The impact of neonatal 17-hydroxyprogesterone cutoff determination in a public newborn screening program for congenital adrenal hyperplasia in Southern Brazil: 3 years' experience.

Congenital adrenal hyperplasia (CAH) occurs due to enzyme defects in adrenal steroidogenesis. The 21-hydroxylase deficiency accounts for 90-95% of cases, triggering accumulation of 17-hydroxyprogesterone (17-OHP). Early diagnosis through neonatal screening allows adequate treatment and reduced mortality. The purpose of the study was to determine 17-OHP cutoffs for the diagnosis of CAH in a public newborn screening program in Southern Brazil. A retrospective, descriptive, cross-sectional study was conducted to analyze 17-OHP levels in dried blood samples collected on filter paper of 317,745 newborns screened at a public newborn screening center from May 2014 to April 2017. Neonatal 17-OHP was measured in DBS samples using a time-resolved fluoroimmunoassay (GSP® kit 3305-0010; PerkinElmer). Different cutoffs were determined and stratified by birth weight. The incidence of CAH was 1:15,887 live births in the state of Rio Grande do Sul, with 20 cases of classical CAH diagnosed during the study period. Most newborns (80.73%) were white, and the prematurity rate was 9.8% in the study population. The combination of different percentiles, 98.5th for birth weight 2001-2500 g and 99.8th for the other birth weight groups, decreased false-positive results and increased specificity compared with current reference values to identify classical CAH cases. The local 17-OHP cutoffs determined were higher than those currently used by this screening program for all birth weight groups. The calculation of reference values from local population data and the combination of percentiles proved to be a valuable tool for proper diagnosis of CAH and reduction in the number of false positives.

Epidemiological profile of congenital hypothyroidism at a southern Brazilian state.

Objective: To determine the incidence of congenital hypothyroidism (CH) over a 10-year period at the Reference Service in Neonatal Screening of the state of Rio Grande do Sul (RSNS-RS). Subjects and methods: Historical cohort study including all newborns screened for CH by the RSNS-RS from January 2008 until December 2017. Data of all newborns with neonatal TSH (neoTSH; heel prick test) values ≥ 9 mIU/L were collected. According to neoTSH values, the newborns were allocated into two groups: Group 1 (G1), comprising newborns with neoTSH ≥ 9 mIU/L and serum TSH (sTSH) < 10 mIU/L, and Group 2 (G2), comprising those with neoTSH ≥ 9 mIU/L and sTSH ≥ 10 mIU/L. Results: Of 1,043,565 newborns screened, 829 (0.08%) had neoTSH values ≥ 9 mIU/L. Of these, 284 (39.3%) had sTSH values < 10 mIU/L and were allocated to the G1 group, while 439 (60.7%) had sTSH ≥ 10 mIU/L and were allocated to the G2 group, and 106 (12.7%) were considered missing data. The overall incidence of CH was 42.1 per 100,000 newborns screened (95% confidence interval [CI] 38.5-45.7/100,000) or 1:2377 screened newborns. The sensibility and specificity of neoTSH ≥ 9 mIU/L were 97% and 11%; of neoTSH 12.6 mUI/L, 73% and 85% respectively. Conclusion: In this population, the incidence of permanent and transitory CH was 1:2377 screened newborns. The neoTSH cutoff value adopted during the study period showed excellent sensibility, which matters for a screening test.

Epidemiological profile of congenital hypothyroidism at a southern Brazilian state

ABSTRACT Objective: To determine the incidence of congenital hypothyroidism (CH) over a 10-year period at the Reference Service in Neonatal Screening of the state of Rio Grande do Sul (RSNS-RS). Subjects and methods: Historical cohort study including all newborns screened for CH by the RSNS-RS from January 2008 until December 2017. Data of all newborns with neonatal TSH (neoTSH; heel prick test) values ≥ 9 mIU/L were collected. According to neoTSH values, the newborns were allocated into two groups: Group 1 (G1), comprising newborns with neoTSH ≥ 9 mIU/L and serum TSH (sTSH) < 10 mIU/L, and Group 2 (G2), comprising those with neoTSH ≥ 9 mIU/L and sTSH ≥ 10 mIU/L. Results: Of 1,043,565 newborns screened, 829 (0.08%) had neoTSH values ≥ 9 mIU/L. Of these, 284 (39.3%) had sTSH values < 10 mIU/L and were allocated to the G1 group, while 439 (60.7%) had sTSH ≥ 10 mIU/L and were allocated to the G2 group, and 106 (12.7%) were considered missing data. The overall incidence of CH was 42.1 per 100,000 newborns screened (95% confidence interval [CI] 38.5-45.7/100,000) or 1:2377 screened newborns. The sensibility and specificity of neoTSH ≥ 9 mIU/L were 97% and 11%; of neoTSH 12.6 mUI/L, 73% and 85% respectively. Conclusion: In this population, the incidence of permanent and transitory CH was 1:2377 screened newborns. The neoTSH cutoff value adopted during the study period showed excellent sensibility, which matters for a screening test.

Accuracy of Doppler assessment of the uterine arteries in healthy girls for the diagnosis of pubertal onset.

PURPOSE: To evaluate the accuracy of the uterine artery pulsatility index (PI) for the diagnosis of pubertal onset in girls. METHODS: Cross-sectional study of girls with normal pubertal development. Puberty was diagnosed by the presence of Tanner breast development score ≥2. All girls underwent pelvic ultrasound and Doppler imaging of the uterine arteries. We evaluated the uterine artery PI and uterine, endometrial, and ovarian measurements. We used ROC curves with cutoffs determined by Youden index for data analysis. RESULTS: We included 169 girls aged 5-16 years who underwent 202 pelvic ultrasound examinations. Prepubertal girls had a significantly higher mean PI (6.70 ± 2.15) than girls in initial puberty (4.14 ± 1.55) and in late puberty (2.81 ± 1.05) (P < 0.001 for all comparisons), which reflects a progressive increase in blood flow to the uterus with the progression of puberty. ROC curve analysis showed that the PI was able to identify the onset of puberty with a mean area under the curve of 0.838 ± 0.04 (P < 0.001), and the PI cutoff point of 5.05 had a sensitivity of 77%, specificity of 85%, positive predictive value (PPV) of 92%, and accuracy of 79%. The combination of PI < 5.05 plus uterine volume >3.75 cm³ had a sensitivity of 73%, specificity of 95%, PPV of 97%, and accuracy of 79% to detect initial puberty. CONCLUSIONS: We found a significant reduction in the PI during pubertal development, which can possibly be a valuable noninvasive tool in the evaluation of pubertal disorders, alone or in combination with uterine and ovarian volumes.

Newest Diabetes-Related Technologies for Pediatric Type 1 Diabetes and Its Impact on Routine Care: a Narrative Synthesis of the Literature.

Purpose of Review: This review aims to address the actual state of the most advanced diabetes devices, as follows: continuous subcutaneous insulin infusions (CSII), continuous glucose monitoring systems (CGM), hybrid-closed loop (HCL) systems, and "Do-it-yourself" Artificial Pancreas Systems (DIYAPS) in children, adolescents, and young adults. This review has also the objective to assess the use of telemedicine for diabetes care across three different areas: education, social media, and daily care. Recent Findings: Recent advances in diabetes technology after integration of CSII with CGM have increased the popularity of this treatment modality in pediatric age and shifted the standard diabetes management in many countries. We found an impressive transition from the use of CSII and/or CGM only to integrative devices with automated delivery systems. Although much has changed over the past 5 years, including a pandemic period that precipitated a broader use of telemedicine in diabetes care, some advances in technology may still be an additional burden of care for providers, patients, and caregivers. The extent of a higher rate of "auto-mode" use in diabetes devices while using the HCL/DIYAPS is essential to reduce the burden of diabetes treatment. Summary: More studies including higher-risk populations are needed, and efforts should be taken to ensure proper access to cost-effective advanced technology on diabetes care. Supplementary Information: The online version contains supplementary material available at 10.1007/s40124-021-00248-7.

Characterization of Mutations Causing CYP21A2 Deficiency in Brazilian and Portuguese Populations.

Deficiency of 21-hydroxylase enzyme (CYP21A2) represents 90% of cases in congenital adrenal hyperplasia (CAH), an autosomal recessive disease caused by defects in cortisol biosynthesis. Computational prediction and functional studies are often the only way to classify variants to understand the links to disease-causing effects. Here we investigated the pathogenicity of uncharacterized variants in the CYP21A2 gene reported in Brazilian and Portuguese populations. Physicochemical alterations, residue conservation, and effect on protein structure were accessed by computational analysis. The enzymatic performance was obtained by functional assay with the wild-type and mutant CYP21A2 proteins expressed in HEK293 cells. Computational analysis showed that p.W202R, p.E352V, and p.R484L have severely impaired the protein structure, while p.P35L, p.L199P, and p.P433L have moderate effects. The p.W202R, p.E352V, p.P433L, and p.R484L variants showed residual 21OH activity consistent with the simple virilizing phenotype. The p.P35L and p.L199P variants showed partial 21OH efficiency associated with the non-classical phenotype. Additionally, p.W202R, p.E352V, and p.R484L also modified the protein expression level. We have determined how the selected CYP21A2 gene mutations affect the 21OH activity through structural and activity alteration contributing to the future diagnosis and management of CYP21A2 deficiency.

Telemedicine: a Bridge Over Knowledge Gaps in Healthcare.

PURPOSE OF THE REVIEW: The purpose of the review is to describe the Brazilian Telemedicine University Network RUTE concerning the Special Interest Group of Children and Adolescents, the new SIG-COVID19-BR activities for continuing medical education, and to update relevant information regarding diagnosis and treatment, using digital technologies. RECENT FINDINGS: A total of 145 sessions of video and webconferences were held with the participation of 6575 health professionals, including medical students, interns, and residents. Major topics involved the healthcare of children and adolescents were combined with the emergence of a new pandemic plus the need to decrease the professional knowledge gaps in geographically distant hospitals. SUMMARY: Telemedicine is a cost-effective tool and a bridge to decrease health disparities access for proper care and assistance for any population. RUTE is a Brazilian model of telemedicine which has a positive impact attracting the participation of health professionals, and even more so, during the Covid-19 virus pandemic outbreak.

Ophthalmologic Impairment and Intellectual Disability in a Girl Presenting Kenny-Caffey Syndrome Type 2.

Kenny-Caffey syndrome (KCS) is a rare genetic condition characterized by growth retardation, bone abnormalities, and hypoparathyroidism. Herein, we report an unusual case of a 10-year-old girl with Kenny-Caffey syndrome type 2 (KCS2) presenting with vision impairment-suspected maculopathy and intellectual disability. Endocrine evaluation showed low calcium and high phosphorus plasma levels. Radiographic evaluation revealed short metacarpal bones and delayed bone age. Sequencing analysis showed a missense variant in FAM111A (R569H), unidentified in her parents. Better understanding of potential neurological and ophthalmological findings in KCS2 patients is important to improve quality of life of these patients as usually they exhibit long survival.

Clinical and molecular profile of newborns with confirmed or suspicious congenital adrenal hyperplasia detected after a public screening program implementation / Perfil clínico e molecular de recém-nascidos com suspeita ou confirmação de hiperplasia adrenal congênita após a implementação de um programa público de triagem neonatal

Abstract Objective: To describe the results obtained in a neonatal screening program after its implementation and to assess the clinical and molecular profiles of confirmed and suspicious congenital adrenal hyperplasia cases. Methods: A cross-sectional study was conducted. Newborns with suspected disease due to high 17-hydroxyprogesterone levels and adjusted for birth weight were selected. Classical congenital adrenal hyperplasia (salt-wasting and simple virilizing forms) was diagnosed by an increase in 17-hydroxyprogesterone levels as confirmed in the retest, clinical evaluation, and genotype determined by SNaPshot and multiplex ligation-dependent probe amplification. Results: After 24 months, 15 classic congenital adrenal hyperplasia cases were diagnosed in a total of 217,965 newborns, with an estimated incidence of 1:14,531. From 132 patients, seven non-classical and 14 heterozygous patients were screened for CYP21A2 mutations, and 96 patients presented false positives with wild type CYP21A2. On retest, increased 17-hydroxyprogesterone levels were found in classical congenital adrenal hyperplasia patients and showed significant correlation with genotype-related classical genital adrenal hyperplasia. The most frequent mutations were IVS2-13A/C>G followed by gene deletion or rearrangement events in the classical form. In non-classical and heterozygous diseases, p.Val282Leu was the most common mutation. Conclusions: The results underscore the effectiveness of congenital adrenal hyperplasia neonatal screening in the public health system and indicate that the adopted strategy was appropriate. The second sample collection along with genotyping of suspected cases helped to properly diagnose both severe and milder cases and delineate them from false positive patients.

Resumo Objetivo: Descrever os resultados obtidos em um programa de triagem neonatal após sua implementação e avaliar os perfis clínicos e moleculares de casos confirmados e suspeitos de hiperplasia adrenal congênita. Métodos: Foi feito um estudo transversal. Recém-nascidos com suspeita da doença devido aos altos níveis de 17-alfa-hidroxiprogesterona e ajustados pelo peso ao nascer foram selecionados. A hiperplasia adrenal congênita clássica (forma perdedora de sal e forma virilizante simples) foi diagnosticada por um aumento nos níveis de 17-alfa-hidroxiprogesterona confirmado no reteste, avaliação clínica e genótipo determinado com o uso do ensaio SNaPshot e amplificação multiplex de sondas dependente de ligação. Resultados: Após 24 meses, 15 casos clássicos de hiperplasia adrenal congênita foram diagnosticados em 217.965 recém-nascidos, com uma incidência estimada de 1:14.531. De 132 pacientes, sete não clássicos e 14 heterozigotos foram submetidos à triagem para mutações no gene CYP21A2 e 96 pacientes apresentaram resultados falso-positivos com CYP21A2 do tipo selvagem. No reteste, níveis aumentados de 17-alfa-hidroxiprogesterona foram encontrados em pacientes com hiperplasia adrenal congênita clássica e mostraram correlação significativa com HAC clássica relacionada ao genótipo. As mutações mais frequentes foram IVS2-13A/C>G, seguidas de deleção gênica ou eventos de rearranjo na forma clássica. Em casos de doenças não clássicas e heterozigose, a mutação p.Val282Leu foi a mais comum. Conclusões: Os resultados ressaltam a eficácia da triagem neonatal para a hiperplasia adrenal congênita no sistema público de saúde e indicam que a estratégia adotada foi adequada. A segunda coleta de amostras, juntamente com a genotipagem dos casos suspeitos, ajudou a diagnosticar adequadamente os casos graves e mais leves e diferenciá-los de pacientes com resultado falso-positivo.

Clinical and molecular profile of newborns with confirmed or suspicious congenital adrenal hyperplasia detected after a public screening program implementation.

OBJECTIVE: To describe the results obtained in a neonatal screening program after its implementation and to assess the clinical and molecular profiles of confirmed and suspicious congenital adrenal hyperplasia cases. METHODS: A cross-sectional study was conducted. Newborns with suspected disease due to high 17-hydroxyprogesterone levels and adjusted for birth weight were selected. Classical congenital adrenal hyperplasia (salt-wasting and simple virilizing forms) was diagnosed by an increase in 17-hydroxyprogesterone levels as confirmed in the retest, clinical evaluation, and genotype determined by SNaPshot and multiplex ligation-dependent probe amplification. RESULTS: After 24 months, 15 classic congenital adrenal hyperplasia cases were diagnosed in a total of 217,965 newborns, with an estimated incidence of 1:14,531. From 132 patients, seven non-classical and 14 heterozygous patients were screened for CYP21A2 mutations, and 96 patients presented false positives with wild type CYP21A2. On retest, increased 17-hydroxyprogesterone levels were found in classical congenital adrenal hyperplasia patients and showed significant correlation with genotype-related classical genital adrenal hyperplasia. The most frequent mutations were IVS2-13A/C>G followed by gene deletion or rearrangement events in the classical form. In non-classical and heterozygous diseases, p.Val282Leu was the most common mutation. CONCLUSIONS: The results underscore the effectiveness of congenital adrenal hyperplasia neonatal screening in the public health system and indicate that the adopted strategy was appropriate. The second sample collection along with genotyping of suspected cases helped to properly diagnose both severe and milder cases and delineate them from false positive patients.

Development of CYP21A2 Genotyping Assay for the Diagnosis of Congenital Adrenal Hyperplasia.

BACKGROUND: Steroid 21-hydroxylase deficiency due to CYP21A2 gene mutations represents more than 90% of all congenital adrenal hyperplasia cases. This deficiency is screened by measuring levels of 17-hydroxyprogesterone, which may vary, causing false positive or false negative results. In order to assist the diagnosis, molecular methodologies have been employed. This work aimed to perform genotyping assays to detect mutations in the CYP21A2 gene and compare the findings with other population studies. METHODS: The SNaPshot assay was developed to simultaneously detect 12 frequent point mutations in the CYP21A2 gene (p.Arg409Cys, p.Gln319Ter, p.Arg357Trp, p.Leu308PhefsTer6, p.Val237Glu, IVS2-13A/C > G, p.Ile173Asn, p.Pro31Leu, p.Pro454Ser, p.Val282Leu, p.Gly111ValfsTer21 and p.His63Leu). The direct sequencing and multiplex ligation-dependent probe amplification assays were used to confirm point mutations present in the developed method. The latter was also used to search large deletions and gene conversion, complementing the investigation. A total of 166 cases were studied. RESULTS: The SNaPshot assay was successfully developed to detect the 12 mutations. The results of mutation analysis indicated 84 pathogenic alleles in 48 cases, with p.Val282Leu (27.1%) and IVS2-13A/C > G (20.8%) being the most frequently found mutations. Between the findings of this study and those of other South American studies, there were significant differences in frequency for p.Pro31Leu and p.Val282Leu (p < 0.001). A new variant T in IVS2-13A/C > G was identified in two patients via the SNaPshot assay. CONCLUSION: The molecular strategy developed for CYP21A2 gene mutation screening allowed us to detect the principle mutations described around the world. Furthermore, the first Southern Brazilian mutation frequencies concerning the CYP21A2 gene were obtained.

Short stature, unusual face, delta phalanx, and abnormal vertebrae and ribs in a girl born to half-siblings.

Delta phalanx is a rare abnormality typically associated with additional features. We describe a patient with a phenotype resembling Catel-Manzke syndrome, but with delta phalanx and abnormal vertebrae and ribs. The patient was the only child of half siblings born with a marked prenatal growth deficiency. At 10 years of age, she had a short stature, long face, long and tubular nose with small alae nasi, high palate, short and broad thorax, and short index fingers with radial deviation. There were hyperpigmentations following Blaschko's lines. Radiology showed a proximal delta phalanx in the index finger of hands, abnormal vertebrae, and fused and small ribs. GTG-Banding karyotype and microarray analysis yielded normal results. Exome sequencing identified 25 genes that harbored homozygous variants, but none of these is assumed to be a good candidate to explain (part of) the phenotype. The here described patient may have a new condition, possibly following an autosomal recessive pattern of inheritance, although due to the high degree of consanguinity a compound etiology of the phenotype by variants in various genes may be present as well.

Neonatal screening for congenital adrenal hyperplasia in Southern Brazil: a population based study with 108,409 infants.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder associated with inborn errors of steroid metabolism. 21-hydroxylase enzyme deficiency occurs in 90 to 95% of all cases of CAH, with accumulation of 17 hydroxyprogesterone (17-OHP). Early diagnosis of CAH based on newborn screening is possible before the development of symptoms and allows proper treatment, correct sex assignment, and reduced mortality rates. This study describes the results obtained in the first year of a public CAH screening program in the state of Rio Grande do Sul, Brazil. METHODS: We reviewed the screening database in search of babies with suspected CAH, that is, altered birth-weight adjusted 17-OHP values at screening. The following data were analyzed for this population: screening 17-OHP values, retest 17-OHP values, serum 17-OHP values for those with confirmed CAH on retest, maternal and newborn data, and family history of CAH. For the screening program, 17-OHP levels are determined on dried blood spots obtained in filter paper with GSP solid phase time-resolved immunofluorescence. RESULTS: Of 108,409 newborns screened, eight were diagnosed with CAH (four males, four females). The incidence of CAH in the state was 1:13,551. Six cases were identified as classic salt-wasting CAH and two were cases of virilizing CAH. The positive predictive value (PPV) of the initial screening (before diagnostic confirmation) was 1.6%. The overall rate of false positive results was 0.47%. The number of false positive results was higher among newborns with birth weight < 2000 g. CONCLUSION: The present results support the need for CAH screening by the public health care system in the state, and show that the strategy adopted is adequate. PPV and false positive results were similar to those reported for other states of Brazil with similar ethnic backgrounds.

Central precocious puberty: revisiting the diagnosis and therapeutic management.

Clinical and laboratory diagnosis and treatment of central precocious puberty (CPP) remain challenging due to lack of standardization. The aim of this revision was to address the diagnostic and therapeutic features of CPP in Brazil based on relevant international literature and availability of the existing therapies in the country. The diagnosis of CPP is based mainly on clinical and biochemical parameters, and a period of follow-up is desirable to define the "progressive" form of sexual precocity. This occurs due to the broad spectrum of pubertal development, including isolated premature thelarche, constitutional growth and puberty acceleration, progressive and nonprogressive CPP, and early puberty. Measurement of basal and stimulated LH levels remains challenging, considering that the levels are not always in the pubertal range at baseline, short-acting GnRH is not readily available in Brazil, and the cutoff values differ according to the laboratory assay. When CPP is suspected but basal LH values are at prepubertal range, a stimulation test with short-acting or long-acting monthly GnRH is a diagnostic option. In Brazil, the treatment of choice for progressive CPP and early puberty is a long-acting GnRH analog (GnRHa) administered once a month or every 3 months. In Brazil, formulations of GnRHa (leuprorelin and triptorelin) are available and commonly administered, including 1-month depot leuprorelin 3.75 mg and 7.5 mg, 1-month depot triptorelin 3.75 mg, and 3-month depot leuprorelin 11.25 mg. Monthly or 3-month depot GnRHa are effective and safe to treat CPP. Arch Endocrinol Metab. 2016;60(2):163-72.

Central precocious puberty: revisiting the diagnosis and therapeutic management

ABSTRACT Clinical and laboratory diagnosis and treatment of central precocious puberty (CPP) remain challenging due to lack of standardization. The aim of this revision was to address the diagnostic and therapeutic features of CPP in Brazil based on relevant international literature and availability of the existing therapies in the country. The diagnosis of CPP is based mainly on clinical and biochemical parameters, and a period of follow-up is desirable to define the “progressive” form of sexual precocity. This occurs due to the broad spectrum of pubertal development, including isolated premature thelarche, constitutional growth and puberty acceleration, progressive and nonprogressive CPP, and early puberty. Measurement of basal and stimulated LH levels remains challenging, considering that the levels are not always in the pubertal range at baseline, short-acting GnRH is not readily available in Brazil, and the cutoff values differ according to the laboratory assay. When CPP is suspected but basal LH values are at prepubertal range, a stimulation test with short-acting or long-acting monthly GnRH is a diagnostic option. In Brazil, the treatment of choice for progressive CPP and early puberty is a long-acting GnRH analog (GnRHa) administered once a month or every 3 months. In Brazil, formulations of GnRHa (leuprorelin and triptorelin) are available and commonly administered, including 1-month depot leuprorelin 3.75 mg and 7.5 mg, 1-month depot triptorelin 3.75 mg, and 3-month depot leuprorelin 11.25 mg. Monthly or 3-month depot GnRHa are effective and safe to treat CPP. Arch Endocrinol Metab. 2016;60(2):163-72.

Diabetes insípido na infância: importância do diagnóstico diferencial / Diabetes Insipidus in children: the importance of a differential diagnosis

O diabetes insipidus (DI) é uma síndrome clínica caracterizada por poliúria e polidipsia, que pode decorrer de uma deficiência de hormô- nio antidiurético (DI central) ou de uma insensibilidade renal ao hormônio (DI nefrogênica). Os autores relatam o caso de paciente do sexo masculino, de 3 anos e 10 meses de idade, que apresentou quadro clínico e exames complementares sugestivos de diabetes insipidus, e discutem a epidemiologia, apresentação clínica e diagnóstico desta doença (AU)

Diabetes insipidus (DI) is a clinical syndrome characterized by polyuria and polydipsia, which may result from a deficiency of antidiuretic hormone (central DI) or a renal insensitivity to the hormone (nephrogenic DI). The authors report the case of a male patient, 3 years and 10 months of age, who presented clinical and complementary tests suggestive of diabetes insipidus, and discuss the epidemiology, clinical presentation and diagnosis of this disease (AU)

Bone mineral density in girls with classical congenital adrenal hyperplasia due to CYP21 deficiency.

AIM: To verify possible associations among glucocorticoid doses, use of dexamethasone, and bone mineral density (BMD), measured by dual X-ray absorptiometry (DXA) and quantitative computed tomography (QCT), in female children with congenital adrenal hyperplasia due to CYP21 deficiency (CAH-CYP21). Classical CAH-CYP21 in females allows the study of the effects of hyperandrogenism and chronic glucocorticoid exposure. DESIGN: Cross-sectional observational study. PATIENTS: Sixteen girls (4-19 years) with CAH-CYP21 and 32 age-matched control girls. MEASUREMENTS: BMD was the main outcome measure assessed by total body and lumbar spine L1-L4 DXA (DXAtot and DXAIs), lumbar spine L1-L4 bone mineral apparent density (BMAD) and spinal L1-L4 QCT of trabecular (QCTtrab) and cortical (QCTcort) bone. The glucocorticoid dose used by patients with CAH-CYP21 was expressed as hydrocortisone equivalents/m2. RESULTS: Mean BMD in both groups was similar by any method. In patients, BMD decreased with the increasing mean dose of glucocorticoid, seen in QCTcort (r = -0.55; p = 0.03) and QCTtrab (r = -0.52; p = 0.04). There was also a negative correlation between cumulative glucocorticoid dose and BMD in QCTcort (beta = -0.0016; p = 0.005) and QCTtrab (beta = -0.0009; p = 0.03). CONCLUSIONS: The dose of glucocorticoid used in the treatment of girls with CAH-CYP21 correlated negatively with BMD, and dexamethasone was not selectively harmful.