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1.
Am J Med Genet A ; 194(9): e63645, 2024 09.
Artículo en Inglés | MEDLINE | ID: mdl-38709052

RESUMEN

Proline-5-carboxylate reductase 2, encoded by PYCR2 gene, is an enzyme that catalyzes the last step of proline synthesis from pyrroline-5-carboxylate synthetase to proline. PYCR2 gene defect causes hypomyelinating leukodystrophy 10. Up until now, to our knowledge around 38 patients with PYCR2 defect have been reported. Herein, we describe clinical, neuroradiological, biochemical findings, and metabolomic profiling of three new genetically related cases of PYCR2 defects from a large family. Cerebrospinal fluid (CSF) amino acid levels were measured and untargeted metabolomic profiling of plasma and CSF were conducted and evaluated together with the clinical findings in the patients. While plasma and CSF proline levels were found to be totally normal, untargeted metabolomic profiling revealed mild increases of glutamate, alpha-ketoglutarate, and l-glutamate semialdehyde and marked increases of inosine and xanthine. Our findings and all the previous reports suggest that proline auxotrophy is not the central disease mechanism. Untargeted metabolomics point to mild changes in proline pathway and also in purine/pyrimidine pathway.


Asunto(s)
Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias , Metabolómica , Prolina , Pirrolina Carboxilato Reductasas , Niño , Femenino , Humanos , Masculino , delta-1-Pirrolina-5-Carboxilato Reductasa , Ácido Glutámico/metabolismo , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/patología , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico , Ácidos Cetoglutáricos/metabolismo , Ácidos Cetoglutáricos/sangre , Imagen por Resonancia Magnética , Redes y Vías Metabólicas/genética , Metaboloma/genética , Metabolómica/métodos , Mutación/genética , Linaje , Prolina/líquido cefalorraquídeo , Purinas/metabolismo , Pirimidinas , Pirrolina Carboxilato Reductasas/genética , Pirrolina Carboxilato Reductasas/deficiencia , Xantina/sangre , Lactante
2.
Pituitary ; 25(1): 167-179, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34518999

RESUMEN

PURPOSE: Prevalence, presentation and clinical outcome of prolactinomas vary in children and adults. In this study, we evaluated the clinical features and outcome of children and adolescents with prolactinoma to identify the differences from that of adults, and thus to establish the management strategies for this age group. METHODS: Patients with prolactinoma diagnosed before 18 years of age from a single center in the last 20-years were included. Clinical and laboratory data, radiological findings and treatment outcome were evaluated retrospectively. RESULTS: Twenty-eight patients (23 female; 82.1%) with prolactinoma were included. Median age at diagnosis was 15.2 years (12.6-17.7 years) in girls, 12.9 years (12.0-16.7 years) in boys. First line treatment was cabergoline in 82% of patients and normal prolactin level was achieved with maximum dose of 2 mg/week in 78%. Surgery was required in 28% of patients. Adenomas < 13.5 mm responded conventional doses of CAB. Adenomas > 30 mm were drug resistant or required surgery. Adenomas between 13.5 mm and 30 mm with invasion/extension were more likely to have drug resistance. CAB had to be continued following surgery in all patients. One macroprolactinoma had an increase in size which was accompanied with increasing prolactin level. CONCLUSIONS: All microprolactinomas responded well to DA treatment. However, all adenomas larger than 30 mm was resistant to CAB or required surgery. Probability of drug resistance and requirement of second line therapy were higher in adenomas between 13.5 mm and 30 mm with invasion/extension. Doses over 2 mg/week of CAB in drug-resistant patients may not provide additional benefit. The frequency of follow-up MRI could be determined based on prolactin levels and emergence of new neurological symptoms.


Asunto(s)
Cabergolina/uso terapéutico , Neoplasias Hipofisarias , Prolactinoma , Adolescente , Niño , Agonistas de Dopamina/uso terapéutico , Femenino , Humanos , Masculino , Neoplasias Hipofisarias/tratamiento farmacológico , Prolactina , Prolactinoma/tratamiento farmacológico , Estudios Retrospectivos , Adulto Joven
3.
Clin Endocrinol (Oxf) ; 94(5): 804-810, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33460480

RESUMEN

OBJECTIVE: Data about GnRHa on adult height in girls with central precocious puberty (CPP) have shown variable results, ranging from improvement of growth prognosis to lack of any benefit. This study was designed to delineate the criteria to decide which girls with idiopathic CPP (iCPP) will have a height benefit from GnRHa treatment. DESIGN: Retrospective PATIENTS: 102 girls with iCPP who had reached final height (FH) were included. MEASUREMENTS: Auxological, hormonal and radiological findings at treatment onset, and FHs were extracted from records. RESULTS: Most important factor affecting height gain was chronological age (CA) at treatment onset. All the girls treated ≤6.4 years of age achieved a height gain of ≥1SDS, while none of the girls treated ≥8.3 years of age made the target. 75.6% of patients who started GnRHa between the ages of 6.4 and 8.3 years had a height gain of ≥1SDS. Most important factors affecting height gain in those treated 6.4-8.3 years were advanced bone age (BA), basal estradiol (E2 ) and pubertal stage (r2 : 0.906; P < .001). All individuals with BA advancement of ≥2.6 years or E2 of ≥32.6 pg/ml or pubertal stage of ≥3 had significant height gain, and none of the cases with BA advancement of <2 years or E2 of <21.5 pg/ml or pubertal stage of <2 had a height gain of ≥1SDS. CONCLUSIONS: Treatment with GnRHa is unquestionably beneficial to improve FH in girls with iCPP when initiated ≤6.4 years of age. GnRHa treatment after 8.3 years of age may not improve FH. Girls between the ages of 6.4 and 8.3 years at presentation can have a better height gain if BA (≥2.6 years over CA) and pubertal findings (pubertal stage ≥3 or E2 ≥32.6 pg/ml) are well-advanced.


Asunto(s)
Pubertad Precoz , Estatura , Niño , Femenino , Hormona Liberadora de Gonadotropina , Trastornos del Crecimiento , Humanos , Pubertad Precoz/tratamiento farmacológico , Estudios Retrospectivos
4.
Pediatr Diabetes ; 21(7): 1176-1182, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32738013

RESUMEN

BACKGROUND: A number of inborn errors of metabolism caused by abnormal protein trafficking that lead to endoplasmic reticulum storage diseases (ERSD) have been defined in the last two decades. One such disorder involves biallelic mutations in the gene encoding endoplasmic reticulum resident co-chaperone DNAJC3 (P58IPK ) that leads to diabetes in the second decade of life, in addition to multiple endocrine dysfunction and nervous system involvement. OBJECTIVE: The aim of this study was to define the natural history of this new form of diabetes, especially the course of abnormalities related to glucose metabolism. METHODS: Whole-exome and Sanger sequencing was used to detect DNAJC3 defect in two patients. Detailed analysis of their clinical history as well as biochemical, neurological and radiological studies were carried out to deduce natural history of neurological and endocrine phenotype. RESULTS: DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss. Endocrine phenotype involved severe early-onset growth failure due to growth hormone deficiency, and hypothyroidism of central origin. Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life. CONCLUSION: Biallelic loss-of-function in the ER co-chaperone DNAJC3 leads to a new form of diabetes with early onset hyperinsulinemic hypoglycemia evolving into insulin deficiency as well as severe growth failure, hypothyroidism and diffuse neurodegeneration.


Asunto(s)
Complicaciones de la Diabetes/complicaciones , Complicaciones de la Diabetes/genética , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/genética , Proteínas del Choque Térmico HSP40/genética , Adolescente , Niño , Complicaciones de la Diabetes/diagnóstico , Femenino , Humanos , Masculino , Fenotipo
5.
Proc Natl Acad Sci U S A ; 114(10): E1933-E1940, 2017 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-28228528

RESUMEN

Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11ß-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11ß-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11ß-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11ß-hydroxylase deficiency CAH.


Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , Esteroide 11-beta-Hidroxilasa/genética , Hiperplasia Suprarrenal Congénita/patología , África del Norte , Consanguinidad , Femenino , Hormonas Esteroides Gonadales/biosíntesis , Hormonas Esteroides Gonadales/genética , Humanos , Masculino , Medio Oriente , Mutación Missense , Linaje , Esteroide 11-beta-Hidroxilasa/química
6.
Am J Med Genet A ; 179(7): 1157-1172, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30980518

RESUMEN

3M syndrome is characterized by severe pre- and postnatal growth retardation, typical facial features, and normal intelligence. Homozygous or compound heterozygous mutations in either CUL7, OBSL1, or CCDC8 have been identified in the etiology so far. Clinical and molecular features of 24 patients (23 patients and a fetus) from 19 unrelated families with a clinical diagnosis of 3M syndrome were evaluated and genotype-phenotype correlations were investigated with the use of DNA sequencing, chromosomal microarray, and whole exome sequencing accordingly. A genetic etiology could be established in 20 patients (n = 20/24, 83%). Eleven distinct CUL7 or OBSL1 mutations, among which eight was novel, were identified in 18 patients (n = 18/24, 75%). Ten patients had CUL7 (n = 10/18, 56%) while eight had OBSL1 (n = 8/18, 44%) mutations. Birth weight and height standard deviation scores at admission were significantly (p < 0.05) lower in patients with CUL7 mutation compared to that of patients with OBSL1 mutation. Two patients with a similar phenotype had a de novo 20p13p deletion involving BMP2. No genetic etiology could be established in four patients (n = 4/28, 17%). This study yet represents the largest cohort of 3M syndrome patients from a single center in Turkey. Microdeletions involving BMP2 may cause a phenotype similar to 3M syndrome with some distinctive features. Larger cohort of patients are required to establish genotype-phenotype correlations in 3M syndrome.


Asunto(s)
Proteína Morfogenética Ósea 2/genética , Proteínas Cullin/genética , Proteínas del Citoesqueleto/genética , Enanismo/genética , Estudios de Asociación Genética , Hipotonía Muscular/genética , Mutación , Columna Vertebral/anomalías , Adolescente , Secuencia de Bases , Proteína Morfogenética Ósea 2/deficiencia , Niño , Preescolar , Cromosomas Humanos Par 20 , Estudios de Cohortes , Proteínas Cullin/metabolismo , Proteínas del Citoesqueleto/metabolismo , Enanismo/diagnóstico , Enanismo/metabolismo , Enanismo/patología , Femenino , Feto , Expresión Génica , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/metabolismo , Hipotonía Muscular/patología , Fenotipo , Columna Vertebral/metabolismo , Columna Vertebral/patología , Secuenciación del Exoma
7.
J Hum Genet ; 62(8): 755-762, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28356564

RESUMEN

Pituitary development depends on a complex cascade of interacting transcription factors and signaling molecules. Lesions in this cascade lead to isolated or combined pituitary hormone deficiency (CPHD). The aim of this study was to identify copy number variants (CNVs) in genes known to cause CPHD and to determine their structure. We analyzed 70 CPHD patients from 64 families. Deletions were found in three Turkish families and one family from northern Iraq. In one family we identified a 4.96 kb deletion that comprises the first two exons of POU1F1. In three families a homozygous 15.9 kb deletion including complete PROP1 was discovered. Breakpoints map within highly homologous AluY sequences. Haplotype analysis revealed a shared haplotype of 350 kb among PROP1 deletion carriers. For the first time we were able to assign the boundaries of a previously reported PROP1 deletion. This gross deletion shows strong evidence to originate from a common ancestor in patients with Kurdish descent. No CNVs within LHX3, LHX4, HESX1, GH1 and GHRHR were found. Our data prove multiplex ligation-dependent probe amplification to be a valuable tool for the detection of CNVs as cause of pituitary insufficiencies and should be considered as an analytical method particularly in Kurdish patients.


Asunto(s)
Haplotipos , Proteínas de Homeodominio/genética , Hipopituitarismo/genética , Eliminación de Secuencia , Factor de Transcripción Pit-1/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Linaje
8.
Int J Eat Disord ; 50(4): 359-369, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28152193

RESUMEN

Clinicians currently use different low-weight cut-offs both to diagnose anorexia nervosa (AN) and to determine AN severity in adolescent girls. The purpose of this study was to evaluate the clinical utility of existing cut-offs and severity criteria by determining which are most strongly associated with risk for low bone mineral density (BMD). Height adjusted BMD Z scores were calculated for 352 females: 262 with AN and 90 healthy controls (controls) (12-20.5 years), using data from the BMD in Childhood Study, for the lumbar spine, whole body less head, and total hip. For most cut-offs used to define low weight (5th or 10th BMI percentile, BMI of 17.5 or 18.5, and 85 or 90% of median BMI), AN had lower BMD Z scores than controls. AN at >85 or >90% expected body weight for height (EBW-Ht) did not differ in BMD Z scores from controls, but differed significantly from AN at ≤85 or ≤90% EBW-Ht. Among AN, any amenorrhea was associated with lower BMD. AN had lower BMD than controls across DSM-5 and The Society for Adolescent Health and Medicine (SAHM) severity categories. The SAHM moderate severity classification was differentiated from the mildly malnourished classification by lower BMD at hip and spine sites. Amenorrhea and %EBW-Ht ≤ 85 or ≤ 90% are markers of severity of bone loss within AN. Among severity categories, BMI Z scores (SAHM) may have the greatest utility in assessing the degree of malnutrition in adolescent girls that corresponds to lower BMD.


Asunto(s)
Amenorrea/etiología , Anorexia Nerviosa/diagnóstico , Peso Corporal/fisiología , Densidad Ósea/fisiología , Vértebras Lumbares/diagnóstico por imagen , Menstruación/fisiología , Absorciometría de Fotón , Adolescente , Amenorrea/diagnóstico por imagen , Amenorrea/fisiopatología , Anorexia Nerviosa/complicaciones , Anorexia Nerviosa/diagnóstico por imagen , Anorexia Nerviosa/fisiopatología , Niño , Femenino , Humanos , Índice de Severidad de la Enfermedad , Adulto Joven
9.
Eur J Pediatr ; 174(11): 1421-31, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26255048

RESUMEN

The possible risk of adverse effects due to regular use of inhaled corticosteroids (ICS) is a real concern. Our aim was to describe the factors that have an impact on hypothalamic-pituitary-adrenal axis suppression (HPA-AS) in children and adolescents taking ICS regularly. The HPA axis status of patients who were on moderate-to-high-dose ICS [>176 and >264 µg/day fluticasone propionate-hydrofluoroalkane (FP-HFA) for patients 0-11 and ≥12 years, respectively] was investigated. Various types of ICS were converted to FP-HFA equivalent according to National Asthma Education and Prevention Program (NAEPP) guidelines. Participants with a baseline (8 a.m.) serum cortisol <15 µg/dL underwent a low-dose ACTH stimulation test (LDAT) to diagnose HPA-AS. Among 91 patients, 60 (75.9 %) participants underwent LDAT, and seven (7.7, 95 % CI 3.5-15.3 %) were diagnosed with HPA-AS. Ciclesonide was more frequently used by the participants with HPA-AS compared to patients with a normal HPA axis (42.9 vs. 4.8 %, p = 0.009). Use of ICS at moderate-to-high doses for at least 7 months distinguished participants with HPA-AS from those with a normal HPA axis. Among the duration, type, and dose of ICS, solely the use of ICS with a body mass index (BMI)-adjusted daily dose of ≥22 µg FP was found to increase the risk for HPA-AS (odds ratio (OR) 7.22, 95 % confidence interval (CI) 1.23-42.26, p = 0.028). The receiver operating characteristics (ROC) curve analysis revealed a cutoff value of 291 µg/day FP (area under the curve (AUC) = 0.840, p = 0.003) for predicting HPA-AS Conclusion: The prevalence of HPA-AS was found to be 7.7 % in children taking not only high-dose ICS but also moderate-dose ICS. Dose alone was found to be an actual risk factor for HPA-AS.


Asunto(s)
Antiasmáticos/efectos adversos , Asma/tratamiento farmacológico , Glucocorticoides/efectos adversos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Administración por Inhalación , Adolescente , Antiasmáticos/administración & dosificación , Niño , Preescolar , Femenino , Glucocorticoides/administración & dosificación , Humanos , Lactante , Masculino
10.
Pituitary ; 18(1): 1-7, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24356781

RESUMEN

BACKGROUND: Previous studies in adults and case reports in children have shown increased frequency of hypothalamo-pituitary dysfunction after infectious diseases of the central nervous system. The aim of this study was to evaluate the function of hypothalamo-pituitary axis in children with a history of bacterial meningitis. METHODS: Patients diagnosed with bacterial meningitis between April 2000 and June 2011 was included. Baseline and stimulated hormonal tests were performed as required for hormonal evaluations following a diagnosis of meningitis. RESULTS: Pituitary function was assessed following a period of 8-135 months (mean 53 months) after bacterial meningitis. Thirty-seven cases (27 male, 15 pubertal) with mean age of 11.1 ± 4.4 years were included. Mean height SDS was 0.01 ± 1.07 and mean BMI SDS was 0.54 ± 1.15 all patients had a SDS above -2 SD. Baseline cortisol and low dose ACTH stimulation revealed normal adrenal functions in all patients. Gonadotropin deficiency was not detected in any of the pubertal cases. Four cases (10.8%) had low IGF1 and IGFBP3 z-scores (<-2 SD) according to age, sex and Tanner stage, but peak GH response in clonidin test was >10 ng/ml in three of them suggesting neurosecretary dysfunction of GH in these cases. The fourth case has died before the test. No one had TSH deficiency and diabetes insipidus, only one case had mild hyperprolactinemia. CONCLUSIONS: Our findings suggest that hypothalamo-pituitary dysfunction is not as common in childhood as in adulthood. The most remarkable finding was neurosecretary dysfunction of GH in some cases.


Asunto(s)
Hipopituitarismo/fisiopatología , Hipotálamo/fisiopatología , Meningitis Bacterianas/fisiopatología , Hipófisis/fisiopatología , Adolescente , Niño , Femenino , Gonadotropinas/metabolismo , Humanos , Hipopituitarismo/metabolismo , Hipotálamo/metabolismo , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Meningitis Bacterianas/metabolismo , Hipófisis/metabolismo
11.
J Clin Immunol ; 34(8): 1009-14, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25239688

RESUMEN

Leukocyte adhesion deficiencies (LAD) are autosomal recessive immunodeficiency syndromes characterized by severe and recurrent bacterial infections, impaired wound healing and leukocytosis. Block in different steps in the leukocyte adhesion cascade causes different types of leukocyte adhesion deficiencies, LAD type I, II and III. In LAD type II, the rolling phase of the leukocyte adhesion cascade is affected due to mutations in the specific fucose transporter GFTP (GDP fucose transporter), causing defect in the biosynthesis of selectin ligands on leukocytes. Thus this syndrome is also called congenital disorder of glycosylation IIc (CGDIIc). LAD II/CGDIIc is very rare and has been diagnosed in nine children to date. Fever, leukocytosis, typical dysmorphic features, growth, psychomotor retardation and the Bombay blood group, are characteristic findings in patients. Here, we describe two Turkish siblings with a novel mutation in GFTP. They both have the characteristic features of the syndrome. The older sibling died of severe bacterial pneumonia at the age of 3 years. The younger sibling, diagnosed at the age of 3 months, responded to high dose oral fucose supplementation. Secundum atrial septal defect which was not described in previously reported patients, but present in both of our patients, may primarily related to the defect in fucosylation.


Asunto(s)
Trastornos Congénitos de Glicosilación/genética , Síndrome de Deficiencia de Adhesión del Leucocito/genética , Proteínas de Transporte de Monosacáridos/genética , Mutación , Preescolar , Femenino , Humanos , Lactante , Masculino , Hermanos
12.
J Clin Res Pediatr Endocrinol ; 16(1): 11-20, 2024 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-37559367

RESUMEN

Objective: Cardiovascular diseases (CVD) are the most important cause of morbidity and mortality in patients with type 1 diabetes (T1D). Children with T1D have a similar or higher prevalence of being overweight (OW) or obese (Ob) compared to healthy peers. The aim of this study was to determine the prevalence of CVD risk factors in children and adolescents with T1D and the impact of obesity and sex differences on these factors. Methods: Data of patients aged 10-21 years and who had been using intensive insulin therapy with a diagnosis of T1D for at least three years were evaluated. Patients were divided into normal weight (NW), OW and Ob groups based on body mass index percentiles. Risk factors for CVD (obesity, dyslipidemia, hypertension) were compared between groups, and impact of gender was also analyzed. Results: Data of 365 patients (200 girls, 54.8%), were evaluated. Prevalence of OW/Ob was 25.9% and was significantly higher in girls (30.6% vs 20.1%, p<0.001). Rate of hypertension was highest in OW/Ob girls followed by OW/Ob boys, and similar in NW girls and boys (p=0.003). Mean low density lipoprotein cholesterol (LDL-c) and triglyceride (TG) levels were highest in OW/Ob girls, followed by OW/Ob boys, NW girls and NW boys, respectively (p<0.001 and p<0.001, respectively). Mean high density lipoprotein-cholesterol (HDL-c) levels were similar among groups. Rates of high LDL-c and TG were similar between OW/Ob girls and boys and higher than NW girls, followed by NW boys (p<0.001 and p<0.001, respectively). The rate of low HDL-c was similar in OW/Ob girls and boys, and higher than NW girls, followed by NW boys (p<0.001). Overall, girls were 1.9 times more likely than boys to have two or more risk factors for CVD. Factors associated with risk for CVD in multiple logistic regression analyses were being a girl, followed by higher daily insulin dose, higher hemoglobin A1c, and longer duration of diabetes (r=0.856; p<0.001). Conclusion: In spite of the increased prevalence for obesity in both sexes, the trend for CVD risk factors was greater in Ob girls, followed by Ob boys and NW girls. Girls with T1D are more likely to be OW/Ob and to have CVD risk than boys, highlighting the need for early intervention and additional studies to elucidate the causes.


Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 1 , Hipertensión , Insulinas , Niño , Humanos , Femenino , Adolescente , Masculino , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/complicaciones , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Factores de Riesgo , LDL-Colesterol , Prevalencia , Caracteres Sexuales , Factores Sexuales , Obesidad , Sobrepeso/epidemiología , Sobrepeso/complicaciones , Índice de Masa Corporal , Hipertensión/epidemiología , Hipertensión/complicaciones , Factores de Riesgo de Enfermedad Cardiaca
13.
J Diabetes ; 16(5): e13562, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38664892

RESUMEN

BACKGROUND: Global variations in epidemiology of type 1 diabetes mellitus (T1DM) exist. This study is designed to examine demographic and clinical features of T1DM over the past 3 decades as well as evolving trends in epidemiology over last 50 years. METHODS: Clinical characteristics of 925 patients with T1DM over last 30 years (1990-2019) were evaluated and compared to previously published data of 477 patients diagnosed between 1969 and 1990 from one of the major referral centers for diabetes in Turkey. RESULTS: Mean age at diagnosis decreased from 9.5 ± 4.0 to 7.1 ± 3.6 years within the past 50 years (p < .001). Age at diagnosis peaked at 12-14 years between 1969 and 1990, then fell to 10-11.9 years between 1990 and 1999, and to 4-5.9 years between 2000-2009 and 2010-2019 (p = .005). Although the percentage of patients diagnosed <6 years of age is gradually increasing, the percentage between the ages of 6 and 11.9 years is decreasing, and the percentage diagnosed ≥12 years remained stable. A total of 47.5% of patients had ketoacidosis, 38.2% had ketosis, and 14.3% had only hyperglycemia. 23% of patients had severe diabetic ketoacidosis (DKA), whereas 42% had moderate. Over last 3 decades, there has been no change in frequency of ketoacidosis at presentation, but there has been significant decline in severity (p = .865, and p < .001, respectively). Although the frequency of patients with mild DKA increased over time, frequency of patients with moderate DKA decreased; however, no significant difference was observed among patients with severe ketoacidosis. DKA was more frequent and severe in patients <6 years of age (p = .005, and p < .001, respectively). CONCLUSION: Age at diagnosis shifted to younger ages in T1DM in the past 50 years. Half of patients had ketoacidosis at diagnosis and frequency of presentation with DKA did not decrease, but severity decreased slightly. Increase in prevalence of T1DM in the younger age group and the fact that half of patients present with DKA indicate that awareness should be increased in terms of early diagnosis and treatment.


Asunto(s)
Diabetes Mellitus Tipo 1 , Humanos , Diabetes Mellitus Tipo 1/epidemiología , Adolescente , Niño , Masculino , Femenino , Preescolar , Turquía/epidemiología , Cetoacidosis Diabética/epidemiología , Edad de Inicio , Lactante , Estudios Retrospectivos , Prevalencia
14.
Horm Res Paediatr ; : 1-11, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38838658

RESUMEN

INTRODUCTION: The diagnostic yield of genetic analysis in the evaluation of children with short stature depends on associated clinical characteristics, but the additional effect of parental consanguinity has not been well documented. METHODS: This observational case series of 42 short children from 34 consanguineous families was collected by six referral centres of paediatric endocrinology (inclusion criteria: short stature and parental consanguinity). In 18 patients (12 families, group 1), the clinical features suggested a specific genetic defect in the growth hormone (GH) insulin-like growth factor I (IGF-I) axis, and a candidate gene approach was used. In others (group 2), a hypothesis-free approach was chosen (gene panels, microarray analysis, and whole exome sequencing) and further subdivided into 11 patients with severe short stature (height <-3.5 standard deviation score [SDS]) and microcephaly (head circumference <-3.0 SDS) (group 2a), 10 patients with syndromic short stature (group 2b), and 3 patients with nonspecific isolated GH deficiency (group 2c). RESULTS: In all 12 families from group 1, (likely) pathogenic variants were identified in GHR, IGFALS, GH1, and STAT5B. In 9/12 families from group 2a, variants were detected in PCNT, SMARCAL1, SRCAP, WDR4, and GHSR. In 5/9 families from group 2b, variants were found in TTC37, SCUBE3, NSD2, RABGAP1, and 17p13.3 microdeletions. In group 2c, no genetic cause was found. Homozygous, compound heterozygous, and heterozygous variants were found in 21, 1, and 4 patients, respectively. CONCLUSION: Genetic testing in short children from consanguineous parents has a high diagnostic yield, especially in cases of severe GH deficiency or insensitivity, microcephaly, and syndromic short stature.

15.
Pediatr Surg Int ; 29(7): 719-24, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23624815

RESUMEN

PURPOSE: Female pseudohermaphroditism is the most frequent form of ambiguous genitalia in children with congenital adrenal hyperplasia (CAH). However, a small group of children with complete urethral development in contrast to 46XX karyotype can be encountered. We aimed to define the characteristics of patients with 46XX CAH but having fully developed male external genitalia. METHODS: The records of 11 children with CAH and 46XX karyotype but having male phenotype, encountered from 1990 to 2012 were reviewed retrospectively. The age, presenting signs and symptoms, diagnostic studies, surgical procedures, early results and outcome were noted. All patients were evaluated by gender assignment team and the decision of the family was also taken into consideration during gender assignment. RESULTS: Eleven children (mean age 3.64 ± 3 years) (range 5 days-10 years) were enrolled. The main presenting signs were nonpalpable gonads (n = 7), hyperpigmentation (n = 2), jaundice (n = 1) and electrolyte imbalance (n = 1). All patients had bilateral nonpalpable gonads and male phenotype with mean phallus length of 4.5 ± 1.7 cm. Urethral meatus is located at normal position (n = 6) or hypospadiac (n = 5). Labioscrotal fusion was complete in all cases and they were classified as 4th (n = 3) or 5th (n = 8) degree of virilization according to Prader's classification. All children had CAH and 46XX genotype. Pelvic ultrasound (n = 8) and genitocystogram (n = 9) were used, and genitocystoscopy was performed (n = 6). Male gender was assigned in most (n = 10) and female gender in one. Corrective surgery could be performed in 10 patients. The surgical procedures were hysterectomy + bilateral salphingo-oophorectomy + vaginectomy (n = 9), chordee release (n = 3) and then second-stage (n = 2) or one-stage urethra repair (n = 1), and pure one-stage urethra repair (n = 1). One case underwent surrenalectomy before the diagnosis of CAH. Mastectomy (n = 1) and fistula repair (n = 3) were additional operations. Only one child could be undergone feminizing genitoplasty and another was lost to follow-up. CONCLUSION: Unfortunately, most of the children underwent surgery in adverse to genotype because of constituted sexual identity. Children with male phenotype and bilateral nonpalpable gonads should undergo promptly biochemical analyses for CAH and early chromosomal analysis.


Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/complicaciones , Trastornos del Desarrollo Sexual 46, XX/diagnóstico , Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/diagnóstico , Genotipo , Fenotipo , Trastornos del Desarrollo Sexual 46, XX/cirugía , Hiperplasia Suprarrenal Congénita/cirugía , Niño , Preescolar , Femenino , Genitales/diagnóstico por imagen , Genitales/cirugía , Humanos , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos , Ultrasonografía
16.
Artículo en Inglés | MEDLINE | ID: mdl-36688726

RESUMEN

Insulin-like growth factor-1 (IGF-1) is the main driver of growth during prenatal life and acts through insulin-like growth factor 1 receptor (IGF1R). Patients with IGF1R defects exhibit variable phenotypic features. A 10.9-year-old boy presented with severe short stature, microcephaly, minor dysmorphic features and mild mental retardation. Genetic analysis for IGF1R revealed heterozygous deletion of the complete IGF1R. At the age of 12.3 years, daily subcutaneous rhGH was started and continued for a total of 5.7 years in two courses with improvement of height velocity as well as final height. Puberty was delayed and eventually he could not develop full puberty suggesting partial hypogonadotropic hypogonadism. Hypothyroidism initially developed during rhGH therapy. However, low T4 levels sustained after cessation of rhGH therapy thus central hypothyroidism is a likely diagnosis. rhGH has partial effect for induction of growth in cases with IGF1R defects. However, long-term treatment with an early onset may have more beneficial effects. In addition, patients with IGF1R defects should be followed for delayed puberty-hypogonadism, and hypothyroidism.

17.
Clin Endocrinol (Oxf) ; 76(1): 126-30, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21790701

RESUMEN

OBJECTIVE: Intravenous GnRH stimulation test has often been used as gold standard test for the evaluation of hypothalamic-pituitary-gonadal axis in the diagnosis of central precocious puberty (CPP) and in the assessment of pubertal suppression. However, this test is time-consuming, costly and uncomfortable for the patients. We aimed to analyse the validity of single LH sample 90 min after GnRH analogue (GnRHa) administration in the evaluation of gonadotrophin suppression during CPP therapy and to determine a cut-off level for LH indicating adequate suppression. DESIGN: Prospective study. PATIENTS AND METHODS: One hundred and forty-two patients with CPP were included in this study. Peak LH level during iv GnRH stimulation test after the third dose of GnRHa was compared with LH level 90 min after injection of the 3rd dose of GnRHa. RESULTS: There was a positive correlation between LH level following a GnRHa injection and peak LH during standard iv GnRH stimulation test (r = 0·83; P < 0·0001). A LH value of 2·5 mIU/ml or less 90 min after GnRHa injection was considered to be the cut-off for the determination of pubertal suppression (sensitivity and specificity was 100% and 88%, respectively). In 117 patients, gonadotrophin suppression was existed according to both GnRHa and iv GnRH tests. In 25 patients, gonadotrophin suppression was not found in the GnRHa test. However, 16 of them were suppressed according to the iv GnRH test. CONCLUSION: Single LH determination 90 min after GnRHa administration using a cut-off level of 2·5 mIU/ml reflects pubertal suppression with a high sensitivity and specificity. However, this test may fail to show pubertal suppression in some cases. Those patients who appear to be inadequately suppressed should be reassessed using standard iv GnRH stimulation test for optimal dose adjustment.


Asunto(s)
Leuprolida/uso terapéutico , Hormona Luteinizante/sangre , Pubertad Precoz/tratamiento farmacológico , Niño , Preescolar , Esquema de Medicación , Femenino , Humanos , Leuprolida/administración & dosificación , Estudios Prospectivos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
19.
J Pediatr Endocrinol Metab ; 25(3-4): 313-6, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22768662

RESUMEN

BACKGROUND: Onset of puberty is dependent on pulsatile secretion of gonadotropin releasing hormone (GnRH). The kisspeptin-GPR54 signaling system has a considerable role in GnRH physiology and induction of puberty. OBJECTIVES: To evaluate kisspeptin levels in girls with central precocious puberty (CPP) at the time of the diagnosis and during follow-up, to determine whether or not kisspeptin may serve as a marker for diagnosis and follow-up of CPP. PATIENTS AND METHODS: Kisspeptin levels of 28 girls with CPP were measured at the time of diagnosis and repeated at the 6th month of therapy after complete pubertal suppression and compared to kisspeptin levels of 13 age-matched prepubertal controls. RESULTS: Kisspeptin levels of girls with CPP (10.2 +/- 2.6 pg/mL) were higher than those in controls (8.6 +/- 1.5 pg/mL (p = 0.019). There was a significant decline in the kisspeptin levels (7.3 +/- 1.3 pg/mL) of girls with CPP after pubertal suppression (p < 0.0001). CONCLUSION: These findings suggest that kisspeptin levels can be used as corroborative evidence for diagnosis of CPP and a valuable parameter for monitoring treatment efficacy.


Asunto(s)
Hormona Liberadora de Gonadotropina/metabolismo , Kisspeptinas/sangre , Hormona Luteinizante/metabolismo , Pubertad Precoz/sangre , Pubertad Precoz/diagnóstico , Pubertad/metabolismo , Estudios de Casos y Controles , Niño , Femenino , Estudios de Seguimiento , Humanos , Pronóstico
20.
J Pediatr Endocrinol Metab ; 25(5-6): 561-3, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22876557

RESUMEN

17-beta-Hydroxysteroid dehydrogenase type 3 (17betaHSD-3) converts delta4 androstenedione (A) to testosterone (T) in the testes. This enzyme plays a key role in androgen synthesis and it is essential for normal fetal development of male genitalia. 17betaHSD-3 deficiency is a rare cause of 46,XY disorders of sexual development. Here, we report a 16-year-old 46,XY patient with 17betaHSD-3 deficiency raised as a female and significantly virilized in puberty. A homozygous 7 base pair deletion on exon 10 was determined in HSD17B3 gene (c.777-783del_GATAACC). Our patient had one of the very rare mutations, which was previously unencountered in Turkish patients with 17betaHSD type 3, and she is the second reported case with this deletion.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/genética , Trastornos del Desarrollo Sexual 46, XX/genética , Eliminación de Gen , Disgenesia Gonadal 46 XY/genética , 17-Hidroxiesteroide Deshidrogenasas/deficiencia , Trastornos del Desarrollo Sexual 46, XX/patología , Adolescente , Femenino , Disgenesia Gonadal 46 XY/patología , Homocigoto , Humanos , Masculino , Pubertad/genética
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