RESUMO
BACKGROUND: Patients with type 1 diabetes mellitus (T1DM) are more prone to develop other auto-immune diseases, including coeliac disease (CD). Paediatric patients with T1DM are screened for CD, whereas in adult T1DM patients screening programs for CD are not standardised. The aim of this study was to investigate clinical and genetic characteristics of patients with both diagnoses so as to lead to better detection of CD in adult patients with T1DM. METHODS: We studied 118 patients with both T1DM and CD identified in The Netherlands. We retrospectively collected data on sex distribution, age of onset of T1DM, age of CD diagnosis, CD complaints, duration of CD complaints before CD diagnosis, family history of CD or T1DM, comorbidity and HLA-DQ type. RESULTS: Thirty-three percent of T1DM+CD patients reported CD related complaints for at least 5 years before CD diagnosis. Two peaks in the age of CD diagnosis in T1DM patients were observed: around 10 and 45 years of age. Women were diagnosed with CD at a younger age than men (median 25 years (IQR 9-38) versus 39 (12-55) years, respectively, P<0.05). CONCLUSION: A delay of CD diagnosis is frequently found in adult T1DM patients and two peaks in the age of CD diagnosis are present in T1DM patients. This observational study emphasises that more frequent screening for CD in particularly adult T1DM patients is required, preferably by a 5 years interval.
Assuntos
Doença Celíaca , Diagnóstico Tardio , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Antígenos HLA-DQ/genética , Adolescente , Adulto , Doença Celíaca/diagnóstico , Doença Celíaca/epidemiologia , Doença Celíaca/genética , Criança , Comorbidade , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Using exome and candidate gene sequencing, we identified 8 distinct mutations and 2 deletions in IGSF1 in males from 11 unrelated families with central hypothyroidism, testicular enlargement and variably low prolactin concentrations. IGSF1 is a membrane glycoprotein that is highly expressed in the anterior pituitary gland, and the identified mutations impair its trafficking to the cell surface in heterologous cells. Igsf1-deficient male mice show diminished pituitary and serum thyroid-stimulating hormone (TSH) concentrations, reduced pituitary thyrotropin-releasing hormone (TRH) receptor expression, decreased triiodothyronine concentrations and increased body mass. Collectively, our observations delineate a new X-linked disorder in which loss-of-function mutations in IGSF1 cause central hypothyroidism, likely secondary to an associated impairment in pituitary TRH signaling.
Assuntos
Hipotireoidismo Congênito/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Imunoglobulinas/genética , Proteínas de Membrana/genética , Mutação , Doenças Testiculares/genética , Adolescente , Adulto , Idoso , Animais , Sequência de Bases , Criança , Pré-Escolar , Exoma , Compostos Ferrosos , Humanos , Lactente , Masculino , Metalocenos , Camundongos , Pessoa de Meia-Idade , Hipófise/metabolismo , Hipófise/patologia , Prolactina/sangue , Receptores do Hormônio Liberador da Tireotropina/biossíntese , Análise de Sequência de DNA , Síndrome , Testículo/anatomia & histologia , Testículo/patologia , Tireotropina/sangue , Tri-Iodotironina/análise , Adulto JovemRESUMO
BACKGROUND/AIMS: In classical congenital adrenal hyperplasia (CAH), elevation of adrenal androgens leads to accelerated growth and bone maturation with compromised adult height. In untreated children with non-classical CAH (NC-CAH), in which adrenal androgens are generally only slightly increased, growth velocity may not be significantly elevated. METHODS: Twenty-four patients were included and divided into a symptomatic and an asymptomatic group. Height was expressed as height standard deviation scores (HSDS) and corrected for target height (HSDS-THSDS). Bone maturation was expressed as bone age acceleration (BA(c) = bone age - calendar age). Linear mixed models with random factor patient were used for the analysis of growth and bone age. RESULTS: In symptomatic patients (n = 17), HSDS-THSDS only slightly increased by 0.06 SDS per year (95% CI 0.02-0.10). Mean BA(c) was 2.21 years (SDS 0.66, p < 0.0001). In asymptomatic patients (n = 7), no significant growth acceleration or BA(c) was found. CONCLUSIONS: In untreated NC-CAH children, growth acceleration is small and generally not visible on their growth charts. BA(c) is more pronounced. Therefore, the absence of an increase in growth velocity does not exclude the diagnosis of NC-CAH. When considering this diagnosis, bone age acceleration should also be taken into account.
Assuntos
Hiperplasia Suprarrenal Congênita/fisiopatologia , Desenvolvimento Ósseo , Determinação da Idade pelo Esqueleto , Criança , Pré-Escolar , Feminino , Humanos , MasculinoRESUMO
CONTEXT AND OBJECTIVE: GH therapy increases growth and adult height in Turner syndrome (TS). The benefit to risk ratio of adding the weak androgen oxandrolone (Ox) to GH is unclear. DESIGN AND PARTICIPANTS: A randomized, placebo-controlled, double-blind, dose-response study was performed in 10 centers in The Netherlands. One hundred thirty-three patients with TS were included in age group 1 (2-7.99 yr), 2 (8-11.99 yr), or 3 (12-15.99 yr). Patients were treated with GH (1.33 mg/m(2) . d) from baseline, combined with placebo (Pl) or Ox in low (0.03 mg/kg . d) or conventional (0.06 mg/kg . d) dose from the age of 8 yr and estrogens from the age of 12 yr. Adult height gain (adult height minus predicted adult height) and safety parameters were systematically assessed. RESULTS: Compared with GH+Pl, GH+Ox 0.03 increased adult height gain in the intention-to-treat analysis (mean +/- sd, 9.5 +/- 4.7 vs. 7.2 +/- 4.0 cm, P = 0.02) and per-protocol analysis (9.8 +/- 4.9 vs. 6.8 +/- 4.4 cm, P = 0.02). Partly due to accelerated bone maturation (P < 0.001), adult height gain on GH+Ox 0.06 was not significantly different from that on GH+Pl (8.3 +/- 4.7 vs. 7.2 +/- 4.0 cm, P = 0.3). Breast development was slower on GH+Ox (GH+Ox 0.03, P = 0.02; GH+Ox 0.06, P = 0.05), and more girls reported virilization on GH+Ox 0.06 than on GH+Pl (P < 0.001). CONCLUSIONS: In GH-treated girls with TS, we discourage the use of the conventional Ox dosage (0.06 mg/kg . d) because of its low benefit to risk ratio. The addition of Ox 0.03 mg/kg . d modestly increases adult height gain and has a fairly good safety profile, except for some deceleration of breast development.
Assuntos
Estatura/efeitos dos fármacos , Hormônio do Crescimento Humano/uso terapêutico , Oxandrolona/administração & dosagem , Oxandrolona/efeitos adversos , Síndrome de Turner/tratamento farmacológico , Adolescente , Fatores Etários , Androgênios/administração & dosagem , Androgênios/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Feminino , Humanos , Países Baixos , Puberdade/efeitos dos fármacos , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Virilismo/induzido quimicamenteRESUMO
CONTEXT: Patients with GHRH receptor (GHRH-R) mutations present with familial isolated GH deficiency, which untreated leads to a severely compromised adult height. Few data are available about the efficacy of treatment with GH in combination with a GnRH analog (GnRHa) in adolescence. OBJECTIVE: The objective of the study was to describe the evolution of growth and skeletal age of a brother and sister of Moroccan descent with a homozygous GHRH-R mutation who presented at an advanced age (16 and 14.9 yr, respectively) and pubertal stage (Tanner stage G4 and B3, respectively) with a height of -5.1 sd score and -7.3 sd score on treatment with a combination of GH and GnRHa for 2.5 and 3 yr followed by GH alone. METHODS: GH was given in a dosage of 0.7 mg/m2.d (25 microg/kg.d) sc and triptorelin in a dosage of 3.75 mg per 4 wk im. Height and pubertal stage were measured three-monthly, bone age yearly. RESULTS: Combined GH and GnRHa treatment resulted in a height gain of 24 and 28.2 cm, respectively, compared with the initial predicted adult height by the method of Bayley and Pinneau. Adult height was within the population range and well within the target range. CONCLUSIONS: Our patients demonstrate that, in case of isolated GH deficiency caused by a GHRH-R mutation, combined treatment of GH and GnRHa can be very effective in increasing final height, even at an advanced bone age and pubertal stage.
Assuntos
Estatura/efeitos dos fármacos , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Mutação Puntual , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Pamoato de Triptorrelina/uso terapêutico , Adulto , Feminino , Transtornos do Crescimento/genética , Humanos , Masculino , Marrocos/etnologia , Países BaixosRESUMO
UNLABELLED: Context Alterations in the GH-IGF-I axis in short small-for-gestational-age (SGA) children might be associated with abnormalities in bone mineral density (BMD) and body composition. In addition, birth weight has been inversely associated with diabetes and cardiovascular disease in adult life. Data on detailed body composition in short SGA children and long-term effects of GH treatment are very scarce. OBJECTIVE: To investigate effects of long-term GH treatment on body composition and BMD by dual energy X-ray absorptiometry (DXA) in short SGA children. DESIGN: Longitudinal 6-year GH study with a randomized controlled part for 3 years. RESULTS: At baseline, fat percentage standard deviation score (SDS) and lumbar spine BMD SDS corrected for height (BMAD(LS) SDS) were significantly lower than zero. Lean body mass (LBM) SDS adjusted for age was also reduced, but LBM adjusted for height (LBM SDS(height)) was not decreased. GH treatment induced a decrease in fat percentage SDS and an increase in BMAD(LS) SDS. LBM SDS(height) remained similar in GH-treated children, but deteriorated in untreated controls. When these untreated controls subsequently started GH treatment, their LBM SDS(height) rapidly normalized to values comparable with zero. CONCLUSION: During long-term GH treatment in short SGA children, fat percentage SDS decreased and BMAD(LS) SDS increased. These effects of GH treatment were most prominent in children who started treatment at a younger age and in those with greater height gain during GH treatment. LBM SDS(height )remained around 0 SDS in GH-treated children, but declined to low normal values in untreated controls.
Assuntos
Composição Corporal/efeitos dos fármacos , Estatura/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Hormônio do Crescimento Humano/uso terapêutico , Recém-Nascido Pequeno para a Idade Gestacional , Absorciometria de Fóton , Criança , Feminino , Seguimentos , Humanos , Recém-Nascido , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Vértebras Lombares , Masculino , TempoRESUMO
Although GH treatment for short stature in Turner syndrome is an accepted treatment in many countries, which GH dosage to use and which age to start puberty induction are issues of debate. This study shows final height (FH) in 60 girls with Turner syndrome treated in a randomized dose-response trial, combining GH treatment with low dose estrogens at a relatively young age. Girls were randomly assigned to group A (4 IU/m(2).d; approximately 0.045 mg/kg/d), group B (first year, 4 IU/m(2).d; thereafter 6 IU/m(2).d), or group C (first year, 4 IU/m(2).d; second year, 6 IU/m(2).d; thereafter, 8 IU/m(2).d). After a minimum of 4 yr of GH treatment, at a mean age of 12.7 +/- 0.7 yr, low dose micronized 17beta-estradiol was given orally. After a mean duration of GH treatment of 8.6 +/- 1.9 yr, FH was reached at a mean age of 15.8 +/- 0.9 yr. FH, expressed in centimeters or SD score, was 157.6 +/- 6.5 or -1.6 +/- 1.0 in group A, 162.9 +/- 6.1 or -0.7 +/- 1.0 in group B, and 163.6 +/- 6.0 or -0.6 +/- 1.0 in group C. The difference in FH in centimeters, corrected for height SD score and age at start of treatment, was significant between groups A and B [regression coefficient, 4.1; 95% confidence interval (CI), 1.4, 6.9; P < 0.01], and groups A and C (coefficient, 5.0; 95% CI, 2.3, 7.7; P < 0.001), but not between groups B and C (coefficient, 0.9; 95% CI, -1.8, 3.6). Fifty of the 60 girls (83%) had reached a normal FH (FH SD score, more than -2). After starting estrogen treatment, the decrease in height velocity (HV) changed significantly to a stable HV, without affecting bone maturation (change in bone age/change in chronological age). The following variables contributed significantly to predicting FH SD score: GH dose, height SD score (ref. normal girls), chronological age at start of treatment, and HV in the first year of GH treatment. GH treatment was well tolerated. In conclusion, GH treatment leads to a normalization of FH in most girls, even when puberty is induced at a normal pubertal age. The optimal GH dosage depends on height and age at the start of treatment and first year HV.