RESUMEN
STUDY OBJECTIVES: We analyzed the potential predictive factors for precocious puberty, observed in some cases of childhood narcolepsy with cataplexy (NC) and for obesity, a much more common feature of NC, through a systematic assessment of pubertal staging, body mass index (BMI), and metabolic/endocrine biochemical analyses. DESIGN: Cross-sectional on consecutive recruitment. SETTING: Hospital sleep center and pediatric unit. PATIENTS: Forty-three children and adolescents with NC versus 52 age-matched obese children as controls. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Patients underwent clinical interview, polysomnographic recordings, cerebrospinal fluid hypocretin-1 measurement, and human leukocyte antigen typing. Height, weight, arterial blood pressure, and Tanner pubertal stage were evaluated. Plasma lipid and glucose profiles were analyzed. When an altered pubertal development was clinically suspected, plasma concentrations of hypothalamic-pituitary-gonadal axis hormones were determined. Children with NC showed a high prevalence of overweight/obesity (74%) and a higher occurrence of precocious puberty (17%) than obese controls (1.9%). Isolated signs of accelerated pubertal development (thelarche, pubic hair, advanced bone age) were also present (41%). Precocious puberty was significantly predicted by a younger age at first NC symptom onset but not by overweight/obesity or other factors. In addition, overweight/obesity was predicted by younger age at diagnosis; additional predictors were found for overweight/obesity (short disease duration, younger age at weight gain and lower high-density lipoprotein cholesterol), which did not include precocious puberty. NC symptoms, pubertal signs appearance, and body weight gain developed in close temporal sequence. CONCLUSIONS: NC occurring during prepubertal age is frequently accompanied by precocious puberty and overweight/obesity, suggesting an extended hypothalamic dysfunction. The severity of these comorbidities and the potential related risks require a multidiagnostic approach and a tailored therapeutic management.
Asunto(s)
Narcolepsia/epidemiología , Obesidad/epidemiología , Pubertad Precoz/epidemiología , Índice de Masa Corporal , Niño , Comorbilidad , Estudios Transversales , Femenino , Humanos , Modelos Logísticos , Hormona Luteinizante/sangre , Masculino , Prevalencia , Estadísticas no ParamétricasRESUMEN
BACKGROUND/AIMS: Mutations of the short stature homeobox-containing (SHOX) gene on the pseudoautosomal region of the sex chromosomes cause short stature. GH treatment has been recently proposed to improve height in short patients with SHOX deficiency. The aim of this study was to evaluate GH secretion and analyze growth and safety of recombinant human GH (rhGH) therapy in short children and adolescents with SHOX deficiency. PATIENTS AND DESIGN: We studied 16 patients (10 females; 9.7 ± 2.9 years old; height -2.46 ± 0.82 standard deviation score, SDS) with SHOX deficiency. All subjects underwent auxological evaluations, biochemical investigations, and were treated with rhGH (0.273 ± 0.053 mg/kg/week). RESULTS: Impaired GH secretion was present in 37.5% of the studied subjects. Comparing baseline data with those at the last visit, we found that rhGH treatment improved growth velocity SDS (from -1.03 ± 1.44 to 2.77 ± 1.95; p = 0.001), height SDS (from -2.41 ± 0.71 to -1.81 ± 0.87; p < 0.001), and IGF-1 values (from -0.57 ± 1.23 to 0.63 ± 1.63 SDS, p = 0.010) without affecting body mass index SDS. Height SDS measured at the last visit was significantly correlated with chronological age (r = -0.618, p = 0.032), bone age (r = -0.582, p = 0.047) and height SDS (r = 0.938, p < 0.001) at the beginning of treatment. No adverse events were reported on rhGH therapy which was never discontinued. CONCLUSION: These data showed that impaired GH secretion is not uncommon in SHOX deficiency subjects, and that rhGH therapy may be effective in increasing height in most of these patients independent of their GH secretory status, without causing any adverse events of concern.
Asunto(s)
Trastornos del Crecimiento/genética , Hormona del Crecimiento/uso terapéutico , Proteínas de Homeodominio/genética , Hormona de Crecimiento Humana/metabolismo , Adolescente , Estatura/genética , Niño , Preescolar , Femenino , Dedos/anomalías , Trastornos del Crecimiento/tratamiento farmacológico , Enfermedades del Cabello/tratamiento farmacológico , Enfermedades del Cabello/genética , Hormona de Crecimiento Humana/genética , Humanos , Síndrome de Langer-Giedion/tratamiento farmacológico , Síndrome de Langer-Giedion/genética , Masculino , Nariz/anomalías , Osteocondrodisplasias/tratamiento farmacológico , Osteocondrodisplasias/genética , Proteínas Recombinantes/uso terapéutico , Proteína de la Caja Homeótica de Baja EstaturaRESUMEN
We report on the outcome of intravenous high-dose immunoglobulin (IVIg) treatment in four children with narcolepsy and cataplexy, in whom the early diagnosis and the extreme disease severity were indications for this potentially efficacious therapy. One of four patients showed an objective and persistent improvement in clinical features during and after IVIg treatment. Our data partially support the recent report of the efficacy of IVIg treatment in early diagnosed narcolepsy with cataplexy and support the need for a controlled multicenter clinical trial on IVIg in narcolepsy.
Asunto(s)
Cataplejía/terapia , Inmunoglobulinas Intravenosas/administración & dosificación , Narcolepsia/terapia , Adolescente , Índice de Masa Corporal , Niño , Ritmo Circadiano , Femenino , Alucinaciones , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Índice de Severidad de la Enfermedad , Sueño , Parálisis del SueñoRESUMEN
BACKGROUND: Persistentmullerian duct syndrome (PMDS) is characterized by the presence of uterus, fallopian tubes and the upper part of the vagina in 46,XY patients with perfectly virilized external genitalia. It is mostly caused by mutations of the AMH or AMH type 2 receptor (AMHR2) gene. The AMH serum level is very often low or undetectable in the AMH gene defect and normal in the AMHR2 gene defect. AIM: We investigate an Italian patient, genotypically and phenotypically male, observed at 1 month of age for a right inguinal hernia that at surgery showed the presence of both testes in the same hernial sac and uterus and fallopian tubes in the abdomen. RESULTS: Genetic tests first showed the absence of the common 27-bp deletion in the AMHR2 gene, then the presence of three new sequence variations in the AMH geneleading to the following variants: the p.A405P carried by the paternal allele; the p.G326V plus the p.V508A carried by the maternal allele. CONCLUSIONS: The determination of serum AMH, performed after the genetic analysis, showed a normal level for age, suggesting that these mutations may affect the function and the bioactivity of the hormone and not the secretion rate.
Asunto(s)
Hormona Antimülleriana/sangre , Hormona Antimülleriana/genética , Conductos Paramesonéfricos/patología , Secuencia de Aminoácidos , Preescolar , Criptorquidismo/genética , Hernia Inguinal/genética , Humanos , Lactante , Recién Nacido , Masculino , Datos de Secuencia Molecular , Linaje , Receptores de Péptidos/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Alineación de Secuencia , SíndromeRESUMEN
CONTEXT: Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia syndrome (OMIM 160980). About 70% of cases are familiar; most have mutations of the PRKAR1A gene on chromosome 17q22-24. There is little phenotype-genotype correlation known to date. OBJECTIVE: To study the genotype-phenotype correlation in a family with newly diagnosed CNC and three generations of subjects bearing the same PRKAR1A mutation. The proband was diagnosed with hepatocellular carcinoma, a tumour that appears to be associated with CNC. DESIGN: The study consisted of clinical and genetic analysis of a total of 10 individuals belonging to a large Italian family. PATIENTS: The index case was referred for PRKAR1A gene mutation analysis because he met the diagnostic criteria for a clinical diagnosis of CNC. RESULTS: The PRKAR1A-inactivating mutation c.502 +1G > A in the intron 5 splice-donor site was detected after bidirectional sequencing of germline DNA. The mutation causes a frameshift in the transcribed sequence and a nonsense mRNA that was shown to be degraded; this leads to PRKAR1A haploinsufficiency in all tissues. All available relatives were screened first by DNA testing and, if the latter was positive, by clinical, biochemical and imaging means. CONCLUSIONS: A novel PRKAR1A mutation with an apparently low penetrance and variable expression is reported; the same mutation is also associated with a hepatocellular carcinoma. This is the first time a PRKAR1A mutation is reported in individuals who were diagnosed with CNC after retrospective family screening and following the identification of a proband; the finding has implications for genetic counselling on PRKAR1A and/or CNC.
Asunto(s)
Carcinoma Hepatocelular/genética , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Composición Familiar , Neoplasias Hepáticas/genética , Adulto , Carcinoma Hepatocelular/metabolismo , Niño , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/metabolismo , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Linaje , Fenotipo , Mutación Puntual , SíndromeRESUMEN
CONTEXT: GH replacement therapy in GH-deficient (GHD) patients is usually continued until adult height despite the fact that most of these subjects display a normal secretion when retested at the end of growth. Puberty is the most likely time for normalization of GH secretion. OBJECTIVES: The objectives of this study are to establish the characteristics and the percentage of the subjects with isolated GHD who normalized secretion at puberty and to compare their statural outcomes with those of the subjects with persistent deficiency treated also after retesting. DESIGN AND SETTING: This was a prospective, nonrandomized, open-label study conducted in a university research hospital. PATIENTS AND INTERVENTION: Sixty-nine subjects (40 male, 29 female) with a diagnosis before puberty of isolated GHD by means of arginine and l-dopa tests were reevaluated with the same tests after at least 2 yr of therapy and after puberty onset. If GH peak at retesting was more than 10 microg/liter, therapy was withdrawn. MAIN OUTCOME MEASURES: Percentage and characteristics of normalized subjects at retesting, outcome of treatment in the subjects treated or untreated to adult height, and factors predictive of growth outcome were measured. RESULTS: At retesting, 44 subjects (63.7%) confirmed a GH peak less than 10 microg/liter (24 of 40 male and 20 of 29 female). Apart from a less delayed bone age at diagnosis in females, the subjects with confirmed GHD were not different at diagnosis from the other group for height deficit at diagnosis, first year growth response to GH, age and height at puberty onset, height, and IGF-I at retesting. Mean adult height was 165.1 +/- 4.5 cm in the male group treated until adult height vs. 164.0 +/- 3.4 cm in the group who suspended therapy at retesting. Mean adult height was 153.2 +/- 4.1 cm in the female group treated until adult height vs. 152.9 +/- 5.2 cm in the group that suspended therapy at retesting. As regards the parameters expressing the final outcome, the only difference was found in the mean increment adult height-target height sd score in favor of the male group treated until adult height. In both sexes, therapy duration and GH levels at diagnosis and at retesting were unrelated to adult height parameters and to height increments during the period of observation. CONCLUSIONS: One third of our GHD subjects diagnosed before puberty presented a normal secretion at puberty. The withdrawal of GH therapy in these subjects after retesting was not associated with a catch down growth, and they obtained an adult height similar to those obtained by the GHD subjects treated until adult height. It seems convenient, in subjects with nonsevere GHD, to retest GH secretion at midpuberty and to withdraw treatment for the subjects that are no longer deficient.
Asunto(s)
Estatura/fisiología , Hormona de Crecimiento Humana/sangre , Pubertad/sangre , Privación de Tratamiento , Adolescente , Determinación de la Edad por el Esqueleto , Estatura/efectos de los fármacos , Niño , Enanismo Hipofisario/sangre , Enanismo Hipofisario/diagnóstico , Enanismo Hipofisario/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Hormonas Esteroides Gonadales/sangre , Trastornos del Crecimiento/sangre , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/tratamiento farmacológico , Pruebas Hematológicas , Terapia de Reemplazo de Hormonas , Hormona de Crecimiento Humana/análisis , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Masculino , Modelos Estadísticos , Análisis de Regresión , Caracteres Sexuales , Estadística como AsuntoRESUMEN
OBJECTIVE: Mutations in the gonadotropin-releasing hormone receptor (GnRHR) gene are the cause of isolated hypogonadotropic hypogonadism (HH). We describe the molecular investigations of the GnRHR gene in two siblings affected by HH and their clinical course. DESIGN: The female was referred at age 14 for pubertal delay with no secondary sexual signs, whereas the male had been followed since prepuberty. Hormonal evaluation showed very low levels of gonadotropins, luteinizing hormone-releasing hormone test (LHRH test) and sexual steroids in both patients, suggesting a possible defect in the mechanism of action of the GnRH gene on its receptor. METHODS: The GnRHR gene of the two siblings and their parents were analyzed by PCR followed by direct sequencing. RESULTS: Two new single nucleotide substitutions resulting in the T104I and the Y108C substitutions in the first extracellular loop (ECL1) were identified in both siblings. The molecular analysis confirmed the carrier status of the parents. CONCLUSIONS: We identified two new missense mutations in the GnRHR gene in two siblings with HH. The nature of the substitutions lying in the ECL1 involved in the ligand-receptor interaction, as well as the high conservation of the two residues in all mammalian GnRHR, are suggestive of some implications in the phenotype observed.
Asunto(s)
Hipogonadismo/genética , Mutación Missense , Receptores LHRH/genética , Adolescente , Adulto , Femenino , Gonadotropinas/sangre , Humanos , Ligandos , Masculino , Embarazo , Receptores LHRH/metabolismo , HermanosRESUMEN
BACKGROUND: Testis enlargement in McCune-Albright syndrome (MAS) is generally bilateral and associated with clinical and biochemical manifestations of sexual precocity. CASE REPORT: We describe for the first time an unreported clinical expression of MAS in a 4.6-year-old boy presenting with monolateral testis enlargement and no signs of sexual precocity or other clinical manifestations of MAS at the time of presenting with macroorchidism. Both testosterone and LHRH-stimulated gonadotropin levels were in the prepubertal range. Serum inhibin B was increased to a pubertal level indicating Sertoli cell activation. The histological and immunocytochemical evaluation of the enlarged testis revealed Sertoli cell hyperplasia with no mature Leydig cells. Mutation R201C of GNAS1 gene, classically responsible for MAS, was identified in DNA samples from the right testis biopsy and leukocytes. CONCLUSIONS: (a) MAS should be taken into consideration in the clinicopathological approach to a boy with monolateral macroorchidism; (b) testicular enlargement may be only the presenting clinical manifestation of MAS and is not necessarily linked to manifestations of peripheral precocious puberty; (c) testicular autonomous hyperfunction in MAS may be restricted to Sertoli cells, as also demonstrated previously by others.
Asunto(s)
Displasia Fibrosa Poliostótica/diagnóstico , Displasia Fibrosa Poliostótica/patología , Testículo/anomalías , Antígenos de Neoplasias , Preescolar , Cromograninas , Diagnóstico Diferencial , Displasia Fibrosa Poliostótica/sangre , Displasia Fibrosa Poliostótica/genética , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Subunidades alfa de la Proteína de Unión al GTP Gs/fisiología , Gonadotropinas/sangre , Humanos , Hiperplasia , Inmunohistoquímica , Inhibinas/sangre , Antígeno MART-1 , Masculino , Mutación , Proteínas de Neoplasias/análisis , Pubertad Precoz/diagnóstico , Células de Sertoli/química , Células de Sertoli/patología , Testículo/patología , Testosterona/sangreRESUMEN
OBJECTIVE: The differential diagnosis of male under-masculinization, including a wide spectrum of phenotypes and a heterogeneous genetic basis, is crucial for the correct management of the patients. To characterize an Italian population of under-masculinized males, we performed the molecular analysis of the SRD5A2 gene (2p23), encoding the 5alpha-reductase-2 enzyme that converts testosterone (T) to dihydrotestosterone (DHT), and is required for full masculinization of the male foetus. DESIGN AND PATIENTS: Twenty-six Italian patients with 46,XY kariotype and various degrees of ambiguous genitalia were retrospectively selected for this study. Twelve of these patients, 10 of whom were referred for partial androgen insensitivity syndrome (PAIS), were raised as females; 15 were raised as males and all had a severe hypospadias. For most of the patients, the case histories and hormonal findings were incomplete but all could be included in the clinical characteristics of under-masculinization. MEASUREMENT: For hormonal evaluation, T and DHT were measured by means of radioimmunoassay (RIA) and high-performance liquid chromatography (HPLC)-RIA methods, respectively. Genomic DNA of all patients and relatives was extracted from peripheral blood, the five exons of the SRD5A2 gene were amplified by polymerase chain reaction (PCR) and submitted to automatic sequencing. RESULTS: Five known mutations affecting the NADPH binding function and one new mutation affecting the enzyme C-terminus were identified in a total of eight patients (two of whom were sisters). Five families were characterized, and in two patients only one affected allele was observed. The extension of the analysis to the regions flanking exons allowed the identification of a new polymorphism in intron 2, whose frequency was determined. CONCLUSION: This first report of an Italian population underlines the importance of differential diagnoses in patients with under-masculinization. The lack of precise genotype-phenotype correlation in some of the mutations highlights the necessity to improve knowledge about the biochemical aspects of steroid 5alpha-reductase action and about the interactions of genetic and environmental factors.
Asunto(s)
3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/genética , Trastornos del Desarrollo Sexual/genética , Mutación Puntual , Polimorfismo Genético , Estudios de Casos y Controles , Niño , Preescolar , Trastornos del Desarrollo Sexual/cirugía , Heterocigoto , Humanos , Lactante , Italia , Cariotipificación , Masculino , OrquiectomíaRESUMEN
BACKGROUND: Ghrelin is a peptide with a potent capacity to release GH and other metabolic activities. An acyl modification is indispensable for biological activity. Acylated and desacylated forms of ghrelin are both present in the blood. No data exist about the ratio between active ghrelin and total ghrelin in the first period of life. OBJECTIVE: To investigate whether ghrelin may be involved in physiological roles during fetal life. INFANTS AND METHODS: Ghrelin, growth hormone (GH), and leptin concentrations were measured in cord plasma in 98 newborns of healthy mothers. Acyl-ghrelin and the sum of acylated and desacylated forms of ghrelin (total ghrelin) were measured using specific radioimmunoassays. RESULTS: Acylated ghrelin and total ghrelin did not correlate with birth weight, gestational age, body mass index, head circumference, birth length, leptin or GH in plasma cord blood. CONCLUSIONS: The absence of clinically significant correlations between both active and total ghrelin and GH, leptin or anthropometric data does not enable us to ascribe a precise role to ghrelin in prenatal life.
Asunto(s)
Sangre Fetal , Hormonas Peptídicas/sangre , Acetilación , Femenino , Ghrelina , Hormona de Crecimiento Humana/sangre , Humanos , Recién Nacido , Masculino , Concentración Osmolar , Hormonas Peptídicas/metabolismo , Radioinmunoensayo/métodosRESUMEN
Mild insulin resistance appears to be an early metabolic defect in girls with Turner syndrome (TS). Impaired glucose tolerance has been reported in 10-34% of patients with TS, and type 2 diabetes mellitus is 2-4 times more common and occurs at a younger age in girls with TS than in the general population. In a mixed longitudinal and cross-sectional study, we analysed carbohydrate tolerance and insulin sensitivity in 46 children and adolescents with TS who reached their final height after long-term treatment (mean 6.3 +/- 2.5 years) with growth hormone (GH: 0.33 mg/kg/week [0.05 mg/kg/day]), and in 36 of these patients who were followed-up after the cessation of GH therapy (mean follow-up, 2.6 +/- 2.5 years; range, 1-9.5 years). Patients with TS were compared with an age-matched female control group. Insulin sensitivity appeared to be lower in patients with TS than in controls, even before the start of GH therapy. As in controls, insulin sensitivity decreased with age in patients with TS, and levels were lower in those aged >12 years than in those aged <12 years. GH therapy resulted in good catch-up growth in patients with TS, with final height significantly higher than projected height evaluated before the initiation of GH therapy. Insulin sensitivity increased after 7-8 years of therapy and, on the cessation of GH therapy, returned to pre-treatment levels. The increase in insulin sensitivity seen on the cessation of GH therapy appeared to be influenced negatively by body mass index and triglyceride levels, and correlated positively with the number of years since cessation of GH therapy. As in the general population, excess weight and an abnormal lipid profile, in particular excess triglyceride levels, worsened insulin sensitivity. In conclusion, our study confirms that GH therapy reduces insulin sensitivity, but at its cessation there is a return to pre-therapy values. We therefore report a progressive improvement in carbohydrate tolerance and insulin function in patients with TS, despite an increase in age.
Asunto(s)
Hormona de Crecimiento Humana/administración & dosificación , Resistencia a la Insulina , Metabolismo de los Lípidos/efectos de los fármacos , Triglicéridos/sangre , Síndrome de Turner/sangre , Adolescente , Adulto , Factores de Edad , Estatura/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Niño , Preescolar , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Prueba de Tolerancia a la Glucosa/métodos , Hormona de Crecimiento Humana/efectos adversos , Humanos , Síndrome de Turner/complicaciones , Síndrome de Turner/tratamiento farmacológicoRESUMEN
OBJECTIVE: To verify whether a reduced birth weight for gestational age was associated with a testicular dysfunction in postpubertal boys. STUDY DESIGN: Boys born small for gestational age (SGA) (n = 25) were compared to 24 born with an appropriate weight. All subjects were postpubertal (mean age 17.5 +/- 1.3 and 17.6 +/- 2.0 years, respectively). The following clinical and endocrinologic variables were evaluated: final height, target height, body mass index, testicular volume, follicle-stimulating hormone, luteinizing hormone, testosterone, and inhibin B. RESULTS: The SGA group had reduced testicular size (16.3 +/- 2.7 mL vs 22.8 +/- 3.2 mL; P <.0001) with a lower testosterone level (3.76 +/- 1.35 ng/mL vs 4.77 +/- 1.55 ng/mL; P <.05) and a higher LH value (4.41 +/- 1.61 IU/L vs 3.44 +/- 1.29 IU/L; P <.05). Among the SGA group, 54% had a mean testicular volume >2 SD below the control mean (ie, <16 mL) and in these subjects, the inhibin B level was low (143 +/- 46 pg/mL vs 229 +/- 76 pg/mL; P <.0001). SGA patients with smaller testes had lower final height relative to target height(P <.05 vs patients with larger testes) and for the SGA group, inhibin B correlated with testicular size (P <.0001). Positive correlations also were found between the reduction of final height relative to target height and testicular volume (P <.005) and inhibin B values (P <.05). CONCLUSIONS: SGA subjects have pituitary-gonadal axis function that tends toward hypogonadism. There is a disruption of the exocrine function in subjects with smaller testicular size who failed to show a complete height catch-up growth. This study supports a link between low birth weight and lower fertility in adult males.