Reliability of clonidine testing for the diagnosis of growth hormone deficiency in children and adolescents.

OBJECTIVE: The diagnosis of growth hormone deficiency (GHD) is currently based on clinical, auxological, biochemical and neuro-radiological investigation. Provocative tests of GH secretion using physiological/pharmacological stimuli are required to confirm GHD. The clonidine test (CT) is widely used to assess GH secretory status. In this retrospective study, we analyzed the reliability of CT and the effect of puberty in a large number of children with short stature who had been evaluated for suspected GHD. DESIGN AND PATIENTS: Data were collected retrospectively from 327 children and adolescents with short stature (204 boys and 123 girls, median age 10.5 years (IQR 7.90-12.40) followed in four Italian Paediatric Endocrine Units (Cagliari, Genova, Napoli and Roma) between 2005 and 2013. MEASUREMENTS: All children underwent CT as the first GH stimulation test after exclusion of other known cause of their short stature. RESULTS: In 73 prepubertal children and 25 pubertal children, the GH peak after CT was <7 µg/L. GHD was confirmed in 87 (37 organic, 50 idiopathic). Six prepubertal and five pubertal patients showed false positive responses. The median BMI-SDS in these children was similar to that of children with GH peak ≥7 µg/L, and none were obese. Overall, the prevalence of false-positive responses was 3.3%. The median (IQR) peak GH after CT was similar between prepubertal and pubertal GHD (3.80 µg/L [1.7-6.00] vs 3.51 µg/L [0.76-5.74]) and non-GHD (13.70 µg/L [10.70-18.40] vs 12.40 µg/L [9.90-19.25]) children. CONCLUSIONS: Our results show that CT is a reliable and safe GH-releasing agent in both prepubertal and pubertal children.

Central Precocious Puberty in Italian Boys: Data From a Large Nationwide Cohort.

CONTEXT: There are only a few nationwide studies on boys with central precocious puberty (CPP) and the last Italian study is a case series of 45 boys that dates back to 2000. OBJECTIVE: We aimed to evaluate the causes of CPP in boys diagnosed during the last 2 decades in Italy and the relative frequency of forms with associated central nervous system (CNS) abnormalities on magnetic resonance imaging (MRI) compared to idiopathic ones. METHODS: We performed a national multicenter retrospective study collecting data from 193 otherwise normal healthy boys with a diagnosis of CPP. Based on MRI findings, the patients were divided into: Group 1, no CNS abnormalities; Group 2, mild abnormalities (incidental findings) unrelated to CPP; and Group 3, causal pathological CNS abnormalities. RESULTS: The MRI findings show normal findings in 86%, mild abnormalities (incidental findings) in 8.3%, and causal pathological CNS abnormalities in 5.7% of the cases. In Group 3, we found a higher proportion of patients with chronological age at diagnosis < 7 years (P = .00001) and body mass index greater than +2 SDS (P < .01). Gonadotropin-releasing hormone analogue therapy was started in 183/193 subjects. The final height appeared in the range of the target height in all groups and in 9 patients in whom the therapy was not started. CONCLUSION: In our study on a large nationwide cohort of boys referred for precocious puberty signs, the percentage of forms associated with CNS abnormalities was one of the lowest reported in the literature.

The role of FTO genotype on eating behavior in obese Sardinian children and adolescents.

AIM: We aimed to study the influence of the fat mass and obesity-associated (FTO) gene on eating behavior in 412 obese Sardinian children and adolescents. Genome-wide association studies (GWAS) have identified several susceptibility loci for obesity. Among these, the polymorphisms in the intron 1 of the FTO gene has been found associated to weight gain and obesity in various populations. METHODS: All obese patients were genotyped for the FTO single nucleotide polimorphysm (SNP) rs9939609. In all subjects we evaluated eating behavior using the Child Eating Behaviour Questionnaire (CEBQ). RESULTS: We found no differences in eating behavior according to the genotype, either in the entire cohort, or when subjects were subdivided into four different age groups. CONCLUSIONS: FTO genotype is associated with body mass index but does not influence eating behavior in a selected cohort of obese children from the isolated genetic population of Sardinia.

Diagnosis of GH Deficiency Without GH Stimulation Tests.

Growth hormone deficiency (GHD) is the most commonly affected pituitary hormone in childhood with a prevalence of 1 in 4000-10000 live births. GH stimulation testing (GHST) is commonly used in the diagnostic workup of GHD. However, GHD can be diagnosed in some clinical conditions without the need of GHST. The diagnosis of GHD in newborns does not require stimulation testing. Likewise infants/children with delayed growth and/or short stature associated with neuroradiological abnormalities and one or more additional pituitary hormone deficiencies may not need GHST. This review summarizes the current evidence on the diagnosis of GHD without stimulation tests.

rs9939609 in the FTO gene is associated with obesity but not with several biochemical parameters in Sardinian obese children.

Several studies have reported an association of the intronic single nucleotide polymorphism (SNP) rs9939609 of the fat mass and obesity-associated (FTO) gene with obesity and with a number of obesity-related features. We studied the association of rs9939609 with obesity in 912 obese children and adolescents (426 males and 486 females, mean ± SD age 10.5 ± 3.3 years) and in 543 normal weight subjects. A number of biochemical and clinical parameters was also evaluated in 700 of these patients. In the obese group, mean body mass index standard deviation score (BMI-SDS) was similar between the three genotypes. The A allele was present in 55% of the patients' and in 43% of controls' chromosomes. The distribution of heterozygotes was similar between patients and controls (47%), while the distribution of AA homozygotes was significantly higher in patients (31% vs. 20%). Logistic regression analysis on the genotypes yielded a χ(2) of 35.5 with an odds ratio of 1.6 (CI = 1.3-1.8), P < 1 × 10(-5) . None of the clinical and metabolic parameters tested was associated with the genotype. In conclusion, we have confirmed the strong association between FTO and obesity, and shown that only AA homozygotes are predisposed to develop obesity while TT homozygotes might be protected. Finally, we found no association between rs9939609 and a number of obesity-related abnormalities.

Effect of body mass index on the growth hormone response to clonidine stimulation testing in children with short stature.

OBJECTIVES: An inverse relationship has been shown between body mass index (BMI) and the peak growth hormone (GH) response to stimulation in adults and in children with short stature. This relation is observed even within a normal range of BMI. The aim of this study was to investigate the effect of BMI on the GH response to clonidine in a large number of children with short stature. DESIGN: We conducted a retrospective study on the GH response to clonidine in a single centre. METHODS: We studied 202 children with short stature (135 M and 67 F) who underwent clonidine testing from 2007 to 2009. RESULTS: One hundred and twenty-eight patients had a GH peak >10 µg/l. In univariate regression analysis, the peak GH after clonidine was negatively correlated with BMI-standard deviation score (BMI-SDS) and positively correlated with height velocity-SDS and IGF-I-SDS. Only the relationship between peak GH and BMI-SDS remained significant in children with a BMI-SDS from -2 to +2. In the multivariate stepwise regression analysis, BMI-SDS and IGF-I-SDS were the only significant variables in the entire cohort, explaining 19·5% of the variance in peak GH. When only subjects with BMI-SDS between -2·0 and +2·0 were included in the analysis (n = 173), BMI-SDS alone explained 21·4% of the variability in peak GH. The number of patients who failed the clonidine test increased with increasing BMI-SDS. CONCLUSIONS: BMI affects the GH response to clonidine in children with short stature and should be considered when interpreting the results to the stimulation test.

Differences of sex development in the newborn: from clinical scenario to molecular diagnosis.

Differences/disorders of sex development (DSD) are defined as a group of congenital conditions in which the development of chromosomal, gonadal or anatomical sex is atypical. The incidence of DSD is 1:4500 births. The current classification divides DSDs into 3 categories according to chromosomal sex: 46,XX DSD, 46,XY DSD and sex chromosome DSD. DSD phenotypes can be concordant with the genotype (apparently normal external genitalia associated with gonadal dysgenesis), or can range from simply hypospadias to completely masculinised or feminised genitalia with a discordant karyotype. Numerous genes implicated in genital development have been reported. The search of genetic variants represents a central element of the extended investigation, as an improved knowledge of the genetic aetiology helps the immediate and long-term management of children with DSDs, in term of sex of rearing, hormone therapy, surgery, fertility and cancer risk. This review aims to assess the current role of molecular diagnosis in DSD management.

Advances in differential diagnosis and management of growth hormone deficiency in children.

Growth hormone (GH) deficiency (GHD) in children is defined as impaired production of GH by the pituitary gland that results in growth failure. This disease might be congenital or acquired, and occurs in isolation or in the setting of multiple pituitary hormone deficiency. Isolated GHD has an estimated prevalence of 1 patient per 4000-10,000 live births and can be due to multiple causes, some of which are yet to be determined. Establishing the correct diagnosis remains key in children with short stature, as initiating treatment with recombinant human GH can help them attain their genetically determined adult height. During the past two decades, our understanding of the benefits of continuing GH therapy throughout the transition period from childhood to adulthood has increased. Improvements in transitional care will help alleviate the consequent physical and psychological problems that can arise from adult GHD, although the consequences of a lack of hormone replacement are less severe in adults than in children. In this Review, we discuss the differential diagnosis in children with GHD, including details of clinical presentation, neuroimaging and genetic testing. Furthermore, we highlight advances and issues in the management of GHD, including details of transitional care.

Central diabetes insipidus in children: Diagnosis and management.

Central diabetes insipidus (CDI) is a complex disorder in which large volumes of dilute urine are excreted due to arginine-vasopressin deficiency, and it is caused by a variety of conditions (genetic, congenital, inflammatory, neoplastic, traumatic) that arise mainly from the hypothalamus. The differential diagnosis between diseases presenting with polyuria and polydipsia is challenging and requires a detailed medical history, physical examination, biochemical approach, imaging studies and, in some cases, histological confirmation. Magnetic resonance imaging is the gold standard method for evaluating the sellar-suprasellar region in CDI. Pituitary stalk size at presentation is variable and can change over time, depending on the underlying condition, and other brain areas or other organs - in specific diseases - may become involved during follow up. An early diagnosis and treatment are preferable in order to avoid central nervous system damage and the risk of dissemination of germ cell tumor, or progression of Langerhans Cell Histiocytosis, and in order to start treatment of additional pituitary defects without further delay. This review focuses on current diagnostic work-up and on the role of neuroimaging in the differential diagnosis of CDI in children and adolescents. It provides an update on the best approach for diagnosis - including novel biochemical markers such as copeptin - treatment and follow up of children and adolescents with CDI; it also describes the best approach to challenging situations such as post-surgical patients, adipsic patients, patients undergoing chemotherapy and/or in critical care.

IGF1 for the diagnosis of growth hormone deficiency in children and adolescents: a reappraisal.

A number of studies have evaluated the role of IGF1 measurement in the diagnosis of growth hormone deficiency (GHD). This study aimed to evaluate the accuracy and the best cut-off of IGF1 SDS in the diagnosis of GHD in a large cohort of short children and adolescents. One-hundred and forty-two children and adolescents with GHD ((63 organic/genetic (OGHD), 79 idiopathic (IGHD)) and 658 short non-GHD children (median age 10.4 years) were included in the analysis. The two groups were subdivided according to age (G1 <6, G2 6 <9, G3 9 <12, G4 ≥12) and to pubertal status. Serum IGFI was measured by the same chemiluminescence assay in all samples and expressed as age- and sex-based SDS. Receiver operating characteristic (ROC) analysis was used to evaluate the optimal IGF1 SDS cut-off and the diagnostic accuracy. Median IGF1 SDS was significantly lower in the GHD than in non-GHD patients. The area under the curve (AUC) was 0.69, with the best IGF1 cut-off of -1.5 SDS (sensitivity 67.61%, specificity 62.62%). The AUC was 0.75 for OGHD and 0.63 for IGHD. The accuracy was better in the pubertal (AUC = 0.81) than the prepubertal group (AUC = 0.64). In our cohort, IGF1 measurement has poor accuracy in discriminating GHD from non-GHD. Our findings confirm and reinforce the belief that IGF1 values should not be used alone in the diagnosis of GHD but should be interpreted in combination with other clinical and biochemical parameters.

Endocrine Outcomes In Central Diabetes Insipidus: the Predictive Value of Neuroimaging "Mismatch Pattern".

CONTEXT: The etiology of central diabetes insipidus (CDI) in children is often unknown. Clinical and radiological features at disease onset do not allow discrimination between idiopathic forms and other conditions or to predict anterior pituitary dysfunction. OBJECTIVE: To evaluate the evolution of pituitary stalk (PS) thickening and the pattern of contrast-enhancement in relation with etiological diagnosis and pituitary function. METHODS: We enrolled 39 children with CDI, 29 idiopathic and 10 with Langerhans cell histiocytosis (LCH). Brain magnetic resonance images taken at admission and during follow-up (332 studies) were examined, focusing on PS thickness, contrast-enhancement pattern, and pituitary gland size; T2-DRIVE and postcontrast T1-weighted images were analyzed. RESULTS: Seventeen of 29 patients (58.6%) with idiopathic CDI displayed "mismatch pattern," consisting in a discrepancy between PS thickness in T2-DRIVE and postcontrast T1-weighted images; neuroimaging findings became stable after its appearance, while "mismatch" appeared in LCH patients after chemotherapy. Patients with larger PS displayed mismatch more frequently (P = 0.003); in these patients, reduction of proximal and middle PS size was documented over time (P = 0.045 and P = 0.006). The pituitary gland was smaller in patients with mismatch (P < 0.0001). Patients with mismatch presented more frequently with at least one pituitary hormone defect, more often growth hormone deficiency (P = 0.033). CONCLUSIONS: The PS mismatch pattern characterizes patients with CDI, reduced pituitary gland size, and anterior pituitary dysfunction. The association of mismatch pattern with specific underlying conditions needs further investigation. As patients with mismatch show stabilization of PS size, we assume a prognostic role of this peculiar pattern, which could be used to lead follow-up.

Cardiovascular Risk Factors in Children and Adolescents With Obesity: Sex-Related Differences and Effect of Puberty.

Objectives: To evaluate the effect of gender and puberty on cardiovascular risk factors (CVRF) in obese children and adolescents. Methods: One thousand four hundred and nine obese patients [age 9.7 (2.2-17.9) y; 646 Male] were studied. Subjects were stratified according to Tanner pubertal staging and age into prepubertal ≤ and >6 ys (G1 and G2), pubertal stage 2-3 (G3), and pubertal stage 4-5 (G4). Waist circumference (WC), systolic and diastolic blood pressure (SP, DP), fasting plasma glucose, insulin, post Oral Glucose Tolerance Test glucose and insulin, and lipids were evaluated. Insulin resistance was evaluated by HOMA index. Patients with no CVRF were considered metabolically healthy (MHO). Results: The percentage of MHO patients was 59.8% in G1 while was consistently around 30% in the other groups. WC was more frequently abnormal in G2 males. Pubertal progression was associated with a decrease in WC abnormalities. SP was more frequently abnormal in G4 males and pubertal progression was associated with higher prevalence of abnormal SP in males. Pubertal progression was associated with an increase in hypertension rate in both sexes. HOMA was more frequently abnormal in G2 and G3 females. HDL, LDL, and TG were more frequently abnormal in G2 females. Dyslipidemia rate was higher in G2 females. Pubertal progression was associated with higher prevalence of abnormal HDL in males. Conclusions: Sex and pubertal status influence the frequency of abnormalities of CVRF in obese children and adolescents. CVRF are already present in prepubertal age. Identifying patients with higher risk of metabolic complications is important to design targeted and effective prevention strategies.

Accuracy and Limitations of the Growth Hormone (GH) Releasing Hormone-Arginine Retesting in Young Adults With Childhood-Onset GH Deficiency.

Background: Re-testing for GH secretion is needed to confirm the diagnosis of GH deficiency (GHD) after adult height achievement in childhood-onset GHD (COGHD). Aim: To define the cut-off of GH peak after retesting with GH-releasing hormone plus arginine (GHRHarg) in the diagnosis of permanent GHD in COGHD of different etiology. Patients and methods: Eighty-eight COGHD (median age 17.2 y), 29 idiopathic GHD (IGHD), 44 cancer survivors (TGHD) and 15 congenital GHD (CGHD) were enrolled in the study; 54 had isolated GHD (iGHD) and 34 had multiple pituitary hormone deficiencies (MPHD). All were tested with insulin tolerance test (ITT) and GHRHarg. IGHD with a GH response to ITT ≥6µg/L were considered true negatives and served as the control group, and patients with a GH response <6µg/L as true positives. Baseline IGF-I was also measured. The diagnostic accuracy of GHRHarg testing and of IGF-I SDS in patients with GHD of different etiologies was evaluated by ROC analysis. Results: Forty-six subjects with a GH peak to ITT ≥6µg/L and 42 with GH peak <6 µg/L showed a GH peak after GHRHarg between 8.8-124µg/L and 0.3-26.3µg/L, respectively; 29 IGHD were true negatives, 42 were true positives and 17 with a high likelihood GHD showed a GH peak to ITT ≥6µg/L. ROC analysis based on the etiology indicated the best diagnostic accuracy for peak GH cutoffs after GHRHarg of 25.3 µg/L in CGHD, 15.7 in TGHD, and 13.8 in MPHD, and for IGF-1 SDS at -2.1 in CGHD, -1.5 in TGHD, and -1.9 in MPHD. Conclusions: Our findings indicate that the best cut-off for GH peak after retesting with GHRHarg changes according to the etiology of GHD during the transition age. Based on these results the diagnostic accuracy of GHRHarg remains questionable.

Growth Hormone Deficiency in the Transition Age.

Growth hormone (GH) is essential not only for normal growth during childhood, but also for the acquisition of bone mass and muscle strength in both sexes. This process is completed after the achievement of adult height in the phase of transition from adolescence to adulthood. Adolescents with childhood onset GH deficiency (GHD) show reduction of bone mineral density, decrease in lean body mass, increase in fat mass, and deterioration of the lipid profile. For this reason, continuation of GH replacement therapy in the transition age is recommended in all patients with a confirmed diagnosis of GHD. To confirm the diagnosis of GHD, GH treatment should be discontinued for at least 1 month after the attainment of adult height, and the patient should be re-evaluated for GH secretion. Current guidelines indicate that retesting is not required for those with a transcription factor mutation, more than 3 pituitary hormone deficits, or isolated GHD associated with an identified mutation. The key predictors of persistent GHD are its severity, the presence of additional pituitary hormone deficits, low insulin-like growth factor I (IGF-I) concentration, and the presence of structural hypothalamic-pituitary abnormalities Treatment should be initiated with a low dose (0.2-0.5 mg/day s.c.) and then adjusted according to IGF-I concentrations.

Next-Generation Sequencing Identifies Different Genetic Defects in 2 Patients with Primary Adrenal Insufficiency and Gonadotropin-Independent Precocious Puberty.

BACKGROUND: The development of gonadotropin-independent (peripheral) precocious puberty in male children with primary adrenal insufficiency (PAI) is consistent with a defect in the genes encoding for the enzymes involved in steroid hormone biosynthesis. METHODS: Two young boys presented with peripheral precocious puberty followed by PAI. In both patients, the analysis of CYP21A2 gene encoding 21-hydroxylase was normal. As a second step, a targeted next-generation sequencing (NGS) was performed in both patients using a customized panel of congenital endocrine disor ders. RESULTS: Case 1 had a new homozygous variant in the CYP11B1 gene (c.1121+5G>A). Mutations of this gene cause congenital adrenal hyperplasia due to 11ß-hydroxylase deficiency, an essential enzyme in the cortisol biosynthesis pathway. Case 2 showed a new hemizygous mutation in the NR0B1 gene (c.1091T>G), which encodes for DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita [AHC] and critical region on the X chromosome gene 1). NR0B1 mutations cause X-linked AHC and hypogonadotropic hypogonadism. Pathogenicity prediction software defined both mutations as probably damaging. CONCLUSIONS: Peripheral precocious puberty was the atypical presentation of 2 rare genetic diseases. The use of NGS made the characterization of these 2 cases with similar clinical phenotypes caused by 2 different genetic defects possible.

Cut-off limits of the peak GH response to stimulation tests for the diagnosis of GH deficiency in children and adolescents: study in patients with organic GHD.

OBJECTIVE: The diagnosis of GH deficiency (GHD) in children and adolescents is established when GH concentrations fail to reach an arbitrary cut-off level after at least two provocative tests. The objective of the study was to define the optimal GH cut-offs to provocative tests in children and adolescents. DESIGN: Retrospective study in 372 subjects who underwent evaluation of GH secretion. GH and IGF-I were measured by chemiluminescence assay in all samples. Receiver operating characteristic (ROC) analysis was used to evaluate the optimal GH cut-offs and the diagnostic accuracy of provocative tests. METHODS: Seventy four patients with organic GHD (GH peak <10µg/L after two provocative tests) and 298 control subjects (GH response >10µg/L to at least one test) were included in the study. The provocative tests used were arginine, insulin tolerance test (ITT) and clonidine. Diagnostic criteria based on cut-offs identified by ROC analysis (best pair of values for sensitivity and specificity) were evaluated for each test individually and for each test combined with IGF-I SDS. RESULTS: The optimal GH cut-off for arginine resulted 6.5µg/L, 5.1µg/L for ITT and 6.8µg/L for clonidine. IGF-I SDS has low accuracy in diagnosing GHD (AUC=0.85). The combination of the results of provocative tests with IGF-I concentrations increased the specificity. CONCLUSIONS: The results of the ROC analysis showed that the cut-off limits which discriminate between normal and GHD are lower than those commonly employed. IGF-I is characterized by low diagnostic accuracy.

Growth hormone treatment in non-growth hormone-deficient children.

Until 1985 growth hormone (GH) was obtained from pituitary extracts, and was available in limited amounts only to treat severe growth hormone deficiency (GHD). With the availability of unlimited quantities of GH obtained from recombinant DNA technology, researchers started to explore new modalities to treat GHD children, as well as to treat a number of other non-GHD conditions. Although with some differences between different countries, GH treatment is indicated in children with Turner syndrome, chronic renal insufficiency, Prader-Willi syndrome, deletions/mutations of the SHOX gene, as well as in short children born small for gestational age and with idiopathic short stature. Available data from controlled trials indicate that GH treatment increases adult height in patients with Turner syndrome, in patients with chronic renal insufficiency, and in short children born small for gestational age. Patients with SHOX deficiency seem to respond to treatment similarly to Turner syndrome. GH treatment in children with idiopathic short stature produces a modest mean increase in adult height but the response in the individual patient is unpredictable. Uncontrolled studies indicate that GH treatment may be beneficial also in children with Noonan syndrome. In patients with Prader-Willi syndrome GH treatment normalizes growth and improves body composition and cognitive function. In any indication the response to GH seems correlated to the dose and the duration of treatment. GH treatment is generally safe with no major adverse effects being recorded in any condition.

Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche.

OBJECTIVE: Premature pubarche (PP) is the most frequent sign of nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency in childhood. The aim of this study was to assess the relationship between the CYP21A2 genotype and baseline and ACTH-stimulated 17-hydroxyprogesterone (17-OHP) and cortisol serum levels in patients presenting with PP. PATIENTS AND METHODS: A total of 152 Italian children with PP were studied. Baseline and ACTH-stimulated 17-OHP and cortisol serum levels were measured and CYP21A2 gene was genotyped in all subjects. RESULTS: Baseline and ACTH-stimulated serum 17-OHP levels were significantly higher in NCCAH patients than in both heterozygotes and children with idiopathic PP (IPP). Of the patient population, four NCCAH patients (7.3%) exhibited baseline 17-OHP values <2 ng/ml (6 nmol/l). An ACTH-stimulated 17-OHP cutoff level of 14 ng/ml (42 nmol/l) identified by the receiver-operating characteristics curves showed the best sensitivity (90.9%) and specificity (100%) in distinguishing NCCAH patients. This value, while correctly identifying all unaffected children, missed 9% of affected individuals. Cortisol response to ACTH stimulation was <18.2 µg/dl (500 nmol/l) in 14 NCCAH patients (28%) and none of the heterozygotes or IPP children. Among the 55 NCCAH patients, 54.5% were homozygous for mild CYP21A2 mutations, 41.8% were compound heterozygotes for one mild and one severe CYP21A2 gene mutations, and 3.6% had two severe CYP21A2 gene mutations. CONCLUSION: In children with PP, baseline 17-OHP levels are not useful to rule out the diagnosis of NCCAH, which is accomplished by means of ACTH testing only. The different percentages of severe and mild CYP21A2 gene mutations found in PP children compared with adult NCCAH patients is an indirect evidence that the enzyme defect is under-diagnosed in childhood, and it might not lead to the development of hyperandrogenic symptoms in adulthood. Stress-dose glucocorticoids should be considered in patients with suboptimal cortisol response to ACTH stimulation.