PubMed Health⌕ Search

Biomedical subjects

Ana Claudia Latronico

Publications and source records attributed to Ana Claudia Latronico.

At least 19 recordsLinked to original sources
PubMed2007

Clinical assessment and molecular analysis of GnRHR and KAL1 genes in males with idiopathic hypogonadotrophic hypogonadism.

OBJECTIVE: The pathogenesis of idiopathic hypogonadotrophic hypogonadism (IHH) is mostly unclear. We characterized the clinical findings and molecular analysis of GnRHR and KAL1 genes in 26 Brazilian males with IHH with and without hyposmia/anosmia. Design Clinical assessment was performed for endocrine status, olfactory structure and function, renal lesion, and mirror movement. The diagnosis of Kallmann syndrome (KS) included HH and the clinical complaint of hyposmia/anosmia or decreased olfactory acuity obtained by the Smell Identification Test (SIT). We analysed GnRHR and KAL1 genes using the polymerase chain reaction (PCR) direct sequencing method. RESULTS: A variable degree of HH was observed, including various clinical abnormalities, such as cryptorchidism, hearing loss, strabismus, cleft lip/palate, high-arched palate, dental agenesis, psychiatric disorders, learning dysfunction, and bimanual synkinesia. Twenty-two out of 26 patients with IHH (85%) were classified as KS. Abnormalities of olfactory bulbs/sulci were observed in 79% of KS patients. One-third of KS patients had renal defects and 45.5% had a positive family history. GnRHR gene sequence analysis showed no mutations. KAL1 sequence analysis identified two novel missense mutations: c.1061A to G in exon 7 (N304S) and c.1583C to A in exon 10 (S478X). We also observed a 14-bp deletion within exon 11 that caused a premature termination. According to the National Center for Biotechnology Information (NCBI)-Single Nucleotide Polymorphism (SNP) database, two previously described polymorphisms (rs808119 and rs809446) were detected. CONCLUSION: KAL1 mutations accounted for 12% of KS patients. This low prevalence of KAL1 mutations indicates that other genes, such as the fibroblast growth factor receptor 1 (FGFR1) gene or other as yet undiscovered genes, epigenetic events and/or environmental factors might be involved in the aetiology and phenotypic variability of KS.

Adolescent↗
PubMed2006

Molecular analysis of the neuropeptide Y1 receptor gene in human idiopathic gonadotropin-dependent precocious puberty and isolated hypogonadotropic hypogonadism.

OBJECTIVE: To investigate the role of mutations or polymorphisms in the NPY-Y1R gene in human idiopathic central pubertal disorders. DESIGN: Molecular studies. SETTING: University hospital. PATIENT(S): Thirty-three patients with gonadotropin-dependent precocious puberty, 22 with hypogonadotropic hypogonadism, and 50 controls. INTERVENTION(S): Genomic DNA extraction, NPY-Y1R gene sequence analysis, cell-surface expression, and functional activity of an identified receptor variant. MAIN OUTCOME MEASURE(S): Results of sequencing, cell-surface receptor expression, and receptor function. RESULT(S): A heterozygous substitution of lysine (K) by threonine (T) at position 374 in the carboxyl terminal region of NPY-Y1R was identified in a girl with familial GDPP. Her mother, who had pubertal developmental at appropriate age, carried the same genetic variant. Introduction of the K374T variant into an expression vector containing the human NPY-Y1R complementary DNA led to a partial reduction in cell-surface expression of NPY-Y1R in transiently transfected HEK293 cells. This mutation did not lead to a significant reduction in NPY-stimulated activity of the receptor in this heterologous expression system. No other allelic variants of the NPY-Y1R gene were identified in patients or controls. CONCLUSION(S): We have identified an inherited heterozygous variant of the NPY-Y1R gene in a girl with precocious puberty; however, this most likely did not contribute to her phenotype. Mutations of the highly conserved NPY-Y1R gene do not appear to represent a frequent mechanism underlying human idiopathic central pubertal disorders.

Adolescent↗
PubMed2006

Insights learned from L457(3.43)R, an activating mutant of the human lutropin receptor.

The L457(3.43)R mutation of the hLHR was initially identified in a Brazilian boy with gonadotropin-independent precocious puberty. As would be expected, L457(3.43)R, when expressed in 293 cells, caused a marked elevation in basal cAMP levels. Interestingly, in spite of the fact that the elevated basal levels of cAMP elicited by L457R were not as great as those elicited by the wild-type hLHR when stimulated with hCG, L457(3.43)R cells were unresponsive to further hormonal stimulation. We have since determined that the L457(3.43)R mutant, as well as other constitutively active mutants of the hLHR, causes an increase in phosphodiesterase activity that attenuates the target cell to hormonal stimulation of the wild-type hLHR or other Gs-coupled GPCRs. We have also shown that the constitutive activity and lack of hormonal responsiveness of L457(3.43)R are due to the formation of a salt bridge between the introduced arginine in the mid portion of helix 3 with D578(6.44) in the mid portion of helix 6. The formation of this salt bridge results in the disruption of interactions between the cytoplasmic ends of helices 3 and 6 that are associated in general with activation of the hLHR. As such, this mutant has provided novel insights into the properties of target cells expressing activating hLHR mutants and into the structural basis for hLHR activation.

Arginine↗
PubMed2006

An inhibin B and estrogen-secreting adrenocortical carcinoma leading to selective FSH suppression.

OBJECTIVE: Hormone-secreting adrenocortical tumors are frequently associated with endocrine syndromes. We describe a 30-year-old man who had abdominal pain, a nodule in the right breast and loss of libido. Abdominal magnetic resonance imaging revealed a very large tumor in the right adrenal gland. METHODS: Hormonal profile disclosed increased levels of estradiol and slightly low testosterone levels. The basal and stimulated LH levels were normal, whereas basal and stimulated FSH levels were totally suppressed. Cortisol and adrenal androgen levels were normal. The unusual finding of selective FSH suppression suggested secretion of inhibin B by the adrenocortical tumor. A very high level of serum inhibin B (405 pg/ml) was demonstrated by ELISA assay. Right adrenalectomy and nephrectomy were performed and the tumor was classified as a malignant tumor (Weiss score: 7.0) and unilateral mastectomy disclosed a lipoma. RESULTS: One week after surgery, a GnRH-stimulation test disclosed normal basal and stimulated FSH levels and low levels of inhibin B and estradiol. Immunohistochemical analysis with anti-B-inhibin antibody revealed intense staining in the adrenocortical tumor cells. One month after surgery, an abdominal magnetic resonance imaging revealed a local recurrence of the tumor and a second surgery was performed with partial resection of the tumor and the patient died 1 year after the first surgery. CONCLUSION: We herein report the first inhibin B and estradiol-secreting adrenocortical carcinoma. The unusual selective inhibition of FSH secretion should be considered a valuable hormonal finding for the diagnosis of inhibin B-secreting adrenocortical tumors.

Adrenal Cortex Neoplasms↗
PubMed2006

Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia.

CONTEXT: Kallmann syndrome is a clinically and genetically heterogeneous disorder. To date, loss-of-function mutations in the genes encoding anosmin-1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1) have been described in the X-linked and autosomal dominant forms of this syndrome, respectively. OBJECTIVE: The objective was to investigate genetic defects in the KAL1 and FGFR1 genes in patients with congenital isolated hypogonadotropic hypogonadism (IHH). PATIENTS: Eighty patients (71 males and nine females) with IHH were studied, of which 30 were familial. Forty-six of them had olfactory abnormalities. METHODS: The coding regions of both KAL1 and FGFR1 genes were amplified and automatically sequenced. The KAL1 mutations were investigated only in patients with olfactory abnormalities, whereas FGFR1 was studied in the entire group. RESULTS: Two novel KAL1 mutations, an intragenic deletion of exons 3-6 and a splicing mutation IVS7 + 1G>A, were identified in two of 46 patients with Kallmann syndrome. Eight novel heterozygous FGFR1 mutations (G48S, L245P, R250W, A343V, P366L, K618fsX654, P722S, and V795I) were identified in nine of 80 patients with IHH. Eight of them had olfactory abnormalities. Interestingly, the G48S mutation was identified in a normosmic IHH patient. Two unrelated females, who carried FGFR1 mutations, had anosmia and normal reproductive function. CONCLUSION: We identified novel mutations in KAL1 and FGFR1 genes in IHH patients. FGFR1 mutations were identified in 17% of the patients with olfactory abnormalities and in one of 34 normosmic IHH patients. In addition, isolated anosmia was identified in two unrelated females as a partial phenotypic manifestation of FGFR1 defects.

Adolescent↗
PubMed2006

Recurrence of the R947X mutation in unrelated families with autosomal dominant pseudohypoaldosteronism type 1: evidence for a mutational hot spot in the mineralocorticoid receptor gene.

BACKGROUND: The renal form of pseudohypoaldosteronism type 1 (PHA1) is a rare disease characterized by congenital mineralocorticoid resistance of the kidney. Twenty-two different loss-of-function mutations in the mineralocorticoid receptor gene have been described in families with PHA1. These mutations were not recurrent and resulted in a large phenotypic variability. OBJECTIVE: The objective of this study is to analyze the recurrence of an inactivating mutation in the mineralocorticoid receptor gene in unrelated families with autosomal dominant PHA1. PATIENTS: Seventeen members from three unrelated families with autosomal dominant PHA1 were studied, including 11 affected patients with variable clinical manifestations. Fifty healthy subjects were used as controls. METHODS: Genomic DNA was extracted, and the entire coding region of the mineralocorticoid receptor gene was submitted to automatic sequencing. Four dinucleotide microsatellite markers spanning a region of 3.2 cM in the human mineralocorticoid receptor gene locus, and two intragenic polymorphisms were used for haplotype analysis. RESULTS: A heterozygous point mutation at codon 947 (c.2839C>T) changing arginine to stop codon (R947X) was found in the three families. Different haplotypes segregated with the R947X mutation in each family, demonstrating the absence of a founder effect for this mutation. CONCLUSION: Codon 947 of the mineralocorticoid receptor is the first mutational hot spot for autosomal dominant PHA1.

17-alpha-Hydroxyprogesterone↗
PubMed2006

Allelic variants of the gamma-aminobutyric acid-A receptor alpha1-subunit gene (GABRA1) are not associated with idiopathic gonadotropin-dependent precocious puberty in girls with and without electroencephalographic abnormalities.

CONTEXT: gamma-Aminobutyric acid (GABA) is a dominant inhibitory neurotransmitter involved in the modulation of brain electric activity and puberty onset in primates. GABA inhibitory effects on GnRH neurons are mainly mediated by GABA-A receptor alpha1-subunit. OBJECTIVE: The objective of this study was to investigate functional mutations or polymorphisms of the GABA-A receptor alpha1-subunit gene (GABRA1) in girls with idiopathic gonadotropin-dependent precocious puberty (GDPP) with and without electroencephalographic (EEG) abnormalities. DESIGN: The entire coding region of GABRA1 was sequenced in all patients. Two known GABRA1 polymorphisms were investigated by GeneScan software analysis or enzymatic restriction. Seventy-three normal women were used as controls for genetic study. EEG tracings were recorded in 23 girls with GDPP and 17 girls with adequate pubertal development. SETTING: The study was performed at a university hospital. PATIENTS: Thirty-one girls from 28 unrelated families with idiopathic GDPP were studied. RESULTS: Automatic sequencing revealed no functional mutations in girls with GDPP. Seven different GABRA1 polymorphisms, including two exonic (156T>C and 1323G>A) and five intronic [IVS2-712(GT)n, IVS3+12A>T, IVS8+45T>G, IVS9+76A>G, and IVS10+15G>A], were found in GDPP girls and controls. Abnormal EEG tracings were found in 26% of 23 girls with GDPP, two of them with epilepsy. The genotype and allele frequencies of the GABRA1 polymorphisms were not statistically different between unrelated GDPP girls and controls or between GDPP girls with or without EEG abnormalities. CONCLUSIONS: GABRA1 functional mutations or polymorphisms are not associated with the intrinsic mechanism of GDPP in girls with and without EEG abnormalities.

Adolescent↗
PubMed2006

[Leydig cell hypoplasia].

The Leydig cell hypoplasia is a rare and well defined form of male pseudohermaphroditism with autosomal recessive inheritance pattern. An inadequate fetal testicular Leydig cell differentiation and, consequently a low androgenic production during intra uterine and post natal periods, result in absence or incomplete virilization in patients with 46,XY karyotype. These patients exhibit a wide clinical spectrum, ranging from complete female external genitalia to male external genital with micropenis, low serum testosterone levels associated with high LH levels. Inactivating mutations of the LH/hCG receptor gene have been identified in affected families in the last decade. However, the low frequency of inactivating mutations in this gene, and the lack of segregation of intragenic polymorphisms among affected members from families with typical phenotype of Leydig cell hypoplasia, suggest the genetic heterogeneity of this condition.

Disorders of Sex Development↗
PubMed2006

[Endocrine tumors associated to protein Gsalpha/Gi2alpha mutations].

Many oncogenic mutations promote tumor growth by inducing autonomous activity of proteins that normally transmit proliferative signal initiated by extracellular factors. G proteins are a family of guanine nucleotide binding proteins, which are structurally homologous and widely distributed in eukaryotic cells. They are composed of three different subunits (alpha, beta e gamma). The alpha subunit, which contains the guanine nucleotide-binding site, is unique to each G protein. The G proteins couple an array of seven transmembrane receptors at the cell surface with a variety of intracellular effectors, which produce second messenger molecules. A subset of endocrine tumors, such as GH- or ACTH-secreting pituitary adenomas, functioning thyroid adenomas, adrenocortical and gonadal tumors were associated with somatic activating mutations in the highly conserved codons of the Gs (Arg201 and Gln227) and Gi (Arg179 and Gln205) proteins. These findings indicated that the G proteins play a role as oncogenes, contributing with the human endocrine tumorigenesis.

Endocrine Gland Neoplasms↗
PubMed2006

Preclinical diagnosis of testotoxicosis in a boy with an activating mutation of the luteinizing hormone receptor.

BACKGROUND: Testotoxicosis is an autosomal dominant disorder usually recognized by progressive virilization, linear growth acceleration, skeletal maturation and pubertal testosterone levels in boys before 4 years of age. OBJECTIVE: To describe the clinical and hormonal follow-up of a male infant with testotoxicosis who was initially diagnosed by molecular analysis. PATIENT: A healthy asymptomatic 10 month-old boy was referred to the endocrinologist because his older brother had diagnosis of familial testotoxicosis due to the activating mutation Thr577Ile of the luteinizing hormone (LH) receptor. RESULTS: Automatic sequencing of exon 11 of the LH receptor gene revealed the same heterozygous Thr577Ile mutation in the asymptomatic boy. He had no signs of virilization or accelerated growth. His bone age was delayed. Serum LH and follicle stimulating hormone (FSH) concentrations were in the prepubertal range, testosterone levels were slightly elevated (31 ng/dl [1.07 nmol/l]). In the following 6 months, his testosterone levels progressively increased, achieving higher levels (146 ng/dl [5 nmol/l]) without testicular enlargement or pubic hair development. Despite the lack of virilization signs, an anti-androgen was started due to the increase in testosterone levels and growth velocity at the age of 1.3 years. CONCLUSION: We describe the preclinical diagnosis of testotoxicosis in a boy by DNA analysis. Very early diagnosis in affected families can result in prompt treatment, and reduce the deleterious consequences of premature puberty in boys with this rare monogenic disorder.

Androgen Antagonists↗
PubMed2006

Inactivating mutations of LH and FSH receptors--from genotype to phenotype.

The pituitary glycoprotein hormones, LH and FSH, and their receptors are essential for normal reproductive function in both sexes. Over the past 10 years, several inactivating mutations of the gonadotropin receptors have been described in rare forms of human primary gonadal disorders. Homozygous or compound heterozygous inactivating mutations of the LH receptor were associated with a rare autosomal recessive form of male pseudohermaphroditism (Leydig cell hypoplasia), micropenis and hypergonadotropic hypogonadism in genetic males. In addition, these mutations caused primary or secondary amenorrhea and infertility in women who were sisters of male pseudohermaphrodites. Similarly, FSH receptor inactivating mutations were associated with partial or complete phenotypes of premature ovarian failure in women. These inactivating mutations corroborate and extend our knowledge of clinical consequences of gonadotropin resistance and inappropriate gonadotropin action. In addition, the characterization of the molecular basis of gonadal resistance can be useful for directing therapy and for genetic counseling.

Genotype↗
PubMed2005

[Adrenocortical tumors--new perspectives].

A high frequency of adrenocortical tumors has been observed in Brazilian children and adults from South and Southwestern regions. The valuable national experience in the management of these tumors have resulted in several and relevant basic and clinical reports. However, the creation of an adrenocortical tumor national registry, the uniformity of approaches and collaborative studies are target to pursue. In this review article, we briefly described the fundamental points which were discussed in two scientific events on adrenocortical tumors: "International Consensus Conference on Treatment of Adrenal Cancer" and "I Simposio de Diagnóstico e Tratamento dos Tumores Adrenocorticais". The task force involving several Brazilian centers will increase the progress in the diagnosis, prognosis and treatment of this devastating disorder.

Adrenal Cortex Neoplasms↗
PubMed2005

Founder effect for the highly prevalent R337H mutation of tumor suppressor p53 in Brazilian patients with adrenocortical tumors.

The incidence of adrenocortical tumors in children from the Southern region of Brazil is higher than in other parts of the world. This fact has been related to the identification of an inherited missense mutation of the p53 (R337H) at high frequency (78-97%) in Brazilian children with adrenocortical tumors. Given the high frequency of this germline mutation in the Brazilian population, it is very likely that the R337H mutation has arisen from a common origin. In this study, we analyzed two highly polymorphic intragenic markers (VNTRp53 and p53CA) in 22 patients (16 children and 6 adults) with adrenocortical tumors carrying the germline R337H mutation and 60 normal individuals using GeneScan Fragment Analysis software. We found six and sixteen different alleles for the VNTRp53 and p53CA polymorphic markers, respectively. Two distinct alleles, both with 122 bp, were found in 56.8% (VNTRp53) and 54.5% (p53CA) of the 44 alleles from patients with adrenocortical tumors associated with the R337H mutation. Differently, these same VNTRp53 and p53CA alleles were found in 18.3% and 14.2% of 120 alleles from normal individuals, respectively (p<0.01, Chi-square test). An identical haplotype for p53 locus was also identified in 95% of the apparently unrelated Brazilian patients with adrenocortical tumors carrying the R337H mutation. In conclusion, we demonstrated a strong evidence of co-segregation between two intragenic polymorphic p53 markers and the germline R337H mutation, indicating that this mutation has originated from a single common ancestral in the great majority of the Brazilian patients with adrenocortical tumors.

Adolescent↗
PubMed2005

Deletion mapping of chromosome 17 in benign and malignant adrenocortical tumors associated with the Arg337His mutation of the p53 tumor suppressor protein.

The human p53 tumor suppressor gene is located at the short arm of chromosome 17. A germinative mutation (Arg337His) in the tetramerization domain of p53 has been frequently identified in Brazilian children with sporadic adrenocortical tumors. Loss of heterozygosity at this region was demonstrated in the majority of the cases. In the present study, we performed deletion mapping of chromosome 17 in 30 adrenocortical tumors from 29 Brazilian patients (15 children and 14 adults). One boy had bilateral adrenocortical tumor. Sixteen patients had the germinative Arg337His mutation. Loss of heterozygosity analysis using six polymorphic microsatellite markers disclosed loss of the entire chromosome 17 in 18 tumors (10 adenomas and eight carcinomas) from 17 patients. The Arg337His mutation was present in 13 of them. Chromosomal instability involving chromosomes 2, 9, and 11 was also found in 47, 47, and 70% of the 17 patients who exhibited chromosome 17 losses, respectively. The concomitant loss of chromosomes 2, 9, 11, and 17 was evidenced exclusively in malignant tumors. Therefore, chromosomal instability involving three or more chromosomes may contribute to define the malignant adrenocortical lesions. In conclusion, we demonstrated a high frequency of biallelic inactivation of p53 derived from two distinct events, the germinative Arg337His mutation and the acquired loss of the entire chromosome 17. In addition, the isolated loss of the entire chromosome 17 did not correlate with aggressive tumor behavior in these patients with adrenocortical tumors.

Adolescent↗
PubMed2005

Clinical and hormonal features of selective follicle-stimulating hormone (FSH) deficiency due to FSH beta-subunit gene mutations in both sexes.

OBJECTIVE: To report the clinical, hormonal, and molecular features of a female adolescent with selective FSH deficiency. In addition, a complete review of previous cases is provided, focusing on hormonal aspects. DESIGN: Clinical study. SETTING: University hospital. PATIENT(S): A 16-year-old girl with primary amenorrhea and poor breast development due to isolated FSH deficiency. INTERVENTION(S): Blood drawing before and after GnRH stimulation and pelvic ultrasound examination. MAIN OUTCOME MEASURE(S): Gonadotropin and E(2) measurements and sequencing of the FSH beta-subunit gene. RESULT(S): The patient was referred for primary amenorrhea and partial breast development (Tanner III). Her basal and GnRH-stimulated LH levels were elevated (31 IU/L and 98 IU/L, respectively), whereas her FSH levels were undetectable (<1 IU/L) in both conditions. Estradiol levels were low (<13 pg/mL). Automatic sequencing showed a nucleotide substitution of C for A in exon 3, resulting in a homozygous nonsense mutation in amino acid position 76 (Tyr76X) of the FSH beta-subunit. CONCLUSION(S): The Tyr76X mutation of the FSH beta-subunit was associated with a partial phenotype of FSH deficiency. To date, only four loss-of-function mutations of the FSH beta-subunit have been described in eight patients with undetectable serum FSH and high serum LH levels. Therefore, this unusual hormonal profile strongly suggests a defect in the FSH beta-subunit in both sexes.

Adolescent↗
PubMed2005

Absence of follicle-stimulating hormone receptor activating mutations in women with iatrogenic ovarian hyperstimulation syndrome.

OBJECTIVE: To analyze the FSH receptor gene in women with iatrogenic ovarian hyperstimulation syndrome (OHSS). DESIGN: Clinical and molecular studies. SETTING: University hospital and private clinic. PATIENT(S): Twenty-nine women who developed moderate or severe OHSS after ovulation induction for IVF. In addition, 50 fertile normal women were used as controls. INTERVENTION(S): Peripheral blood was used for DNA extraction. The exons 4, 7, 9, and 10 of the FSH receptor gene were amplified by polymerase chain reaction (PCR) followed by automatic direct sequencing. MAIN OUTCOME MEASURE(S): Hormonal results and automatic sequencing analysis. RESULT(S): Thirteen patients developed moderate OHSS and 16 patients developed the severe form of the syndrome. Automatic sequencing revealed no activating mutations in all patients studied. We found two known polymorphisms in linkage disequilibrium, Ala307Thr and Ser680Asn, in 79.3% of the patients (44.8% in heterozygous and 34.5% in homozygous state). These polymorphisms were found with similar frequency in the 50 normal fertile women. CONCLUSION(S): We conclude that the FSH receptor genotype did not play a significant role in the risk of iatrogenic OHSS in this cohort.

Adolescent↗