Novel deletion alleles carrying CYP21A1P/A2 chimeric genes in Brazilian patients with 21-hydroxylase deficiency.

BACKGROUND: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused by deletions, large gene conversions or mutations in CYP21A2 gene. The human gene is located at 6p21.3 within a locus containing the genes for putative serine/threonine Kinase RP, complement C4, steroid 21-hydroxylase CYP21 tenascin TNX, normally, in a duplicated cluster known as RCCX module. The CYP21 extra copy is a pseudogene (CYP21A1P). In Brazil, 30-kb deletion forming monomodular alleles that carry chimeric CYP21A1P/A2 genes corresponds to ~9% of disease-causing alleles. Such alleles are considered to result from unequal crossovers within the bimodular C4/CYP21 locus. Depending on the localization of recombination breakpoint, different alleles can be generated conferring the locus high degree of allelic variability. The purpose of the study was to investigate the variability of deleted alleles in patients with 21-hydroxylase deficiency. METHODS: We used different techniques to investigate the variability of 30-kb deletion alleles in patients with 21-hydroxylase deficiency. Alleles were first selected after Southern blotting. The composition of CYP21A1P/A2 chimeric genes was investigated by ASO-PCR and MLPA analyses followed by sequencing to refine the location of recombination breakpoints. Twenty patients carrying at least one allele with C4/CYP21 30-kb deletion were included in the study. RESULTS: An allele carrying a CYP21A1P/A2 chimeric gene was found unusually associated to a C4B/C4A Taq I 6.4-kb fragment, generally associated to C4B and CYP21A1P deletions. A novel haplotype bearing both p.P34L and p.H62L, novel and rare mutations, respectively, was identified in exon 1, however p.P30L, the most frequent pseudogene-derived mutation in this exon, was absent. Four unrelated patients showed this haplotype. Absence of p.P34L in CYP21A1P of normal controls indicated that it is not derived from pseudogene. In addition, the combination of different approaches revealed nine haplotypes for deleted 21-hydroxylase deficiency alleles. CONCLUSIONS: This study demonstrated high allelic variability for 30-kb deletion in patients with 21-hydroxylase deficiency indicating that a founder effect might be improbable for most monomodular alleles carrying CYP21A1P/A2 chimeric genes in Brazil.

Why pediatricians need to know the disorders of sex development: experience of 709 cases in a specialized service.

OBJECTIVE: To evaluate, in a sample of patients with disorders of sex development (DSD), data related to the age at referral and their correlation with the initial complaints, gender at referral, defined gender after diagnosis and etiological diagnosis. METHODS: Retrospective review of the age at the first consultation and the reason for it, initial social gender and gender after the diagnosis, karyotype and etiological diagnosis of all cases treated at a DSD outpatient clinic between 1989 and 2016. Cases that did not involve DSD and DSD diagnoses that do not usually involve ambiguous genitalia, thus not requiring specialized monitoring, were excluded. RESULTS: Of the 1793 treated cases, 1139 were diagnosed with some type of DSD. This study excluded 430 cases (272 with Turner's syndrome, 66 with Klinefelter syndrome, and 92 with pure gonadal dysgenesis), thus a total 709 individuals were included. Of these, 82.9% were referred due to ambiguous genitalia; only one-quarter were still in the first month of life, and 6.6% were referred due to pubertal delay, with most of them aged 10 years or older. Of these patients, 68.6% had a diagnosis of XY DSD, 22.4% of XX DSD, and 9% of sex chromosome abnormalities. CONCLUSIONS: This study presents the largest series in the literature of patients with DSD treated in a single center. The time of referral of the majority of patients with ambiguous genitalia fell short of the ideal, and milder cases of ambiguous genitalia and many with pubertal manifestations were referred even later. The results reinforce the importance of continuing education for professionals who will have the first contact with these patients, mainly pediatricians and neonatologists.

Turner's syndrome and subclinical autoimmune thyroid disease: a two-year follow-up study.

Although autoimmune thyroid disease (AITD) is frequent in Turner's syndrome (TS), followup studies are scant, and there are none regarding subclinical thyroiditis. We investigated thyroid function and morphology in 17 patients with TS (mean age 14.6 years) with transient and asymptomatic variations of TSH and/or thyroid hormones. Our 2-year follow-up included measurements of TSH, free T4, T3 and TPO and Tg antibodies, ultrasound (US) (first and last evaluations) and scintigraphy (first evaluation). Thyroid volume was evaluated relative to the patients' stature. Fourteen had abnormal hormones, including four with hypothyroidism and one with hyperthyroidism, ten had positive antibodies, and all had abnormalities on US; uptake was normal in 14/16. Abnormal hormones were independent of antibodies, number of US findings, age, time of disease and volume. At the end of the follow-up, antibodies were associated with a high number of abnormal US features, particularly heterogeneous texture. Our results indicate that recurring thyroid hormone variations in TS are due to chronic AITD.

21-hydroxylase deficiency transiently mimicking combined 21- and 11beta-hydroxylase deficiency.

21-Hydroxylase deficiency (21OHD) is the commonest form of congenital adrenal hyperplasia, while 11betaOHD represents 5% of cases. Although both result from mutations in distinct genes, cases of 'apparent' combined 21OHD and 11betaOHD (AC21,11OHD) have been occasionally reported. A 6 year-old girl, born with ambiguous genitalia and salt-loss, had serum elevations (ng/dl) of androstenedione (>1,000), 17-hydroxyprogesterone (17OHP; 38,483), 21-deoxycortisol (21DF; 23,338), and 11-deoxycortisol (S; 4,928), suggesting AC21,11OHD. CYP21A and CYP11B1 genotyping identified mutations only in the former. On follow-up, serum S became normal but 17OHP and 21DF were still elevated. ACTH stimulation disclosed elevated levels of 17OHP and 21DF, but unresponsive S and undetectable deoxycorticosterone. The hormonal pattern initially suggested AC21,11OHD, but subsequent normalization of S showed transient 11-hydroxylase inhibition. This may have occurred by enzyme or co-enzyme immaturity or functional discrepancy, but also by selective inhibition of 11betaOH by excess intra-adrenal concentration of androgens, acting as pseudo-substrates for this enzyme.

Clinical and cytogenetic features of 516 patients with suspected Turner syndrome - a single-center experience.

BACKGROUND: Clinical suspicion of Turner syndrome (TS) may be challenging. Short stature and absent puberty are not mandatory and the dysmorphic picture is widely variable. The aim of the study was to describe a representative sample of patients with suspected TS in a single center and to verify which set of features may help discriminate those with TS. METHODS: This was a retrospective study of patients with suspected TS evaluated between 1989 and 2012 with the same clinical and cytogenetic protocols. Data regarding reason for referral, age and height at diagnosis, birth data, pubertal features and dysmorphisms were analyzed. RESULTS: TS was diagnosed in 36% of 516 patients; structural chromosome anomalies predominated (42%). Short stature was the main reason for referral of patients with and without TS. The mean age of patients at first visit, with TS or without TS was similar (11.89 and 11.35 years, respectively), however, infants and adolescents predominated in the TS group. The mean full-term birth weight was lower in patients with TS as well as height at diagnosis, but normal height z-score was found in 17% of patients. Spontaneous puberty occurred in 30% of TS patients aged 13 years or more, but most had pubertal delay. Residual lymphedema, webbed neck, cubitus valgus, hyperconvex nails, shield chest, abnormal nipples, pigmented nevi, short fourth metacarpal and shorter height were the best discriminators for girls with TS. CONCLUSIONS: Though short stature, pubertal delay and typical stigmata should prompt investigation of TS, lack of one of these features should not exclude this hypothesis. Dysmorphisms other than those considered "typical" should be sought on physical examination.

[Evidences for subclinic chronic autoimmune thyroid disease in girls with Turner Syndrome]. / Evidências de doença tireóidea auto-imune crônica subclínica em portadoras da Síndrome de Turner.

Patients with Turner syndrome (TS) frequently exhibit transient, recurrent and asymptomatic variations of TSH and/or thyroid hormones (TH). This work was carried out to evaluate thyroid function and structure in patients with TS who had had such variations in hormone concentrations. Our sample comprised 24 patients, 17 less than 20-years old. Evaluation included serum levels of TSH, free T4, total T3, TPO and Tg autoantibodies, thyroid ultrasound (US) and scintigraphy with 99mTc-pertechnetate. Thirteen patients had abnormal TSH and/or TH levels; 23 exhibited US features compatible with chronic thyroid disorder, particularly thyromegaly (established according to volume expected for stature) and heterogeneous echogenicity. Uptake was normal in 21 cases and tracer distribution was homogeneous in 22. The finding of abnormal hormone concentrations was independent of age, length of time since the first similar finding, thyroid autoantibodies, number of abnormalities at US and abnormal scintigraphic findings. Patients aged more than 20 years had higher frequency of thyroid antibodies and heterogeneous echogenicity, and thyroid volume was significantly correlated to length of time since detection of the first hormone variation, indicating progressive thyroid disease. These results suggest that subclinical thyroid dysfunction in TS is due to chronic autoimmune thyroid disease.

Serum 21-Deoxycortisol, 17-Hydroxyprogesterone, and 11-deoxycortisol in classic congenital adrenal hyperplasia: clinical and hormonal correlations and identification of patients with 11beta-hydroxylase deficiency among a large group with alleged 21-hydroxylase deficiency.

INTRODUCTION: 21-Hydroxylase deficiency (21OHD) is the most common cause of congenital adrenal hyperplasia, followed in frequency by 11beta-hydroxylase deficiency (11betaOHD). Although the relative frequency of 11betaOHD is reported as between 3 and 5% of the cases, these numbers may have been somewhat underestimated. MATERIALS AND METHODS: In 133 patients (89 females/44 males; 10 d-20.9 yr) with alleged classic 21OHD and five (three females/two males; 7.3-21 yr) with documented 11betaOHD, we measured serum 21-deoxycortisol (21DF), 17-hydroxyprogesterone (17OHP), and 11-deoxycortisol (S), 48 h after glucocorticoid withdrawal. We also studied 20 sex- and age-matched control subjects. Serum steroid levels were determined by RIA after HPLC purification. OBJECTIVES: The objectives of this study were to: 1) quantify 21DF in patients with congenital adrenal hyperplasia, 2) correlate hormonal with clinical data, and 3) identify possible misdiagnosed patients with 11betaOHD among those with 21OHD. RESULTS: In 21OHD, 17OHP (217-100,472 ng/dl) and 21DF (<39-14,105 ng/dl) were mostly elevated and positively correlated (r = 0.7202; P < 0.001). Except for higher 17OHP in pubertal patients, 17OHP and 21DF values were similar according to sex, disease severity, or prevailing glucocorticoid dose. One additional patient with 11betaOHD was detected (1%) and also one with apparent combined 11beta- and 21OHD. S levels were elevated in 11betaOHD and normal but significantly higher in 21OHD than in controls. CONCLUSION: To recognize patients with 21- and/or 11betaOHD, we recommend evaluation of 17OHP or 21DF and S. Also, 21DF may be useful to follow up pubertal patients with 21OHD. Because 1% of patients with alleged 21OHD may have 11betaOHD, its frequency seems underestimated, as per our experience in a Brazilian population.

[Growth and body composition in children with type 1 diabetes mellitus]. / Crescimento e composição corporal de crianças com diabetes mellitus tipo 1.

OBJECTIVE: To evaluate the growth and body composition of pre-pubertal diabetic children, and to check for influence of the age of diabetes onset and length, sex, insulin requirement and glycosylated hemoglobin. PATIENTS AND METHODS: 59 diabetic children (39 M; 29 F), age 1.2-11.5 years, and 67 controls (36 M; 31 F), age 1.2-11.7 years were included. Weight, height, body mass index (BMI), arm circumference, skin folds, fat mass and muscle areas were evaluated and transformed into standard deviation scores (SDS). RESULTS: Among the diabetic children the mean height SDS was -0.13 (+/- 0.97) while in the control group it was 0.28 (+/- 0.86) (p= 0.013). The difference between the first and the current height SDS showed that the height SDS decreased significantly (p< 0.001) and multiple regression analysis indicated correlation with the duration of the disease. The mean arm fat SDS also revealed difference (p< 0.001). The means for weight, BMI, addition of 3 skinfolds and muscle mass did not demonstrate difference between the groups. CONCLUSIONS: The diabetic children showed reduction of height SDS during the period studied and they were significantly shorter than the controls, even though their statures were within the population standards. The arm fat area also showed an increase in relation with the controls.

A Single Nucleotide Variant in the Promoter Region of 17ß-HSD Type 5 Gene Influences External Genitalia Virilization in Females with 21-Hydroxylase Deficiency.

BACKGROUND: In 21-hydroxylase deficiency (21-OHD), there is an influence of genotype on the severity of external genitalia virilization. However, females carrying mutations predicting a similar impairment of enzymatic activity present a wide variability of genital phenotypes. In such cases, interindividual variability in genes related to the sex steroid hormone pathway could play a role. OBJECTIVE: To evaluate the influence of POR, HSD17B5 and SRD5A2 variants on the severity of external genitalia virilization in 21-OHD females. DESIGN AND PATIENTS: Prader stages were evaluated in 178 females with 21-OHD from a multicenter study. The 21-OHD genotypes were divided into two groups according to their severity: severe and moderate. The influences of the POR p.A503V, HSD17B5 c.-71A>G, HSD17B5 c.-210A>C, and SRD5A2 p.A49T and p.V89L variants on the degree of external genitalia virilization were analyzed. RESULTS: The POR p.A503V, HSD17B5 c.-71A>G, HSD17B5 c.-210A>C, and SRD5A2 p.A49T and p.V89L variants were found in 25, 33, 17, 1, and 31% of the alleles, respectively. In uni- and multilinear regression, HSD17B5 c.-210A>C has a significant influence on the degree of external genitalia virilization. This variant was also identified with a higher frequency in the most severely virilized females. CONCLUSION: We demonstrated that a variant in the promoter region of HSD17B5 related to fetal androgen synthesis influences the genital phenotype in 21-OHD females.

[Body proportions in a group of Brazilian patients with Turner Syndrome]. / Proporções corporais em um grupo de pacientes brasileiras com síndrome de Turner.

OBJECTIVE: The first Brazilian study aimed to evaluate body proportions in patients with Turner Syndrome (TS) with no growth hormone treatment. METHODS: A cross-sectional study with 50 TS patients (5 to 43 years) evaluating age, karyotype, pubertal development, height, sitting height, arm span, weight, BMI, head circumference, length of hand, foot and leg, waist to hip ratio, biacromial and biiliac diameters. The data were transformed in score z. A descriptive analysis was done and Mann-Whitney test and analysis of variance was applied. RESULTS: Twenty-eight patients were pubertal and 22 nonpubertal, and all of the absolute measurements were significantly increased in the former. There were no significant differences of the anthropometric findings according to the karyotype and puberty, in relation to score z data. The SD scores of all variables showed means above -2, except height and arm span in the nonpubertal patients and also sitting height and hand in the pubertal patients. The same result was observed when only the patients > 20 years were analyzed, being only weight, BMI, and biacromial and biiliac diameters significantly smaller in relation to the Danish data of Gravholt and Naeera from 1997. CONCLUSION: The retardation of growth in TS occurs mainly on the longitudinal axis, and the results showed in this study are similar to the Danish report.

[Evaluation of insulin resistance and lipid profile in turner syndrome]. / Avaliação da resistência insulínica e do perfil lipídico na síndrome de turner.

OBJECTIVE: To evaluate the presence of insulin resistance (IR) and changes in lipid profile in Turner Syndrome (TS), and to check the influence of age, karyotype, systemic arterial hypertension (SAH), height, weight, body mass index (BMI), and pubertal development. PATIENTS AND METHODS: A transversal study of 35 TS patients, confirmed with karyotype (5 to 43 years), without previous use of anabolic steroid or hGH, with evaluation of blood pressure, pubertal development, anthropometric data, measurement of waist (W), hip (H), W to H ratio, total cholesterol, HDL, triglycerides (TGC), LDL, insulin and glucose. HOMA and QUICKI indexes were calculated, as well as glucose to insulin ratio (G/I). Data were examined by the Mann-Whitney and Spearman tests. RESULTS: Ten patients were >20 years. Seventeen had a 45,X karyotype and 6 structural aberrations; differences of the variables in relation to the karyotypes were not observed; 15 were nonpubertal and 20 pubertal; TGC and HOMA were significantly higher in puberty, while G/I was lower. Seven had normal height, 8 had BMI >25 Kg/m2 (6 between 25 and 30, and 2 >30), and 19 W/H >0.85. Cholesterol levels were 180 +/- 42mg% (4 >240); HDL 57 +/- 16mg%; LDL 99 +/- 34 mg%; TGC 108 +/- 96 mg% (2 >200); HOMA 1.01 +/- 0.71; QUICKI 0.4 +/- 0.04 and G/I 23.5 +/- 12.1 (2 <7.0). CONCLUSIONS: Changes were observed in lipid profile independent of age, karyotype, SAH and obesity, but associated with IR. The frequency of IR was lower than described in literature, and seems to be directly linked to chronological age, obesity and estrogen therapy.

[Pubertal growth and final height in 40 patients with type 1 diabetes mellitus]. / Crescimento puberal e altura final em 40 pacientes com diabetes mellitus tipo 1.

OBJECTIVE: Type 1 diabetes mellitus (DM1), the most important chronic endocrine-metabolic disease in children and adolescents, may lead to delayed growth and puberty. In this study we analyzed the influence of DM1 on growth spurt and puberty of patients whose onset of the disease was before or at the beginning of this phase. PATIENTS AND METHODS: Data from 40 patients, 25 females, who had attained final height were retrospectively obtained, including duration of disease, patient's height and weight SDS at each consultation, parental target height, yearly growth velocities (GV), peak of growth spurt, duration of puberty, magnitude of growth spurt and glycated hemoglobin (HbA1C) levels. RESULTS: 37 patients had an adequate final height to parental target height, and only 3 were below the lower limit. There was no significant association among the variables and the appropriate final height to the target height, except for GV on growth spurt, when it was lower than or equal to 6 cm/year. The age of onset of DM1 and the age of peak of growth spurt was similar to previously data reported; regarding the age of the onset of puberty, there was no delay. However, the magnitude of the growth spurt and the peak of GV were lower. According to HbA1C levels, all patients exhibited a bad chronic control of DM1. CONCLUSIONS: In this group of inadequately controlled patients, the final height was lower than expected when compared to the height at onset of DM1, probably due to a slow GV during puberty, which however had no influence on the final height to parental target height.

[Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: final height in 27 patients with the classical form]. / Hiperplasia congênita das supra-renais por deficiência da 21-hidroxilase: altura final de 27 pacientes com a forma clássica.

OBJECTIVE: To determine final height (FH) in congenital adrenal hyperplasia (CAH) patients and investigate conditions allowing better height outcome. METHODOLOGY: 13 salt-wasting (SW) and 14 simple virilizing (SV) patients were studied. FH and target height (TH) were transformed into standard deviation score (z). Data were analyzed according to sex, clinical form, age at treatment onset and length of treatment before attaining FH. RESULTS: zFH (n = 27) was -1.57 +/- 1.01. FH (-1.50 +/- 1.03) was below TH (-0.78 +/- 0.84) (n = 25, p < 0.001). FH has not differed according to sex, clinical form and age at therapy onset although there was a trend towards better FH in SW patients and in early treated cases; there was significant difference (p = 0.018) between patients treated for less than 5 years (-2.49 +/- 1.03) and those accompanied longer than 10 years (-1.21 +/- 0.88) before attaining FH. CONCLUSIONS: There was a FH impairment and adult height improvement seems to depend mainly on early diagnosis and treatment.

[Feminizing genitoplasty and congenital adrenal hyperplasia: analysis of anatomical results]. / Genitoplastia feminizante e hiperplasia congênita das adrenais: análise dos resultados anatômicos.

OBJECTIVE: To evaluate the anatomical and cosmetic results of feminizing genitoplasty in girls with ambiguous genitalia due to Congenital Adrenal Hyperplasia (CAH). CASUISTIC AND METHOD: Twenty-seven females with genital ambiguity (Prader III-V) due to CAH underwent an one-stage feminizing genitoplasty and were followed for a mean time of 4 years. In twelve girls, two cutaneous labioscrotal island-flaps were associated with the conventional genitoplasty, to decrease the excess of labia majora and to enlarge the vaginal introitus. Urinary tract infections were observed in sixteen girls in the preoperative and in only seven in the postoperative period. The cosmetic results were obtained by the systematic anatomical evaluation of the different structures that compose the genitalia. RESULTS: The results of clitoroplasty were considered good in 63% of the cases; however, 4 girls developed clitoral atrophy. An excess of labia majora was present in 25% and persistence of the urogenital sinus occurred in 11% (three children without labioscrotal island flap). The labioscrotal island flap was considered technically feasible and reproducible. Five girls had to be re-operated. The cosmetic results were considered excellent or good in 63% of the cases, satisfactory in 18.5% and unsatisfactory or bad in 18.5%. CONCLUSIONS: The anatomical and cosmetic results were good in majority of the cases; however, some technical aspects should be adjusted, to avoid irreversible sequels and re-operations.

Why pediatricians need to know the disorders of sex development: experience of 709 cases in a specialized service / Por que os pediatras precisam conhecer os distúrbios da diferenciação do sexo: experiência de 709 casos de um serviço especializado

Abstract Objective: To evaluate, in a sample of patients with disorders of sex development (DSD), data related to the age at referral and their correlation with the initial complaints, gender at referral, defined gender after diagnosis and etiological diagnosis. Methods: Retrospective review of the age at the first consultation and the reason for it, initial social gender and gender after the diagnosis, karyotype and etiological diagnosis of all cases treated at a DSD outpatient clinic between 1989 and 2016. Cases that did not involve DSD and DSD diagnoses that do not usually involve ambiguous genitalia, thus not requiring specialized monitoring, were excluded. Results: Of the 1793 treated cases, 1139 were diagnosed with some type of DSD. This study excluded 430 cases (272 with Turner's syndrome, 66 with Klinefelter syndrome, and 92 with pure gonadal dysgenesis), thus a total 709 individuals were included. Of these, 82.9% were referred due to ambiguous genitalia; only one-quarter were still in the first month of life, and 6.6% were referred due to pubertal delay, with most of them aged 10 years or older. Of these patients, 68.6% had a diagnosis of XY DSD, 22.4% of XX DSD, and 9% of sex chromosome abnormalities. Conclusions: This study presents the largest series in the literature of patients with DSD treated in a single center. The time of referral of the majority of patients with ambiguous genitalia fell short of the ideal, and milder cases of ambiguous genitalia and many with pubertal manifestations were referred even later. The results reinforce the importance of continuing education for professionals who will have the first contact with these patients, mainly pediatricians and neonatologists.

Resumo Objetivo: Avaliar em uma amostra de pacientes com distúrbios da diferenciação do sexo (DDS), dados relacionados à idade, ao encaminhamento e sua correlação com as queixas iniciais, ao sexo ao encaminhamento e ao sexo final e diagnóstico etiológico. Métodos: Revisão retrospectiva da idade por ocasião da primeira consulta e motivo dela, sexo social inicial e após definição do diagnóstico, cariótipo e diagnóstico etiológico de todos os casos atendidos em um ambulatório especializado em DDS entre 1989 e 2016. Foram excluídos casos que não compreendiam DDS e diagnósticos de DDS que não cursam comumente com ambiguidade genital, não necessitam de acompanhamento especializado. Resultados: Dos 1.793 casos atendidos, 1.139 foram diagnosticados com algum DDS. Excluíram-se 430 (272 síndrome de Turner, 66 síndrome de Klinefelter e 92 disgenesia gonadal pura), totalizando 709. Desses, 82,9% foram encaminhados por ambiguidade genital, somente um quarto ainda no primeiro mês de vida e 6,6% por atraso puberal, a maioria com 10 anos ou mais; 68,6% tiveram diagnóstico de DDS XY; 22,4% DDS XX e 9% de anomalias dos cromossomos sexuais. Conclusões: Este estudo apresenta a maior casuística na literatura de pacientes com DDS atendidos em um único serviço. O momento de encaminhamento da maioria dos pacientes com ambiguidade genital foi aquém do ideal e casos mais leves de ambiguidade e muitos com manifestações puberais foram encaminhados ainda mais tardiamente. Os resultados reforçam a importância do ensino continuado a profissionais que terão o primeiro contato com esses pacientes, principalmente pediatras e neonatologistas.

[Turner syndrome: the patients' view]. / A percepção da doença em portadoras da síndrome de Turner.

OBJECTIVE: To identify how patients with Turner syndrome perceive their condition. METHODS: Thirty-six women with Turner syndrome, aged between 15 and 25 years and with over 2 years of medical follow-up, were individually interviewed about: the impact of Turner syndrome at the moment of the diagnosis, their understanding of the syndrome, its effect in their lives, and their expectations for the future. RESULTS: Only 31% of the patients immediately understood the diagnosis. Their feelings associated to that moment were neutral (47%) or concerned (33%). About one third of the interviewed women were unable to explain the etiology of Turner syndrome (42%), did not relate their symptoms with Turner syndrome (36%), and/or believe there might be a cure for it (44%). Although most of the interviewed women affirm that the syndrome has no interference in their lives (67%) and that they consider themselves happy persons (78%), in more than half of the interviews there are evidences of difficulties in social interaction and love relationship, low self-esteem, dissatisfaction with their physical appearances, especially the short stature and infertility. Their hopes for the future refer mainly to study and have a job. Although being, on average, 19 years old, one in two women (53%) still hopes to grow up. CONCLUSION: Besides medical treatment, it is important that the knowledge of the patients about the syndrome and some issues as infertility, short stature, self-esteem and social interactions receive proper and continuous attention from the moment of the diagnosis. The ideal situation should be a joint-action of a psychologist and the medical team.

[Multicentric study of Brazilian patients with 21-hydroxylase deficiency: a genotype-phenotype correlation]. / Estudo multicêntrico de pacientes brasileiros com deficiência da 21-hidroxilase: correlação do genótipo com o fenótipo.

We analyzed the clinical and molecular data of 205 patients with the three different clinical forms of 21-hydroxylase deficiency, in whom the clinical and molecular diagnosis were already defined. The most frequent mutations were I2 splice in the salt wasting form, I172N in the simple virilizing and V281L in the nonclassical form, presenting similar frequencies as those observed in other populations. We found a lower frequency of 21-hydroxylase gene deletion, similar to that previously identified in Argentinean and Mexican populations. Five new mutations were described in our population: G424S, H28+C, Ins 1003 1004 A, R408C and IVS2-2A>G. The genotype was classified in three groups according to the impairment of enzymatic activity observed in vitro, Group A: 0-2%, Group B: 3-7% and Group C: >20%. Group A mutations correlated with the salt wasting form, the Group B with simple virilizing form and Group C with the non classical form. The severity of genotype showed a positive correlation with higher 17OH-progesterone and testosterone levels. The I2 splice mutation in homo or hemizygosis confers classical form phenotype with both salt wasting and simple virilizing forms, precluding the prediction of the clinical form through genotype in pre and neonatal diagnosis. The good genotype-phenotype correlation in patients with 21-hydroxylase deficiency shows the usefulness of genotype to predict the clinical form for genetic counseling, prenatal diagnosis and to confirm neonatal screening diagnosis, except in cases with I2 splice mutation.

Prader-Willi syndrome: a case report with atypical developmental features.

OBJECTIVE: To describe the case of a male Prader-Willi syndrome (PWS) patient with atypical development features. DESCRIPTION: We report the case of a male adolescent with confirmed diagnosis of PWS which presents atypical phenotype. The patient progressed with spontaneous and complete pubertal development, stature in the normal range, and weight control without any pharmacological treatment, except metformin. COMMENTS: PWS is an imprinting paternally inherited disorder of 15q11-13 characterized by hypotonia in infant age, hyperphagia, varied degrees of mental retardation, behavior problems, hypogonadism, short stature, and other less common findings.

Performance of phalangeal quantitative ultrasound parameters in the evaluation of reduced bone mineral density assessed by DX in patients with 21 hydroxylase deficiency.

The purpose of this study was to verify the performance of quantitative ultrasound (QUS) parameters of proximal phalanges in the evaluation of reduced bone mineral density (BMD) in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21 OHD). Seventy patients with 21 OHD (41 females and 29 males), aged between 6-27 y were assessed. The QUS measurements, amplitude-dependent speed of sound (AD-SoS), bone transmission time (BTT), and ultrasound bone profile index (UBPI) were obtained using the BMD Sonic device (IGEA, Carpi, Italy) on the last four proximal phalanges in the non-dominant hand. BMD was determined by dual energy X-ray (DXA) across the total body and lumbar spine (LS). Total body and LS BMD were positively correlated to UBPI, BTT and AD-SoS (correlation coefficients ranged from 0.59-0.72, p < 0.001). In contrast, when comparing patients with normal and low (Z-score < -2) BMD, no differences were found in the QUS parameters. Furthermore, UBPI, BTT and AD-SoS measurements were not effective for diagnosing patients with reduced BMD by receiver operator characteristic curve parameters. Although the AD-SoS, BTT and UBPI showed significant correlations with the data obtained by DXA, they were not effective for diagnosing reduced bone mass in patients with 21 OHD.

Estimation of percent body fat based on anthropometric measurements in children and adolescents with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND & AIM: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is associated with a high risk for obesity. Anthropometric measures are simple and inexpensive methods to assess body fat. However, the accuracy of alternative methods in these patients is unknown. This study aim to develop and evaluate the accuracy of predictive anthropometric equations in the estimation of percent body fat in individuals with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. METHODS: A total of 31 female and 22 male patients, aged 7-20 years, were evaluated. Dual-energy X-ray absorptiometry was used as the reference method for body fat, and anthropometric measurements were performed. RESULTS: Three new predictive equations showed similar results: Equation (1) (R² = 0.85; SEE = 2.89%), Equation (2) (R² = 0.86; SEE = 2.82%), and Equation (3) (R² = 0.86; SEE = 2.81%). Internal cross-validation procedures showed a high R² (range, 0.84-0.85) and low SEE (<3%). The limits of agreement ranged from -5.6% to 5.6% and no trend was observed. CONCLUSION: In children and adolescents with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, three new predictive equations were validated for the estimation of percent body fat, with dual-energy X-ray absorptiometry as the reference method.