RESUMEN
BACKGROUND: Males have higher weight and length at birth than females. AIM: To verify the influence of the Y chromosome and the action of intrauterine androgens on weight and length at birth of children with Disorders of Sex Development (DSD). SUBJECTS AND METHODS: A cross-sectional and retrospective study. Patients with Turner syndrome (TS), complete (XX and XY), mixed (45,X/46,XY) and partial (XY) gonadal dysgenesis (GD), complete (CAIS) and partial (PAIS) androgen insensitivity syndromes and XX and XY congenital adrenal hyperplasia (CAH) were included. Weight and length at birth were evaluated. RESULTS: Weight and length at birth were lower in TS and mixed GD when compared to XY and XX DSD cases. In turn, patients with increased androgen action (117 cases) had higher weight and length at birth when compared to those with absent (108 cases) and decreased (68 cases) production/action. In birthweight, there was a negative influence of the 45,X/46,XY karyotype and a positive influence of increased androgen and gestational age. In birth length, there was a negative influence of the 45,X and 45,X/46,XY karyotypes and also a positive influence of increased androgen and gestational age. CONCLUSIONS: The sex dimorphism of weight and length at birth could possibly be influenced by intrauterine androgenic action.
Asunto(s)
Síndrome de Resistencia Androgénica , Andrógenos , Masculino , Niño , Recién Nacido , Femenino , Humanos , Estudios Retrospectivos , Caracteres Sexuales , Estudios TransversalesRESUMEN
The syndrome of resistance to thyroid hormone (RTH ß) is an inherited disorder characterized by variable tissue hyposensitivity to 3,5,30-L-triiodothyronine (T(3)), with persistent elevation of free-circulating T(3) (FT(3)) and free thyroxine (FT(4)) levels in association with nonsuppressed serum thyrotropin (TSH). Clinical presentation is variable and the molecular analysis of THRB gene provides a short cut diagnosis. Here, we describe 2 cases in which RTH ß was suspected on the basis of laboratory findings. The diagnosis was confirmed by direct THRB sequencing that revealed 2 novel mutations: the heterozygous p.Ala317Ser in subject 1 and the heterozygous p.Arg438Pro in subject 2. Both mutations were shown to be deleterious by SIFT, PolyPhen, and Align GV-GD predictive methods.
Asunto(s)
Mutación , Receptores beta de Hormona Tiroidea/genética , Síndrome de Resistencia a Hormonas Tiroideas/genética , Adolescente , Preescolar , Femenino , HumanosRESUMEN
The 21-hydroxylase deficiency (21OHD) is caused by CYP21A2 mutations resulting in severe or moderate enzymatic impairments. 21OHD females carrying similar genotypes present different degrees of external genitalia virilization, suggesting the influence of other genetic factors. Single nucleotide variants (SNVs) in the CYP3A7 gene and in its transcription factors, related to fetal 19-carbon steroid metabolism, could modulate the genital phenotype. To evaluate the influence of the 21OHD genotypes and the CYP3A7, PXR and CAR SNVs on the genital phenotype in 21OHD females. Prader scores were evaluated in 183 patients. The CYP3A7, PXR and CAR SNVs were screened and the 21OHD genotypes were classified according to their severity: severe and moderate groups. Patients with severe genotype showed higher degree of genital virilization (Prader median III, IQR III-IV) than those with moderate genotype (III, IQR II-III) (p < 0.001). However, a great overlap was observed between genotype groups. Among all the SNVs tested, only the CAR rs2307424 variant correlated with Prader scores (r(2) = 0.253; p = 0.023). The CYP21A2 genotypes influence the severity of genital virilization in 21OHD females. We also suggest that the CAR variant, which results in a poor metabolizer phenotype, could account for a higher degree of external genitalia virilization.
Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , Genitales/metabolismo , Polimorfismo de Nucleótido Simple , Receptores Citoplasmáticos y Nucleares/genética , Esteroide 21-Hidroxilasa/genética , Virilismo/genética , Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/patología , Alelos , Hidrocarburo de Aril Hidroxilasas/genética , Niño , Preescolar , Receptor de Androstano Constitutivo , Citocromo P-450 CYP3A , Femenino , Frecuencia de los Genes , Genitales/patología , Genotipo , Humanos , Recién Nacido , Receptor X de Pregnano , Receptores de Esteroides/genética , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Virilismo/complicaciones , Virilismo/patologíaRESUMEN
BACKGROUND: The aim of this study was to investigate the frequency of gonadal tumors among patients with Turner syndrome (TS) carrying Y-derivative sequences in their chromosomal constitution. METHODS: Six out of 260 patients with TS were selected based on mosaicism of the entire Y chromosome; 10 were included because Y-derivative sequences have been detected by PCR with specific oligonucleotides (sex-determining region on the Y, testis specific-protein, Y and DYZ3) and further confirmed by FISH. The 16 patients were subjected to bilateral gonadectomy at ages varying from 8.7 to 18.2 years. Both histopathological investigation with hematoxylin and eosin (H&E) and immunohistochemical analysis with anti-octamer-binding transcription factor 4 (OCT4) antibody were performed. RESULTS: Gonadal neoplasia was not detected in any of the 32 gonads evaluated by H&E; however, four gonads (12%) from three patients (19%) had positive OCT4 staining in 50-80% of nuclei, suggesting the existence of germ cell tumors (gonadoblastoma or in situ carcinoma). CONCLUSIONS: Evaluation of the real risk of development of gonadal tumors in TS patients with Y-derivative sequences in their chromosomal constitution may require a specific histopathological study, such as immunohistochemistry with OCT4.
Asunto(s)
Carcinoma in Situ/genética , Cromosomas Humanos Y/química , Gonadoblastoma/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Síndrome de Turner/genética , Adolescente , Carcinoma in Situ/complicaciones , Carcinoma in Situ/patología , Niño , Cromosomas Humanos Y/genética , Femenino , Gonadoblastoma/complicaciones , Gonadoblastoma/patología , Humanos , Inmunohistoquímica , Medición de Riesgo , Síndrome de Turner/complicaciones , Síndrome de Turner/patologíaRESUMEN
BACKGROUND: The majority of anthropometric assessments in Turner syndrome (TS) patients has focused on height. AIM: To analyze body proportions in young adult TS patients either treated or not treated with rhGH, and to compare them with a group of age-matched healthy women. SUBJECTS AND METHODS: Standing height, sitting height, weight, foot and leg lengths, arm span, head circumference, biliac and biacromial diameters were measured in 52 non-treated TS patients, 30 treated with rhGH and 133 healthy women. RESULTS: Age at the start of rhGH therapy varied from 7.8 to 15.1 yr (10.0±1.3 yr), the duration of treatment from 2.8 to 8.2 yr (3.7±1.5 yr) and the mean recombinant human GH (rhGH) dose was 0.42 mg/kg/week (from 0.32 to 0.50 mg/kg/week). Nontreated patients did not show any difference in anthropometric variables when compared with the treated ones, except for hand length (p=0.02) and height (p=0.05), which were increased in the treated group. All anthropometric variables, except head circumference, were different when comparing TS patients (either treated or not) with age-matched healthy women. CONCLUSION: Brazilian TS patients either treated or not with rhGH showed almost no differences in terms of their body proportions. This result is probably due to the late age at the start of treatment, and/or the short period of rhGH administration. Hand length was different between the groups, showing the importance of including the extremities in body proportion assessment during rhGH treatment of TS patients.
Asunto(s)
Tamaño Corporal/efectos de los fármacos , Hormona de Crecimiento Humana/farmacología , Hormona de Crecimiento Humana/uso terapéutico , Síndrome de Turner/tratamiento farmacológico , Síndrome de Turner/fisiopatología , Adolescente , Adulto , Estatura/efectos de los fármacos , Pesos y Medidas Corporales , Estudios de Casos y Controles , Niño , Femenino , Estudios de Seguimiento , Cabeza/anatomía & histología , Salud , Humanos , Adulto JovenRESUMEN
The aim of this work was to analyse C4 genotypes, C4 protein levels, phenotypes and genotypes in patients with the classical form of 21-hydroxylase deficiency. Fifty-four patients from 46 families (36 female, 18 male; mean age 10.8 years) with different clinical manifestations (31 salt-wasting; 23 simple-virilizing) were studied. Taq I Southern blotting was used to perform molecular analysis of the C4/CYP21 gene cluster and the genotypes were defined according to gene organization within RCCX modules. Serum C4 isotypes were assayed by enzyme-linked immunosorbent assay. The results revealed 12 different haplotypes of the C4/CYP21 gene cluster. Total functional activity of the classical pathway (CH50) was reduced in individuals carrying different genotypes because of low C4 concentrations (43% of all patients) to complete or partial C4 allotype deficiency. Thirteen of 54 patients presented recurrent infections affecting the respiratory and/or the urinary tracts, none of them with severe infections. Low C4A or C4B correlated well with RCCX mono-modular gene organization, but no association between C4 haplotypes and recurrent infections or autoimmunity was observed. Considering this redundant gene cluster, C4 seems to be a well-protected gene segment along the evolutionary process.
Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , Complemento C4/genética , Adolescente , Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/inmunología , Enfermedades Autoinmunes/complicaciones , Niño , Preescolar , Activación de Complemento/genética , Activación de Complemento/inmunología , Complemento C4/análisis , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Infecciones Oportunistas/complicaciones , Fenotipo , Recurrencia , Esteroide 21-Hidroxilasa/genética , Adulto JovenRESUMEN
BACKGROUND: Most patients with 21-hydroxylase deficiency carry CYP21A1P-derived mutations, but an increasing number of novel and rare mutations have been reported in disease-causing alleles. OBJECTIVE: Functional effects of three novel (p.G56R, p.L107R, p.L142P) and one recurrent (p.R408C) CYP21A2 mutations were investigated. The degree of enzyme impairment caused by p.H62L alone or combined to p.P453S was also analyzed. DESIGN: The study included 10 Brazilian and two Scandinavian patients. To determine the deleterious role of each mutant protein, in vitro assays were performed in transiently transfected COS-1 cells. For a correct genotype-phenotype correlation, the enzymatic activities were evaluated toward the two natural substrates, 17-hydroxyprogesterone and progesterone. RESULTS: Low levels of residual activities obtained for p.G56R, p.L107R, p.L142P, and p.R408C mutants classified them as classical congenital adrenal hyperplasia mutations, whereas the p.H62L showed an activity within the range of nonclassical mutations. Apparent kinetic constants for p.H62L confirmed the nonclassical classification as the substrate binding capacity was within the same magnitude for mutant and normal enzymes. A synergistic effect was observed for the allele bearing the p.H62L+p.P453S combination because it caused a significant reduction in the enzymatic activity. CONCLUSIONS: We describe the functional analysis of five rare missense mutations identified in Brazilian and Scandinavian patients. The p.G56R, p.L107R, and p.L142P are reported for the first time. Most probably these novel mutations are closer to null than the p.I172N, but for the p.G56R, that might not be the case, and the p.H62L is definitely a nonclassical mutation.
Asunto(s)
Mutación Missense , Esteroide 21-Hidroxilasa/genética , Animales , Brasil , Células COS , Niño , Preescolar , Chlorocebus aethiops , Activación Enzimática/genética , Femenino , Pruebas Genéticas , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Mutación Missense/fisiología , Países Escandinavos y Nórdicos , Esteroide 21-Hidroxilasa/metabolismo , Esteroide 21-Hidroxilasa/fisiología , TransfecciónRESUMEN
Thirty-seven 45 X Turner syndrome patients with confirmed peripheral blood lymphocyte karyotype were initially selected to determine the origin of the retained X chromosome and to correlate it with their parents' stature. Blood samples were available in 25 families. The parental origin of the X chromosome was determined in 24 informative families through the analysis of the exon 1-CAG repeat variation of the androgen receptor gene. In 70.8% of the cases, the retained X chromosome was maternal in origin and 29.2% was paternal. When we classified the patients according to maternal (Xm) or paternal (Xp) X chromosome, there was a positive correlation between patients' and maternal heights only in the Xm group. There was no correlation with paternal height in either group, and a significant correlation with target height was only observed in the Xm group. In conclusion, maternal height is the best variable correlating with the height of 45 X Turner syndrome patients who retain the maternal X chromosome, suggesting a strong influence of genes located on the maternal X chromosome on stature.
Asunto(s)
Estatura/genética , Cromosomas Humanos X/genética , Padres , Síndrome de Turner/genética , Exones , Femenino , Humanos , Masculino , Fenotipo , Reacción en Cadena de la Polimerasa , Receptores Androgénicos/genética , Repeticiones de TrinucleótidosRESUMEN
Thirty-seven 45 X Turner syndrome patients with confirmed peripheral blood lymphocyte karyotype were initially selected to determine the origin of the retained X chromosome and to correlate it with their parents stature. Blood samples were available in 25 families. The parental origin of the X chromosome was determined in 24 informativefamilies through the analysis of the exon 1 - CAG repeat variation of the androgen receptor gene. In 70.8% of the cases, the retained X chromosome was maternal in origin and 29.2% was paternal. When we classified the patients according to maternal (Xm) or paternal (Xp) X chromosome, there was a positive correlation between patients and maternal heights only in the Xm group. There was no correlation with paternal height in either group, and a significant correlation with target height was only observed in the Xm group. In conclusion, maternal height is the best variable correlating with the height of 45 X Turner syndrome patients who retain the maternal X chromosome, suggesting a strong influence of genes located on the maternal X chromosome on stature.
Asunto(s)
Humanos , Masculino , Femenino , Estatura/genética , Cromosomas Humanos X/genética , Padres , Síndrome de Turner/genética , Exones , Fenotipo , Reacción en Cadena de la Polimerasa , Receptores Androgénicos/genética , Repeticiones de TrinucleótidosRESUMEN
The R337H TP53 mutation is a low-penetrance molecular defect that predisposes to adrenocortical tumour (ACT) formation in Brazilian and possibly other populations. Additional genetic defects may be responsible for the variable expression of ACTs in these cases. The inhibin alpha-subunit gene (INHA) on 2q33-qter has been implicated in mouse adrenocortical tumourigenesis. We studied 46 pediatric patients with ACTs from Brazil for INHA genetic alterations; 39 of these patients were heterozygous carriers of the R337H TP53 mutation. We first mapped the INHA gene by radiation hybrid analysis and determined 10 linked microsatellite markers in an area flanked by D2S1371 and D2S206 on 2q33-qter. These markers were then used for loss of heterozygozity (LOH) studies in nine paired germline and tumour DNA samples. Mapping placed the INHA gene in close proximity to D2S2848 (SHGC11864) with a log of odds (LOD) score of 5.84. LOH for at least one marker in the region was identified in 8/9 tumours (89%). Six patients were heterozygous for three INHA mutations: one in exon 1, 127C>G, and two in exon 2, 3998G>A and 4088G>A, all leading to amino acid substitutions (P43A, G227R, and A257T, respectively). A257T is located in a conserved INHA region, highly homologous to transforming growth factor-beta; both G227R and A257T change polarity, and, in addition, G227R changes the pH. We conclude that these sequence alterations and the detected 2q allelic changes suggest that INHA may be one of the contributing factors needed for ACT formation in pediatric patient carriers of the R337H TP53 mutation.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Genes p53 , Inhibinas/genética , Mutación , Sustitución de Aminoácidos , Niño , Mapeo Cromosómico , Análisis Mutacional de ADN , Heterocigoto , Humanos , Pérdida de HeterocigocidadRESUMEN
Bone age is widely used as an osseous maturation method to assess biological development in clinical and auxological studies. Numerical methods for calculating bone age have better replicability; however, they require a wide data manipulation. The aim of this study was to evaluate the accuracy of bone age estimation by using just a few ossification centers. In 205 hand and wrist radiographs of children and adolescents, aged 0.9-17.4 years old (111 males and 94 females), bone age was determined by two trained observers employing the five-bone (B5) and the TW2 methods. To compare the results of the two methods, the mean differences by age and sex were tested by the Mann-Whitney test. The relationship of the bone age distribution estimated by B5 and TW2 was calculated and the mean of the bone age determined by the two methods was plotted by age and by differences between bone age calculated by the two methods +/- 2 SD. The bone age determined by B5 was between 1.2 and 16.8, and by TW2 was between 1.2 and 18.0 years. The mean differences between B5 and TW2 (-0.06 +/- 0.6) were not significant (p > 0.05). The distribution of mean differences by age and method demonstrated that all deviations were encompassed into +/- 2 SD with no particular bias. In general terms, a good agreement was obtained between these two methods.
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Determinación de la Edad por el Esqueleto/métodos , Desarrollo Óseo , Adolescente , Huesos del Carpo/crecimiento & desarrollo , Niño , Preescolar , Femenino , Dedos/crecimiento & desarrollo , Humanos , Lactante , Masculino , Radio (Anatomía)/crecimiento & desarrollo , Reproducibilidad de los Resultados , Cúbito/crecimiento & desarrollo , Muñeca/crecimiento & desarrolloRESUMEN
In the classical form of 21-hydroxylase deficiency, CYP21- affected genes either carry mutations present in the CYP21P pseudogene (microconversions) or bear a chimeric gene that replaces the active gene as a result of large conversion or deletion mutational events. Previous genotyping of 41 Brazilian patients revealed 64% microconversion, whereas deletions and large gene conversions accounted for up to 21% of the molecular defect. The present paper describes a new mutation disclosed by sequencing an entire gene in which no pseudogene-originated mutation had been found. The patient with the classical form of 21-hydroxylase deficiency is the daughter of a consanguineous marriage, and she is homozygous for a novel frameshift H28+C within exon 1. The mutation causes a stop codon at amino acid 78. Both parents are heterozygous for the mutation as confirmed by allele-specific oligonucleotide PCR. The H28+C is not present in the published CYP21P sequences and is likely to result in an enzyme with no activity.
Asunto(s)
Hiperplasia Suprarrenal Congénita , Elementos Transponibles de ADN , Esteroide 21-Hidroxilasa/genética , Secuencia de Bases/genética , Brasil , Femenino , Mutación del Sistema de Lectura/genética , Homocigoto , Humanos , Recién Nacido , Datos de Secuencia MolecularRESUMEN
The association of HLA class II haplotypes with type I diabetes was analyzed in 56 Southeastern Brazilian families using affected family-based controls (AFBAC) method. DRB1-DQA1-DQB1 alleles were determined by polymerase chain reaction/sequence-specific primer genotyping. This study first revealed the great haplotype diversity of Brazilians (65 different haplotypes even with incomplete DRB1 subtyping), probably due to the admixture of Africans genes with European and Amerindian genes in this population. The results revealed increased frequencies of the DRB1*03-DQA1*0501-DQB1*02 and DRB1*0401-DQA1*03-DQB1*0302 haplotypes in the patient group The highest risk for type I diabetes was associated with the heterozygote DRB1*03/*04 genotype as largely reported, and DRB1*03/X and DRB1*04/Y genotypes conferred a significant, but much lower disease risk. Protection from type I diabetes revealed some peculiarities in Southeastern Brazilians: a lack of significant protecting effect of the DRB1*1501-DQA1*0102-DQB1*0602 haplotype, and an apparent protection conferred by the DRB1*13-DQB1*0301, DRB1*11-DQB1*0301, and DRB1*01-DQB1*0501 two-locus haplotypes. The risk to type I diabetes in the highly diversified Southeastern Brazilians evidenced specific information to the prediction of the disease in this region of the country.
Asunto(s)
Alelos , Diabetes Mellitus Tipo 1/inmunología , Genes MHC Clase II , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Haplotipos , Adolescente , Adulto , Brasil , Niño , Diabetes Mellitus Tipo 1/genética , Femenino , Genotipo , Cadenas alfa de HLA-DQ , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1 , Humanos , MasculinoRESUMEN
The authors report a case of a virilizing adrenal tumor that developed in a 2-year-old child with Beckwith-Wiedemann syndrome (BWS). He had a fetal diagnosis of omphalocele and a history of neonatal adrenal cysts. The importance of prenatal diagnosis of BWS and postnatal follow-up of tumors is discussed. The differential diagnosis of adrenal pathologies occurring in BWS also is reviewed.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/complicaciones , Síndrome de Beckwith-Wiedemann/complicaciones , Neoplasias de la Corteza Suprarrenal/diagnóstico , Síndrome de Beckwith-Wiedemann/diagnóstico , Preescolar , Estudios de Seguimiento , Humanos , Masculino , Diagnóstico Prenatal , Factores de Tiempo , Virilismo/etiologíaRESUMEN
An increased prevalence of autoimmune thyroid disease (AITD) has been described in Turner's syndrome (TS), but the extent of this association is still controversial. Some studies also suggest that AITD is more frequent among patients with X-isochromosome. In order to determine the prevalence of AITD among girls with TS, and to look for an association with age and karyotype, we evaluated 71 patients with a mean age of 11.4 years (range 0-19.9). 15.5% (11/71) were hypothyroid, 17 (23.9%) were positive for thyroid peroxidase (TPO) and/or thyroglobulin (Tg) antibodies, and 24 (33.8%) had thyromegaly. No abnormality was observed before 4 years, and the highest frequencies were observed after 16 years. There were no significant differences concerning thyroid findings among patients with a 45,X karyotype, mosaics, and structural rearrangements. Half of the patients (35/71) exhibited one or more abnormalities, which demonstrates the importance of careful evaluation of thyroid function in all girls with TS.
Asunto(s)
Enfermedades Autoinmunes/genética , Hipotiroidismo/inmunología , Síndrome de Turner/genética , Adolescente , Adulto , Autoanticuerpos/sangre , Brasil , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Yoduro Peroxidasa/inmunología , Tiroglobulina/inmunología , Cromosoma XRESUMEN
Adrenocortical tumors are rare in childhood, appearing more frequently in some regions such as South and South-eastern regions of Brazil and India. Common clinical signs include virilization, Cushing's syndrome, feminization and hypertension, either isolated or in association. The aim of this report is to present our experience with the pre-operative use of ketoconazole in children with an adrenocortical tumor to control elevated blood pressure levels non-responsive to the usual treatment. Over the last 16 years, of 46 children diagnosed as having adrenocortical tumor, 17 developed hypertension (diastolic pressure greater than the 95th percentile for age and sex according to data from the Task Force on Blood Pressure Control in Children), associated with virilization and/or Cushing's syndrome. In three of these 17 patients, conventional antihypertensive therapy failed, and they were treated with ketoconazole (200-300 mg/day). This resulted in rapid control of the blood pressure. It is concluded that in selected patients, ketoconazole may be useful adjuvant therapy for the palliative control of the arterial hypertension secondary to adrenocortical tumors, without side effects.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/fisiopatología , Hipertensión/tratamiento farmacológico , Cetoconazol/uso terapéutico , Preescolar , Humanos , Lactante , Masculino , Cuidados PreoperatoriosRESUMEN
Naturally occurring activating mutations in the human LH receptor (hLHR) gene are the cause of sporadic or familial male gonadotropin-independent precocious puberty. We have previously reported three different activating mutations of the hLHR gene in four unrelated Brazilian boys with male-limited precocious puberty. In the current study, we examined three other Brazilian boys, two brothers and one unrelated boy, with gonadotropin-independent precocious puberty. Direct sequencing of the entire exon 11 of the hLHR gene in the two brothers revealed a heterozygous substitution of T for C at nucleotide 1103, resulting in the substitution of leucine at position 368 by proline in the first transmembrane helix. Their mother carried the same mutation, establishing the familial nature of this mutation. Human embryonic 293 cells expressing hLHR(L368P) bound hCG with the same high affinity as cells expressing the wild-type hLHR. Cells expressing the novel L368P mutation displayed up to a 12-fold increase in basal cAMP production compared with cells expressing the same number of cell surface wild-type hLHR, indicating constitutive activation of the mutant receptor. In addition, the cAMP levels in cells expressing the hLHR mutant were further augmented by hCG. Molecular dynamics simulations suggest that substitution of L368 of the hLHR by proline results in lack of a salt bridge interaction between D405 and R464 (distance 9. 0 A vs. 4.7 A in wild-type hLHR) as well as by the opening of a crevice between the second and third intracellular loops, which may allow G proteins greater accessibility. These structural features were shared by other activating mutants of the hLHR. Sequencing of exon 11 of the hLHR gene of the unrelated boy revealed that he carried a homozygous nucleotide substitution causing an A568V mutation in the third cytoplasmic loop of the receptor. This mutation was previously found in two unrelated Brazilian boys, but in heterozygous state. Clinical and hormonal data of the patient with the homozygous A568V were not different from those individuals with the Ala568Val mutation in a heterozygous state. Furthermore, the phenotype caused by dominant activating mutations of the hLHR gene are not altered when both alleles carry a mutant sequence. Our studies show that the A568V is the most frequent cause of male-limited precocious puberty in Brazilian boys. Lastly, the identification of a novel activating L368P mutation in the first transmembrane helix of two Brazilian boys with familial male-limited precocious puberty provides further insights into the mechanism of activation of the hLHR.
Asunto(s)
Mutación/genética , Pubertad Precoz/genética , Receptores de HL/genética , Sustitución de Aminoácidos , Membrana Celular/fisiología , Niño , Preescolar , Gonadotropina Coriónica/metabolismo , AMP Cíclico/metabolismo , ADN/análisis , ADN/genética , Humanos , Masculino , Modelos Moleculares , Mutagénesis , Pubertad Precoz/patología , TransfecciónRESUMEN
Deficiency of adrenal steroid 21-hydroxylase is the most common form of congenital adrenal hyperplasia and it is considered to be responsible for 90% of the disease. This paper describes for the first time the CYP21B mutation profile in Brazilian patients. We genotyped 41 families with at least one individual affected with the classical form of the 21-hydroxylase deficiency, representing 74 unrelated alleles. In order to characterize different disease-causing alleles, genotyping was performed by Southern blot analysis with three restriction enzymes, allele-specific oligonucleotide hybridization, and allele-specific PCR. Different alleles were distinguished by TaqI C4B RFLP, gene duplications or deletions of either CYP21A + C4B or CYP21B + C4B, large gene conversions and eight mutations that might have been introduced into CYP21B from CYP21A by microconversion events. At least one mutation was detected in 24 different disease-causing alleles, which represents about 85% of the affected alleles in those families. The frequency of the 30 kb deletion of CYP21B was lower than that described for Caucasians. The mutation Sp2 showed the highest frequency (24.65%) and was present mainly in salt-wasting patients, although it was also detected in some patients with the simple virilizing form of the disease. Conversely, I172N showed a frequency of 18.91% and was found mostly in patients affected with the simple virilizing form of the disease. Five other mutations were determined at low frequency, but CL6 was not found in any of the tested alleles.
Asunto(s)
Hiperplasia Suprarrenal Congénita , Hiperplasia Suprarrenal Congénita/genética , Conversión Génica/genética , Eliminación de Gen , Mutación/genética , Hiperplasia Suprarrenal Congénita/clasificación , Southern Blotting , Brasil , Frecuencia de los Genes , Genotipo , Humanos , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Sex ambiguity may be due to several disorders of gonadal differentiation, including true hermaphroditism (TH), as well as male and female pseudohermaphroditism. Although TH is a rare cause of intersex in Europe and North America, in Africa it presents one of the highest frequencies. The 46,XX karyotype has been found in the majority of the reported patients (70.6%), and aberrations in the sex chromosomes have been observed in about 22% of the cases. The 46,XY karyotype has been described as less frequent. Herein we describe ten cases of TH which have been diagnosed over the last 7 years, six lateral TH, two unilateral TH, and two cases of ovotestes with absent contralateral gonad. From a total of 18 gonads analyzed, there were 8 testes, 6 ovaries and 4 ovotestes. Nine subjects had originally a male sex assignment, and in three cases this was reverted to female. Four cases had a 46,XY karyotype. Additional sex chromosome aberrations had been found in four different cases [two 46,XX/46,XY, one 45,X/47,XYY, one 46,X,del(Yq)]. A 46,XX karyotype was found in only two individuals, and both were SRY negative. Our preliminary data, especially on the constitution of chromosomes and gonads, indicate marked differences from those in the literature.
Asunto(s)
Trastornos del Desarrollo Sexual/genética , Ovario/anomalías , Testículo/anomalías , Adolescente , Brasil , Diferenciación Celular/fisiología , Niño , Preescolar , Trastornos del Desarrollo Sexual/patología , Femenino , Humanos , Lactante , Cariotipificación , Masculino , Estudios RetrospectivosRESUMEN
We report on a rare case of female pseudohermaphroditism due to classical 21-hydroxylase deficiency associated with Turner syndrome (45,X/46,XX). Difficulties in the management of both diseases are briefly discussed. We regard this rare combination as a coincidental occurrence.