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1.
Endocrinology ; 160(10): 2353-2366, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31393557

RESUMO

Primary ovarian insufficiency (POI) is defined by the loss or dysfunction of ovarian follicles associated with amenorrhea before the age of 40. Symptoms include hot flashes, sleep disturbances, and depression, as well as reduced fertility and increased long-term risk of cardiovascular disease. POI occurs in ∼1% to 2% of women, although the etiology of most cases remains unexplained. Approximately 10% to 20% of POI cases are due to mutations in a single gene or a chromosomal abnormality, which has provided considerable molecular insight into the biological underpinnings of POI. Many of the genes for which mutations have been associated with POI, either isolated or syndromic cases, function within mitochondria, including MRPS22, POLG, TWNK, LARS2, HARS2, AARS2, CLPP, and LRPPRC. Collectively, these genes play roles in mitochondrial DNA replication, gene expression, and protein synthesis and degradation. Although mutations in these genes clearly implicate mitochondrial dysfunction in rare cases of POI, data are scant as to whether these genes in particular, and mitochondrial dysfunction in general, contribute to most POI cases that lack a known etiology. Further studies are needed to better elucidate the contribution of mitochondria to POI and determine whether there is a common molecular defect in mitochondrial function that distinguishes mitochondria-related genes that when mutated cause POI vs those that do not. Nonetheless, the clear implication of mitochondrial dysfunction in POI suggests that manipulation of mitochondrial function represents an important therapeutic target for the treatment or prevention of POI.

2.
J Clin Endocrinol Metab ; 104(10): 4676-4682, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31162547

RESUMO

BACKGROUND: Somatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene are common in corticotropinomas of children with Cushing disease (CD). We report a unique patient with a germline USP8 mutation who presented with CD and a constellation of other findings that constitute an intriguing genetic syndrome. CASE DESCRIPTION: We describe a 16-year-old female with CD, developmental delay, dysmorphic features, ichthyosiform hyperkeratosis, chronic lung disease, chronic kidney disease, hyperglycemia, dilated cardiomyopathy with congestive heart failure, and previous history of hyperinsulinism and partial GH deficiency. She was diagnosed with CD at 14 years old and underwent transsphenoidal surgery. Despite initial improvement, she developed recurrent CD. METHODS: DNA was extracted from peripheral blood and tumor DNA; whole-exome and Sanger confirmatory sequencing were performed. Immunohistochemistry was performed on the resected adenoma. RESULTS: A de novo germline heterozygous USP8 mutation (c.2155T>C, p.S719P) in the critical 14-3-3 binding motif hot spot locus of the gene was identified in both the peripheral blood and tumor DNA. Histopathologic evaluation of the resected tumor confirmed an ACTH-secreting adenoma. CONCLUSION: Somatic USP8 mutations are common in adenomas causing CD, but to date, no germline defects have been reported. We describe a patient with a de novo germline USP8 mutation with recurrent CD and multiple other medical problems. This unique patient informs us of the multitude of signaling events that may be controlled by USP8.

3.
Fertil Steril ; 112(1): 156-161, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31029431

RESUMO

OBJECTIVE: To study the reproductive history of patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) who have a nonfunctioning vitamin D receptor (VDR). DESIGN: Retrospective cohort study. SETTING: Tertiary university-affiliated medical center. PATIENT(S): Sixteen HVDRR patients and six spouses, four female and two male. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The data on age at menarche, time of conception, and number of pregnancies, abortions, and healthy newborns as reported by HVDRR women and partners of HVDRR men were analyzed, as were the results of semen sample analyses from HVDRR men. RESULT(S): All 16 patients had normal puberty. The mean age at menarche was 13.8 ± 0.8 years. Two married HVDRR women reported four normal pregnancies and four healthy newborns. Four married HVDRR men reported 15 pregnancies and nine healthy newborns. The wives of two of these men, who are brothers, gave birth to three healthy newborns and had six natural miscarriages during the second trimester of pregnancy. Time to conceive for all the female study patients was <1 year. Analysis of semen from the four men showed normal parameters. CONCLUSION(S): The VDR is expressed throughout the organs of reproduction, suggesting a role for vitamin D in reproduction. However, the reproductive potential of HVDRR patients with a mutant VDR gene with a nonfunctioning VDR appears to be normal.

4.
PLoS Genet ; 15(4): e1008088, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31034465

RESUMO

PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. At the cellular level, PIK3C2A is critical for the formation of cilia and for receptor mediated endocytosis, among other biological functions. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. In particular, the considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe's syndrome, which is caused by mutations in the PI-5-phosphatase OCRL, highlight the key role of PI metabolizing enzymes in specific developmental processes and demonstrate the unique non-redundant functions of each enzyme. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Catarata/genética , Transtornos da Motilidade Ciliar/genética , Nanismo/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Adolescente , Adulto , Criança , Consanguinidade , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Linhagem , Fenótipo , Adulto Jovem
5.
J Clin Endocrinol Metab ; 104(8): 3172-3180, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30865229

RESUMO

CONTEXT: Congenital adrenal hyperplasia (CAH) was among the first genetic disorders included in newborn screening (NBS) programs worldwide, based on 17α-hydroxyprogesterone (17-OHP) levels in dried blood spots. However, the success of NBS for CAH is hampered by high false positive (FP) rates, especially in preterm and low-birthweight infants. OBJECTIVE: To establish a set of cutoff values adjusting for both gestational age (GA) and birthweight (BW), with the aim of reducing FP rates. DESIGN: This cross-sectional, population-based study summarizes 10 years of experience of the Israeli NBS program for diagnosis of CAH. Multitiered 17-OHP cutoff values were stratified according to both BW and GA. PARTICIPANTS: A total of 1,378,132 newborns born between 2008 and 2017 were included in the NBS program. RESULTS: Eighty-eight newborns were ultimately diagnosed with CAH; in 84 of these, CAH was detected upon NBS. The combined parameters-adjusted approach significantly reduced the recall FP rate (0.03%) and increased the positive predictive value (PPV) (16.5%). Sensitivity among those referred for immediate attention increased significantly (94%). There were four false negative cases (sensitivity, 95.4%), all ultimately diagnosed as simple-virilizing. Sensitivity and specificity were 95.4% and 99.9%, respectively, and the percentage of true-positive cases from all newborns referred for evaluation following a positive NBS result was 96%. CONCLUSIONS: The use of cutoff values adjusted for both GA and BW significantly reduced FP rates (0.03%) and increased overall PPV (16.5%). Based on our 10 years of experience, we recommend the implementation of this two parameter-adjusted approach for NBS of classic CAH in NBS programs worldwide.

6.
Hum Mol Genet ; 27(11): 1913-1926, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29566152

RESUMO

Primary ovarian insufficiency (POI) is characterized by amenorrhea and loss or dysfunction of ovarian follicles prior to the age of 40. POI has been associated with autosomal recessive mutations in genes involving hormonal signaling and folliculogenesis, however, the genetic etiology of POI most often remains unknown. Here we report MRPS22 homozygous missense variants c.404G>A (p.R135Q) and c.605G>A (p.R202H) identified in four females from two independent consanguineous families as a novel genetic cause of POI in adolescents. Both missense mutations identified in MRPS22 are rare, occurred in highly evolutionarily conserved residues, and are predicted to be deleterious to protein function. In contrast to prior reports of mutations in MRPS22 associated with severe mitochondrial disease, the POI phenotype is far less severe. Consistent with this genotype-phenotype correlation, mitochondrial defects in oxidative phosphorylation or rRNA levels were not detected in fibroblasts derived from the POI patients, suggesting a non-bioenergetic or tissue-specific mitochondrial defect. Furthermore, we demonstrate in a Drosophila model that mRpS22 deficiency specifically in somatic cells of the ovary had no effect on fertility, whereas flies with mRpS22 deficiency specifically in germ cells were infertile and agametic, demonstrating a cell autonomous requirement for mRpS22 in germ cell development. These findings collectively identify that MRPS22, a component of the small mitochondrial ribosome subunit, is critical for ovarian development and may therefore provide insight into the pathophysiology and treatment of ovarian dysfunction.

7.
J Clin Endocrinol Metab ; 102(8): 2670-2677, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28453643

RESUMO

Context: Early-onset obesity, characteristic for disorders affecting the leptin-melanocortin pathway, is also observed in pseudohypoparathyroidism type 1A (PHP1A), a disorder caused by maternal GNAS mutations that disrupt expression or function of the stimulatory G protein α-subunit (Gsα). Mutations and/or epigenetic abnormalities at the same genetic locus are also the cause of pseudohypoparathyroidism type 1B (PHP1B). However, although equivalent biochemical and radiographic findings can be encountered in these related disorders caused by GNAS abnormalities, they are considered distinct clinical entities. Objectives: To further emphasize the overlapping features between both disorders, we report the cases of several children, initially brought to medical attention because of unexplained early-onset obesity, in whom PHP1B or PHP1A was eventually diagnosed. Patients and Methods: Search for GNAS methylation changes or mutations in cohorts of patients with early-onset obesity. Results: Severe obesity had been noted in five infants, with a later diagnosis of PHP1B due to STX16 deletions and/or abnormal GNAS methylation. These findings prompted analysis of 24 unselected obese patients, leading to the discovery of inherited STX16 deletions in 2 individuals. Similarly, impressive early weight gains were noted in five patients, who initially lacked additional Albright hereditary osteodystrophy features but in whom PHP1A due to GNAS mutations involving exons encoding Gsα was diagnosed. Conclusions: Obesity during the first year of life can be the first clinical evidence for PHP1B, expanding the spectrum of phenotypic overlap between PHP1A and PHP1B. Importantly, GNAS methylation abnormalities escape detection by targeted or genome-wide sequencing strategies, raising the question of whether epigenetic GNAS analyses should be considered for unexplained obesity.


Assuntos
Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Obesidade Pediátrica/genética , Pseudo-Hipoparatireoidismo/genética , Sintaxina 16/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Metilação de DNA , Epigênese Genética , Feminino , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase Multiplex , Mutação
8.
Am J Med Genet A ; 170(9): 2338-48, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27271787

RESUMO

One of the goals of evaluating a patient in the genetics clinic is to find the diagnosis that would explain his or her clinical presentation. Sometimes the patient's diagnosis remains undefined or does not explain all of the clinical findings. As clinicians are often guided by a "single disorder" paradigm, diagnosing multiple genetic conditions in the same patient requires a heightened sense of awareness. Over the last few years, we evaluated several patients (n = 14) who were found to have more than one genetic diagnosis. In this paper, we will describe their natural history and diagnoses, and draw on the lessons learned from this phenomenon, which we expect to grow in this era of next-generation diagnostic technologies. To our knowledge, this is by far the largest series of patients with double diagnoses. Based on our findings, we strongly recommend that physicians question every diagnosis to determine whether it indeed explains all of the patients' symptoms, and consider whether they should continue the diagnostic evaluation to look for a more accurate and complete set of diagnoses. © 2016 Wiley Periodicals, Inc.


Assuntos
Estudos de Associação Genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Adolescente , Adulto , Aneuploidia , Criança , Pré-Escolar , Deleção Cromossômica , Duplicação Cromossômica , Tomada de Decisão Clínica , Feminino , Doenças Genéticas Inatas/terapia , Testes Genéticos , Variação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
9.
G3 (Bethesda) ; 6(5): 1251-66, 2016 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-26921301

RESUMO

The well-documented latitudinal clines of genes affecting human skin color presumably arise from the need for protection from intense ultraviolet radiation (UVR) vs. the need to use UVR for vitamin D synthesis. Sampling 751 subjects from a broad range of latitudes and skin colors, we investigated possible multilocus correlated adaptation of skin color genes with the vitamin D receptor gene (VDR), using a vector correlation metric and network method called BlocBuster. We discovered two multilocus networks involving VDR promoter and skin color genes that display strong latitudinal clines as multilocus networks, even though many of their single gene components do not. Considered one by one, the VDR components of these networks show diverse patterns: no cline, a weak declining latitudinal cline outside of Africa, and a strong in- vs. out-of-Africa frequency pattern. We confirmed these results with independent data from HapMap. Standard linkage disequilibrium analyses did not detect these networks. We applied BlocBuster across the entire genome, showing that our networks are significant outliers for interchromosomal disequilibrium that overlap with environmental variation relevant to the genes' functions. These results suggest that these multilocus correlations most likely arose from a combination of parallel selective responses to a common environmental variable and coadaptation, given the known Mendelian epistasis among VDR and the skin color genes.


Assuntos
Altitude , Interação Gene-Ambiente , Receptores de Calcitriol/genética , Pigmentação da Pele/genética , Adaptação Biológica/genética , Alelos , Biologia Computacional/métodos , Epistasia Genética , Frequência do Gene , Redes Reguladoras de Genes , Ligação Genética , Genoma Humano , Genômica/métodos , Genótipo , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único
10.
J Clin Endocrinol Metab ; 101(2): 394-415, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26745253

RESUMO

BACKGROUND: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence. PROCESS: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.


Assuntos
Recomendações Nutricionais , Raquitismo/prevenção & controle , Cálcio/deficiência , Criança , Pré-Escolar , Consenso , Política de Saúde , Humanos , Lactente , Mães , Osteomalacia/diagnóstico , Osteomalacia/terapia , Raquitismo/terapia , Fatores de Risco , Vitamina D/administração & dosagem , Vitamina D/uso terapêutico , Deficiência de Vitamina D/terapia , Vitaminas/administração & dosagem , Vitaminas/uso terapêutico
11.
Horm Res Paediatr ; 85(2): 83-106, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26741135

RESUMO

BACKGROUND: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. PROCESS: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.


Assuntos
Raquitismo/terapia , Cálcio/deficiência , Feminino , Humanos , Lactação , Gravidez , Complicações na Gravidez/prevenção & controle , Saúde Pública , Raquitismo/diagnóstico , Raquitismo/etiologia , Fatores de Risco , Deficiência de Vitamina D/complicações
12.
Crit Rev Food Sci Nutr ; 56(6): 887-95, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26017813

RESUMO

Homo sapiens are unique in having a life history phase of childhood, which follows infancy, as defined by breastfeeding. This review uses evolutionary life history theory in understanding child growth in a broad evolutionary perspective, using the data and theory of evolutionary predictive adaptive growth-related strategies for transition from infancy to childhood. We have previously shown that a delayed infancy-childhood transition has a lifelong impact on stature. Feeding practices during infancy are fundamental elements of nutrition as they program for future growth and body composition. A relationship between the duration of breastfeeding and the nature of weaning has been suggested as a possible cause for later obesity and growth patterns. This review highlights the role that breast milk feeding and variations in the weaning age have on transition to childhood, growth, and body composition.


Assuntos
Desenvolvimento Infantil/fisiologia , Fenômenos Fisiológicos da Nutrição Infantil , Fenômenos Fisiológicos da Nutrição do Lactente , Desmame , Criança , Humanos , Lactente
13.
J Clin Endocrinol Metab ; 100(10): 3668-75, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26291067

RESUMO

CONTEXT: Puberty is associated with increased dietary calcium absorption. However, little is known about the metabolic adaptations that enhance calcium absorption during puberty. OBJECTIVES: To investigate duodenal 25-hydroxy vitamin D-1α-hydroxylase (CYP 27B1) mRNA expression and duodenal 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) production in children, adolescents, and adults. DESIGN AND METHODS: CYP27B1a nd IGF1 mRNA expression and 1,25(OH)2D3 production were determined in duodenal biopsies. CYP27B1 expression was also determined after IGF1R inhibitor treatment of human and mice duodenal explants. mRNA expression was determined by RT-PCR, and CYP27B1 activity was determined by incubating duodenal explants with 25(OH)D3 and measuring 1,25(OH)2D3 production by radioimmunoassay. RESULTS: CYP27B1 mRNA expression was 13.7 and 10.4 times higher in biopsies from adolescents compared to adults and children, respectively. IGF1 mRNA expression was 30% and 45% higher in explants from adolescents and children, respectively, compared to adults. Inhibition of IGF1 receptor activity decreased CYP27B1 expression in explants from both mice (85%) and humans (24%). 1,25(OH)2D3 production reached a maximum velocity of 768 ± 268 pmol/l/mg protein at 748.8 nmol/l of 25(OH)D3 in children and adolescents, whereas the maximum velocity was 86.4 ± 43.2 pmol/l/mg protein in adults. The substrate concentration at which the enzyme shows half of its maximum activity was similar in all groups, ranging between 624 and 837 nmol/L of 25(OH)D3. CONCLUSIONS: Increased CYP27B1 expression and local duodenal 1,25(OH)2D3 production during puberty may be a metabolic adaptation that promotes dietary calcium absorption. IGF1, a major factor in skeletal growth, is also involved in the modulation of CYP27B1 expression in the gut and may increase calcium supply for the growing bone.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Duodeno/metabolismo , Maturidade Sexual/fisiologia , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Adolescente , Adulto , Fatores Etários , Idoso , Animais , Criança , Pré-Escolar , Duodeno/efeitos dos fármacos , Feminino , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Maturidade Sexual/efeitos dos fármacos , Adulto Jovem
14.
Diabetes Metab Res Rev ; 31(5): 492-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25529355

RESUMO

BACKGROUND: Type 1 diabetes is an autoimmune disease, characterized by a loss of pancreatic ß-cell mass and function, which results in dramatic reductions in insulin secretion and circulating insulin levels. Patients with type 1 diabetes are traditionally treated with insulin injections and insulin pumps ex vivo or undergo transplantation. Growth hormone (GH) has been shown to be involved in ß-cell function and survival in culture. METHODS: Twelve-week-old female C57BL/6 mice were treated with streptozotocin and monitored for their weight and blood glucose levels. Fourteen days post-initial injection, these mice were separated into two groups at random. One group was treated with GH while the other treated with vehicle for up to 3 weeks. These mice were compared with mice not treated with streptozotocin. RESULTS: Under our experimental conditions, we observed that mice treated with GH had larger islets and higher serum insulin levels than streptozotocin-treated mice treated with saline (0.288 vs. 0.073 ng/mL, p < 0.01). CONCLUSIONS: Our data demonstrate that GH may rescue islets and therefore may possess therapeutic potential in the treatment of type 1 diabetes, although consideration should be made regarding GH's effect on insulin resistance.


Assuntos
Diabetes Mellitus Experimental/sangue , Hormônio do Crescimento Humano/farmacologia , Insulina/sangue , Ilhotas Pancreáticas/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/patologia , Feminino , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Proteínas Recombinantes
15.
J Bone Miner Res ; 30(5): 906-12, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25403028

RESUMO

Hypocalcemia and hyperphosphatemia because of resistance toward parathyroid hormone (PTH) in the proximal renal tubules are the most prominent abnormalities in patients affected by pseudohypoparathyroidism type Ib (PHP-Ib). In this rare disorder, which is caused by GNAS methylation changes, resistance can occur toward other hormones, such as thyroid-stimulating hormone (TSH), that mediate their actions through G protein-coupled receptors. However, these additional laboratory abnormalities are usually not recognized until PTH-resistant hypocalcemia becomes clinically apparent. We now describe four pediatric patients, first diagnosed with subclinical or overt hypothyroidism between the ages of 0.2 and 15 years, who developed overt PTH-resistance 3 to 20 years later. Although anti-thyroperoxidase (anti-TPO) antibodies provided a plausible explanation for hypothyroidism in one of these patients, this and two other patients revealed broad epigenetic GNAS abnormalities, which included loss of methylation (LOM) at exons AS, XL, and A/B, and gain of methylation at exon NESP55; ie, findings consistent with PHP-Ib. LOM at GNAS exon A/B alone led in the fourth patient to the identification of a maternally inherited 3-kb STX16 deletion, a well-established cause of autosomal dominant PHP-Ib. Although GNAS methylation changes were not detected in additional pediatric and adult patients with subclinical hypothyroidism (23 pediatric and 39 adult cases), hypothyroidism can obviously be the initial finding in PHP-Ib patients. One should therefore consider measuring PTH, along with calcium and phosphate, in patients with unexplained hypothyroidism for extended periods of time to avoid hypocalcemia and associated clinical complications.


Assuntos
Pseudo-Hipoparatireoidismo/sangue , Tireotropina/sangue , Adulto , Pré-Escolar , Cromossomos Humanos Par 20/genética , Epigênese Genética , Éxons/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pseudo-Hipoparatireoidismo/genética , Sintaxina 16/genética , Adulto Jovem
16.
Genet Med ; 17(8): 651-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25394172

RESUMO

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two. METHODS: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays. RESULTS: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling. CONCLUSION: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.


Assuntos
Hipogonadismo/congênito , Hipogonadismo/genética , Deformidades Congênitas dos Membros/genética , Mutação , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sequência de Aminoácidos , Animais , Sequência Conservada , Feminino , Estudos de Associação Genética , Humanos , Hipogonadismo/metabolismo , Deformidades Congênitas dos Membros/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Proteínas de Membrana/metabolismo , Dados de Sequência Molecular , Linhagem , Fosforilação , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo
17.
Reprod Biol Endocrinol ; 12: 97, 2014 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-25300391

RESUMO

The use of complementary and alternative medicine and herbal products, especially traditional Chinese medicines, is progressively rising for both adults and children. This increased use is based on the popular belief that these medicines are safe and harmless. In this report, we describe the results of a bedside-to-bench study that involved a short-statured 4-year-old boy with deficiencies in growth hormone, thyroid stimulating hormone, and adrenocorticotropic hormone due to an ectopic posterior pituitary gland and invisible pituitary stalk. Although the boy was given replacement therapy with hydrocortisone and L-thyroxin, the parents refused to treat him with growth hormone and consulted a naturopath who prescribed a traditional Chinese medicine (TCM) to stimulate the boy's growth. From the age of 20 months, the child's growth was regularly monitored while he was being treated with hydrocortisone, thyroxin, and the TCM. Over a 36-month period, the child's growth velocity accelerated (3 cm/year to 8 cm/year), his height increment substantially increased (-2 SD to -0.8 SD), and his bones matured. In the laboratory investigation, estrogen receptor (ER)alpha and ERbeta reporter cell lines were used to characterize the estrogenic activity of the TCM medicine and its 18 components, and the results established that the medicine and some of its components have estrogen receptor ERalpha and ERbeta selectivity and partial estrogen agonism. Partial estrogenic activity of the TCM was confirmed using whole-cell competitive binding, cell proliferation, and endogenous gene expression assays in the ERalpha-positive breast cancer cell lines. Although the presence of evidence is not always evidence of causality, we have concluded that this traditional Chinese medicine contains ingredients with estrogenic activity that can sustain bone growth and maturation without affecting other estrogen-dependent tissues.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Receptor alfa de Estrogênio/agonistas , Receptor beta de Estrogênio/agonistas , Transtornos do Crescimento/tratamento farmacológico , Fitoestrógenos/uso terapêutico , Pré-Escolar , Agonismo Parcial de Drogas , Medicamentos de Ervas Chinesas/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Genes Reporter/efeitos dos fármacos , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/patologia , Humanos , Células MCF-7 , Masculino , Osteogênese/efeitos dos fármacos , Fitoestrógenos/farmacologia , Resultado do Tratamento
18.
J Clin Endocrinol Metab ; 99(9): E1610-6, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24885630

RESUMO

CONTEXT: Previous studies have reported an association between vitamin D deficiency and asthma. Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) patients provide a natural model to assess the role of the vitamin D receptor (VDR) in regulating human lung immune responses and airway hyperreactivity. OBJECTIVES: The aim of the study was to determine the role of the VDR on lung functions, airways, and systemic markers of inflammation and allergy in HVDRR patients. DESIGN AND METHODS: Thirteen HVDRR patients (aged 6-37 y) and 17 normal controls (aged 6-38 y) underwent spirometry, a methacholine challenge test (MCT), blood tests, allergy skin tests, determination of fractional exhaled nitric oxide, and measurement of serum and exhaled breath condensate cytokines, including IL-4, IL-5, IL-10, IL-17, and interferon-γ levels. RESULTS: All HVDRR patients had negative MCT results, whereas six controls (35.3%) had positive MCT results (P < .014). Serum IgE levels, eosinophil counts, and fractional exhaled nitric oxide and allergy skin test results were similar for the HVDRR patients and controls, as were the serum cytokine concentrations. The HVDRR patients had different cytokine levels in their exhaled breath condensate (increased IL-4 and IL-17 and decreased IL-5, IL-10, and interferon-γ levels) compared to the controls (P < .005). CONCLUSIONS: HVDRR patients show diverse exhaled cytokine profiles but seem to be protected against provoked bronchial hyperreactivity and clinical asthma. These findings suggest that an intact VDR has an important role in asthma pathophysiology.


Assuntos
Asma/genética , Hiper-Reatividade Brônquica/genética , Raquitismo Hipofosfatêmico Familiar/genética , Pneumonia/genética , Receptores de Calcitriol/genética , Adolescente , Adulto , Asma/imunologia , Asma/fisiopatologia , Biomarcadores , Testes Respiratórios , Hiper-Reatividade Brônquica/diagnóstico , Hiper-Reatividade Brônquica/imunologia , Criança , Citocinas/sangue , Raquitismo Hipofosfatêmico Familiar/imunologia , Feminino , Humanos , Masculino , Mutação , Pneumonia/diagnóstico , Pneumonia/imunologia , Receptores de Calcitriol/imunologia , Testes Cutâneos , Espirometria , Vitamina D/análogos & derivados , Vitamina D/sangue , Adulto Jovem
19.
J Am Soc Nephrol ; 25(10): 2366-75, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24700880

RESUMO

Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na(+))-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P<0.001). Renal calcifications were also more frequent in het carriers (16%; P=0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (odds ratio [OR], 0.75, 95% confidence interval [95% CI], 0.59 to 0.96; P=0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95% CI, 0.23 to 0.72; P=0.002), and increased serum 1,25(OH)2 vitamin D (OR, 1.22; 95% CI, 1.05 to 1.41; P=0.008). Additional studies are needed to determine whether these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, CKD.


Assuntos
Cálculos Renais/genética , Nefrocalcinose/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIc/genética , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto
20.
Curr Opin Endocrinol Diabetes Obes ; 21(1): 51-5, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24300739

RESUMO

PURPOSE OF REVIEW: We propose to review several recent key clinically oriented topics related to vitamin D and health in children. RECENT FINDINGS: We found a very large number of recent clinical studies related to vitamin D. However, most are association studies with few physiological or clinical trials that are adequately powered for clinical outcomes. Key results are available related to pulmonary disease and allergic disorders. Recent studies have also evaluated the relationship of vitamin D to bone health as well as new insights into genetic conditions related to vitamin D metabolism. SUMMARY: Recent studies generally support the recommendations of the Institute of Medicine related to vitamin D intake but there is new and increasing evidence that some health conditions, such as pulmonary diseases in children, might benefit from close monitoring of vitamin D status. However, controlled trials are mostly lacking and there is an inadequate basis from recent studies to recommend high dose vitamin D pending the results of controlled trials.


Assuntos
Cálcio na Dieta/metabolismo , Hipercalcemia/etiologia , Hipersensibilidade/etiologia , Pneumopatias/etiologia , Raquitismo/etiologia , Deficiência de Vitamina D/complicações , Densidade Óssea , Criança , Fenômenos Fisiológicos da Nutrição Infantil , Pré-Escolar , Suplementos Nutricionais , Feminino , Humanos , Hipercalcemia/tratamento farmacológico , Hipercalcemia/metabolismo , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/metabolismo , Lactente , Pneumopatias/tratamento farmacológico , Pneumopatias/metabolismo , Raquitismo/tratamento farmacológico , Raquitismo/metabolismo , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/metabolismo
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