RESUMO
OBJECTIVE: to describe the marked variability in clinical and biochemical patterns that are associated with a p.R209H GH1 missense variant in a large Argentinean pedigree, which makes the diagnosis of GHD elusive. DESIGN: We describe a non-consanguineous pedigree composed by several individuals with short stature, including 2 pediatric patients with typical diagnosis of isolated growth hormone deficiency (IGHD) and 4 other siblings with severe short stature, low serum IGF-1 and IGFBP-3, but normal stimulated GH levels, suggesting growth hormone insensitivity (GHI) in the latter group. RESULTS: Patients with classical IGHD phenotype carried a heterozygous variant in GH1: c.626G>A (p.R209H). Data from the extended pedigree suggested GH1 as the initial candidate gene, which showed the same pathogenic heterozygous GH1 variant in the four siblings with short stature and a biochemical pattern of GHI. CONCLUSIONS: We suggest considering GH1 sequencing in children with short stature associated to low IGF-1 and IGFBP-3 serum levels, even in the context of normal response to growth hormone provocative testing (GHPT).
Assuntos
Estatura , Nanismo Hipofisário/genética , Hormônio do Crescimento Humano/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Argentina , Criança , Pré-Escolar , Técnicas de Diagnóstico Endócrino , Nanismo Hipofisário/metabolismo , Nanismo Hipofisário/fisiopatologia , Feminino , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/fisiopatologia , Heterozigoto , Homozigoto , Hormônio do Crescimento Humano/metabolismo , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto JovemRESUMO
BACKGROUND: Floating-Harbor syndrome (FHS) is a rare condition characterized by dysmorphic facial features, short stature, and expressive language delay. OBJECTIVE: The aim of this study was to describe a cohort of patients with FHS and review the literature about the response to recombinant human growth hormone (rhGH) therapy. METHODS: Anthropometric and laboratory data from 7 patients with FHS were described. The molecular diagnosis was established by multigene analysis. Moreover, we reviewed the literature concerning patients with FHS treated with rhGH. RESULTS: All 7 patients were born small for gestational age. At first evaluation, 6 patients had a height standard deviation score (SDS) ≤-2 and 1 had short stature in relation to their target height. Bone age was usually delayed, which rapidly advanced during puberty. Nonspecific skeletal abnormalities were frequently noticed, and normal to elevated plasma IGF-I levels were observed in all except 1 patient with growth hormone deficiency. Information about 20 patients with FHS treated with rhGH was analyzed (4 from our cohort and 16 from the literature). The median height changes during the treatment period (approx. 2.9 years) were 1.1 SDS (range from -0.4 to 3.1). Nontreated patients had an adult height SDS of -4.1 ± 1.2 (n = 10) versus -2.6 ± 0.8 SDS (n = 7, p 0.012) for treated patients. CONCLUSION: We observed a laboratory profile compatible with IGF-1 insensitivity in some patients with FHS. Nevertheless, our study suggests that children with FHS may be considered as candidates for rhGH therapy. Further studies are necessary to establish the real benefit and safety of rhGH therapy in these patients.
Assuntos
Anormalidades Múltiplas , Desenvolvimento do Adolescente/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Anormalidades Craniofaciais , Nanismo Hipofisário , Transtornos do Crescimento , Comunicação Interventricular , Hormônio do Crescimento Humano/uso terapêutico , Puberdade/efeitos dos fármacos , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Anormalidades Craniofaciais/tratamento farmacológico , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , Anormalidades Craniofaciais/fisiopatologia , Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/metabolismo , Nanismo Hipofisário/patologia , Nanismo Hipofisário/fisiopatologia , Feminino , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/patologia , Transtornos do Crescimento/fisiopatologia , Comunicação Interventricular/tratamento farmacológico , Comunicação Interventricular/metabolismo , Comunicação Interventricular/patologia , Comunicação Interventricular/fisiopatologia , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , MasculinoRESUMO
OBJECTIVES: Voice is produced by the vibration of the vocal folds expressed by its fundamental frequency (Hz), whereas the formants (F) are fundamental frequency multiples, indicating amplification zones of the vowels in the vocal tract. We have shown that lifetime isolated growth hormone deficiency (IGHD) causes high pitch voice, with higher values of most formant frequencies, maintaining a prepuberal acoustic prediction. The objectives of this work were to verify the effects of the therapy with a semi-occluded vocal tract (SOVTT) and choir training on voice in these subjects with IGHD. We speculated that acoustic vocal parameters can be improved by SOVTT or choir training. STUDY DESIGN: This is a prospective longitudinal study without control group. METHODS: Acoustic analysis of isolated vowels was performed in 17 adults with IGHD before and after SOVTT (pre-SOVTT and post-SOVTT) and after choir training (post training), in a 30-day period. RESULTS: The first formant was higher in post training compared with the pre-SOVTT (P = 0.009). The second formant was higher in post-SOVTT than in pre-SOVTT (P = 0.045). There was a trend of reduction in shimmer in post-choir training in comparison with pre-SOVTT (P = 0.051), and a reduction in post-choir training in comparison with post-SOVTT (P = 0.047). CONCLUSIONS: SOVTT was relevant to the second formant, whereas choir training improved first formant and shimmer. Therefore, this speech therapy approach was able to improve acoustic parameters of the voice of individuals with congenital, untreated IGHD. This seems particularly important in a scenario in which few patients are submitted to growth hormone replacement therapy.
Assuntos
Nanismo Hipofisário/complicações , Canto , Acústica da Fala , Fonoterapia/métodos , Distúrbios da Voz/terapia , Qualidade da Voz , Treinamento da Voz , Adulto , Idoso , Nanismo Hipofisário/diagnóstico , Nanismo Hipofisário/fisiopatologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Distúrbios da Voz/diagnóstico , Distúrbios da Voz/etiologia , Distúrbios da Voz/fisiopatologiaRESUMO
PURPOSE: While growth hormone (GH) and the insulin-like growth factor type I (IGF-I) are known to exert synergistic actions on muscle anabolism, the consequences of prolonged GH deficiency (GHD) on muscle function have not been well defined. We have previously described a large cohort of subjects with isolated GHD (IGHD) caused by a mutation in the GH-releasing hormone receptor gene, with low serum levels of GH and IGF-I. The aim of this study was to assess muscular function in these IGHD subjects. METHODS: A total of 31 GH-naïve IGHD (16 males) and 40 control (20 males) subjects, matched by age and degree of daily physical activity, were enrolled. Fat free mass was measured by bioelectrical impedance; muscle strength by dynamometry of handgrip, trunk extension, and knee extension; myoelectric activity and muscle fatigue by fractal dimension; conduction velocity in vastus medialis, rectus femoris, and vastus lateralis muscles by surface electromyography. RESULTS: The IGHD group showed higher knee extension strength both when corrected for weight and fat free mass, and higher handgrip and trunk extension strength corrected by fat free mass. They also exhibit higher conduction velocity of the muscles vastus medialis, rectus femoris, and vastus lateralis, but lower free fat mass and myoelectric activity of the vastus medialis, rectus femoris and vastus lateralis. There were no differences between the two groups in fractal dimension in all studied muscles. CONCLUSION: Individuals with untreated IGHD have better muscle strength parameters adjusted for weight and fat free mass than controls. They also exhibit greater peripheral resistance to fatigue, demonstrating satisfactory muscle function.
Assuntos
Nanismo Hipofisário/fisiopatologia , Músculo Esquelético/fisiopatologia , Adulto , Idoso , Composição Corporal , Brasil , Estudos de Coortes , Nanismo Hipofisário/genética , Impedância Elétrica , Eletromiografia , Feminino , Força da Mão , Humanos , Masculino , Pessoa de Meia-Idade , Fadiga Muscular , Força Muscular , Dinamômetro de Força Muscular , Receptores da Somatotropina/genéticaRESUMO
Background During the transition phase (TP), patients with growth hormone deficiency (GHD) exhibit decreased muscle strength. Studies assessing the effects of resistance exercise alone on muscle strength in these individuals are scarce. The objective of this study was to evaluate the effects of a program of resistance exercise (PRE) on parameters of muscle strength in subjects in the TP and with childhood-onset GHD treated with recombinant GH (rGH). Methods Sixteen male patients were enrolled and divided into two groups: GHD (n=9) and GH sufficiency (GHS, n=7). Patients with GHD underwent a 12-week PRE followed by another 12-week PRE plus rGH, while GHS patients underwent a 12-week PRE alone. Dynamic knee muscle strength was evaluated using an isokinetic dynamometer. Results Before PRE, there were significant differences between the groups regarding the results of flexor peak torque (FPT) normalized to body weight (BW-FPT) in the dominant (DO, p=0.008) and non-dominant (ND, p=0.01) limbs, and in the agonist/antagonist (A/A) ratio in the DO (p=0.02) and ND (p=0.006) limbs. After PRE in the GHD group, values of FPT and BW-FPT in both limbs increased significantly (p<0.001) and independently of rGH, while the A/A ratio value improved significantly (p<0.001) in the ND limb. Conclusions A short period of PRE alone was sufficient to improve parameters of muscle strength in young male adults with childhood-onset GHD.
Assuntos
Nanismo Hipofisário/terapia , Terapia por Exercício/métodos , Hormônio do Crescimento Humano/deficiência , Força Muscular/fisiologia , Treinamento Resistido , Adolescente , Adulto , Composição Corporal , Peso Corporal , Nanismo Hipofisário/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: Ocular function is fundamental for environmental adaptation and survival capacity. Growth factors are necessary for a mature eyeball, needed for adequate vision. However, the consequences of the deficiency of circulating growth hormone (GH) and its effector insulin-like growth factor I (IGF-I) on the physical aspects of the human eye are still debated. A model of untreated isolated GH deficiency (IGHD), with low but measurable serum GH, may clarify this issue. The aim of this study was to assess the ocular aspects of adult IGHD individuals who have never received GH therapy. DESIGN: Cross sectional study. METHODS: Setting: University Hospital, Federal University of Sergipe, Brazil. PATIENTS: Twenty-five adult (13 males, mean age 50.1years, range 26 to 70years old) IGHD subjects homozygous for a null mutation (c.57+1G>A) in the GHRH receptor gene, and 28 (15 males, mean age 51.1years, range 26 to 67years old) controls were submitted to an endocrine and ophthalmological assessment. Forty-six IGHD and 50 control eyes were studied. MAIN OUTCOME MEASURES: Visual acuity, intraocular pressure, refraction (spherical equivalent), ocular axial length (AL), anterior chamber depth (ACD), lens thickness (LT), vitreous depth (VD), mean corneal curvature (CC) and central corneal thickness (CCT). RESULTS: IGHD subjects exhibited unmeasurable serum IGF-I levels, similar visual acuity, intraocular pressure and LT, higher values of spherical equivalent and CC, and lower measures of AL, ACD, VD and CCT in comparison to controls, but within their respective normal ranges. While mean stature in IGHD group was 78% of the control group, mean head circumference was 92% and axial AL was 96%. CONCLUSIONS: These observations suggest mild ocular effects in adult subjects with severe IGF-I deficiency due to non-treated IGHD.
Assuntos
Hormônio do Crescimento Humano/deficiência , Hipopituitarismo/complicações , Hipopituitarismo/genética , Mutação com Perda de Função , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Visão Ocular/fisiologia , Adulto , Idoso , Estudos Transversais , Nanismo Hipofisário/genética , Nanismo Hipofisário/patologia , Nanismo Hipofisário/fisiopatologia , Olho/patologia , Feminino , Humanos , Hipopituitarismo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Acuidade VisualRESUMO
The GH/IGF-I axis has important interactions with the alimentary system and with the balance between energy intake (EI) and energy requirement (ER). Reduced EI has been described in adult-onset acquired GH deficiency (GHD). Individuals from the Brazilian Itabaianinha cohort, with isolated GHD (IGHD) due to a homozygous mutation (c.57+1GâA) in the GHRH receptor gene, are an ideal model to study the consequences of lifetime GHD. The purpose of this study is to evaluate EI and ER in this untreated IGHD cohort. Cross-sectional study of 24 adult IGHD patients and 23 controls from the same region, matched for age and gender. Estimated EI (EEI) was evaluated by dietary recall, and estimated ER (EER) by the equation of the Dietary Reference Intakes. Fat mass was assessed by DXA. Both EEI and EER were lower in IGHD than controls. However, when corrected by body weight, EEI was higher in IGHD (p = 0.005). IGHD individuals consume in percentage more proteins (p < 0.0001), less carbohydrates (p = 0.013), and equal amount of lipids in comparison to controls. The higher EEI per body weight suggests a possible increase of orexigenic mechanisms in untreated IGHD individuals, ensuring greater caloric intake, which would have adaptive advantages for small-sized individuals in environments with limited access to food. IGHD individuals seem to have a healthier dietary pattern than CO.
Assuntos
Nanismo Hipofisário/genética , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/fisiologia , Preferências Alimentares/fisiologia , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Adulto , Idoso , Brasil , Estudos Transversais , Nanismo Hipofisário/fisiopatologia , Ingestão de Energia/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
OBJECTIVE: To analyze the voice formants (F1, F2, F3, and F4 in Hz) of seven oral vowels, in Brazilian Portuguese, [a, ε, e, i, É, o, and u] in adult individuals with congenital lifetime untreated isolated growth hormone deficiency (IGHD). STUDY DESIGN: This is a cross-sectional study. METHODS: Acoustic analysis of isolated vowels was performed in 33 individuals with IGHD, age 44.5 (17.6) years (16 women), and 29 controls, age 51.1 (17.6) years (15 women). RESULTS: Compared with controls, IGHD men showed higher values of F3 [i, e, and ε], P = 0.006, P = 0.022, and P = 0.006, respectively and F4 [i], P = 0.001 and lower values of F2 [u], P = 0.034; IGHD women presented higher values of F1 [i and e] P = 0.029 and P = 0.036; F2 [É] P = 0.006; F4 [É] P = 0.031 and lower values of F2 [i] P = 0.004. IGHD abolished most of the gender differences in formant frequencies present in controls. CONCLUSIONS: Congenital, severe IGHD results in higher values of most formant frequencies, suggesting smaller oral and pharyngeal cavities. In addition, it causes a reduction in the effect of gender on the structure of the formants, maintaining a prepubertal acoustic prediction.
Assuntos
Nanismo Hipofisário/fisiopatologia , Hormônio do Crescimento Humano/deficiência , Acústica da Fala , Qualidade da Voz , Acústica , Adulto , Idoso , Biomarcadores/sangue , Brasil , Estudos de Casos e Controles , Estudos Transversais , Nanismo Hipofisário/sangue , Nanismo Hipofisário/diagnóstico , Nanismo Hipofisário/genética , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Boca/crescimento & desenvolvimento , Faringe/crescimento & desenvolvimento , Índice de Gravidade de Doença , Fatores Sexuais , Medida da Produção da FalaRESUMO
OBJECTIVES: Growth hormone deficiency (GHD) in adults is associated with decreased extracellular water volume (ECW). In response to GH replacement therapy (GHRT), ECW increases and blood pressure (BP) reduces or remains unchanged. Our primary aim was to study the association between polymorphisms in genes related to renal tubular function with ECW and BP before and 1 year after GHRT. The ECW measures using bioimpedance analysis (BIA) and bioimpedance spectroscopy (BIS) were validated against a reference method, the sodium bromide dilution method (Br(-)). DESIGN AND METHODS: Using a candidate gene approach, fifteen single-nucleotide polymorphisms (SNPs) in nine genes with known impact on renal tubular function (AGT, SCNN1A, SCNN1G, SLC12A1, SLC12A3, KCNJ1, STK39, WNK1 and CASR) were genotyped and analyzed for associations with ECW and BP at baseline and with their changes after 1 year of GHRT in 311 adult GHD patients. ECW was measured with the Br(-), BIA, and BIS. RESULTS: Both BIA and BIS measurements demonstrated similar ECW results as the reference method. At baseline, after adjustment for sex and BMI, SNP rs2291340 in the SLC12A1 gene was associated with ECW volume in GHD patients (p = 0.039). None of the SNPs influenced the ECW response to GHRT. One SNP in the SLC12A3 gene (rs11643718; p = 0.024) and three SNPs in the SCNN1G gene [rs5723 (p = 0.02), rs5729 (p = 0.016) and rs13331086 (p = 0.035)] were associated with the inter-individual differences in BP levels at baseline. A polymorphism in the calcium-sensing receptor (CASR) gene (rs1965357) was associated with changes in systolic BP after GHRT (p = 0.036). None of these associations remained statistically significant when corrected for multiple testing. CONCLUSION: The BIA and BIS are as accurate as Br(-) to measure ECW in GHD adults before and during GHRT. Our study provides the first evidence that individual polymorphisms may have clinically relevant effects on ECW and BP in GHD adults.
Assuntos
Água Corporal/fisiologia , Nanismo Hipofisário/fisiopatologia , Líquido Extracelular/fisiologia , Adolescente , Adulto , Idoso , Pressão Sanguínea , Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/genética , Nanismo Hipofisário/metabolismo , Feminino , Frequência do Gene , Estudos de Associação Genética , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Adulto JovemRESUMO
OBJECTIVE: To evaluate the hearing status of growth hormone (GH)-naive adults with isolated GH deficiency (IGHD) belonging to an extended Brazilian kindred with a homozygous mutation in the GH-releasing hormone receptor gene. STUDY DESIGN: Cross-sectional. SETTING: Divisions of Endocrinology and Otorhinolaryngology of the Federal University of Sergipe. SUBJECTS AND METHODS: Twenty-six individuals with IGHD (age, 47.6 ± 15.1 years; 13 women) and 25 controls (age, 46.3 ± 14.3 years; 15 women) were administered a questionnaire on hearing complaints and hearing health history. We performed pure-tone audiometry, logoaudiometry, electroacoustic immittance, and stapedial reflex. To assess outer hair cell function in the cochlea, we completed transient evoked otoacoustic emissions (TEOAEs). To assess the auditory nerve and auditory brainstem, we obtained auditory brainstem responses (ABRs). RESULTS: Misophonia and dizziness complaints were more frequent in those with IGHD than in controls (P = .011). Patients with IGHD had higher thresholds at 250 Hz (P = .005), 500 Hz (P = .006), 3 KHz (P = .008), 4 KHz (P = .038), 6 KHz (P = .008), and 8 KHz (P = .048) and mild high-tones hearing loss (P = .029). Stapedial reflex (P < .001) and TEOAEs (P = .025) were more frequent in controls. There were no differences in ABR latencies. Hearing loss in patients with IGHD occurred earlier than in controls (P < .001). CONCLUSION: Compared with controls of the same area, subjects with untreated, congenital lifetime IGHD report more misophonia and dizziness, have predominance of mild high-tones sensorineural hearing loss, and have an absence of stapedial reflex and TEOAEs.