Neonatal 17-hydroxyprogesterone levels adjusted according to age at sample collection and birthweight improve the efficacy of congenital adrenal hyperplasia newborn screening.

INTRODUCTION: The primary concern related to congenital adrenal hyperplasia (CAH) newborn screening (NBS) is the high rate of false-positive results (FPR) associated with prematurity; false-negative results (FNR) can also occur due to precocious sample collection. OBJECTIVE: To determine the neonatal 17-hydroxyprogesterone (N17OHP) normal range in newborns in Sao Paulo using different references according to age and birthweight (BW) and to establish the optimal NBS cut-off levels. METHODS: Neonatal 17-hydroxyprogesterone levels from 271 810 newborns (NBs) according to sample collection time (G1: 48-<72 h and G2: ≥72 h) and BW (≤1500 g, 1501-2000 g, 2001-2500 and >2500 g) were evaluated. N17OHP was measured by an fluoroimmunoassay, and serum 17OHP was measured by liquid chromatography-mass spectrometry. Affected and asymptomatic NBs with persistently increased 17OHP levels were submitted to CYP21A2-sequencing. RESULTS: Neonatal 17-hydroxyprogesterone levels in G1 were lower than G2 in all BW groups (P < 0·001). The FPR rate in G1/G2 was 0·2% using the 99·8th and 0·5% using the 99·5th percentile. The 99·8th percentile N17OHP value was the best cut-off for distinguishing between unaffected and affected NBs. Forty-four salt wasters, and five simple virilisers were diagnosed; N17OHP levels ranged from 93·3 to 2209·8 nmol/l, and no affected neonates with FNR were identified. The positive predictive value in G1 and G2 using the 99·8th percentile was 5·6% and 14·1%, respectively, and 2·3% and 7%, respectively, using the 99·5th percentile. Molecular tests identified two NBs with the nonclassical form among the 29 FPR. CONCLUSION: Neonatal 17-hydroxyprogesterone levels adjusted to sample collection age and birthweight reduced the FPR, and the use of N17OHP values based upon the 99·8th percentile improved the NBS efficacy.

Quality of life of patients with 46,XX and 46,XY disorders of sex development.

Disorders of sex development (DSD) result from abnormalities in the complex process of sex determination and differentiation. An important consideration to guide the assignment of social sex in newborns with ambiguous genitalia is the quality of life (QoL) of these patients in adulthood. The rarity of most DSD conditions makes it difficult to conduct a long-term follow-up of affected patients through adulthood. This review of papers on the QoL of DSD patients evaluated in developing and developed countries by qualitative and quantitative instruments revealed a large spectrum of QoL, ranging from very poor to similar to, or even better than, the normal population. A more adequate QoL was found in patients from tertiary centres, indicating that the medical care of DSD patients should be multidisciplinary and carried out by specialized teams.

Quality of life in a large cohort of adult Brazilian patients with 46,XX and 46,XY disorders of sex development from a single tertiary centre.

OBJECTIVE: Few studies have focused on the quality of life (QoL) of patients with disorders of sex development (DSD). Our aim was to evaluate QoL in DSD patients with defined diagnoses followed until adulthood in a single tertiary centre. PATIENTS AND METHODS: Adult patients with DSD (56 patients with 46,XX DSD - 49 with female social sex and 7 with male social sex as well as 88 patients with 46,XY DSD - 54 with female social sex and 34 with male social sex). MEASUREMENTS: QoL using WHOQOL-Bref questionnaire. RESULTS: Both patients with 46,XX DSD and patients with 46,XY DSD had similar QoL scores on the WHOQOL-Bref, comparable to the scores of the Brazilian general population. The chronological age at the start of treatment was negatively and significantly associated with general QoL score. Patients with male social sex DSD had better scores on the psychological domain than patients with female social sex DSD, as found in the Brazilian general population. In addition, among the 46,XY DSD group, the male social sex patients had better QoL compared with the female social sex patients. There was a positive and significant correlation between sexual performance and general QoL, although it explained only 4% of the variability of the general QoL score. The most influencing variables were general health, positive feelings and spirituality, religion and personal beliefs, each of them contributing with 18% of the variability of the general QoL score. CONCLUSION: Our large cohort of adult patients with DSD, which was followed by a multidisciplinary team in a single tertiary centre, had good QoL in adulthood; in addition, late treatment compromised the QoL of patients with DSD, whereas sexual performance has little influence on QoL.

The Cost-Effectiveness of Congenital Adrenal Hyperplasia Newborn Screening in Brazil: A Comparison Between Screened and Unscreened Cohorts.

Background: Newborn screening for congenital adrenal hyperplasia (CAH-NBS) is not yet a worldwide consensus, in part due to inconclusive evidence regarding cost-effectiveness because the analysis requires an understanding of the short- and long-term costs of care associated with delayed diagnosis. Objective: The present study aimed to conduct a cost-effectiveness analysis (CEA) to compare the costs associated with CAH-NBS and clinical diagnosis. Methods: A decision model comparing the two strategies was tested by sensitivity analysis. The cost analysis perspective was the public health system. Unscreened patients' data were extracted from medical records of Hospital das Clinicas, Saõ Paulo, and screened data were extracted from the NBS Referral Center of São Paulo. The population comprised 195 classical patients with CAH, clinically diagnosed and confirmed by hormonal/CYP21A2 analysis, and 378,790 newborns screened during 2017. Adverse outcomes related to late diagnosis were measured in both cohorts, and the incremental cost-effectiveness ratio (ICER) was calculated. We hypothesized that CAH-NBS would be cost-effective. Results: Twenty-five screened infants were confirmed with CAH (incidence: 1:15,135). The mortality rate was estimated to be 11% in unscreened infants, and no deaths were reported in the screened cohort. Comparing the unscreened and screened cohorts, mean serum sodium levels were 121.2 mEq/L (118.3-124.1) and 131.8 mEq/L (129.3-134.5), mean ages at diagnosis were 38.8 and 17 days, and hospitalization occurred in 76% and 58% of the salt-wasting patients with the in the two cohorts, respectively. The NBS incremental cost was US$ 771,185.82 per death averted, which yielded an ICER of US$ 25,535.95 per discounted life-year saved. Conclusions: CAH-NBS is important in preventing CAH mortality/morbidity, can reduce costs associated with adverse outcomes, and appears cost-effective.

Adverse Outcomes and Economic Burden of Congenital Adrenal Hyperplasia Late Diagnosis in the Newborn Screening Absence.

OBJECTIVE: To establish short- and long-term adverse outcome frequencies related to a late diagnosis of congenital adrenal hyperplasia (CAH) in the absence of newborn screening (NBS) and to determine respective treatment costs, which have never been reported. DESIGN: A retrospective analysis of a CAH cohort diagnosed without NBS. METHODS: We evaluated medical record data concerning 195 patients (141 females) diagnosed with CAH through clinical suspicion and confirmed using hormonal and CYP21A2 analysis, who were followed from 1980 to 2016 at Sao Paulo University. We measured mortality, dehydration, mental impairment frequencies, and hospitalization length outcomes in the salt-wasting form; the frequency of genetic females raised as males in both forms, frequency of depot GnRh analog (GnRha) and GH therapies in the simple virilizing form, and related outcome costs were calculated. RESULTS: Mortality rates and associated costs, varying from 10% to 26% and from $2,239,744.76 to $10,271,591.25, respectively, were calculated using the Brazilian yearly live-births rate, estimated productive life years, and gross domestic product. In the salt-wasting form, 76% of patients were hospitalized, 8.6% were mentally impaired, and 3% of females were raised as males (total cost, $86,230/salt-wasting patient). GnRha and growth hormone were used for 28% and 14% of simple virilizing patients, respectively, and 18% of females were raised as males (preventable cost, $4232.74/simple virilizing patient). CONCLUSIONS: A late CAH diagnosis leads to high mortality and morbidity rates, notably increasing public health costs, and may result in physical and psychological damage that is not easily measurable.

Impact of Long-Term Dexamethasone Therapy on the Metabolic Profile of Patients With 21-Hydroxylase Deficiency.

CONTEXT: No consensus has been reached regarding the glucocorticoid (GC) to use for congenital adrenal hyperplasia (CAH) during adulthood. Dexamethasone (DEX), because of its longer half-life, could improve compliance; however, no data are available regarding the long-term effects of DEX therapy. OBJECTIVE: To analyze the metabolic effect of DEX therapy for adults with CAH. DESIGN: Retrospective analysis of a CAH cohort receiving DEX therapy. SETTING: Medical School Hospital, São Paulo University, Brazil. PARTICIPANTS: Sixty patients with well-controlled classic CAH (41 women; 30 with salt-wasting) receiving DEX after achievement of final height. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Clinical, laboratory, and metabolic data were compared immediately before DEX and at the last evaluation. RESULTS: The mean age at the last evaluation was 31.9 ± 9.6 years, and the duration of DEX therapy was 11.5 ± 4.9 years. The mean DEX dose was 0.18 ± 0.07 mg/m2/d. The body mass index SD score (1.6 ± 1.6 vs 1.5 ± 1.5 mg/m2; P = 0.65) and obesity prevalence (27% vs 27%) did not differ between evaluations. However, the waist/height ratio (WtHR) had increased from 0.54 ± 0.08 to 0.56 ± 0.1 (P = 0.001). An increase in the homeostatic model assessment for insulin resistance index (2.5 ± 1.3 vs 2.8 ± 1.7; P = 0.03) was observed and positively correlated with the WtHR (r = 0.54). The prevalence of metabolic syndrome (7% vs 10%; P = 0.7) and hypertension (15% vs 13.3%; P = 0.8) did not differ significantly between the two evaluations. CONCLUSIONS: Long-term and low-dose DEX therapy did not lead to increases in obesity or metabolic syndrome, although it was associated with an increased WtHR and greater homeostatic model assessment for insulin resistance observed with chronic use of GCs. DEX appears to be an acceptable option to treat adult CAH.

Premature Pubarche due to Exogenous Testosterone Gel or Intense Diaper Rash Prevention Cream Use: A Case Series.

BACKGROUND/AIMS: Premature pubarche is associated with conditions such as virilizing congenital adrenal hyperplasia, androgen-secreting tumors, and exogenous exposure to androgen products. We describe the clinical and hormonal features of a series of children who were referred to endocrine evaluation due to premature pubarche. METHODS: This is a retrospective case series study of 14 children with premature pubarche and/or virilization. Five were unintentionally exposed to testosterone gel (parental use). Nine patients were intensely exposed to diaper rash prevention creams. Clinical and laboratory data were revised. RESULTS: Moderate to severe virilization was detected in the 5 patients (2 boys and 3 girls) who were exposed to testosterone gel. These patients had pubic hair development associated with clitoromegaly (3/3), penile enlargement (2/2), and accelerated growth (5/5). Testosterone levels were elevated in 4/5 patients associated with normal prepubertal gonadotropin levels and adrenal androgen precursors. The 9 children who were intensely exposed to diaper rash prevention creams had mild pubarche (intermediate hair) without any other clinical manifestation of pubertal development. Three of them exhibited pubic hair thinning after cream withdrawal. CONCLUSION: Unintentional topical androgen exposure or the intense use of diaper rash prevention cream should be ruled out in children with precocious pubarche and/or virilization signs to avoid misdiagnosis and expendable investigation.

Anatomical and functional outcomes of feminizing genitoplasty for ambiguous genitalia in patients with virilizing congenital adrenal hyperplasia.

UNLABELLED: The ideal surgical technique and appropriate age for performing feminizing genitoplasty are debatable, and few long-term outcome studies have been reported. PURPOSE: To report a retrospective study on anatomical and functional outcomes of feminizing genitoplasty in patients with virilizing congenital adrenal hyperplasia. METHODS: We selected 34 patients (mean age = 3.4 +/- 2.5 yr) with genital ambiguity classified according to Prader stage. Follow-up ranged from 2 to 16 years. Clitoral length ranged from 1.9 to 5.0 cm; 28 patients had a single perineal orifice, and 6 had a double orifice. The surgical technique included clitorovaginoplasty in a single procedure and was carried out before 2 years of age in 18 patients. Clitoroplasty was performed with glans preservation in all patients. Blood supply was exclusively maintained by the frenular pedicle in 97% of the cases, whereas clitoral dorsal nerves and vessels were preserved in the remaining 3%. The opening of the urogenital sinus was performed using either the Y-V perineal flap procedure (25 patients) or the cut-back incision procedure (8 patients). RESULTS: Good morphological and functional results were achieved in 68% of the patients; 21% of the patients had surgical complications, such as incision bleeding (2 cases), glans necrosis (1 girl with Prader V), and vaginal introitus stenosis (4 cases). Three of the latter underwent dilation with acrylic molds in the post-pubertal period with good functional results. CONCLUSIONS: We conclude that single-stage feminizing genitoplasty consisting of vulvoplasty, clitoroplasty, and Y-V perineal flap produced good cosmetic and functional results in virilized girls with congenital adrenal hyperplasia, with few complications. In addition, this surgical approach prevented the need for neovaginaplasty even in patients with high vaginal insertion.

Surgical Treatment after Failed Primary Correction of Urogenital Sinus in Female Patients with Virilizing Congenital Adrenal Hyperplasia: Are Good Results Possible?

PURPOSE: Genital reconstruction in female patients with virilizing congenital adrenal hyperplasia (CAH) is very challenging. Our aim was to evaluate the techniques employed to treat complications after failure of primary urogenital sinus (UGS) surgery, as well as the result of these reoperations. PATIENTS AND METHODS: Twenty girls with virilizing CAH who were previously submitted to genitoplasty in our service and elsewhere had recurrent UGS stenosis and vaginal introitus stenosis that required surgical treatment. The main symptoms were recurrent urinary tract infection (UTI) in nine, dyspareunia in six, and hematocolpos in three (two associated with sepsis). The anatomical findings were the persistence of UGS with stenosis in 17 patients and vaginal introitus stenosis in 3. The mean age at procedure was 15.2 years, averaging 13.1 years after the first surgery. The surgical techniques employed were isolated perineal flap in 17 patients and perineal flap with partial mobilization of UGS in 3. The mean follow-up after the procedure was 4.8 years (varying from 1 to 17 years). RESULTS: Vaginal dilations were performed after surgery in 15 patients. Good functional and anatomical results were obtained in 15 patients, with vaginal introitus amenable to dilators of 3.0 cm in diameter. Five patients with high vaginal insertion had recurrent vaginal stenosis and required a surgical revision. No patients presented menstrual obstruction or UTI after surgery. Eight of the 15 adult patients are sexually active. CONCLUSION: The reoperation to treat failed primary UGS treatment using Y-V flap and partial mobilization techniques associated with vaginal dilations, promoted good anatomical, and functional results with low morbidity in 75% of the patients.

The Presence of Clitoromegaly in the Nonclassical Form of 21-Hydroxylase Deficiency Could Be Partially Modulated by the CAG Polymorphic Tract of the Androgen Receptor Gene.

BACKGROUND: In the nonclassical form (NC), good correlation has been observed between genotypes and 17OH-progesterone (17-OHP) levels. However, this correlation was not identified with regard to the severity of hyperandrogenic manifestations, which could depend on interindividual variability in peripheral androgen sensitivity. Androgen action is modulated by the polymorphic CAG tract (nCAG) of the androgen receptor (AR) gene and by polymorphisms in 5α-reductase type 2 (SRD5A2) enzyme, both of which are involved in the severity of hyperandrogenic disorders. OBJECTIVES: To analyze whether nCAG-AR and SRD5A2 polymorphisms influence the severity of the nonclassical phenotype. PATIENTS: NC patients (n = 114) diagnosed by stimulated-17OHP ≥10 ng/mL were divided into groups according to the beginning of hyperandrogenic manifestations (pediatric and adolescent/adult) and CYP21A2 genotypes (C/C: homozygosis for mild mutations; A/C: compound heterozygosis for severe/mild mutations). METHODS: CYP21A2 mutations were screened by allelic-specific PCR, MLPA and/or sequencing. HpaII-digested and HpaII-undigested DNA samples underwent GeneScan analysis to study nCAG, and the SRD5A2 polymorphisms were screened by RLFP. RESULTS: Mean nCAG did not differ among pediatric, adolescent/adult and asymptomatic subjects. In the C/C genotype, we observed a significantly lower frequency of longer CAG alleles in pediatric patients than in adolescent/adults (p = 0.01). In patients carrying the A/C genotype, the frequencies of shorter and longer CAG alleles did not differ between pediatric patients and adolescent/adults (p>0.05). Patients with clitoromegaly had significantly lower weighted CAG biallelic mean than those without it: 19.1±2.7 and 21.6±2.5, respectively (p = 0.007), independent of the CYP21A2 genotype's severity. The SRD5A2 polymorphisms were not associated with the variability of hyperandrogenic NC phenotypes. CONCLUSIONS: In this series, we observed a modulatory effect of the CAG-AR tract on clinical manifestations of the NC form. Although the NC form is a monogenic disorder, our preliminary data suggested that the interindividual variability of the hyperandrogenic phenotype could arise from polygenic interactions.

Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction.

BACKGROUND: Most congenital adrenal hyperplasia (CAH) patients carry CYP21A2 mutations derived from conversion events involving the pseudogene, and the remaining carry new mutations. OBJECTIVE: To review causal mutations and genotype-phenotype correlation in 480 Brazilian patients. METHODS: DNA was extracted from 158 salt-wasters (SWs), 116 simple virilizing (SV), and 206 nonclassical (NC) patients. Fourteen point mutations were screened by allele-specific PCR, large rearrangements by Southern blotting/MLPA, and sequencing was performed in those with incomplete genotype. The gene founder effect was analyzed by microsatellite studies. Patients were divided into six genotypes (Null; A: <2%; B: 3-7%; C: >20% of residual enzymatic activity (EA); D: unknown EA; E: incomplete genotype). RESULTS: Targeted methodologies defined genotype in 87.6% of classical and in 80% of NC patients and the addition of sequencing in 100 and 83.5%, respectively. The most frequent mutations were p.V281L (26.6% of alleles), IVS2-13A/C>G (21.1%), and p.I172N (7.5%); seven rare mutations and one novel mutation (p.E351V) were identified. Gene founder effect was observed in all but one (p.W19X) mutation. Null, A, B, and C genotypes correlated with SW (88%), SW (70%), SV (98%), and NC forms (100%), respectively. In group D, the p.E351V mutation correlated with classical form and group E comprised exclusively NC-patients. ACTH-stimulated 17OHP level of 44.3ng/mL was the best cutoff to identify NC-patients carrying severe mutations. CONCLUSIONS: We identified a good genotype-phenotype correlation in CAH, providing useful data regarding prediction of disease's severity; moreover, we suggest that ACTH-stimulated 17OHP levels could predict carrier status for severe mutations. Sequencing is essential to optimize molecular diagnosis in Brazilian CAH patients.

Three novel mutations in CYP21 gene in Brazilian patients with the classical form of 21-hydroxylase deficiency due to a founder effect.

Three different new mutations were found after CYP21 gene sequencing in three unrelated patients with the classical form of the 21-hydroxylase deficiency. These mutations were also screened in their affected relatives. In one patient and her brother, both affected with the simple virilizing form and in their aunt, with the nonclassical form, an AG>GG transition was found in the acceptor site of intron 2. In another patient with the salt wasting form, we found a 1003 1004 insA, in exon 4, that altered the reading frame and created a stop codon in codon 297. In the third patient and his sister, we found a C>T transition in codon 408. This transition led to the substitution of arginine by cysteine (R408C) in a conserved region where arginine is conserved in at least four different species. These siblings with the R408C mutation, both affected with the salt wasting form, have the IVS2-13A/C>G mutation in the other allele, suggesting that the R408C should lead to complete impairment of enzymatic activity. To rule out the possibility of polymorphism, R408C was screened through allele specific PCR, and it was not found in 100 normal alleles. The screening of these three new mutations by allele-specific PCR or enzymatic restriction in 212 CAH patients disclosed their presence in 2.3% (9/387) of the alleles. All three new mutations were found in compound heterozygous state with previously known mutations. Microsatellite studies, using markers flanking CYP21 gene, revealed that each new mutation presents the same haplotype, suggesting a gene founder effect, similar to what was previously observed with the G424S mutation also described in our population. Although microconversion events are the main cause of mutations in the CYP21 gene, random mutations with a common origin can also be the cause of 21-hydroxylase deficiency.

Variable ACTH-stimulated 17-hydroxyprogesterone values in 21-hydroxylase deficiency carriers are not related to the different CYP21 gene mutations.

The currently used cutoff level for ACTH-stimulated 17- hydroxyprogesterone (17OHP) for the diagnosis of the nonclassical (NC) form of 21-hydroxylase deficiency (21OHD), established before molecular studies, is based on the mean + 2 SD of 17OHP levels of obligate heterozygotes. However, carriers of CYP21 mutations present variable ACTH-stimulated 17OHP levels, ranging from normal values up to 30 nmol/liter. The aim of this study was to determine whether ACTH-stimulated 17OHP levels in obligate carriers for 21OHD would be correlated with the impairment of the enzyme activity caused by these mutations, which would affect the 17OHP cutoff level for the diagnosis of the NC form. Fifty-nine parents of patients with the classical and NC forms of 21OHD had their DNA screened for the mutations found in the index case and were divided into three mutation groups according to the impairment of enzyme activity (A = 0%, B = 3%, and C > 20%). All parents carried mutations in one allele (29 of group A, 9 of group B, and 21 of group C). Blood samples were collected at baseline condition and 60 min after ACTH (250 microg i.v.) to measure 17OHP levels. The levels among groups A, B, and C were compared using the Kruskall Wallis test. ACTH-stimulated 17OHP levels identified 39% of the carriers (9 in group A, 2 in group B and 12 in group C). The mean +/- SD basal 17OHP levels in groups A, B, and C were: 2.94 +/- 1.89, 1.77 +/- 0.81 and 3.90 +/- 2.43 nmol/liter, respectively (P > 0.05) and for ACTH-stimulated levels were 12.6 +/- 7.2, 13.2 +/- 12.9 and 16.8 +/- 7.8 nmol/liter, respectively (P > 0.05). Two carriers presented ACTH-stimulated 17OHP levels between 30 and 45 nmol/liter and their entire CYP21 sequencing revealed only one mutation in heterozygous state indicating that the current cutoff level might overestimate the diagnosis of the NC form. We conclude that the variable ACTH-stimulated 17-OHP levels in carriers are not related to CYP21 gene mutations with different impairment of enzyme activity.

Influence of the A3669G Glucocorticoid Receptor Gene Polymorphism on the Metabolic Profile of Pediatric Patients with Congenital Adrenal Hyperplasia.

Background. Pediatric CAH patients have an increased risk of cardiovascular disease, and it remains unknown if genetic predisposition is a contributing factor. Glucocorticoid receptor gene (NR3C1) polymorphisms are associated with an adverse metabolic profile. Our aim was to analyze the association between the NR3C1 polymorphisms and the metabolic profile of pediatric CAH patients. Methods. Forty-one patients (26SW/15SV) received glucocorticoid (GC) replacement therapy to achieve normal androgen levels. Obesity was defined by BMI ≥ 95th percentile. NR3C1 alleles were genotyped, and association analyses with phenotype were done with Chi-square, t-test, and multivariate and regression analysis. Results. Obesity was observed in 31.7% of patients and was not correlated with GC doses and treatment duration. Z-score BMI was positively correlated with blood pressure, triglycerides, LDL-c levels, and HOMA-IR. NR3C1 polymorphisms, BclI and A3669G, were found in 23.1% and 9.7% of alleles, respectively. A3669G carriers presented higher LDL-c levels compared to wild-type subjects. BclI-carriers and noncarriers did not differ. Conclusion. Our results suggest that A3669G-polymorphism could be involved with a susceptibility to adverse lipid profile in pediatric CAH patients. This study provides new insight into the GR screening during CAH treatment, which could help to identify the subgroup of at-risk patients who would most benefit from preventive therapeutic action.

Mineralocorticoid replacement during infancy for salt wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

OBJECTIVE: The protocols for glucocorticoid replacement in children with salt wasting 21-hydroxylase deficiency are well established; however, the current recommendation for mineralocorticoid replacement is general and suggests individualized dose adjustments. This study aims to retrospectively review the 9-α-fludrocortisone dose regimen in salt wasting 21-hydroxylase deficient children who have been adequately treated during infancy. METHODS: Twenty-three salt wasting 21-hydroxylase deficient patients with good anthropometric and hormonal control were followed in our center since diagnosis. The assessments of cortisone acetate and 9-α-fludrocortisone doses, anthropometric parameters, and biochemical and hormonal levels were rigorously evaluated in pre-determined intervals from diagnosis to two years of age. RESULTS: The 9-α-fludrocortisone doses decreased over time during the first and second years of life; the median fludrocortisone doses were 200 µg at 0-6 months, 150 µg at 7-18 months and 125 µg at 19-24 months. The cortisone acetate dose per square meter was stable during follow-up (median = 16.8 mg/m²/day). The serum sodium, potassium and plasma rennin activity levels during treatment were normal, except in the first month of life, when periodic 9-α-fludrocortisone dose adjustments were made. CONCLUSIONS: The mineralocorticoid needs of salt wasting 21-hydroxylase deficient patients are greater during early infancy and progressively decrease during the first two years of life, which confirms that a partial aldosterone resistance exists during this time. Our study proposes a safety regiment for mineralocorticoid replacement during this critical developmental period.

Obesity and familial predisposition are significant determining factors of an adverse metabolic profile in young patients with congenital adrenal hyperplasia.

BACKGROUND/AIMS: Glucocorticoid (GC) therapy is known to predispose to an adverse metabolic profile. Therefore, we investigated the prevalence of obesity and metabolic syndrome (MetS) in young patients with congenital adrenal hyperplasia (CAH) and to correlate this prevalence with GC treatment and family history. METHODS: The study population consisted of 33 young CAH patients who received cortisone acetate during their growth periods; those who were salt wasters also received fludrocortisone. Obesity was defined by a body mass index (BMI) >95th percentile and MetS by the National Cholesterol Education Program Third Adult Treatment Panel modified criteria. Each patient's familial history of MetS components was assessed. The impact of GC therapy on the metabolic profile was analyzed by comparing CAH patients with BMI z-score-matched controls. RESULTS: MetS and obesity were observed in 12.1 and 30.3% of the CAH patients, respectively, both of which were higher than in the reference population. A positive family history of MetS was found to be more prevalent in the obese patients compared with the nonobese CAH patients, and similar findings were observed for the controls. The metabolic profile did not differ between the CAH patients and matched subjects. CONCLUSION: CAH patients presented a higher prevalence of obesity and MetS, which were not correlated with the GC treatment. This study suggests that obesity and familial predisposition are significant determining factors for an adverse metabolic profile in CAH patients.

Mineralocorticoid replacement during infancy for salt wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency

OBJECTIVE: The protocols for glucocorticoid replacement in children with salt wasting 21-hydroxylase deficiency are well established; however, the current recommendation for mineralocorticoid replacement is general and suggests individualized dose adjustments. This study aims to retrospectively review the 9-∝-fludrocortisone dose regimen in salt wasting 21-hydroxylase deficient children who have been adequately treated during infancy. METHODS: Twenty-three salt wasting 21-hydroxylase deficient patients with good anthropometric and hormonal control were followed in our center since diagnosis. The assessments of cortisone acetate and 9-∝-fludrocortisone doses, anthropometric parameters, and biochemical and hormonal levels were rigorously evaluated in pre-determined intervals from diagnosis to two years of age. RESULTS: The 9-∝-fludrocortisone doses decreased over time during the first and second years of life; the median fludrocortisone doses were 200 µg at 0-6 months, 150 µg at 7-18 months and 125 µg at 19-24 months. The cortisone acetate dose per square meter was stable during follow-up (median = 16.8 mg/m²/day). The serum sodium, potassium and plasma rennin activity levels during treatment were normal, except in the first month of life, when periodic 9-∝-fludrocortisone dose adjustments were made. CONCLUSIONS: The mineralocorticoid needs of salt wasting 21-hydroxylase deficient patients are greater during early infancy and progressively decrease during the first two years of life, which confirms that a partial aldosterone resistance exists during this time. Our study proposes a safety regiment for mineralocorticoid replacement during this critical developmental period.

Substitutions in the CYP21A2 promoter explain the simple-virilizing form of 21-hydroxylase deficiency in patients harbouring a P30L mutation.

The classical and nonclassical phenotypes of 21-hydroxylase deficiency represent a continuous spectrum of the impairment of 21-hydroxylase activity due to mutations between the CYP21A2 gene. These mutations occur mainly by microconversion in the homologous nonfunctional CYP21A1P gene. The P30L mutation is associated with the nonclassical form, and it reduces the activity to 30-40% of the normal enzyme. We have described three female patients exhibiting a simple virilizing phenotype and bearing the P30L mutation in compound heterozygosis with a severe mutation. To identify additional mutations causing this phenotype, the promoter region was sequenced and four mutations were identified: -126C --> T, -113G --> A, -110T --> C and -103 A --> G. These substitutions are normally present in the promoter region of the pseudogene and in vitro studies demonstrated that they reduced the transcriptional activity fivefold. They might have been converted to the CYP21A2 promoter together with the P30L mutation in these patients. Therefore, these substitutions in synergism with the P30L mutation might decrease the enzyme activity resulting in a more severe phenotype, and a DNA sequence of -167 bases of the CYP21A2 gene should be performed in patients with 21-hydroxylase deficiency in whom the phenotype is more severe than predicted by the genotype.

Anatomical and functional outcomes of feminizing genitoplasty for ambiguous genitalia in patients with virilizing congenital adrenal hyperplasia

OBJETIVO: Apresentar um estudo retrospectivo sobre os resultados cosméticos e funcionais da genitoplastia feminizante em pacientes com hiperplasia adrenal congênita virilizante. MÉTODOS: Trinta e quatro pacientes com idade média de 3,35 ± 2,5 anos com ambigüidade genital classificada de acordo com os estádios de Prader foram selecionados. O seguimento pós-operatório foi de 2 a 16 anos. O tamanho do clitóris variou de 1,9 a 5,0 cm; 28 pacientes tinham orifício único perineal e 6 tinham dois orifícios. A técnica cirúrgica incluiu clitorovaginoplastia em tempo único e foi realizada antes dos dois anos de idade em 18 pacientes. A clitoroplastia preservou a glande, a qual teve seu suprimento sanguíneo mantido em 97% dos casos pela mucosa do freio e no demais casos com a manutenção do feixe vasculo-nervoso dorsal. Duas técnicas foram utilizadas para a ampliação do seio urogenital: o retalho perineal em "Y-V" em 25 pacientes e a incisão longitudinal posterior em 8 pacientes.RESULTADOS: As complicações cirúrgicas ocorreram em 20,5% dos casos: sangramento, necrose da glande e estenose vaginal. Foram necessárias dilatações vaginais com moldes de acrílico no período pós puberal em 3 das pacientes com estenose, com bons resultados funcionais. CONCLUSÃO: As técnicas utilizadas seguidas pelas dilatações, permitiram bons resultados cosméticos e funcionais em 67% dos casos apresentando poucas complicações e evitando a necessidade de neovagina inclusive nos pacientes com inserção alta do intróito vaginal.

Tratamento da hiperplasia supra-renal congênita por deficiência da 21-hidroxilase / Treatment of congenital adrenal hyperplasia by 21-hydroxylase deficiency

O tratmento da hiperplasia supra-renal congênita por deficiência da 21-hidroxilase (HSRC-21 OH) tem como objetivos repor glico e mineralocorticóides, ecitar a virilizaçäo dos genitais externos, prevenir a desidratacao por perda de sal, controlar o hiperandrogenismo sem afetar a velocidade d crescimento, preservar a funçäo gonadal, fertilidade e estatura final. Relatamos a nossa experiência no acompanhamento de 96 pacientes com HSRC-21OH. nas crianças utilizamos como glicocorticóide o acetato de cortisona (18-20 mg/m2/dia) e nos adultos a dexametasona (0,25-0,75 mg/dia). quando necessário, a reposiçäo do mineralocorticóide foi feita com 9 alfa-fluor-hidrocortisona50-250µg/dia dependendo da faiza etária. Apesar da substiruiçäo adequadacom glico e/ou minerolocorticides o resultado final do tratamento da HSRC-21OH ainda deixa a desejar, principalmente em relaçäo ao crescimento, já que a estatura final na maior parte das caduísticas está entre -1 e -2 DP em relaçäo a estatura alvo. Novas terapêuticas da HSRC-21OH, como a associaçäo de hidrocortisona, fludocortisona , flutamida e tstolactona ou a supra rrenalectomia cirúrgica, ainda estäo em fase experimental e a evoluçäo a longo prazo é necessária para avaliar seu real efeito.