Association of androgen excess and bone mineral density in women with classical congenital adrenal hyperplasia with 21-hydroxylase deficiency.

The relationship between androgen excess and bone health in patients with congenital adrenal hyperplasia (CAH) with 21-hydroxylase (21-OH) deficiency is not fully understood. This study demonstrated positive correlations between androgen hormones and bone mineral density (BMD) in CAH women with 21-OH deficiency. PURPOSE: This study aims to assess BMD and its association with androgen excess in women with CAH. METHODS: We enrolled 92 women with CAH with 21-OH deficiency and retrospectively reviewed their clinical features, hormone concentrations, body composition, glucocorticoid (GC) dose, and BMD. RESULTS: BMD was not different according to the subtypes of CAH. BMD at the lumbar spine was lower in women with CAH with regular menstruation than those with irregular menstruation (1.081 vs. 1.165 g/cm2, P < 0.05). BMD was lower in women with CAH with 17-hydroxyprogesterone (17-OHP) < 10 ng/mL than in those with ≥ 10 ng/mL (lumbar spine, 1.019 vs. 1.150 g/cm2; femur neck, 0.806 vs. 0.899 g/cm2; total hip, 0.795 vs. 0.943 g/cm2; all P < 0.05). After adjusting for age and BMI in correlation analyses, testosterone concentrations were positively correlated with lumbar spine, femur neck, and total hip BMD (r = 0.46, r = 0.38, and r = 0.35, respectively; all P < 0.05), while 17-OHP was positively correlated with lumbar spine BMD (r = 0.38, P < 0.01). In subgroup analysis, 17-OHP was positively correlated with BMD (lumbar spine, r = 0.22; femur neck, r = 0.22; total hip, r = 0.24; all P < 0.05) only in the group with a total cumulative dose of GC ≥ 156.0 g/m2. CONCLUSION: Androgen excess may have a protective effect on BMD in women with classic CAH and high cumulative doses of GC.

Epidemiology and Long-Term Adverse Outcomes in Korean Patients with Congenital Adrenal Hyperplasia: A Nationwide Study.

BACKGROUND: Previous studies on the epidemiology and complications of congenital adrenal hyperplasia (CAH) were conducted in Western countries and in children/adolescents. We aimed to explore the epidemiology of CAH, as well as the risk of comorbidities and mortality, in a Korean nationwide case-control study. METHODS: CAH patients (n=2,840) were included between 2002 and 2017 from the National Health Insurance Service database and the Rare Intractable Disease program. CAH patients were compared, at a 1:10 ratio, with age-, sex-, and index year-matched controls (n=28,400). RESULTS: The point prevalence of CAH patients in Korea was 1 in 18,745 persons in 2017. The annual incidence rate declined between 2003 and 2017 from 3.25 to 0.41 per 100,000 persons. CAH patients were at elevated risk for cardiovascular disease (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.4 to 1.9), stroke (OR, 1.7; 95% CI, 1.3 to 2.0), diabetes mellitus (OR, 2.8; 95% CI, 2.6 to 3.1), dyslipidemia (OR, 2.4; 95% CI, 2.2 to 2.6), and psychiatric disorders (OR, 1.5; 95% CI, 1.3 to 1.6). Fracture risk increased in CAH patients aged over 40 years (OR, 1.4; 95% CI, 1.1 to 1.7). CAH patients were at higher risk of mortality than controls (hazard ratio, 1.6; 95% CI, 1.3 to 2.0). CONCLUSION: Our nationwide study showed a recent decline in the incidence of CAH and an elevated risk for cardiovascular, metabolic, skeletal, and psychiatric disorders in CAH patients. Lifelong management for comorbidity risk is a crucial component of treating CAH patients.

Adrenal Morphology as an Indicator of Long-Term Disease Control in Adults with Classic 21-Hydroxylase Deficiency.

BACKGROUND: Monitoring adults with classical 21-hydroxylase deficiency (21OHD) is challenging due to variation in clinical and laboratory settings. Moreover, guidelines for adrenal imaging in 21OHD are not yet available. We evaluated the relationship between adrenal morphology and disease control status in classical 21OHD. METHODS: This retrospective, cross-sectional study included 90 adult 21OHD patients and 270 age- and sex-matched healthy controls. We assessed adrenal volume, width, and tumor presence using abdominal computed tomography and evaluated correlations of adrenal volume and width with hormonal status. We investigated the diagnostic performance of adrenal volume and width for identifying well-controlled status in 21OHD patients (17α-hydroxyprogesterone [17-OHP] <10 ng/mL). RESULTS: The adrenal morphology of 21OHD patients showed hypertrophy (45.6%), normal size (42.2%), and hypotrophy (12.2%). Adrenal tumors were detected in 12 patients (13.3%). The adrenal volume and width of 21OHD patients were significantly larger than those of controls (18.2±12.2 mL vs. 7.1±2.0 mL, 4.7±1.9 mm vs. 3.3±0.5 mm, P<0.001 for both). The 17-OHP and androstenedione levels were highest in patients with adrenal hypertrophy, followed by those with normal adrenal glands and adrenal hypotrophy (P<0.05 for both). Adrenal volume and width correlated positively with adrenocorticotropic hormone, 17-OHP, 11ß-hydroxytestosterone, progesterone sulfate, and dehydroepiandrosterone sulfate in both sexes (r=0.33-0.95, P<0.05 for all). For identifying well-controlled patients, the optimal cut-off values of adrenal volume and width were 10.7 mL and 4 mm, respectively (area under the curve, 0.82-0.88; P<0.001 for both). CONCLUSION: Adrenal volume and width may be reliable quantitative parameters for monitoring patients with classical 21OHD.

Phenotype and genotype analysis of 6 patients with 21-hydroxylase deficiency / 中华全科医师杂志

The clinical data of 6 patients with 21-hydroxylase deficiency(21-OHD) diagnosed in The People′s Hospital of Xinjiang Uygur Autonomous Region from 2015 to 2020 were retrospectively analyzed. There were 2 male cases manifesting shorter height, high progesterone level and infertility. And 4 cases were females, manifesting primary amenorrhea, heterosexual precocious puberty, fatigue during emergency, decreased physical strength, dark skin, clitoral hypertrophy and vulva fusion. None of the parents had a history of consanguinity. All but one patient received glucocorticoid replacement therapy. The sequencing of exons and introns of 21CYPA2 gene showed tuat 1 case was homozygous mutation and 5 cases were complex heterozygous mutation. In terms of clinical phenotype, 1 case was non-classical (complex heterozygous mutation) and 5 cases were simple virilizing phenotype.

Complete corporeal preservation clitoroplasty: new insights into feminizing genitoplasty

ABSTRACT Introduction: 46,XX Congenital adrenal hyperplasia (CAH) remains the first cause of genital virilization and current surgical techniques aim to restore female aspect of genitalia while preserving dorsal neurovascular bundle but not at the expense of not preserving erectile tissue. We aim to report our experience with a new surgical technique for clitoroplasty, completely preserving corporeal bodies, neurovascular bundles without dismembering the clitoris, in four patients with over a year follow up. Materials and Methods: After IRB approval four patients with 46,XX CAH and Prader 5 and 3 external genitalia, underwent feminizing genitoplasty. Complete preservation of erectile tissue was accomplished without a need to dissect dorsal neurovascular bundle. Glans size allowed no need for glanular reduction and there was no need to dismember the corporeal bodies. Results: Four patients 12 to 24-months-old underwent complete corporeal preservation clitoroplasty (CCPC), mean age was 18.5 months, mean follow up was 10.25 months. Vaginoplasty was performed in all patients with partial urogenital mobilization (PUM) and Urogenital Sinus flap (UF), only one severely virilized patient required a parasagittal pre-rectal approach to mobilize the vagina. We had no complications until last follow up. Conclusion: To our knowledge, we are introducing the concept of CCPC without the need of disassembling the corporeal bodies, neurovascular bundle and glans. It stands as a new alternative for feminizing genitoplasty with complete preservation of erectile tissue and no dissection of neurovascular bundle. Although there is still lacking long-term follow-up, it represents a new step in conservative reconfiguration of the external virilized female genitalia.

Complete corporeal preservation clitoroplasty: new insights into feminizing genitoplasty.

INTRODUCTION: 46,XX Congenital adrenal hyperplasia (CAH) remains the first cause of genital virilization and current surgical techniques aim to restore female aspect of genitalia while preserving dorsal neurovascular bundle but not at the expense of not preserving erectile tissue. We aim to report our experience with a new surgical technique for clitoroplasty, completely preserving corporeal bodies, neurovascular bundles without dismembering the clitoris, in four patients with over a year follow up. MATERIALS AND METHODS: After IRB approval four patients with 46,XX CAH and Prader 5 and 3 external genitalia, underwent feminizing genitoplasty. Complete preservation of erectile tissue was accomplished without a need to dissect dorsal neurovascular bundle. Glans size allowed no need for glanular reduction and there was no need to dismember the corporeal bodies. RESULTS: Four patients 12 to 24-months-old underwent complete corporeal preservation clitoroplasty (CCPC), mean age was 18.5 months, mean follow up was 10.25 months. Vaginoplasty was performed in all patients with partial urogenital mobilization (PUM) and Urogenital Sinus flap (UF), only one severely virilized patient required a parasagittal pre-rectal approach to mobilize the vagina. We had no complications until last follow up. CONCLUSION: To our knowledge, we are introducing the concept of CCPC without the need of disassembling the corporeal bodies, neurovascular bundle and glans. It stands as a new alternative for feminizing genitoplasty with complete preservation of erectile tissue and no dissection of neurovascular bundle. Although there is still lacking long-term follow-up, it represents a new step in conservative reconfiguration of the external virilized female genitalia.

Lower Urinary Tract Symptoms in Adult Females after Feminizing Genitoplasty for Congenital Adrenal Hyperplasia.

PURPOSE: We investigated quality of life, long-term lower urinary tract symptoms, sexual function and subjective attitudes toward surgery in adult women after feminizing genitoplasty for congenital adrenal hyperplasia. MATERIALS AND METHODS: We retrospectively reviewed the medical files of all patients with congenital adrenal hyperplasia who underwent feminizing genitoplasty from 1996 to 2018 in our tertiary center. Of those, patients older than 16 years of age were asked to answer 1 nonvalidated and 3 standardized and validated questionnaires evaluating their current mental well-being (WHO-5 Well-Being Index), lower urinary tract symptoms (ICIQ-FLUTS) and sexual function (GRISS). The anonymized answers of this cross-sectional study were compared to a control group of 50 healthy females. Student's t-test, Pearson's χ2 test, Fisher's exact test and Spearman's rank correlation coefficient were performed. A p-value less than 0.05 was considered significant. RESULTS: Out of 106 patients who underwent feminizing genitoplasty, 64 patients were included and 32 patients, aged 17 to 40 years (median 25.5 years), answered the questionnaires (50% response rate). The difference between congenital adrenal hyperplasia and control group mental well-being was not statistically significant (WHO-5 median score 60 and 64, respectively; p=0.82). We found no significant difference in the lower urinary tract symptoms subscales of filling, voiding or incontinence, nor in the overall lower urinary tract symptoms score (ICIQ-FLUTS overall median score 3.5 and 3, respectively; p=0.43). CONCLUSIONS: We found in our group no abnormal mental well-being or prevalence of long-term symptoms of lower urinary tract dysfunction in adult female patients with congenital adrenal hyperplasia following feminizing genitoplasty.

[Clinical characteristics of testicular adrenal rest tumor and factors associated with its occurrence in 21-hydroxylase deficiency patients].

Objective: To analyze the occurrence and clinical characteristics of testicular adrenal rest tumor (TART) in 21-hydroxylase deficiency (21-OHD) patients, and further explore the possible factors related to the occurrence of TART. Methods: Twenty-seven male 21-OHD patients who visited Peking Union Medical College Hospital from January to December 2018 were enrolled and their clinical and biochemical data were collected. The CYP21A2 mutations were identified by Sanger sequencing and multiple ligation probe amplification (MLPA). Patients were divided into different subgroups according to the residual activity of 21-hydroxylase: Null (residual enzymatic activity 0, 3 cases), group A (0-<1%, 9 cases), group B (1%-5%, 7 cases), group C (20%-50%, 2 cases) and group D (6 cases). The ultrasound of testis was used to detect whether there was TART and its morphological characteristics. Results: Among 27 patients with 21-OHD [average age (17.4±9.3) years], 55.6% (15/27) had TART lesions, most of them were adolescents, and the youngest was only 4 years old. The lesions were mostly bilateral and hypoechoic. The levels of 17α-hydroxyprogesterone (17-OHP) and progesterone in patients with TART were higher than those in patients without TART [17-OHP: 199.6 (62.1, 232.7) nmol/L vs 7.4 (3.2, 105.0) nmol/L, P=0.003; progesterone: 97.1 (42.0, 126.8) nmol/L vs 5.4 (0.7, 20.0) nmol/L, P=0.004]. There was a correlation between the occurrence of TART and genotype of CYP21A2. Patients with Null and A genotypes were more likely to have TART than those with B and C genotypes (8/12 vs 4/9, P=0.021). Conclusions: TART is common in 21-OHD male patients, which is related to 17-OHP and CYP21A2 genotype. It is of great significance for the early screening of TART in 21-OHD patients.

[Detection of CYP21A2 gene mutations and the differences in the levels of hormones in patients with 21-hydroxylase deficiency].

Objective: To analyze the detection of CYP21A2 gene mutations in 21-hydroxylase deficiency (21-OHD) patients, so as to determine the accuracy of clinical diagnosis. Methods: Totally, 514 patients with 21-OHD who visited Peking Union Medical College Hospital from January 2015 to January 2018 were enrolled and their clinical and biochemical data were collected. DNAs were extracted from peripheral blood leukocytes and CYP21A2 mutations were detected by Sanger sequencing and multiple ligation probe amplification (MLPA) technique. We divided 514 patients into three groups: two mutations of CYP21A2 alleles (group A), one mutation of CYP21A2 (group B), and no mutation of CYP21A2 (group C). Results: Mutation was detected in each allele of CYP21A2 gene in 401 (78.0%) patients, ninety (17.5%) had only one mutant allele and 23 (4.5%) had no mutation. There was no significant difference between the patients with different clinical phenotypes and the number of CYP21A2 gene mutations detected. In male, the cortisol of the patients with simple virilizing 21-OHD in group A [0.04 (0.02, 0.20) nmol/L] was lower than that of group B [0.24 (0.17, 0.28) nmol/L] and the difference was statistically significant (P=0.014). In female, 17-hydroxyprogesterone (17-OHP) of patients with salt wasting 21-OHD in group A [153.7 (90.1, 204.5) nmol/L] was higher than that of group B [38.2 (31.0, 183.3) nmol/L] and C [42.6 (27.8, 48.1) nmol/L] and the differences were statistically significant (both P<0.05). The progesterone of patients with simple virilizing 21-OHD in group C [23.0 (8.6, 33.2) nmol/L] was lower than that of gourp A [57.8 (34.4, 110.2) nmol/L] and B [63.6 (31.4, 110.8) nmol/L] and the difference were statistically significant (both P<0.05). The 17-OHP of patients with non-classical 21-OHD in group C [24.5 (20.4, 54.2) nmol/L] was lower than that of group A [158.7 (59.1, 187.6) nmol/L] and B [147.8 (131.9, 179.3) nmol/L]. The difference were statistically significant (both P<0.05). Conclusions: Mutations of two alleles have not been found in all patients with clinically diagnosed 21-OHD. Other congenital adrenal hyperplasia (CAH) types which can cause similar changes in 17-OHP and other hormones may be misdiagnosed as 21-OHD. Therefore, 21-OHD cannot be diagnosed with help of 17-OHP level only, and gene detection plays a vital role in the differential diagnosis of different CAH types.

Precocious puberty due to congenital adrenal hyperplasia. Case report / Pubertad precoz por hiperplasia adrenal congénita. Reporte de caso

Abstract Introduction: Premature pubarche occurs in girls before the age of 8 or boys before the age of 9 and is a sign of precocious puberty associated with increased growth acceleration. Precocious puberty can be caused, among others, by nonclassic congenital adrenal hyperplasia (CAH). Case presentation: This is a case of a 4 1/2-year-old who developed premature pubarche six months before consultation, and whose parents were first-degree cousins. She had advanced bone age, her external genitalia were normal and her height was inconsistent with her mid-parental height. After performing an adrenocorticotropic hormone test (ACTH test) and other hormone tests, it was found that she had high levels of 17-hydroxyprogesterone (17-OHP), which allowed diagnosing her with nonclassic CAH. Based on this diagnosis, glucorticoid therapy was ordered, and after one year of starting the treatment she had a favorable clinical outcome and did not show any secondary sex characteristics or bone age progression. Conclusion: Nonclassic CAH is the most frequent cause of precocious puberty. Considering that this type of hyperplasia may be asymptomatic during the early days or years of life, its diagnosis must be suspected in children with precocious puberty, increased growth acceleration and advanced bone age.

Resumen Introducción. La pubarca antes de los 8 años en niñas y de los 9 años en niños, es una manifestación de la pubertad precoz asociada al aumento en la velocidad de crecimiento. La hiperplasia adrenal congénita (HAC) no clásica es una de las causas de pubertad precoz. Presentación de caso. Paciente femenina de 4 años y medio y con padres consanguíneos (primos hermanos) quien inició pubarca 6 meses antes de ser llevada a consulta. La niña presentaba edad ósea avanzada, talla discordante con la talla media parental y sus genitales externos eran normales. Luego de realizar el test de estimulación con hormona adrenocorticotropa y otros exámenes hormonales, se encontró que sus niveles de 17-hidroxiprogesterona eran elevados, lo que permitió diagnosticarla con HAC no clásica. Con base en este diagnóstico, se inició tratamiento con glucocorticoides y luego de un año de tratamiento la paciente tuvo una buena evolución clínica, ya que no se observó progresión de los caracteres sexuales secundarios ni de la edad ósea. Conclusión. La HAC no clásica es la causa más frecuente de la PPP. Ya que este tipo de hiperplasia puede ser asintomática durante los primeros días o años de vida, se debe sospechar su diagnóstico en la infancia cuando haya pubarca precoz, mayor velocidad de crecimiento y edad ósea avanzada.

Clinical features and molecular genetic analysis of congenital lipoid adrenal hyperplasia caused by steroidogenic acute regulatory protein gene mutation / 中华围产医学杂志

Objective@#To investigate the clinical and molecular genetic features of neonatal congenital lipoid adrenal hyperplasia (CLAH) caused by mutations in steroidogenic acute regulatory protein (StAR) encoding gene.@*Methods@#This study retrospectively analyzed the clinical data of a CLAH neonate admitted to Fujian Provincial Maternity and Children's Hospital, Affiliated Hospital of Fujian Medical University in April 2017. StAR gene was analyzed using high-throughput sequencing and Sanger sequencing. Relevant literature retrieved from databases including China National Knowledge Infrastructure (CNKI), Wanfang and PubMed were reviewed, and the reported cases with relatively complete clinical data and results of serum hormone test and StAR gene mutation analysis were collected.@*Results@#The index patient presented with hyperpigmentation and growth retardation soon after birth. Laboratory tests revealed hyponatremia, hyperkalemia, increased serum adrenocorticotrophic hormone (263.4 pmol/L) and decreased 17-hydroxyprogesterone (0.16 ng/ml), dehydroepiandrosterone (<0.95 μmol/L), androstenedione (<1.0 nmol/L), testosterone (<0.025 ng/ml), progesterone (0.02 ng/ml) and cortisol (1.6 μg/ml). High-throughput sequencing showed that the patient carried a compound heterozygous mutation of p.Thr240fs in exon 6 and p.Gln258X in exon 7, inherited from the father and mother, respectively. Sanger sequencing confirmed the diagnosis of CLAH caused by StAR gene mutation. After steroid replacement therapy, the patient's symptoms resolved and the concentrations of electrolytes returned to normal. The neonate was followed up to two years of age and no abnormality was found in physical or neurological development. Two Chinese and 11 English publications were retrieved and altogether 96 cases of neonatal CLAH, including the index one, were reviewed and 42 of them had detailed clinical data. The most common clinical manifestations were skin pigmentation (85.7%, 36/42). Other manifestations included vomiting (35.7%, 15/42) and growth retardation (14.3%, 6/42). All patients with physical examination records had female external genitalia (100.0%, 35/35). The common laboratory abnormalities included hyponatremia (95.2%, 40/42), hyperkalemia (88.1%, 37/42), elevated serum adrenocorticotrophic hormone (100.0%, 37/37) and decreased 17-hydroxyprogesterone (90.5%, 19/21), cortisol (86.2%, 25/29), testosterone (9/10) and dehydroepiandrosterone (14/14). p.Gln258X was the most common StAR gene mutation in neonates in Eastern Asia, including China. Most cases had a good prognosis after appropriate steroid replacement.@*Conclusions@#CLAH should be considered for neonates with adrenocortical hypofunction, especially with female phenotypes and low 17-hydroxyprogesterone. Karyotyping and StAR gene analysis may be helpful in diagnosis. Timely and appropriate treatment could improve the prognosis.

Clinical features and molecular genetic analysis of congenital lipoid adrenal hyperplasia caused by steroidogenic acute regulatory protein gene mutation / 中华围产医学杂志

Objective To investigate the clinical and molecular genetic features of neonatal congenital lipoid adrenal hyperplasia (CLAH) caused by mutations in steroidogenic acute regulatory protein (StAR) encoding gene.Methods This study retrospectively analyzed the clinical data of a CLAH neonate admitted to Fujian Provincial Matemity and Children's Hospital,Affiliated Hospital of Fujian Medical University in April 2017.StAR gene was analyzed using high-throughput sequencing and Sanger sequencing.Relevant literature retrieved from databases including China National Knowledge Infrastructure (CNKI),Wanfang and PubMed were reviewed,and the reported cases with relatively complete clinical data and results of serum hormone test and StAR gene mutation analysis were collected.Results The index patient presented with hyperpigrnentation and growth retardation soon after birth.Laboratory tests revealed hyponatremia,hyperkalemia,increased serum adrenocorticotrophic hormone (263.4 pmol/L) and decreased 17-hydroxyprogesterone (0.16 ng/ml),dehydroepiandrosterone (＜0.95 μmol/L),androstenedione (＜1.0 nmol/L),testosterone (＜0.025 ng/ml),progesterone (0.02 ng/ml) and cortisol (1.6 μ g/ml).High-throughput sequencing showed that the patient carried a compound heterozygous mutation of p.Thr240fs in exon 6 and p.Gln258X in exon 7,inherited from the father and mother,respectively.Sanger sequencing confirmed the diagnosis of CLAH caused by StAR gene mutation.After steroid replacement therapy,the patient's symptoms resolved and the concentrations of electrolytes returned to normal.The neonate was followed up to two years of age and no abnormality was found in physical or neurological development.Two Chinese and 11 English publications were retrieved and altogether 96 cases of neonatal CLAH,including the index one,were reviewed and 42 of them had detailed clinical data.The most common clinical manifestations were skin pigmentation (85.7％,36/42).Other manifestations included vomiting (35.7％,15/42) and growth retardation (14.3％,6/42).All patients with physical examination records had female external genitalia (100.0％,35/35).The common laboratory abnormalities included hyponatremia (95.2％,40/42),hyperkalemia (88.1％,37/42),elevated serum adrenocorticotrophic hormone (100.0％,37/37) and decreased 17-hydroxyprogesterone (90.5％,19/21),cortisol (86.2％,25/29),testosterone (9/10) and dehydroepiandrosterone (14/14).p.Gln258X was the most common StAR gene mutation in neonates in Eastern Asia,including China.Most cases had a good prognosis after appropriate steroid replacement.Conclusions CLAH should be considered for neonates with adrenocortical hypofunction,especially with female phenotypes and low 17-hydroxyprogesterone.Karyotyping and StAR gene analysis may be helpful in diagnosis.Timely and appropriate treatment could improve the prognosis.

Crecimiento físico de niños con hiperplasia suprarrenal congénita perdedora de sal durante los dos primeros años de vida en el Instituto Nacional de Salud del Niño / Physical growth in children with salt-wasting adrenal hyperplasia during their first two years of life in the Peruvian National Children's Health Institute

Objetivo: Describir el crecimiento físico de niños con hiperplasia suprarrenal congénita (HSC) perdedora de sal durante los dos primeros años de vida, evaluados en el Servicio de Endocrinología del Instituto Nacional de Salud del Niño (INSN), Lima-Perú. Materiales y métodos: Es un estudio observacional, descriptivo y retrospectivo. Se incluyeron 55 niños con HSC que tuvieron seguimiento en el Servicio de Endocrinología del INSN del 2000 al 2016; se recopilaron datos como peso y talla al nacer y cada 6 meses, edad al diagnóstico, dosis de hidrocortisona y fludrocortisona y velocidad de crecimiento. Resultados: Se analizaron 55 niños con HSC perdedora de sal siendo el diagnóstico más precoz en mujeres (mediana: 21 días) que en varones (mediana: 52 días). Al nacimiento, su longitud promedio fue 0,07 + 0,75 DE; a los 6 meses fue -1,67 + 1,33 DE con mayor compromiso en varones (-2,29 + 1,18 DE; p=0,022); a los 12 meses fue -1,84 + 1,27 DE, con recuperación a los 24 meses (-1,51 + 1,10 DE). La velocidad de crecimiento fue -1,03 + 1,62 DE y -0,89 + 1,06 DE en el en el primer y segundo año, respectivamente. Conclusiones: Los niños con HSC perdedora de sal que tuvieron seguimiento en el INSN, tuvieron menor longitud a los 6 y 12 meses de edad y lograron recuperarse a los 24 meses.

Objective: To describe physical growth features in children with salt-wasting congenital adrenal hyperplasia (CAH) during their first two years of life, in the Endocrinology Service of the Peruvian National Children's Health Institute (CHI) in Lima, Peru. Materials and Methods: This is a retrospective, observational, and descriptive study. Fifty-five children with CAH underwent follow-up in the Endocrinology Service of the CHI from 2000 to 2016; data such as body weight and height were collected at birth time and every six months, as well as age at diagnosis, hydrocortisone and fludrocortisone doses, and growth velocity. Results: Fifty-five children with salt-wasting CAH were assessed, the diagnosis was more promptly made in females (median: 21 days) compared to males (median: 52 days). At birth, their average length was 0.07 ± 0.75 SD; at 6 months it was -1.67 ± 1.33 SD, and male subjects were more affected (-2.29 ± 1.18 SD; p= 0.022); at 12 months, this parameter was -1.84 ± 1.27 SD, and recovery was observed at 24 months (-1.51 ± 1.10 SD). Growth velocity values were -1.03 ± 1.62 SD and -0.89 ± 1.06 SD in the first and second years of life, respectively. Conclusions: Children with salt-wasting CAH who were followed-up at CHI had shorter length at 6- and 12- months of age, and their recovered at 24-monbths.

Detección de la mutación I172N en pacientes cubanos con hiperplasia suprarrenal congénita por insuficiencia de 21 hidroxilasa / Detection of the I172N Mutation in Cuban Patients with Congenital Adrenal Hyperplasia due to 21 Hydroxylase Insufficiency

Resumen Fundamento: la hiperplasia suprarrenal congénita constituye la causa más frecuente de ambigüedad sexual en la infancia y aproximadamente el 95 % de los casos son producto de mutaciones que ocurren en el gen que codifica la enzima 21α-hidroxilasa. El diagnóstico molecular constituye un elemento a considerar para el manejo y asesoramiento genético a pacientes y familiares en riesgo. Objetivo: identificar la mutación I172N, determinar su frecuencia en la población estudiada y su posible relación con los fenotipos clínicos encontrados. Métodos: se realizó un estudio descriptivo, de corte transversal, durante el período 2014-2016 a pacientes cubanos con diagnóstico de hiperplasia suprarrenal congénita por insuficiencia de 21-OH atendidos en el Instituto de Endocrinología de La Habana. El universo de estudio quedó constituido por 32 pacientes. Los resultados se presentaron en tablas o gráficos según fue más factible mostrar la información. Resultados: la mutación I172N fue identificada en individuos de ambos sexos y se estableció su relación con las formas clásicas de la enfermedad. En la población estudiada, se ubicó dentro de las tres mutaciones más frecuentes de las pesquisadas hasta el momento en el Centro Nacional de Genética Médica de la Habana a pacientes con hiperplasia suprarrenal congénita por insuficiencia de 21 OH. Conclusiones: el método estandarizado demostró ser reproducible y confiable para el diagnóstico molecular de los individuos con hiperplasia suprarrenal congénita por insuficiencia de 21-OH. La mutación I172N se ubica dentro de las tres más frecuentes en la población cubana estudiada y se relaciona con las formas clásicas de la enfermedad.

ABSTRACT Background: congenital adrenal hyperplasia is the most frequent cause of sexual ambiguity in childhood. Molecular diagnosis is an element to be considered for the management and genetic counseling of patients and relatives at risk. Objective: to identify the I172N mutation, to determine its frequency in the studied population and its possible relationship with the clinical phenotypes found. Methods: a descriptive, cross-sectional study was conducted during the 2014-2016 period for Cuban patients diagnosed with congenital adrenal hyperplasia due to 21-OH insufficiency treated at the Institute of Endocrinology of Havana. The universe consisted of 32 patients. The variables analyzed were: age, social sex, age at diagnosis, clinical form of hyperplasia, diagnosis by screening program, family history, consanguinity, nonspecific neonatal death, genital crisis of the newborn, previous molecular diagnosis, mutations studied previously, mutation I172N gene CYP21A. The results were presented in tables or graphs as it was more feasible to show the information. Results: the I172N mutation was identified in individuals of both sexes and its relation with the classic forms of the disease was established. In the studied population the three most frequent mutations of the researched ones, so far in the National Center of Medical Genetics of Havana to patients with congenital adrenal hyperplasia due to 21 OH insufficiency. Conclusions: the standardized method proved to be reproducible and reliable for the molecular diagnosis of individuals with congenital adrenal hyperplasia due to 21-OH insufficiency. The I172N mutation is among the three most frequent in the studied Cuban population and is related to the classic forms of the disease.

Analysis of the Influencing Factors of 17-Hydroxyprogesterone Level and the Correlation between 17-Hydroxyprogesterone Level and the Clinical Parameters Related to Adrenal Cortical Function in Very-Low-Birth-Weight Infants

PURPOSE: 17-Hydroxyprogesterone (17-OHP) screening results are difficult to interpret owing to the many influencing factors, and confirming the test results takes time. In this study, we examined the factors that affected the 17-OHP level in premature infants. We also evaluated the correlation between 17-OHP level and the clinical parameters related to adrenal cortical function. METHODS: From January 2012 to April 2017, 358 very-low-birth-weight infants (VLBWI) born with birth weights of < 1,500 g were included in the study. Their 17-OHP levels were measured in the neonatal screening test after birth and analyzed by considering various factors that may have influenced the values. RESULTS: The 17-OHP levels negatively correlated with gestational age and birth weight. The values of the parameters that affected the 17-OHP levels were significantly higher in the infants with respiratory distress syndrome (RDS). In relation to the clinical parameters, blood pressure measured within 24 hours, 72 hours, and 1 week after birth negatively correlated with the 17-OHP level. Serum sodium and 17-OHP levels 24 hours after birth were found to be positively correlated. Urine outputs in 1 and 3 days after birth showed significant positive correlations with the 17-OHP level. CONCLUSION: The 17-OHP levels of the VLBWIs were higher when gestational age and birth weight were lower, and were influenced by RDS in the VLBWI. In addition, hypotension and urine output values may be useful in the neonatal intensive care unit as a predictor of early adrenal insufficiency.

Functional Identification of Compound Heterozygous Mutations in the CYP17A1 Gene Resulting in Combined 17α-Hydroxylase/17,20-Lyase Deficiency.

BACKGROUND: We previously reported a patient with congenital adrenal hyperplasia (CAH) with compound heterozygous mutations in the cytochrome P450 17A1 (CYP17A1) gene. One allele had a p.His373Leu and the other a new p.Glu383fsX36 mutation. The aim of this study was to investigate the functional properties of a new allele present in a compound heterozygote of CYP17A1. METHODS: To understand how p.His373Leu and p.Glu383fsX36 affect P450c17 enzymatic activity, wild type and mutant CYP17A1 cDNAs were cloned into flag-tagged pcDNA3 vector and introduced into human embryonic kidney cells 293T (HEK293T) cells. Protein expression levels of CYP17A1 were then analyzed. And the activities of 17α-hydroxylase and 17,20-lyase of CYP17A1 were evaluated by measuring the conversion of progesterone to 17α-hydroxyprogesterone and of 17α-hydroxypregnenolone to dehydroepiandrosterone, respectively. In addition a computer model was used to create the three-dimensional structure of the mutant CYP17A1 enzymes. RESULTS: Production of the p.His373Leu mutant protein was significantly lower than that of the wild type protein, and the p.Glu383fsX36 protein was hardly produced. Similarly the enzymatic activity derived from the p.His373Leu mutant vector was significantly lower than that obtained from the wild type vector, and little activity was obtained from the p.Glu383fsX36 vector. Three-dimensional modeling of the enzyme showed that p.His373 was located in region important for heme-binding and proper folding. Neither the p.His373Leu nor the p.Glu383fsX36 mutant protein formed a heme-binding structure. CONCLUSION: Enzyme activity measured in both mutants disappeared completely in both 17α-hydroxylase and 17,20-lyase. This result accounts for the clinical manifestations of the patient with the compound heterozygous CYP17A1 mutations.

Manejo con cinco antihipertensivos en paciente con pubertad precoz. Reporte de caso / Management with five antihypertensives in patient with precocious puberty. Case report

RESUMEN Introducción: la hiperplasia suprarrenal congénita por deficiencia de 11-beta-Hidroxilasa es una enfermedad autosómica recesiva poco frecuente, y en estadios avanzados sus complicaciones cardiovasculares exigen un manejo aún más complejo. Presentación del caso: paciente masculino que inicia pubarca a los 2 años de edad, por lo que se diagnostica hiperplasia suprarrenal congénita por deficiencia de 11-beta-Hidroxilasa, y subsecuente hipertensión desde sus 5 años. Consulta a los 8 años de edad por una intoxicación alimentaria que desencadena una insuficiencia adrenal. Adicionalmente se diagnostica pubertad precoz periférica, melanodermia, hipopotasemia e hipertrofia ventricular izquierda. Requiere manejo con hidrocortisona a dosis de estrés y uso de cinco antihipertensivos. Discusión: el tratamiento determina el pronóstico del paciente; al no realizarse el manejo oportuno puede producirse pubertad precoz e hipertensión arterial con complicaciones irreversibles como deterioro de la talla final y la hipertrofia ventricular izquierda respectivamente.

SUMMARY Introduction: Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency is an infrequent autosomal recessive disease and the associated cardiovascular complications in the advanced stages make the management even more complex. Case presentation: A male patient who starts pubarche at 2 years old, therefore, he is diagnosed with congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency, and subsequent hypertension from age 5. At eight-years-old, he is hospitalized for a foodborne illness that causes adrenal insufficiency. Additionally, he is diagnosed with peripheral precocious puberty, melanoderma, hypokalemia and left ventricular hypertrophy. He required stress dose of hydrocortisone and five antihypertensives. Discussion: Treatment determines a patient's prognosis. Therefore, once precocious puberty and hypertension produce irreversible complications such as deterioration of the final height and left ventricular hypertrophy respectively, the management is extremely difficult.

What about my daughter's future? Parental concerns when considering female genital restoration surgery in girls with congenital adrenal hyperplasia.

PURPOSE: The parental decision-making process regarding female genital restoration surgery (FGRS) for girls with congenital adrenal hyperplasia (CAH) is controversial and poorly understood. The aim of the study aim was to evaluate parental concerns related to their child's future and parental plans about disclosure prior to FGRS. MATERIALS AND METHODS: The authors performed an online survey of consecutive parents presenting at a tertiary referral center for consultation regarding FGRS for their daughter with CAH before 3 years of age (2016-2018). Twenty issues initially identified by three families and six clinicians were rated on a 6-point Likert scale of importance ('not at all' to 'extremely'). RESULTS: Sixteen consecutive families participated (Prader 3/4/5: 43.8%/43.8%/12.5%). Fourteen girls (87.5%) subsequently underwent FGRS at a median age of 8 months. Most issues (19/20, 95.0%) were ranked 'quite a bit' to 'extremely' important (Table). Top issues were not surgical: Normal physical/mental development, adrenal crisis and side-effects of medications. Surgery-related and self-image concerns followed in importance. Least prioritized issues were multiple genital exams ('quite a bit' important) and the child not being involved in the decision to proceed with FGRS ('somewhat' important). On average, no issues were considered 'not at all' or 'a little' important. Disclosure of FGRS to their daughter was the 15th prioritized issues. Almost all families (93.8%, 1 unsure) planned to disclose the surgery to their daughter, although many were unsure when and how to do it (33.3% and 37.5%, respectively). COMMENT: Initial efforts to understand the complex process of parental decision-making regarding FGRS in the context of CAH, a complex, multifactorial disease, are presented. Parents of infant girls with CAH simultaneously weigh multiple life-threatening concerns with a decision about FGRS. While issues of genital ambiguity and surgery are important, they are not overriding concerns for parents of girls with CAH. Parents report significant uncertainty about appropriate timing and approach to disclosing FGRS to their daughters. Unfortunately, best practice guidelines for this process are lacking. The findings are not based on actual history of disclosure but on parents' anticipated behavior. Further data are need from parents, children, and women with CAH about successful disclosure. Being a single-center series, these data may not correspond to the wider CAH community. CONCLUSIONS: Parental decision-making regarding FGRS is multifactorial. Even when considering FGRS, parents' largest concerns remain focused on the life-threatening and developmental effects of CAH and side-effects of its medical treatment. The disclosure process deserves further attention.

[Efficacy of medium dose dexamethasone androgen suppression test in the diagnosis of female hyperandrogenism].

Objective: To evaluate the diagnostic value of medium dose dexamethasone androgen suppression tests (DAST) in female hyperandrogenism. Methods: DAST results were retrospectively analyzed in 85 cases of women with hyperandrogenism including 55 cases of congenital adrenal hyperplasia (CAH), 10 cases of testosterone-producing tumors and 20 cases of polycystic ovary syndrome (PCOS) between January 1984 and December 2017 in Peking Union Medical College Hospital. The suppression rate of testosterone and 17 hydroxyprogesterone (17OHP) were evaluated. The cut-off point of suppression rates were calculated by receiver operating characteristic (ROC) curve in the differential diagnosis of CAH and non-CAH causes. Results: The 1-day medium dose DAST was performed simultaneously in 41 cases of CAH patients and the 5-days medium dose DAST was performed simultaneously in 19 cases of CAH patients. The results indicated that the average suppression rate of testosterone were 77.9% and 91.3% (P<0.001) and the average suppression rate of 17OHP was 95.2% and 97.0%, respectively (P=0.220). In patients (41 cases of CAH, 10 cases of testosterone producing tumor and 20 cases of PCOS) with 1-day DAST, the optimal testosterone suppression rate was 61.2% (the sensitivity and specificity was 87.8% and 96.7%, respectively) and the optimal 17OHP suppression rate was 87.1% (the sensitivity and specificity was 95.1% and 93.3%, respectively) in the identification of CAH and non-CAH cases. There is no clinical significance between the testosterone and 17OHP suppression rate in the differential diagnosis of CAH and non-CAH cases. Conclusions: There was no difference in the suppression rate of 17OHP between the 1-day and 5-days DAST in CAH cases. The sensitivity of suppression rate of 17OHP is equal in the differential diagnosis of hyperandrogenism. One-day approach DAST could be used as functional test for the diagnosis of the etilology of hyperandrogenism (CAH or non-CAH).

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase gene mutation: a case report / 中华围产医学杂志

We hereby reported the clinical manifestations and genetic diagnosis of a rare case of congenital adrenal hyperplasia (CAH) caused by cytochrome P450 oxidoreductase ( POR ) gene mutation. The case was an 11-year-old girl presented with craniofacial and skeletal malformation such as a depressed nasal bridge, radiohumeral synostosis and camptodactyly in feet. Moreover, she was diagnosed with ambiguous genitalia, and her mother had obvious masculine features during pregnancy. Laboratory tests showed that the levels of peripheral blood progesterone, 17-hydroxyprogesterone and adrenocorticotrophic hormone (ACTH) had increased significantly, which were consistent with the symptom of CAH. Genetic testing revealed a complex heterozygous mutation in POR gene of maternally inherited c.744C>G (p.Tyr248Ter) and paternal inherited c.1370G>A (p.Arg457His). Therefore, she was diagnosed with cytochrome P450 oxidoreductase deficiency (PORD), which is a rare type of CAH. The patient received oral glucocorticoid therapy and underwent knee arthroplasty.