predisposition to adrenal or testicular tumors. The overall prevalence of PDE11A-inactivating sequence variants among PCa patients was significantly higher than in 287 healthy controls (0.16 vs. 0.051, respectively, P < 0.001, odds ratio 3.81, 95% confidence interval 1.86-7.81) and the R202C, Y658C, and E840K substitutions were not found in controls. All missense mutations led to decreased PDE11A activity in human embryonic kidney 293 and PC3M cells and immunostaining of PCa samples with sequence changes showed decreased PDE11A protein expression. CONCLUSION: Our data suggest that, like in the adrenal cortex and the testicular germ cells, PDE11A-inactivating genetic alterations may play a role in susceptibility to PCa.
Assuntos
Predisposição Genética para Doença , Variação Genética , Diester Fosfórico Hidrolases/genética , Neoplasias da Próstata/genética , 3',5'-GMP Cíclico Fosfodiesterases , Brasil , Células HEK293 , Humanos , Imuno-Histoquímica , Masculino , Mutação , Diester Fosfórico Hidrolases/metabolismo , Neoplasias da Próstata/metabolismoRESUMO
OBJECTIVE: To evaluate bone mineral density (BMD) in children with Cushing disease before and after transphenoidal surgery (TSS). STUDY DESIGN: Hologic dual-energy x-ray absorptiometry (DXA) scans of 35 children with Cushing disease were analyzed retrospectively. Sixteen of the 35 patients had follow-up DXA scans performed 13 to 18 months after TSS. BMD and bone mineral apparent density (BMAD) for lumbar spine (LS) L1 to L4 and femoral neck (FN) were calculated. RESULTS: Preoperatively, 38% and 23% of patients had osteopenia of the LS and FN, respectively. Both BMD and BMAD Z-scores of the LS were worse than those for the FN (-1.60 +/- 1.37 versus -1.04 +/- 1.19, P = .003), and (-1.90 +/- 1.49 versus -0.06 +/- 1.90, P < .001); postoperative improvement in BMD and BMAD were more pronounced in LS than in the FN (0.84 +/- 0.88 versus 0.15 +/- 0.62, P<.001; and 0.73 +/- 1.13 versus -0.26 +/- 1.21, P = .015). Pubertal stage, cortisol levels, and length of disease had no effect on BMD. CONCLUSIONS: In children with Cushing disease, vertebral BMD was more severely affected than femoral BMD and this effect was independent of degree or duration of hypercortisolism. BMD for the LS improved significantly after TSS; osteopenia in this group may be reversible.