Premature Pubarche: A Pragmatic Approach.

Premature pubarche (PP) is a common and usually benign variant of normal puberty most often seen in 5-year-old to 9-year-old children. Some providers routinely order laboratory testing and a bone age to try to rule out other diagnoses including nonclassic congenital adrenal hyperplasia and gonadal or adrenal tumors. I review the natural history of PP and studies which suggest that without clinical features such as rapid growth and progression or genital enlargement, it is unlikely that a treatable condition will be found. Therefore it is recommended that patients with PP not undergo testing unless there are red flags at the time of the initial visit.

Cardiovascular risk in women with nonclassical congenital adrenal hyperplasia.

CONTEXT: The outcomes related to cardiovascular risk (CVR) in patients with nonclassical form of congenital adrenal hyperplasia (NCAH) are unknown, especially those related to therapeutic options, including low doses of glucocorticoids (GCs) or oral contraceptive pills. OBJECTIVES: to analyze CVR by markers of atherosclerosis in females with nonclassical form according to therapeutic options. DESIGN AND SETTING: a cross-sectional study at a tertiary center. PATIENTS AND METHODS: Forty-seven females with NCAH (33.4 ± 10 years) were subdivided into: G1 (n = 28) treated with dexamethasone (0.14 ± 0.05 mg/m2/day); G2 (n = 19) with oral contraceptive pills; and G3 (30 matched controls). CVR was analyzed through serum lipids, HOMA-IR, inflammatory cytokines levels and quantitative image evaluations (pulse wave velocity-PWV, endothelial function by flow mediated dilatation-FMD, carotid intima media thickness-CIMT and visceral fat-VAT by abdominal tomography. RESULTS: There were no statistically significant differences in BMI, HOMA-IR, HDL-cholesterol, or triglyceride levels among groups (p > 0.05). Serum interleukin-6 levels ​​were higher in G1 than in G2 (p = 0.048), and interleukin-8 levels were higher in G1 than in G2/3 (p = 0.008). There were no statistically significant differences in VAT, PWV, FMD or CIMT among groups (p > 0.05). In multivariable regression analysis, there was no statistically significant association between glucocorticoid dose and evaluated outcomes. CONCLUSION: Adult females with NCAH did not show increased CVR using methodologies for detection of precocious atherosclerosis. Although patients receiving dexamethasone therapy had increased IL-6 and 8 levels, these data were not associated with radiological markers of atherosclerosis. Our cohort was composed of young adults and should be reevaluated in a long-term follow-up.

Face-sparing Congenital Generalized Lipodystrophy Type 1 Associated With Nonclassical Congenital Adrenal Hyperplasia.

CONTEXT: Congenital generalized lipodystrophy, type 1 (CGL1), due to biallelic pathogenic variants in AGPAT2, is characterized by the near total loss of body fat from the face, trunk, and extremities. Patients develop premature diabetes, hypertriglyceridemia, hepatic steatosis, and polycystic ovary syndrome. However, sparing of the facial fat and precocious pubertal development has not been previously reported in CGL1. CASE DESCRIPTION: We report a 21-year-old woman of European descent with CGL1 who had sparing of the facial fat and premature thelarche at birth with premature pubarche and menstrual bleeding at age 3 years. Her serum 17-OH progesterone level rose to 1000 ng/dL (30.26 nmol/L) after cosyntropin stimulation test, suggestive of nonclassical congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency. Hydrocortisone replacement therapy from age 3.5 to 10 years resulted in cessation of menstruation and growth of pubic hair, and a reduction of breast size. Sanger and whole-exome sequencing revealed compound heterozygous variants c.493-1G>C; p.(Leu165_Gln196del), and c.del366_588+534; p.(Leu123Cysfs*55) in AGPAT2 plus c.806G>C; p.(Ser269Thr) and c.844G>T; p.(Val282Leu) in CYP21A2. She developed diabetes at age 13 requiring high-dose insulin and had 7 episodes of acute pancreatitis due to extreme hypertriglyceridemia in the next 5 years. Metreleptin therapy was initiated at age 18 and after 3 years, she had remission of diabetes and hypertriglyceridemia; however, menstrual irregularity and severe hirsutism did not improve. CONCLUSION: Concomitant NCAH in this CGL1 patient was associated with precocious pubertal development and sparing of facial fat. Metreleptin therapy drastically improved her hyperglycemia and hyperlipidemia but not menstrual irregularity and hirsutism.

Hyperinsulinemic-Euglycemic Clamp Strengthens the Insulin Resistance in Nonclassical Congenital Adrenal Hyperplasia.

OBJECTIVE: Insulin sensitivity evaluation by hyperinsulinemic-euglycemic clamp in nonclassical congenital adrenal hyperplasia (NC-CAH) due to 21-hydroxilase deficiency. DESIGN AND SETTING: Cross-sectional study at university hospital outpatient clinics. PATIENTS AND METHODS: NC-CAH patients (25 females, 6 males; 24 ± 10 years) subdivided into C/NC (compound heterozygous for 1 classical and 1 nonclassical allele) and NC/NC (2 nonclassical alleles) genotypes were compared to controls. RESULTS: At diagnosis, C/NC patients presented higher basal and adrenocorticotropin-stimulated 17-hydroxyprogesterone and androstenedione levels than NC/NC genotype. Patients and controls presented similar weight, body mass index, abdominal circumference, and total fat body mass. NC-CAH patients showed higher waist-to-hip ratio, lower adiponectin and lower high-density lipoprotein cholesterol levels with no changes in fasting plasma glucose, glycated hemoglobin, homeostatic model assessment for insulin resistance, leptin, interleukin 6, tumor necrosis factor alpha, C-reactive protein, and carotid-intima-media thickness. All patients had used glucocorticoid (mean time of 73 months). Among the 22 patients with successful clamp, 13 were still receiving glucocorticoid-3 patients using cortisone acetate, 9 dexamethasone, and 1 prednisone (hydrocortisone equivalent dose of 5.5mg/m²/day), while 9 patients were off glucocorticoid but had previously used (hydrocortisone equivalent dose of 5.9mg/m2/day). The NC-CAH patients presented lower Mffm than controls (31 ± 20 vs 55 ± 23µmol/min-1/kg-1, P = 0.002). The Mffm values were inversely correlated with the duration of glucocorticoid treatment (r = -0.44, P = 0.04). There was association of insulin resistance and glucocorticoid type but not with androgen levels. CONCLUSION: Using the gold standard method, the hyperinsulinemic-euglycemic clamp, insulin resistance was present in NC-CAH patients and related to prolonged use and long-acting glucocorticoid treatment. Glucocorticoid replacement and cardiometabolic risks should be monitored regularly in NC-CAH.

Management of Fully Pubertal Girls With Nonclassical Congenital Adrenal Hyperplasia: Glucocorticoids Versus Oral Contraceptives.

OBJECTIVE: To compare clinical outcomes of 3 treatment regimens-glucocorticoids (GCs), oral contraceptives (OCs), or a combination of both-administered to adolescents and young women diagnosed in childhood with nonclassical congenital adrenal hyperplasia (NCCAH), who had been treated with GCs until their adult height was achieved. METHODS: A retrospective study of medical records of 53 female patients with NCCAH followed in 3 tertiary pediatric endocrinology institutes. The 3 treatment groups were compared for the prevalence of hirsutism and acne, standardized body mass index (BMI)-standard deviation score (SDS), and androgen levels at the attainment of adult height (baseline), 1-year later, and at the last documented visit. RESULTS: At baseline, there were no significant differences among groups in BMI-SDS, androgen levels, hirsutism prevalence, acne, or irregular menses. From baseline to the last visit, the rate of hirsutism declined significantly only in the OC group (37.5% vs 6.2%, respectively; P = .03). The rate of acne declined in the combined group (50% vs 9%, respectively; P = .03) with a similar tendency in the OC group (50% vs 12.5%, respectively; P = .05). No significant changes were observed in BMI-SDS for the entire cohort or any subgroup during follow-up. A significant rise in androstenedione (P < .001), testosterone (P < .01), and 17-hydroxyprogesterone (P < .01) levels was observed only in the OC group. CONCLUSION: In girls diagnosed in childhood with NCCAH, who require treatment for hyperandrogenism following completion of linear growth, management should be tailored individually using a patient-centered approach. Treatment with OCs might be better than that with GCs for regression of hirsutism and acne. The long-term effects of elevated levels of androgens associated with this treatment regimen should be further studied.

Clinical characteristics and etiological analysis of premature pubarche:A report of 55 cases / 中国实用儿科杂志

OBJECTIVE: To analyse the clinical characteristics,aetiology distribution,and metabolic risk parameters of patients with with premature pubarche(PP). METHODS: A retrospective study was performed in 55 patients affected by PP,who received ACTH stimulation test,and the data were evaluated. Among them 17 cases were detected CYP21 A2 gene,and indicators of lipid metabolism of idiopathic premature adrenarche(IPA,15 cases)and idiopathic premature pubarche(IPP,14 cases)were analyzed. RESULTS: The sample included 55 patients with PP(53 female and 2 male),with a mean pubarche age of(7.2±0.9)years for girls and(7±0.8)years for boys. There was an accelerated bone age(BA/CA ratio>1)(1.20 ± 1.5)in girls. A total of 9 patients were classified as non-classic congenital adrenal hyperplasia(NCCAH,16.4%),15 as IPA(27.3%),14 as IPP(25.4%),16 as HPGA function launch(29.1%)and 1 with exaggerated adrenarche(EA,1.8%). There was no significant difference in the diagnostic rate of NCCAH between ACTH stimulation test and CYP21 A2 gene detection(P=0.596). The sex hormone binding protein(SHBP)of IPA was reduced(P=0.007). CONCLUSION: The etiology of premature pubarche-non-classic congenital adrenal hyperplasia(16.4%)is not uncommon. The ACTH stimulation test is useful for the diagnosis of NCCAH,but the sensitivity is not 100%.

Clinical, biochemical and genetic features with nonclassical 21-hydroxylase deficiency and final height.

BACKGROUND: The clinical, laboratory, genetic properties and final height of a large cohort of patients with nonclassical 21-hydroxylase deficiency (NC21OHD) in Turkey were analyzed. METHODS: This multicenter, nationwide web-based study collected data. RESULTS: The mean age was 9.79±4.35 years (229 girls, 29 boys). The most common symptoms were premature pubarche (54.6%) and hirsutism (28.6%). The peak cortisol was found below 18 µg/dL in three (15.45%) patients. A mutation was detected in the CYP21A2 gene of 182 (87.5%) patients. The most common mutation was V281L. Final height in female patients who were diagnosed and treated before attaining final height or near final height was found to be shorter than the final height in female patients who were diagnosed after attaining final height or near final height. CONCLUSIONS: The final height of the patients who were treated during childhood was found to be shorter than the final height of patients during the adolescent period.

Study of awareness of adrenal disorders among interns and postgraduate students of Hamidia Hospital, Bhopal.

INTRODUCTION: Adrenal disorders could be a life-threatening emergency, hence requires immediate therapeutic management. For this awareness regarding its diagnosis, management, and treatment is prime important. AIMS AND OBJECTIVE: To study the awareness of adrenal disorders among interns and postgraduates students of Hamidia Hospital, Bhopal. MATERIALS AND METHODS: A cross-sectional questionnaire-based study was performed. Fifty-six participants, i.e., 1st, 2nd, and 3rd years postgraduate residents of general medicine (n = 14 × 3) and interns (n = 14) were included in the study. There were 12 questions on adrenal insufficiency, adrenal adenoma, congenital adrenal hyperplasia (CAH), nonclassical CAH (NCCAH), pheochromocytoma, and Conn's syndrome. One mark was awarded for each correct response. RESULTS: In the present study, 14 (25%) participants scored < 5 marks, 33 (58.9%) scored between 6 and 9, and 9 (16.1%) scored between 10 and 12. The mean score among the participants was 6.38 ± 2.505, with a range from 2 to 11 marks. The number of correct answers by postgraduates residents of 1st year was 101, 2nd year was 95, and 3rd year was 93 and interns scored 68 out of total 168 questions in each group. Mean awareness score for residents of 1st, 2nd, 3rd years participants and interns was 7.21 ± 2.806, 6.79 ± 2.119, and 6.64 ± 2.818 and 6.63 ± 2.505, respectively. Most of the participants recorded correct responses related to diagnosis (57.7%) followed by responses related to treatment (64.3%). Answers to a question regarding how commonly is adrenal insufficiency diagnosed in medical Intensive Care Unit, none of the individuals responded correctly. CONCLUSION: There was a lack of awareness regarding diagnosis, management, and treatment of adrenal disorders in central India. We need to prioritize training related to these illnesses in our postgraduate teaching curriculum in practice.

Basal 17-hydroxyprogesterone cannot accurately predict nonclassical congenital adrenal hyperplasia in children and adolescents.

AIM: This study explored whether using the suggested diagnostic serum basal level of 17-hydroxyprogesterone (6.0 nmol/L) would lead to underdiagnosis of nonclassical congenital adrenal hyperplasia. METHODS: We retrospectively studied 123 patients with nonclassical congenital adrenal hyperplasia, defined as an adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone level of more than 45 nmol/L. Of these 13 had basal 17-hydroxyprogesterone levels of less than 6.0 nmol/L and 110 exceeded that level. The 42 controls had idiopathic premature pubarche. Clinical and laboratory data were reviewed and compared. RESULTS: There were no differences between patients with 17-hydroxyprogesterone levels of <6.0 nmol/L or ≥6.0 nmol/L based on age at presentation, gender, anthropometric measurements, bone age advancement, age at glucocorticoid initiation and hydrocortisone dosage. Patients with basal 17-hydroxyprogesterone <6.0 nmol/L had significantly lower stimulated 17-hydroxyprogesterone levels (p = 0.02) and higher stimulated serum cortisol levels (p < 0.008). Children with nonclassical congenital adrenal hyperplasia and premature pubarche were clinically indistinguishable from controls with idiopathic premature pubarche. Androgen levels were significantly higher in the nonclassical congenital adrenal hyperplasia group. CONCLUSION: A basal 17-hydroxyprogesterone threshold of 6.0 nmol/L was not a sensitive predictive marker for diagnosing nonclassical congenital adrenal hyperplasia. Children whose clinical presentation suggests nonclassical congenital adrenal hyperplasia should undergo diagnostic adrenocorticotropic hormone stimulation testing.

Hiperplasia suprarrenal congénita no-clásica: avances en la detección, diagnóstico, conducta y tratamiento / Nonclassic adrenal hyperplasia: state of the art

Nonclassical adrenal hyperplasia (NC-CAH) is caused by a deficiency in the activity of the 21-hydroxylase enzyme and is the most common autosomal recessive disorder. The clinical features of the disease sre highly variable, and therefore the diagnosis may be overseen. The disorder is characterized by hyperandrogenism of adrenal origin that may become evident during childhood, adolescence or adulthood. The symptoms vary from premature pubarche, mestrual disturbances, hirsutism and virilization to those cases without any clinical evidence of the disease, as described in the cryptic form. The diagnostic approach includes an initial measurement of plasmatic 17OH-progesterone (17OHP) and androgen levels, and an ACTH test in those with elevated baseline 17OHP. The definitive diagnosis of this entity is performed with the documentation of abnormalities in both alleles of the CYP21A2 gene. This paper reviews the clinical, molecular and treatment of patients with NC-CAH.