IVO JORGE PRADO ARNHOLD
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
14 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 14
- Combined pituitary hormone deficiency caused by PROP1 mutations: update 20 years post-discovery(2019) CORREA, Fernanda A.; NAKAGUMA, Marilena; MADEIRA, Joao L. O.; NISHI, Mirian Y.; ABRAO, Milena G.; JORGE, Alexander A. L.; CARVALHO, Luciani R.; ARNHOLD, Ivo J. P.; MENDONCA, Berenice B.The first description of patients with combined pituitary hormone deficiencies (CPHD) caused by PROP1 mutations was made 20 years ago. Here we updated the clinical and genetic characteristics of patients with PROP1 mutations and summarized the phenotypes of 14 patients with 7 different pathogenic PROP1 mutations followed at the Hospital das Clinicas of the University of Sao Paulo. In addition to deficiencies in GH, TSH, PRL and gonadotropins some patients develop late ACTH deficiency. Therefore, patients with PROP1 mutations require permanent surveillance. On magnetic resonance imaging, the pituitary stalk is normal, and the posterior lobe is in the normal position. The anterior lobe in patients with PROP1 mutations is usually hypoplastic but may be normal or even enlarged. Bi-allelic PROP1 mutations are currently the most frequently recognized genetic cause of CPHD worldwide. PROP1 defects occur more frequently among offspring of consanguineous parents and familial cases, but they also occur in sporadic cases, especially in countries in which the prevalence of PROP1 mutations is relatively high. We classified all reported PROP1 variants described to date according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines: 29 were pathogenic, 2 were likely pathogenic, and 2 were of unknown significance. An expansion of the phenotype of patients with PROP1 mutations was observed since the first description 20 years ago: variable anterior pituitary size, different pathogenic mutations, and late development of ACTH deficiency. PROP1 mutations are the most common cause of autosomal recessive CPHD with a topic posterior pituitary lobe.
- Adult Height of Patients with SHOX Haploinsufficiency with or without GH Therapy: A Real-World Single-Center Study(2022) DANTAS, Naiara C. B.; FUNARI, Mariana F. A.; VASQUES, Gabriela A.; ANDRADE, Nathalia L. M.; REZENDE, Raissa C.; BRITO, Vinicius; SCALCO, Renata C.; ARNHOLD, Ivo J. P.; MENDONCA, Berenice B.; JORGE, Alexander A. L.Introduction: Isolated SHOX haploinsufficiency is a common monogenic cause of short stature. Few studies compare untreated and rhGH-treated patients up to adult height (AH). Our study highlights a growth pattern from childhood to AH in patients with SHOX haploinsufficiency and analyzes the real-world effectiveness of rhGH alone or plus GnRH analog (GnRHa). Methods: Forty-seven patients (18 untreated and 29 rhGH-treated) with SHOX haploinsufficiency were included in a longitudinal retrospective study. Adult height was attained in 13 untreated and 18 rhGH-treated (rhGH alone [n = 8] or plus GnRHa [n = 10]) patients. Results: The untreated group decreased height SDS from baseline to AH (-0.8 [-1.1; -0.4]), with an increase in the prevalence of short stature from 31% to 77%. Conversely, the rhGH-treated group had an improvement in height SDS from baseline to AH (0.6 [0.2; 0.6]; p < 0.001), with a reduction in the prevalence of short stature (from 61% to 28%). AH in the rhGH-treated patients was 1 SD (6.3 cm) taller than in untreated ones. Regarding the use of GnRHa, the subgroups (rhGH alone or plus GnRHa) attained similar AH, despite the higher prevalence of pubertal patients and worse AH prediction at the start of rhGH treatment in patients who used combined therapy. Conclusion: The use of rhGH treatment improves AH in patients with SHOX haploinsufficiency, preventing the loss of height potential during puberty. In peripubertal patients, the addition of GnRHa to rhGH allows AH attainment similar to the AH of patients who start rhGH alone in the prepubertal age. (C) 2022 S. Karger AG, Basel
- Spontaneous fertility in a male patient with testotoxicosis despite suppression of FSH levels(2018) CUNHA-SILVA, M.; BRITO, V. N.; MACEDO, D. B.; BESSA, D. S.; RAMOS, C. O.; LIMA, L. G.; BARROSO, P. S.; ARNHOLD, I. J. P.; SEGALOFF, D. L.; MENDONCA, B. B.; LATRONICO, A. C.Testotoxicosis is a rare cause of peripheral precocious puberty in boys caused by constitutively activating mutations of the LHCG receptor. Affected males usually have normal gonadotropin profiles and fertility in their adult life. Here, we described the long-term follow-up of a 24-year-old young man with severe testotoxicosis due to a de novo activating mutation in the third transmembrane helix of the LHCGR (p. Leu457Arg). This patient was treated with different medications, including medroxyprogesterone acetate, ketoconazole, cyproterone acetate and aromatase inhibitor from age 2.5 to 9.5 years. His basal and GnRH-stimulated gonadotropin levels were continually suppressed during and after medical treatment. At adulthood, extremely high serum testosterone levels (>35 nmol/L), undetectable gonadotropin levels (LH < 0.15 IU/L and FSH < 0.6 IU/L) and oligozoospermia were evidenced. Despite his suppressed FSH levels and an unfavorable spermogram, the patient fathered a healthy girl and biological paternity was confirmed through analysis of microsatellites. Spontaneous fertility in a young man with severe testotoxicosis and chronic suppression of FSH levels reinforces the key role of high intratesticular testosterone levels in human spermatogenesis.
- 46,XY Disorders of Sex Development (46,XY DSD) due to Androgen Receptor Defects: Androgen Insensitivity Syndrome(2011) ARNHOLD, Ivo J. P.; MELO, Karla; COSTA, Elaine M. F.; DANILOVIC, Debora; INACIO, Marlene; DOMENICE, Sorahia; MENDONCA, Berenice B.
- Role of GLI2 in hypopituitarism phenotype(2015) ARNHOLD, Ivo J. P.; FRANCA, Marcela M.; CARVALHO, Luciani R.; MENDONCA, Berenice B.; JORGE, Alexander A. L.GLI2 is a zinc-finger transcription factor involved in the Sonic Hedgehog pathway. Gli2 mutant mice have hypoplastic anterior and absent posterior pituitary glands. We reviewed the literature for patients with hypopituitarism and alterations in GLI2. Twenty-five patients (16 families) had heterozygous truncating mutations, and the phenotype frequently included GH deficiency, a small anterior pituitary lobe and an ectopic/undescended posterior pituitary lobe on magnetic resonance imaging and postaxial polydactyly. The inheritance pattern was autosomal dominant with incomplete penetrance and variable expressivity. The mutation was frequently inherited from an asymptomatic parent. Eleven patients had heterozygous non-synonymous GLI2 variants that were classified as variants of unknown significance, because they were either absent from or had a frequency lower than 0.001 in the databases. In these patients, the posterior pituitary was also ectopic, but none had polydactyly. A third group of variants found in patients with hypopituitarism were considered benign because their frequency was >= 0.001 in the databases. GLI2 is a large and polymorphic gene, and sequencing may identify variants whose interpretation may be difficult. Incomplete penetrance implies in the participation of other genetic and/or environmental factors. An interaction between Gli2 mutations and prenatal ethanol exposure has been demonstrated in mice dysmorphology. In conclusion, a relatively high frequency of GLI2 mutations and variants were identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with combined pituitary hormone deficiency and an ectopic posterior pituitary lobe. Future studies may clarify the relative role and frequency of GLI2 alterations in the aetiology of hypopituitarism.
- Relatively high frequency of non-synonymous GLI2 variants in patients with congenital hypopituitarism without holoprosencephaly(2013) FRANCA, Marcela M.; JORGE, Alexander A. L.; CARVALHO, Luciani R. S.; COSTALONGA, Everlayny F.; OTTO, Aline P.; CORREA, Fernanda A.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.Objective GLI2 is a downstream transcription factor in Sonic Hedgehog signalling, acting early in ventral forebrain and pituitary development. Heterozygous nonsense GLI2 mutations have been reported in patients with isolated or combined pituitary hormone deficiency (CPHD), with or without holoprosencephaly. The aim of this study was to screen for GLI2 mutations in a large cohort of patients with congenital GH deficiency. Design and Patients The GLI2 coding region of 41 patients with severe isolated GH deficiency (IGHD) and 136 patients with CPHD was amplified by PCR using intronic primers and sequenced. The frequency of GLI2 variants was verified in up to 155 Brazilian controls and in the 1000 Genomes database. The consequences of allelic variants were analysed by the Polyphen, SIFT, Mutationtaster and SNAP prediction sites. Results Eighteen different heterozygous non-synonymous GLI2 variants were identified in 24 patients. Twenty-three patients had CPHD and one had IGHD. Two patients had additional diabetes insipidus, indicating deficiencies of anterior and posterior pituitary lobes. The posterior pituitary lobe on MRI was ectopic in 16, not visible in 4, normally placed in 2 and imaging was not available in two patients, but there were no signs of holoprosencephaly. Sixteen GLI2 variants were considered deleterious in at least one of the prediction sites. Conclusions A relatively high frequency of non-synonymous GLI2 variants was identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with CPHD and an ectopic posterior pituitary lobe. In vitro functional assays may contribute to ascertain the deleterious consequences of these variants.
- A homozygous point mutation in the GH1 promoter (c.-223C > T) leads to reduced GH1 expression in siblings with isolated GH deficiency (IGHD)(2016) MADEIRA, Joao L. O.; JORGE, Alexander A. L.; MARTIN, Regina M.; MONTENEGRO, Luciana R.; FRANCA, Marcela M.; COSTALONGA, Everlayny F.; CORREA, Fernanda A.; OTTO, Aline P.; ARNHOLD, Ivo J. P.; FREITAS, Helayne S.; MACHADO, Ubiratan F.; MENDONCA, Berenice B.; CARVALHO, Luciani R.Context: Mutations in the GH1 promoter are a rare cause of isolated growth hormone deficiency (IGHD). Objective: To identify the molecular aetiology of a family with IGHD. Design: DNA sequencing, electromobility shift (EMSA) and luciferase reporter assays. Setting: University Hospital. Patients: Three siblings (2M) born to consanguineous parents presented with IGHD with normal pituitary on MRI. Methods: The GH1 proximal promoter, locus control region, five exons and four introns as well as GHRHR gene were sequenced in genomic DNA by Sanger method. DNA- protein interaction was evaluated by EMSA in nuclear extracts of GH3 pituitary cells. Dual-luciferase reporter assays were performed in cells transiently transfected with plasmids containing four different combinations of GH1 allelic variants (AV). Results: The patients harboured two homozygous variants (c.-185T>C and c.-223C>T) in the GH1 promoter within a highly conserved region and predicted binding sites for POU1F1/SP1 and SP1 respectively. The parents and brother were carriers and these variants were absent in 100 controls. EMSA demonstrated absent binding of GH3 nuclear extract to the c.-223C>T variant and normal binding of both POU1F1 protein and GH3 nuclear extract to the c.-185T>C variant. In contrast to GH1 promoter with AV only at c.-185, the GH1 promoter containing the AV only at c.-223 and at both positions drove significantly less expression of luciferase compared with the promoter containing either positions wild type in luciferase reporter assays. Conclusion: To our knowledge, c.-223C>T is the first homozygous point mutation in the GH1 promoter that leads to short stature due to IGHD.
- Absence of GH-Releasing Hormone (GHRH) Mutations in Selected Patients with Isolated GH Deficiency(2011) FRANCA, Marcela M.; JORGE, Alexander A. L.; ALATZOGLOU, Kyriaki S.; CARVALHO, Luciani R. S.; MENDONCA, Berenice B.; AUDI, Laura; CARRASCOSA, Antonio; DATTANI, Mehul T.; ARNHOLD, Ivo J. P.Context: Although numerous reports of mutations in GH1 and GHRHR (GHRH receptor) causing isolated GH deficiency (IGHD) have been published, mutations in GHRH itself have not been hitherto reported but are obvious candidates for GH deficiency. Objective: The aim of this study was to identify mutations in GHRH in a large cohort of patients with IGHD. Patients and Methods: DNA was isolated from 151 patients diagnosed with IGHD at national and international centers. Seventy-two patients fulfilled all the following criteria: severe short stature (height SD score <= -2.5), low peakGHafter stimulation (peak <= 5 ng/ml), eutopic posterior pituitary lobe, and absence of mutations in GH1 and GHRHR and therefore were strong candidates for GHRH mutations. The coding sequence and splice sites of GHRH were amplified by PCR with intronic primers and sequenced. Results: In five of 151 patients (four of 42 from Brazil), the GHRH c. 223 C>T, p. L75F change was identified in heterozygosity. This variant has been previously reported as a polymorphism and is more frequent in African than European and Asian populations. Six allelic variants (five novel) that do not predict change of amino acids or splice sites were identified in five patients: c. 147 C>T, p.S49S, IVS1 -70 G>A, IVS1 -74 T>C, IVS3 -47 del1, and IVS3 +7 G>A/IVS3 + 41 G>A. No functional mutations were found in this cohort. Conclusions: GHRH mutations were not identified in a selected cohort of patients with IGHD, suggesting that, if they exist, they may be an extremely rare cause of IGHD. Other, as-yet-unidentified genetic factors may be implicated in the genetic etiology of IGHD in our cohort. (J Clin Endocrinol Metab 96: E1457-E1460, 2011)
- Growth hormone deficiency with advanced bone age: phenotypic interaction between GHRH receptor and CYP21A2 mutations diagnosed by sanger and whole exome sequencing(2017) CORREA, Fernanda A.; FRANCA, Marcela M.; FANG, Qing; MA, Qianyi; BACHEGA, Tania A.; RODRIGUES, Andresa; OZEL, Bilge A.; LI, Jun Z.; MENDONCA, Berenice B.; JORGE, Alexander A. L.; CARVALHO, Luciani R.; CAMPER, Sally A.; ARNHOLD, Ivo J. P.Isolated growth hormone deficiency (IGHD) is the most common pituitary hormone deficiency and, clinically, patients have delayed bone age. High sequence similarity between CYP21A2 gene and CYP21A1P pseudogene poses difficulties for exome sequencing interpretation. A 7.5 year-old boy born to second-degree cousins presented with severe short stature (height SDS -3.7) and bone age of 6 years. Clonidine and combined pituitary stimulation tests revealed GH deficiency. Pituitary MRI was normal. The patient was successfully treated with rGH. Surprisingly, at 10.8 years, his bone age had advanced to 13 years, but physical exam, LH and testosterone levels remained prepubertal. An ACTH stimulation test disclosed a non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency explaining the bone age advancement and, therefore, treatment with cortisone acetate was added. The genetic diagnosis of a homozygous mutation in GHRHR (p.Leu144His), a homozygous CYP21A2 mutation (p.Val282Leu) and CYP21A1P pseudogene duplication was established by Sanger sequencing, MLPA and whole-exome sequencing. We report the unusual clinical presentation of a patient born to consanguineous parents with two recessive endocrine diseases: non-classic congenital adrenal hyperplasia modifying the classical GH deficiency phenotype. We used a method of paired read mapping aided by neighbouring mis-matches to overcome the challenges of exome-sequencing in the presence of a pseudogene.
- Inactivating Mutations of the Human Luteinizing Hormone Receptor in Both Sexes(2012) LATRONICO, Ana Claudia; ARNHOLD, Ivo J. P.The human luteinizing hormone/chorionic gonadotropin receptor (LHCGR) plays a fundamental role in male and female reproductive physiology. Over the past 15 years, several homozygous or compound heterozygous loss-of-function mutations in the LHCGR gene have been described in males and females. In genetic males, mutations in LHCGR were associated with distinct degrees of impairment in pre- and postnatal testosterone secretion resulting in a phenotypic spectrum. Patients with the severe form of LH resistance have predominantly female external genitalia and absence of secondary sex differentiation at puberty. Patients with milder forms have predominantly male external genitalia with micropenis and/or hypospadias or only infertility without ambiguity. The undermasculization is associated with low basal, as well as human CG-stimulated, testosterone levels and elevated LH levels after pubertal age, without abnormal step-up in testosterone biosynthesis precursors. The testes have only slightly reduced size but mature Leydig cells are absent or scarce (Leydig cell hypoplasia). Genetic females with inactivating LHCGR mutations have female external genitalia, spontaneous breast and pubic hair development at puberty, and normal or late menarche followed by oligoamenorrhea and infertility. Estradiol and progesterone levels are normal for the early to midfollicular phase, but do not reach ovulatory or luteal phase levels. Serum LH levels are high whereas follicle-stimulating hormone levels are normal or only slightly increased. Pelvic ultrasound has demonstrated a small or normal uterus and normal or enlarged ovaries with cysts. The inactivating mutations of the LHCGR have provided important insights into distinct physiological roles of LH in reproduction of both sexes.