Serum leptin levels in patients with 21-hydroxylase deficiency before and after treatment

Increase in serum androgen levels results in suppression of serum leptin levels. In this study, the changes in serum leptin concentrations of children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) with respect to their hyperandrogenism were investigated. Eleven children with 21-OHD and 25 healthy control children were included in the study. Before initiation of hydrocortisone, serum leptin levels in children with CAH were lower (1.7 +/- 1.3 ng/ml) than in the control group (5.3 +/- 4.01 ng/ml) (p<0.001). After three months of treatment, serum leptin levels increased to the normal range (7.1 +/- 2.9 ng/ml). Prior to and on hydrocortisone treatment in CAH, serum leptin levels were positively correlated with cortisol (r:0.78, p:0.004 and r:0.80, p:0.003) but negatively correlated with testosterone (r:-0.62, p:0.04 and r:-0.65, p:0.002). These results suggest that serum leptin measurements may be used as an additional parameter in the follow-up of children with CAH to evaluate the efficacy of hydrocortisone treatment with respect to androgenemia.     

Nonclassic 21-hydroxylase deficiency in Croatia

This is the first report of nonclassic congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency in Croatia in which the patients have been evaluated clinically, hormonally, and by molecular genetic analysis. Genetic analysis was performed on 18 Croatian patients with nonclassic CAH due to 21-OH deficiency using allele-specific PCR. ACTH stimulation testing and HLA typing were used to evaluate patients hormonally. Molecular genetic analysis revealed a variety of mutations in individuals with different clinical symptoms, including precocious pubarche, hirsutism, (dysmenorrhea, subfertility and clitoromegaly. Serum stimulated 17-hydroxyprogesterone (17-OHP) levels indicated that all patients fell within the acceptable range for nonclassic congenital adrenal hyperplasia. Clinical and genetic analysis confirmed nonclassic 21-OH deficiency in our Croatian sample of ten males and eight females. This study shows that genotype does not necessarily predict fertility status in our group of affected patients.     

Failure of cortisone acetate therapy in 21-hydroxylase deficiency in early infancy

BACKGROUND: Pediatric endocrinologists initially treat congenital adrenal hyperplasia with either cortisone acetate (CA) or hydrocortisone (HC). Despite high doses of CA, we noted that 17-hydroxyprogesterone (17-OHP) and corticotropin were not fully suppressed in serum from neonates with 21-hydroxylase deficiency (21-OHD) until they were 40- to 80-days-old. In contrast, serum concentrations of 17-OHP were suppressed immediately by oral treatment with HC. METHODS: We sought to understand the reason for this discrepancy. Serum cortisol (F), cortisone (E), and 17-OHP were measured by radioimmunoassay or high-performance liquid chromatography in seven neonates with 21-OHD and in 118 normal subjects. From the time of diagnosis, CA was administered to four of the neonates with 21-OHD, while HC was given to the other three. RESULTS: In normal subjects serum E concentrations were greater than F during the first 2 months after birth, whereas F concentrations exceeded E after 2 months of age. Although infants receiving CA initially were given a high dose, serum F concentrations were extremely low, while 17-OHP concentrations were high until about 2 months of age. Then serum F exceeded E, and 17-OHP became fully suppressed even though infants received only a moderate dose of CA. In contrast, HC administration successfully normalized serum 17-OHP in the neonatal period. With temporary switching of neonates from HC to CA, serum F concentrations immediately decreased and 17-OHP concentrations increased. CONCLUSION: Conversion of E to F may be limited during early infancy, adversely affecting treatment with CA. Cortisone acetate may be inappropriate as a glucocorticoid replacement during early infancy in patients with 21-OHD.     

Epidemiology of 21-hydroxylase deficiency in Singapore

We report the incidence and epidemiology of 21-hydroxylase deficiency in Singapore, based on a retrospective study of all known patients diagnosed with classical 21-hydroxylase deficiency in the past 21 years. The database was obtained from the case registry and questionnaire methodology, with 100% coverage of all practising pediatricians in Singapore. There were 42 patients affected with 21-hydroxylase deficiency in 964,558 live births over 21 years, comprising 64.3% salt wasters and 35.7% simple virilizers, of whom 50.0% were males and 50.0% females. The incidence of classical 21-hydroxylase deficiency is 4.5 per 100,000 live births, with a carrier frequency of 1:76, and a gene frequency of 0.0067. Although retrospective studies have inherent limitations, the gender and phenotype ratios suggest that the data provide a crude incidence level. This study underscores the necessity for prospective neonatal screening, so that the benefits of early diagnosis and treatment can be realized.     

21-hydroxylase deficiency transiently mimicking combined 21- and 11beta-hydroxylase deficiency

21-Hydroxylase deficiency (21OHD) is the commonest form of congenital adrenal hyperplasia, while 11betaOHD represents 5% of cases. Although both result from mutations in distinct genes, cases of 'apparent' combined 21OHD and 11betaOHD (AC21,11OHD) have been occasionally reported. A 6 year-old girl, born with ambiguous genitalia and salt-loss, had serum elevations (ng/dl) of androstenedione (>1,000), 17-hydroxyprogesterone (17OHP; 38,483), 21-deoxycortisol (21DF; 23,338), and 11-deoxycortisol (S; 4,928), suggesting AC21,11OHD. CYP21A and CYP11B1 genotyping identified mutations only in the former. On follow-up, serum S became normal but 17OHP and 21DF were still elevated. ACTH stimulation disclosed elevated levels of 17OHP and 21DF, but unresponsive S and undetectable deoxycorticosterone. The hormonal pattern initially suggested AC21,11OHD, but subsequent normalization of S showed transient 11-hydroxylase inhibition. This may have occurred by enzyme or co-enzyme immaturity or functional discrepancy, but also by selective inhibition of 11betaOH by excess intra-adrenal concentration of androgens, acting as pseudo-substrates for this enzyme.     

Growth pattern and final height in 21-hydroxylase deficiency

Growth pattern and final height were evaluated in 47 children with 21-hydroxylase deficiency to identify factors influencing growth. The subjects were followed-up from the age of 0.6 +/- 1.2 years for 8.8 +/- 3.9 years. Final height SDS was significantly below target height SDS (- 2.5 +/- 1.4 versus - 1.0 +/- 1.0, P < 0.001). Laboratory monitoring and type of disease (salt-wasting or simple virilizing) significantly influenced age-specific height SDS. Age at treatment, frequency of laboratory monitoring and dose of glucocorticoid during infancy influenced final height on univariate analysis; the effect was not sustained on multivariate analysis. Our study emphasizes the need for regular laboratory monitoring and lower glucocorticoid dose during infancy in 21-hydroxylase deficiency.     

Sexual dimorphism in the synchrony of joint growth hormone and cortisol dynamics in children with classic 21-hydroxylase deficiency

In humans, growth hormone (GH) and cortisol are secreted in a pulsatile fashion and a mutual bidirectional interaction between the GH/insulin-like growth factor (IGF)-I axis and hypothalamic-pituitary-adrenal (HPA) axis has been established. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in the synthesis of glucocorticoids and often mineralocorticoids, and adrenal hyperandrogenism. In view of the sexually dimorphic pattern in GH secretion, we investigated the GH-cortisol bihormonal secretory dynamics in male and female children with classic CAH. Thirty-eight children with classic 21-hydroxylase deficiency (M: 13, F: 25; age range: 6.1-18.8 yr) were studied prospectively. Serum GH and cortisol concentrations were determined at 20 min intervals for 24 hours. The irregularity of GH and cortisol pattern was assessed using approximate entropy (ApEn), a scale- and model-independent statistic. The synchrony of joint GH-cortisol dynamics was quantified using the cross-ApEn statistic. Cross-correlation analysis of GH and cortisol concentrations was computed at various time lags covering the 24-h period. There was no gender difference in mean 24-hour serum GH (males vs females: 5.25 +/- 4.72 vs 4.44 +/- 2.64 mIU/l) or cortisol (156.2 +/- 44.6 vs 172.0 +/- 58.5 nmol/l) concentrations. For GH, ApEn values were significantly higher in females (0.66 +/- 0.14) than in males (0.53 +/- 0.16) (p = 0.009). No difference in cortisol ApEn values was noted between sexes (0.53 +/- 0.21 vs 0.54 +/- 0.12). Cross-ApEn values of paired GH-cortisol, with cortisol leading GH, were significantly higher in females (0.94 +/- 0.14) than in males (0.83 +/- 0.20) (p = 0.03). These findings suggest that females with classic 21-hydroxylase deficiency have a more irregular pattern of GH secretion and a more asynchronous joint GH and cortisol dynamics than their male counterparts.     

21-羟化酶缺乏症患者CYP21基因点突变研究

目的 了解CYP21基因编码区的常见突变谱和突变热点,并分析基因型和表现型的关系。方法 对来自51个家庭的52例21-羟化酶缺乏症患者的全长CYP21基因分两个片断进行特异性聚合酶链反应(PCR)扩增,在此基础上进行相应的巢式PCR扩增,再根据突变的特点分别采用限制性片段长度多态性(RFLP)和扩增产生酶切位点(ACRS)的方法,检测6种突变：P30L、12g(内含子2的nt656a／c→g剪切突变)、E3△8nt(外显子3第111～113密码子的8bp缺失)、I172N、V281L和Q318X。结果 在102个等位基因中,除了27个等位基因外都能够确定基因型。最常见的突变为12g,其发生频率为31％,其次为I172N(23％),Q318x(14％),V281L(9％),P30L(3％),E3△8nt(2％),其中有2个以上复合突变的等位基因占6％。失盐型患者最常见的突变为12g(45．7％)和Q318X(26％)。单纯型最常见的突变为I172N(40．7％)和12g(18．5％)。结论 本组52例患者中,73％的等位基因突变为上述6种突变,以12g和I172N为突变热点,2种突变占54％。上述结果为进一步的遗传咨询和产前诊断服务提供了有用的信息。     

Sodium chloride supplement at diagnosis and during infancy in children with salt-losing 21-hydroxylase deficiency

Eight infants (6 female, 2 male) with salt-losing congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency were studied to determine the sodium deficit at diagnosis and the level of salt supplement required in addition to subsequent hormone replacement. The median sodium deficit at diagnosis was 34 mmol (range 16–78) or 10.5 mmol/kg (range 4–24). A mean sodium supplement of 2.2 mmol/kg per day (range 0.5–4.9), double the amount provided with feeds, was required to maintain plasma sodium concentration and plasma renin activity (PRA) in the normal range for age. We present an equation based on sodium output (urine), sodium input (feeding plus supplement) and plasma sodium concentration to calculate the sodium supplement needed to maintain sodium balance on hormone replacement in this condition and some practical management suggestions. The necessity for salt supplements is often underestimated and the salt-losing tendency exacerbated by infection remains an unnecessary reason for hospitalization during the first months of life. In patients with salt-losing CAH life-long mineralocorticoid treatment is necessary but additional salt supplements are needed to maintain plasma sodium concentration and PRA in the normal range during infancy.     

Nonclassic adrenal hyperplasia due to 21-hydroxylase deficiency

Nonclassic adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder distinguished from classic 21-OHD by clinical and hormonal criteria. It is most often described as a disorder of adrenal steroidogenesis with onset of virilization in late childhood, peripubertally or postpubertally. An overview of adrenal steroidogenesis is presented elsewhere in this publication. It is the aim of this article to focus on the clinical and hormonal manifestations of the disorder, with discussion of the current methods of diagnosis and management. Recent advances in classic and molecular genetics will follow.     

Longitudinal analysis of growth and puberty in 21-hydroxylase deficiency patients

Aims: To evaluate growth from diagnosis until final height (FH) in 21-hydroxylase deficiency patients. Methods: A retrospective longitudinal study was performed. Only patients treated with hydrocortisone and fludrocortisone (in case of salt wasting) were evaluated. This resulted in a sample of 34 (21 male, 13 female) salt wasting patients (SW) and 26 (13 male, 13 female) non-salt wasting patients (NSW). Auxological data were compared to recent Dutch reference values. Results: In the first three months of life, the mean length SDS decreased to -1.50, probably because of the high average glucocorticoid dose (40 mg/m²/day). FH corrected for target height (FH_corrTH) was -1.25 and -1.27 SDS in females and males, respectively. Patients treated with salt supplements during the first year, had a better FH_corrTH (-0.83 SDS). In NSW patients, FH_corrTH was -0.96 and -1.51 SDS in females and males, respectively. In SW and NSW, age at onset of puberty was within normal limits, but bone age was advanced. Mean pubertal height gain was reduced in males. Body mass index was only increased in NSW females. Conclusion: In SW, loss of final height potential might be a result of glucocorticoid excess in the first three months and sodium depletion during infancy. In NSW, loss of FH potential was caused by the delay in diagnosis. In SW and NSW, the advanced bone age at onset of puberty (undertreatment in prebertal years) resulted in loss of height gain during puberty. The effect of intensive sodium chloride support in early infancy should be examined prospectively. Neonatal screening is required if the height prognosis in NSW patients is to be improved.     

Adrenal 21-hydroxylase deficiency in childhood: 25 years' experience

Objective: To review past and present management of congenital adrenal hyperplasia at a single centre, as a guide to best practice.
Methodology The records of 89 patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency managed in a children's hospital in Australia over a period of 25 years were reviewed.
Results The diagnosis was made in infancy in 66 patients (37 males and 29 females) and later in 23 (11 males and 12 females). The mean age for genitoplasty in females with ambiguous genitalia was 18 months before 1984 and 3 months thereafter. Significant differences were found between males and females presenting after infancy with regard to virilization, bone age advancement, risk of true precocious puberty and final height. The mean final height standard deviation scores for seven males and seven females treated from infancy were — 1.32 and — 1.26, respectively.
Conclusions The results emphasize the importance of early diagnosis and good control in ensuring a good outcome for patients with 21-hydroxylase deficiency.     

Untreated congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Congenital adrenal hyperplasia (CAH) is an inherited metabolic disease caused by the deficiency of one of the enzymes necessary for cortisol synthesis. With carefully supervised medical treatment, CAH patients have the capacity for normal puberty and fertility. We report on a 12.4-year-old female who, because of the early interruption of treatment, developed progressive virilization with reduced final height and altered psycho-social orientation to male. One of the reasons for interrupting replacement therapy in our case was the difficult social and economic status of the family, who lived for many years without basic medical care.