RESUMEN
Congenital nephrogenic diabetes insipidus (CNDI, arginine vasopressin resistance) is a rare inherited disorder characterized by insensitivity of the kidney to the antidiuretic effect of vasopressin. NDI is clinically characterized by polyuria with hyposthenuria and nocturia and polydipsia. In the majority of cases, about 90%, nephrogenic diabetes insipidus is an X-linked recessive disorder caused by mutations in the AVP V2 receptor gene (AVPR2). In the remaining cases, about 10%, the disease is autosomal recessive or dominant and, for these patients, mutations in the aquaporin 2 gene (AQP2) have been reported. To date, the nucleotide variants registered in AQP2 were sporadic, there is no data on the presence of «frequent¼ mutations and the prevalence of the disease both among the global population and among individual ethnic groups. In this paper, we describe 12 cases of arginine vasopressin resistance caused by a new homozygous mutation p.R113C in AQP2 presented among the indigenous population of the Republic of Buryatia.
Asunto(s)
Acuaporina 2 , Diabetes Insípida Nefrogénica , Humanos , Acuaporina 2/genética , Arginina Vasopresina/genética , Mutación , Diabetes Insípida Nefrogénica/genética , Vasopresinas/genéticaRESUMEN
Growth retardation for more than 2 SD below the average population or presumed familial target height is classified as a short stature and may be a clinical manifestation of a large number of disorders. The use of the latest methods of molecular genetic analysis in recent years has allowed for a better understanding of the pathogenesis of inherited forms of a short stature. One of the recently discovered mechanisms of this pathology was monoallelic mutations in RPL13 gene, leading to the development of Isidor-Toutain type spondyloepimetaphyseal dysplasia (SEDM). Characteristic phenotypic features for this form are normal birth length, early postnatal growth deficiency, platyspondyly, proximal femoral epiphyseal changes, coxa vara, genu varum. This study presents the clinical and radiological characteristics of the first patient in the Russian -Federation with SEMD caused by a mutation in RPL13 gene.
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Proteínas Ribosómicas , Humanos , Proteínas Ribosómicas/genética , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/patología , Mutación , Masculino , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Osteocondrodisplasias/congénito , FemeninoRESUMEN
Multiple endocrine neoplasia type 2B (MEN 2B) is a rare variant of hereditary tumor syndromes caused by germinal mutations in the proto-oncogene RET. One of the components of the syndrome is multiple neurinomas, the early detection of which is not always given due attention. We present a description of the case of MEN 2B, manifested in the first months of life by intestinal ganglioneuromatosis. The disease presented with chronic constipation, including episodes of intestinal obstruction that required repeated surgical interventions. MEN 2B was suspected at the age of 15. At the time of diagnosis, an increase in serum calcitonin levels was noted (1041 pg/ml, norm <9.5 pg/ml), and a node in the thyroid gland was also determined (1,3*1,0*1,2 see, TIRADS 5), subsequently verified as a neoplasm of C-cells. By DNA analysis, a pathogenic variant p.Met918Thr, typical for MEN2 B, was detected in the RET gene. No signs of pheochromocytoma were found at the time of investigation. The patient underwent a thyroidectomy with lymphadenectomy. The difficulties of early diagnosis of sporadic cases of MEN 2B due to the nonspecificity of gastrointestinal manifestations of the disease are discussed.
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Neoplasias de las Glándulas Suprarrenales , Ganglioneuroma , Neoplasia Endocrina Múltiple Tipo 2b , Feocromocitoma , Neoplasias de la Tiroides , Humanos , Neoplasia Endocrina Múltiple Tipo 2b/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2b/genética , Neoplasia Endocrina Múltiple Tipo 2b/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/cirugía , Ganglioneuroma/diagnóstico , Ganglioneuroma/cirugía , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/cirugía , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/cirugíaRESUMEN
Partial androgen resistance syndrome (PAIS) is the most difficult form of disorders/differences of sex development 46,XY (DSD 46,XY) for choosing of patient management. To date, there are no clear biochemical criteria, especially before puberty, that allow differentiating PAIS from other PAIS-like forms of DSD 46, XY, and genetic verification of the partial form of AIS plays an important role. Meanwhile, according to the literature, mutations in the coding region of AR gene have not been identified in more than 50% of patients with suspected AIS. We performed an extensive analysis of the AR gene in a patient with clinical and laboratory signs of AIS and found a deep intron mutation in the AR gene (p. 2450-42G>A). This variant creates an alternative splice acceptor site resulted a disturbance of the AR function. These findings indicate the need for extensive genetic analysis in a cohort of patients with suspected CPA in the absence of mutations in the AR gene using standard methods of genetic diagnosis.
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Síndrome de Resistencia Androgénica , Síndrome de Resistencia Androgénica/diagnóstico , Síndrome de Resistencia Androgénica/genética , Humanos , Masculino , Mutación , Sitios de Empalme de ARN , Receptores Androgénicos/genética , Desarrollo SexualRESUMEN
Gonadotropin-dependent precocious puberty (central) is a condition resulting from the early (up to 8 years in girls and 9 years in boys) reactivation of the hypothalamic-pituitary-gonadal axis. An increase in the secretion of sex steroids by the gonads in this form is a consequence of the stimulation of the sex glands by gonadotropic hormones of the pituitary gland. In the absence of central nervous system abnormalities, CPP is classified as idiopathic and as familial in some cases, emphasizing the genetic origin of this disorder. Loss-of-function mutations in Makorin Ring Finger Protein 3 (MKRN3) are the most common identified genetic cause of central precocious puberty compared to sporadic cases. In the present study we performed the first descrition of 3 family cases of central precocious puberty duo to novel MKRN3 gene mutation detected by NGS in the Russian Federation.
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Pubertad Precoz , Femenino , Gónadas , Humanos , Masculino , Biología Molecular , Mutación , Pubertad Precoz/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterised by lack of pubertal development and infertility, due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH). Clinically, there are variants of CHH with hypo-/anosmia (Kalman syndrome) and normosmic hypogonadotropic hypogonadism. Given a growing list of gene mutations accounting for CHH, the application of next generation sequencing (NGS) comprises an excellent molecular diagnostic approach because it enables the simultaneous evaluation of many genes. Biallelic mutations in GNRHR gene lead to the development of hypogonadotropic hypogonadism with normosmia. In this paper, we describe 16 patients with proven GnRH resistance and estimate the frequency of pathogenic variants in the GNRHR gene in the Russian population.
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Hipogonadismo , Síndrome de Kallmann , Hormona Liberadora de Gonadotropina/genética , Humanos , Hipogonadismo/diagnóstico , Biología Molecular , Mutación , Receptores LHRH/genéticaRESUMEN
CHARGE syndrome is a rare autosomal dominant disease caused by CHD7 gene mutations. Individuals with CHARGE display a wide spectrum of clinical features. It might be presented only as a delay puberty, which does not require any hormone replacement therapy to severe CHARGE phenotype, requiring a multidisciplinary therapeutic approach. Wild spectrum of clinical presentation can be seen even among the patients with identical mutation. Diagnosis might be suspected by a combination of major and minor clinical criteria of this disorder, but molecular genetic analysis is mandatory for final verification. Accurate diagnosis is essential to informing patients about all possible clinical features, reproductive status and choosing the correct treatment approach. The most common endocrine abnormality in patients with CHARGE syndrome is the disturbance in gonadotropins function ranged from delay puberty to persistent hypogonadotropic hypogonadism with different olfactory phenotypes, resulted by specific role of CHD7 in GnRH neuronal embryogenesis.We describe a familial case of CHARGE syndrome with significant intrafamilial clinical heterogeneity due to CHD7 gene mutation.
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Síndrome CHARGE , Hipogonadismo , Síndrome CHARGE/diagnóstico , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Humanos , Hipogonadismo/diagnóstico , FenotipoRESUMEN
Mutations in the gene DHH are an extremely rare cause of disorders of sex development 46,XY (DSD,46XY). The article describes the clinical cases of two unrelated patients with gonadal dysgenesis 46,XY with female phenotype. By using a next generation sequencing method, in both cases the same biallelic variant substitution c. 419T>G in the DHH gene was revealed. Taking into account the data on the role of DHH in the formation of the nervous system, the diagnosis of minifascicular polyneuropathy at the preclinical stage was confirmed in both cases. These cases demonstrate the value of using NGS, which allows simultaneous analysis of a wide range of candidate genes in DSD and the diagnosis of comorbidities before the development of the clinical picture. These are the first descriptions of patients with mutations in the DHH gene in the Russian population.
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Disgenesia Gonadal 46 XY , Proteínas Hedgehog , Femenino , Disgenesia Gonadal 46 XY/diagnóstico , Proteínas Hedgehog/genética , Humanos , Mutación , Desarrollo Sexual , Transducción de SeñalRESUMEN
BACKGROUND: Multiple endocrine neoplasia type 1 (MEN 1) is a rare autosomal dominant disorder caused by mutations in the MEN1 gene, which encodes the menin protein. If a patient has the MEN 1 phenotype in the absence of mutations in the MEN1 gene, the condition is classified as a phenocopy of this syndrome. Although significant progress has been made in understanding the function of menin, its role in the oncogenesis of the endocrine glands is still being elucidated. Due to its key role in physiological and pathological processes, the assessment of the menin expression can provide valuable information. AIM: to determine whether there are any differences in the expression of menin in the pituitary adenomas (PA) in patients with phenocopy of MEN 1 (phMEN 1) and genetically confirmed MEN 1 (gMEN 1) compared with their sporadic forms. MATERIALS AND METHODS: immunohistochemical assessment of the menin expression was carried out in PA of patients with gMEN 1, phMEN 1 and sporadic acromegaly (SA), surgically treated in 2008-2020. IHC was performed using antibodies to menin, PRL, GH, ACTH, FSH, TSH, Pit-1, T-box, ERA on previously prepared histological section. RESULTS: The study included 35 samples of PA: gMEN 1 - 9 samples, phMEN 1 - 12 (somatotropinomas + PHPT); CA - 14 samples. The patients were comparable by gender, adenoma size, and drug intake. The gMEN 1 group differed from phMEN 1 and SA by age (p = 0.0005). In patients with gMEN 1, the expression of menin varied from no staining (5/9) to intense cytoplasm staining. Cytoplasmic expression of menin was mainly present (11/12) in the phMEN 1. In the SA group, there was no staining in 1 case; nuclear expression was detected in 6/14 cases. The phMEN 1 group showed significantly higher cytoplasmic expression of menin than the gMEN 1 group (p = 0.006). The gMEN 1 group also differed from the SA group (p = 0.012). There were no statistically significant differences between the phMEN 1 and SA groups (p = 0.049). CONCLUSION: It was revealed that the menin expression, in general, is retained in phMEN 1 and SA groups, although with different localization in the cell structure (nucleus and / or cytoplasm). At the same time, the expression of menin varies greatly in patients with gMEN 1. According to the data obtained, it can be assumed that the pathogenesis of PA in phMEN 1 and SA may have similarities; however, there could be factors contributing to the appearance of several tumors of the endocrine glands in one person with phMEN 1. To understand this process, it is necessary to further study the genes associated with MEN 1, epigenetic factors, signaling pathways in which menin is involved.
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Acromegalia , Adenoma , Neoplasia Endocrina Múltiple Tipo 1 , Neoplasias Hipofisarias , Adenoma/genética , Humanos , Neoplasia Endocrina Múltiple Tipo 1/genética , Fenotipo , Neoplasias Hipofisarias/genéticaRESUMEN
n the article some corrections were needed. Abstract: "Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described". has been corrected to read "Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 22 were not previously described". Results: "Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described", has been corrected to read "Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 22 were not previously described". Among the newly identified variants in the NR1A1 gene, two lead to the premature stop codon -p. Y197X and p. Y25X, two lead to a shift in the reading frame-p. N385fs and p. L245fs, which does not allow us to doubt their pathogenicityAmong the previously undescribed variant changes, 5 missense mutations (p. C283Y, p. C283B, p.H24Q, p.M126K, p.E81K) and 1 synonymous substitution affecting the splicing site (E330E) were evaluated as pathogenic, and 5 others as probably pathogenic.Has been corrected to read: Among the newly identified variants in the NR1A1 gene, two lead to the premature stop codon -p. Y197X and p. Y25X, two lead to a shift in the reading frame - p.N385SfsX10 and p.L245AfsX53, which does not allow us to doubt their pathogenicity Among the previously undescribed variants, 5 missense mutations (p.C283Y, p.С283F, p.H24Q, p.M126K, p.A82T) and 1 synonymous substitution affecting the splicing site (E330E) were predicted as pathogenic, and 5 others as probably pathogenic by calculating pathogenicity. The authors apologize for these errors.
RESUMEN
MODY is a group of genetically and clinically heterogeneous forms of diabetes characterized by auto-somal dominant inheritance and is subdivided in 13 subtypes dependent on the gene involved. The subtype MODY9 is a very rare form caused by mutations in the gene encoding the PAX4 transcription factor which is engaged in differentiation of pancreatic beta-cells. PAX4 contains two DNA-binding domains-Paired and Homeo. Expression of the human PAX4 gene is tissue-specific. The alternatively spliced mRNA variants encode for protein isoforms which differ within their N- and C-terminal regions. In this study, the transcriptional activities of the human PAX4 variants, both known and new ones, were determined. The full-length PAX4 containing intact DNA-binding domains was found to have maximal activity in transient expression system of the firefly luciferase reporter gene under control of the insulin promoter in HEK293 cells. The transcriptional activity is significantly reduced in the variants lacking eight N-terminal amino acid residues and/or variants whose Homeo domain is truncated from the C-terminus. Similar data were obtained with the glucagon promoter reporter system. The aberrant PAX4 variants were shown to retain stability and nuclear localization.
Asunto(s)
Diabetes Mellitus Tipo 2 , Proteínas de Homeodominio/genética , Factores de Transcripción Paired Box/genética , Activación Transcripcional , Empalme Alternativo , Células HEK293 , Humanos , Insulina , Regiones Promotoras Genéticas , Estabilidad ProteicaRESUMEN
Disorders of sex development (DSDs) are congenital conditions in which phenotype does not correspond to chromosomal and gonadal sex. To date, the etiology of DSD is established only in half of the cases. With the development of modern methods of molecular genetic diagnostics in the last decade, a number of new regulators of gonad differentiation have been discovered, whose expression disorders can lead to DSD. Among these factors, Mitogen-activated triple protein kinase 1 (MAP3K1). A distinctive feature of studying the detected variants in the MAP3K1 gene that they lead to activation of MAP3K1. It does not allow using generally accepted pathogenicity assessment algorithms. However, the frequency of detection of changes in MAP3K1 is up to 18% of all cases of DSD, according to literature, which emphasizes the importance of studying each identified case, establishing the relationship of the disease with the identified genetic disorders. In this article, we present a clinical, hormonal, and molecular genetic description of 7 cases of DSD associated with variants in MAP3K1, an analysis of the significance of our own data, and a short analysis of the current scientific literature on this issue.
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Trastorno del Desarrollo Sexual 46,XY , Trastornos del Desarrollo Sexual , Disgenesia Gonadal , Quinasa 1 de Quinasa de Quinasa MAP , Trastorno del Desarrollo Sexual 46,XY/diagnóstico , Humanos , Quinasa 1 de Quinasa de Quinasa MAP/genética , Fenotipo , Desarrollo SexualRESUMEN
Primary bilateral macronodular adrenal hyperplasia (PBMAH), a genetically heterogeneous disease, is a rare cause of Cushing's syndrome. Until recently, few cases were attributed to mutations in known genes. However, in 2013, ARMC5, a newly discovered tumor suppressor gene, was identified. Further studies have shown that mutations in the ARMC5 gene are found in 25-55% of all PBMAH cases. This article describes a clinical case of hereditary Cushing's syndrome caused by PBMAH in a 37-year old patient. The patient's family history is remarkable for the presence of Cushing's syndrome and PBMAH in the patient's mother. Bilateral adrenalectomy was performed as the treatment of choice. Genetic analysis using whole-exome sequencing confirmed the hereditary cause of the disease, revealing a germline heterozygous mutation in the ARMC5 gene. The patient also had concomitant mild primary hyperparathyroidism, which had not been observed before in genetic carriers with the ARMC5 mutation.
Asunto(s)
Síndrome de Cushing , Hiperparatiroidismo Primario , Adulto , Proteínas del Dominio Armadillo , Síndrome de Cushing/genética , Humanos , Hiperplasia/genética , Mutación , Federación de RusiaRESUMEN
Androgen insensitivity syndrome is an X-linked disorder characterized by either complete or partial insensitivity of target tissues to androgens. This disease is caused by mutations in the AR gene located on the Х chromosome. Currently, there are no distinct clinical, biochemical, or hormonal markers that would allow one to differentiate androgen insensitivity syndrome from a number of other forms of 46,XY disorders of sex development. Therefore, final verification of this condition is based on the results of molecular genetic tests. Although more than 1,000 point mutations in the AR gene have been reported, somatic mutations in this gene have been described rather rarely. However, this very type of mutations makes the course of this disease difficult to predict, since various cells in the human body contain both normal and mutant receptors. Somatic mosaicism can cause spontaneous masculization during puberty in individuals born with a completely normal female phenotype. In this case report, we describe the phenotypic and molecular genetic characteristics of eight patients with various forms of androgen insensitivity syndrome caused by somatic mutations in the AR gene.
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Síndrome de Resistencia Androgénica , Síndrome de Resistencia Androgénica/genética , Andrógenos , Femenino , Humanos , Masculino , Mutación/genética , Mutación Puntual , Receptores Androgénicos/genéticaRESUMEN
SertoliLeydig cell tumor is a rather rare type of ovarian neoplasms belonging to the group of sex cordstromal tumors. This malignancy is characterized by androgen overproduction, which results in the so-called virilization and can be accompanied by various metabolic disorders such as abdominal obesity, disturbances of carbohydrate and protein metabolism, and high blood pressure. During differential diagnosis, it is important to identify the source of androgen overproduction. An androgen-secreting ovarian tumor needs to be differentiated from androgen-secreting adrenal tumor, ovarian stromal thecomatosis (hyperthecosis), and endogenous hypercorticism (the Cushings syndrome). In most cases, the SertoliLeydig cell tumor is associated with DICER1 mutation carriership. If a patient is found to carry the DICER1 mutation, patients relatives need to undergo genetic testing as the individuals with mutations in this gene have an elevated risk of developing a broad range of benign and malignant tumors (most of these tumors are relatively rare in the overall population). The awareness of this rare ovarian neoplasm among medical specialists (obstetriciansgynecologists, endocrinologists, and oncologists) is supposed to ensure timely diagnosis and adequate treatment of this disease.
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Neoplasias Ováricas , ARN Helicasas DEAD-box , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Mutación , Neoplasias Ováricas/diagnóstico , Ribonucleasa III , Tumor de Células de Sertoli-Leydig/diagnóstico , Virilismo/diagnósticoRESUMEN
The impairment of glucose homeostasis leads to hyperglycemia and type-2 diabetes mellitus. Glucokinase (GK), an enzyme that catalyzes the conversion of glucose to glucose-6-phosphate in pancreatic ß-cells, liver hepatocytes, specific hypothalamic neurons, and intestine enterocytes, is a key regulator of glucose homeostasis. In hepatocytes, GK controls the glucose uptake and glycogen synthesis and inhibits the glucose synthesis via the gluconeogenesis pathway. Glucokinase regulatory protein (GKRP) synthesized in hepatocytes acts as an endogenous GK inhibitor. During fasting, GKRP binds GK, inactivates it, and transports it into the cell nucleus, thus isolating it from the hepatocyte carbohydrate metabolism. In the beginning of the 2000s, the research was mainly focused on the development and trials of the small molecule GK activators as potential antidiabetic glucose-lowering drugs. However, the use of such substances increased the risk of hypoglycemia, and clinical studies of most synthetic GK activators are currently discontinued. Allosteric inhibitors of the GK-GKRP interaction are coming as alternative agents increasing the GK activity that can substitute GKA. In this review, we discuss the recent advances and the current state of art in the development of potential antidiabetic drugs targeted to GK as a key regulator of glucose homeostasis.
RESUMEN
Ibutamoren mesylate (MK-0677), an orally active nonpeptide growth hormone (GH) secretagogue, stimulates GH release through a pituitary and hypothalamic receptor that is different from the GH-releasing hormone receptor. We evaluated the safety and tolerability and the GH-insulin-like growth factor (IGF) responses to two dosages of oral ibutamoren mesylate given to children with GH deficiency for 7 to 8 days. The patients, 18 prepubertal children (15 male, 3 female) with idiopathic GH deficiency, had a chronologic age of 10.6 +/- 0.8 years (mean +/- SD), bone age of 7.4 +/- 0.7 years, growth velocity < 10th percentile for age, height < 10th percentile for age, and a maximum GH response of < or = 10 microg/L to two different GH stimulation tests. The children were assigned as follows to one of three treatment groups with ibutamoren mesylate: 0.2 mg/kg per day for 7 days (days 1-7 or 8-14) and matching placebo for the alternate 7 days (groups I and II, respectively) or 0.8 mg/kg per day for 7 days (days 8-14, group III). On day 15 all patients received an 0.8-mg/kg dose of ibutamoren mesylate. Patients in groups I and II were studied first to assess safety at the low dose before advancement to the high dose. Hormonal profiles were evaluated on day -1 (baseline) and day 15, and the results were expressed as the change from baseline within each group. After administration of ibutamoren mesylate 0.8 mg/kg for 8 days (group III), the median increases (on day 15) from baseline were as follows: 3.8 microg/L (range, 0 to 34.3) for serum GH peak concentration (P = .001), 4.3 microg x h/L (range, 1.3 to 35.6) for the GH area under the concentration-time curve from time zero to 8 hours (AUC(0-8)) (P < .001), 12 microg/L (range, -4 to 116) for serum IGF-I (P = .01), and 0.4 microg/L (range, -0.9 to 1.5) for serum IGF-binding protein 3 (IGFBP-3) (P = .01). There was no change in serum prolactin, glucose, triiodothyronine, thyroxine, thyrotropin, peak serum cortisol, and insulin concentrations or 24-hour urinary free cortisol after administration of 0.8 mg/kg per day of ibutamoren mesylate for 8 days. We conclude that short-term administration of ibutamoren mesylate can increase GH, IGF-I, and IGFBP-3 levels in some children with GH deficiency. Thus this compound is applicable for testing its effect on growth velocity.
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Hormona del Crecimiento/efectos de los fármacos , Hormona del Crecimiento/deficiencia , Indoles/administración & dosificación , Indoles/farmacología , Factor I del Crecimiento Similar a la Insulina/efectos de los fármacos , Errores Innatos del Metabolismo/tratamiento farmacológico , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/farmacología , Administración Oral , Niño , Método Doble Ciego , Femenino , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Errores Innatos del Metabolismo/metabolismo , Resultado del TratamientoRESUMEN
OBJECTIVE: Hypopituitarism, including severe GH deficiency, is an almost inevitable outcome of craniopharyngioma. However, some GH deficient children with this tumour may grow normally or even have accelerated growth postoperatively. To study this phenomenon we have investigated the endocrine status, including IGF-1 and its binding proteins IGFBP-1 and IGFBP3, in children referred for follow-up at various time intervals after surgery. PATIENTS: Twenty-five patients (14 boys and 11 girls, aged 3.8-18.9 years), were studied on 34 occasions between 0.5 to 10.8 years after surgery. The tumour was intrasellar in 11 cases and suprasellar in 14. METHODS: Height and height velocity were recorded as SDS values. Body mass index (BMI) was calculated as weight/height2. GH secretory status was evaluated by stimulation both with oral clonidine and with GH releasing hormone. Serum insulin (INS) levels were studied following an oral glucose load. IGF-1, IGFBP-3, IGFBP-1 and prolactin serum concentrations were evaluated in fasting samples. All hormones were measured by radioimmunoassay. RESULTS: All patients had growth hormone (GH) deficiency. Height (HtSDSCA) and height velocity SDS for chronological age (HVSDSCA) decreased progressively after surgery (r = -0.47, P = 0.005, and r = -0.4, P = 0.032, respectively) but four patients had normal HtSDSCA 6.1 to 10.8 years following their first surgery. There was a significant correlation between BMI and HtSDSCA (r = 0.37, P = 0.03). BMI in children with suprasellar craniopharyngioma was significantly greater than that in patients with intrasellar tumour (23.3 +/- 7.0 vs. 17.3 +/- 1.4 kg/m2; P = 0.001). In 13 of 33 cases oral glucose load was accompanied by hyperinsulinaemia with serum INS levels greater than 50 mU/l. The mean area under the curve (AUC) of INS after glucose load (INSAUC) in the suprasellar group was greater than in the patients with intrasellar lesion (6945.5 +/- 4411.8 vs. 2495.5 +/- 1768.8 mU/l. min P = 0-001). The log INSAUC correlated significantly with HtSDSCA (0.37, P = 0.03). Fasting serum IGF-1 and IGFBP3 levels were normal in 8 and 12 of the 31 measurements, respectively. Both IGF-1SDS and IGFBP-3SDS correlated significantly with HtSDSCA (r = 0.77, P = 0.0002 and r = 0.65, P = 0.0001, respectively) and the log INSAUC (r = 0.39, P = 0.035, r = 0.56, P = 0.002, respectively). As determined by forward stepwise regression analysis, IGF-1SDS was the single most important predictor of HtSDSCA (R2 = 0.33, P = 0.001) in the subset mode. CONCLUSION: A few children with craniopharyngioma grew normally after surgery, in spite of being GH-deficient. This growth phenomenon, which is usually accompanied by obesity, was more common in patients with suprasellar tumour and is likely to be associated with the effect of IGF-1 bioavailability, which, in turn, may be modulated largely by insulin.
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Craneofaringioma/fisiopatología , Craneofaringioma/cirugía , Sustancias de Crecimiento/sangre , Crecimiento/fisiología , Neoplasias Hipofisarias/fisiopatología , Neoplasias Hipofisarias/cirugía , Adolescente , Agonistas alfa-Adrenérgicos , Niño , Preescolar , Clonidina , Craneofaringioma/sangre , Femenino , Prueba de Tolerancia a la Glucosa , Hormona del Crecimiento/sangre , Hormona del Crecimiento/deficiencia , Hormona Liberadora de Hormona del Crecimiento , Humanos , Insulina/sangre , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Neoplasias Hipofisarias/sangre , Periodo Posoperatorio , Prolactina/sangreRESUMEN
OBJECTIVE: Synthetic growth hormone releasing peptides (GHRP) have potent GH-releasing activity in vivo and in vitro. The nature of the interaction of GHRP and naturally occurring GH releasing hormone (GHRH) is still far from clear. We investigated GH release in response to individual peptide doses or combined doses of GHRH1-29NH2 and GHRP-2, a novel GH-releasing peptide, in normal adults. DESIGN: Subjects underwent three tests in a randomized order: (1) i.v. bolus of GHRH1-29NH2 (1 microgram/kg BW), (2) i.v. bolus of GHRP-2 (1 microgram/kg BW), (3) i.v. bolus of GHRH1-29NH2 combined with GHRP-2 (same dosages). SUBJECTS: Eight healthy non-obese male volunteers, aged 25-34 years. MEASUREMENTS: Serum GH concentrations were measured by IRMA at -15, 0, +10, 20, 30, 45, 60, 75, 90 and 120 minutes after the boluses. RESULTS: Peak GH levels in response to GHRH1-29NH2, GHRP-2 and the combined GHRH1-29NH2 and GHRP-2 administrations were observed between 20 and 45 minutes. Peak GH levels at 30 minutes were 32.8 +/- 27.3 (mean +/- SD), 109.7 +/- 56.1 and 140.9 +/- 80.6 mU/l, respectively. The area under the curve for GH levels (GH AUC) calculated for the first 90 minutes after the GHRH1-29NH2 test (2061.2 +/- 1601.9 mU/lmin) was significantly lower than those after GHRP-2 (6205.1 +/- 3216.9 mU/lmin) and the combined GHRH1-29NH2 and GHRP-2 challenge (9788.3 +/- 5530.4 mU/lmin) (P = 0.0003 and P = 0.00005, respectively; paired Student's t-test for log transformed data). Although the GH AUC of the GHRP-2 test and the combined GHRH1-29NH2 and GHRP-2 test differed significantly (P = 0.016, t-test), the latter was not significantly different from the sum of the GH AUCs of each subject after the separate tests. CONCLUSION: Although the GH releasing potency of GHRP-2 significantly exceeded that of GHRH1-29NH2, we were not able to demonstrate synergy between the two substances. It is possible that GHRP-2 given in our study GHRP-2 significantly exceeded that of GHRH1-29NH2, we were not able to demonstrate synergy between the two substances. It is possible that GHRP-2 given in our study in higher molar quantities than GHRH1-29NH2 masked the effect of the latter.