Family studies of the steroid 21-hydroxylase and coplement C4 genes define 11 haplotypes in classical congenital adrenal hyperplasia in The Netherlands

Two steroid 21-hydroxylase genes are normally present within the human major histocompatibility complex near the genes encoding the fourth component of complement (C4A and C4B). Steroid 21-hydroxylase is encoded by the CYP21 gene, while the highly homologous CYP21P gene is a pseudogene. We studied steroid 21-hydroxylase and complement C4 haplotypes in 33 Dutch patients (29 families) suffering form classical congenital adrenal hyperplasia (CAH) and in their 80 family members, and also in 55 unrelated healthy controls, using 21-hydroxylase and complement C4 cDNA probes. Eleven different haplotypes, defined in terms of gene deletions, gene duplications, conversions of CYP21 to CYP21P, and long and short C4 genes, were found. In 23% of the patients' haplotypes, the CYP21 gene was deleted; in 12%, it was converted into a CYP21P pseudogene. In the remaining 65%, the defect was apparently caused by a mutation not detectable by this method. The most common haplotype (with one CYP21 and one CYP21P gene) was significantly more often observed in patients with simple virilizing CAH than in those with salt-losing CAH. Comparison of the 21-hydroxylase haplotypes found in CAH patients from several countries shows evidence for considerable genetic variation between the groups studied.     

Non-classical 21-hydroxylase deficiency in boys with prepubertal or pubertal gynecomastia

This report describes two boys who were evaluated for the first time at the ages of 9.8 (patient 1) and 13.4 years (patient 2), due to either prepubertal or pubertal gynecomastia. The diagnosis of non-classical (NC) 21-hydroxylase deficiency (21-OH-D) was substantiated by the finding of increased baseline and adrenocorticotropic hormone (ACTH)-stimulated 17-hydroxy-progesterone levels and was supported by molecular analyses of the CYP21A2 gene, which revealed V281L homozygosis in patient 1 and V281L/P30L compound heterozygosis in patient 2. In both boys, gynecomastia completely regressed 5-8 months after the institution of glucocorticoid substitutive treatment. We conclude that it is mandatory to suspect NC 21-OH-D in the clinical evaluation of either prepubertal or pubertal gynecomastia, since this association might be more frequent than reported so far, and that it is important that diagnosis is made by the first months after gynecomastia development, since a longstanding gynecomastia is unlikely to respond completely to medical therapy.     

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.     

先天性肾上腺皮质增生症21羟化酶缺乏患者的生长与最终身高影响因素

先天性肾上腺皮质增生症(CAH)是一组常染色体隐性遗传病,由于肾上腺皮质激素合成酶的缺陷,皮质醇的合成部分或完全受阻使促肾上腺皮质激素(ACTH)分泌过多导致肾上腺皮质增生,同时皮质醇的前体产物过多堆积并转化为性激素.21羟化酶缺乏(21-OHD)是最常见的CAH,同时也是人类最常见的常染色体隐性遗传病之一,分为经典型和非经典型.21-OHD的治疗目标是用糖皮质激素和盐皮质激素替代,抑制ACTH的过度分泌,使肾上腺分泌的雄激素水平正常,保证正常的生长和骨骼发育,以达到或接近其遗传潜力所决定的身高.然而,由于自身疾病以及治疗的影响,CAH患儿的成年身高常较正常人群平均水平及自身遗传靶身高低下,因而成为备受关注的问题.     

Management of 21-hydroxylase deficiency congenital adrenal hyperplasia: A survey of Canadian paediatric endocrinologists

BACKGROUND

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive disorders. Many issues in the management of CAH in children still remain unresolved.

OBJECTIVE

To assess how children with CAH are treated in Canada.

METHODS

Fifty-nine paediatric endocrinologists and postgraduate trainees from across Canada took part in a survey that evaluated four areas of CAH management: type and dose of glucocorticoid therapy, current use of alternative therapies, monitoring of care, and approach/attitude to prenatal diagnosis and treatment of CAH.

RESULTS AND CONCLUSIONS

The present survey demonstrated that there is general agreement among paediatric endocrinologists in Canada regarding the management of patients with CAH, which includes very little use of newer antiandrogen therapies. The goal remains to be the optimization of currently available therapy to ensure normal growth and sexual maturation without any evidence of glucocorticoid excess or deficiency. Prenatal diagnosis and management is widely, but infrequently, used.     

Urinary 17α-hydroxyprogesterone in management of 21 -hydroxylase deficiency

Objectives: The study was designed to assess the reliability of measurement of 24-hour urinary 17α-hydroxyprogesterone (17-OHP) by radio-immunoassay (RIA) as an alternative biochemical assessment for monitoring the treatment of congenital adrenal hyperplasia (CAH) due to 21 -hydroxylase deficiency (21 -OHD) and to assess the need for sample purification by column chromatography to improve assay specificity.
Methodology: Morning serum 17-OHP was measured using RIA and 24-hour urinary pregnanetriol using gas chromatography. Twenty-four-hour urinary 17-OHP was measured in samples from 17 prepubertal patients with CAH due to 21 -OHD, and 20 normal prepubertal children as controls. In 24 urine samples, RIA of 17-OHP was performed with and without column chromatography.
Results: There was a good correlation between 24-hour urinary 17-OHP and 24-hour urinary pregnanetriol (r = 0.962, P <0.01) and between 24-hour urinary 17-OHP and morning serum 17-OHP ( r = 0.955, P <0.01). There was no significant difference in the RIA of the urine samples with and without purification by column chromatography.
Conclusions: The measurement of 24-hour urinary 17-OHP is a reliable alternative for the biochemical monitoring of 21-OHD, and RIA specificity is unaffected by omission of column chromatography.     

Long-term outcome of classical 21-hydroxylase deficiency: diagnosis, complications and quality of life

A nationwide search of patients with classical 21-hydroxylase deficiency (21-OHD) was performed in Finland to determine the long-term outcome of the disease. In total, 108 patients were found. Fifty-four patients (50%, 31F, 23M) had deficiency of a salt-wasting form and another 54 (50%, 29F, 25M) had a simple virilizing form of 21-OHD. A significant number of severe complications suggestive of glucocorticoid deficiency was found. There were five deaths (4.6% of all) possibly connected with cortisol deficiency. Ten additional patients (9.3% of all) had been acutely admitted 14 times in all due to symptoms of glucocorticoid deficiency. These symptoms included sudden loss of consciousness, convulsions and severe fatigue. Afterwards, permanent neurological defects were detected in two of these patients. Finally, a cross-sectional study was carried out to establish an estimate of the long-term outcome of the disease. Thirty-two (55%) of the 58 patients aged 16 y or more participated in this study. The patient group did not differ from the general Finnish population in terms of education. Three of the patients (5%) had retired prematurely. Surprisingly, the patients felt that their health-related quality of life, as reported in the RAND-36 questionnaire, was better than that of the general Finnish population ( p = 0.023). However, as a significant number of all patients did not participate in this study, the quality of life evaluation results must be interpreted with caution. In conclusion, a significant number of complications was found among patients treated for classical 21-OHD. Nevertheless, the disease has a favourable outcome in terms of quality of life.     

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。     

先天性肾上腺皮质增生症21羟化酶缺乏患者的生长与最终身高影响因素

先天性肾上腺皮质增生症(CAH)是一组常染色体隐性遗传病,由于肾上腺皮质激素合成酶的缺陷,皮质醇的合成部分或完全受阻使促肾上腺皮质激素(ACTH)分泌过多导致肾上腺皮质增生,同时皮质醇的前体产物过多堆积并转化为性激素.21羟化酶缺乏(21-OHD)是最常见的CAH,同时也是人类最常见的常染色体隐性遗传病之一,分为经典型...     

Adiponectin levels are high in children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency

Objective: It has been shown that adiponectin serves as an insulin-sensitizing adipokine. Serum concentrations of adiponectin are low in children with obesity, and increase with fat mass loss, indicating that adiponectin can serve as a biomarker. Since the prevalence of overweight and obesity is increased in children with congenital adrenal hyperplasia (CAH), our study aimed to evaluate serum levels of adiponectin in a cohort of CAH children and adolescents, and their associations with clinical parameters such as chronological age (CA), body mass index (BMI), Tanner stage (TS), medication and metabolic control.
Patients and methods: We studied 51 patients, aged between 5.6 and 19.6 years (median 11.8; 30 females, 21 males), cross-sectionally. All patients had genetically confirmed CAH and received standard steroid substitution therapy. Adiponectin was measured by an enzyme linked immunoassay. Since BMI SDS of the CAH cohort were significantly higher compared to the reference population, we built matched pairs with healthy Caucasian subjects from a normal representative cohort for sex, Tanner stage, chronologic age and BMI.
Results: Adiponectin concentrations were significantly higher in CAH patients (median 11 μg/L) compared to the matched controls (6.7 μg/L, p < 0.0001). Correlation analyses in CAH patients revealed a significant inverse relationship between adiponectin and CA, TS, BMI, serum DHEAS and serum testosterone, but no correlation with hydrocortisone and fludrocortisone dosage.
Conclusion: Currently, the importance of the elevated adiponectin concentrations in CAH children for risk assessment is not clear. However, our data imply that besides adequate metabolic control of glucocorticoid substitution, a long-term follow-up of other metabolic markers of insulin resistance should be conducted in CAH patients.     

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is associated with a prolonged gestational age

Background

The timing of parturition in most mammals is thought to be linked to a late gestational rise in corticosteroid production by the fetal adrenal gland. We hypothesised that gestational age would be prolonged in our patients with impaired cortisol production secondary to congenital adrenal hyperplasia (CAH) due to 21‐hydroxylase deficiency.

Methods

We compared the gestational age of patients affected by salt‐wasting CAH due to 21‐hydroxylase deficiency (born 1978–2004; n = 31) with that of children with congenital hypothyroidism (born 1981–2003; n = 30) and a control group of short normal children (born 1980–2002; n = 120). Each group was compared with national (England 2002–3) and regional (2003–4) data on gestational age from hospital episode statistics. Post‐term delivery was defined as birth beyond 41 completed weeks.

Results

National statistics reveal a frequency of 4.4% for singleton deliveries beyond 41 weeks. In our region the frequency was 4.6%. In the group of children with CAH, the frequency of post‐term delivery was 19.3% (p<0.001). In patients with congenital hypothyroidism, the frequency was 13.3% (p = 0.02). The proportion of short children who did not have a recognised endocrinopathy born post term was comparable to national and regional data at 6.7%.

Conclusions

A prolonged gestation is more likely in pregnancies where the fetus has the salt‐wasting form of CAH. This may be due to impaired cortisol production, although other changes in steroidogenesis may also be contributory.     

A Retrospective Analysis of the Growth Pattern in Patients with Salt-wasting 21-Hydroxylase Deficiency

The objective of this study was to investigate the growth pattern of children with the salt-wasting form of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (21-OHD). We reviewed the medical records of 13 patients in whom salt-wasting 21-OHD was diagnosed during the first 2 mo of life at our hospital from 1980 through 2008. Six reached adult height. Growth patterns, bone age, biochemical data, and the hydrocortisone dose at each growth stage were analyzed retrospectively. The mean adult height was 155.1 ± 6.5 cm (mean ± SD) in females and 158.1 ± 7.1 cm in males. Although length at birth was normal or longer than the national mean in almost all patients, the mean height SD score of both boys and girls decreased to below 0 SD during infancy. Subsequently, both boys and girls transiently showed growth acceleration and reached their peak growth velocity at 3–10 yr of age. In conclusion, in addition to suppression of growth during infancy, there was inappropriate growth acceleration during childhood. Especially from 3 mo to 3 yr of age, decreasing the hydrocortisone dose in patients who exhibit slower growth may lead to satisfactory height outcomes. Also, strict adjustment of the hydrocortisone dose to avoid accelerated growth from childhood to adolescence might improve adult height outcomes of patients with 21-OHD.     

Temporal and individual variations in the dose of glucocorticoid used for the treatment of salt-losing congenital virilizing adrenal hyperplasia due to 21-hydroxylase deficiency

The dose of glucocorticoid was evaluated in the treatment of 19 patients with salt-losing congenital adrenal hyperplasia due to complete or nearly complete 21-hydroxylase deficiency. In most cases, follow-up was from infancy to puberty. The dose of steroid was expressed as oral cortisol (mg/m² body surface area 124 hours); the equivalent doses of the various glucocorticoid preparations was as follows: 100 mg oral cortisol = 120 mg oral cortisone acetate = 25 mg oral prednisone = 50 mg intramuscular cortisol = 60 mg intramuscular cortisone acetate. The dose of glucocorticoid producing good laboratory and clinical control varied significantly with age. The dose fell from 26 mg/m²/24 hours in early infancy to 19 mg/m²/24 hours between 6 and 8 years of age, and then rose to 23–24 mglm²/hour in adolescence. In addition to these age-related changes, there were large individual variations at each age. Indeed, the values from 4 of the 19 patients were not included in the calculation of the mean because they were more than 3 SD either above or below the mean. For the rest of the patients, the coefficient of variation ranged from 14.5% to 37.2%. It is concluded that glucocorticoid therapy must be adjusted carefully to the age and needs of each patient.     

Molecular genetics of congenital adrenal hyperplasia (21-hydroxylase deficiency): implications for diagnosis, prognosis and treatment

The molecular genetics of congenital adrenal hyperplasia due to 21-hydroxylase deficiency are reviewed. In Sweden, mutation detection based on allele-specific PCR has been used for genetic diagnosis of this disease since 1993. Around 400 affected 21-hydroxylase genes have been analysed so far. An update of the spectrum of mutations among the Swedish patients shows that nine common pseudogene-derived mutations are responsible for the disease in around 95% of alleles. A total of 13 rare, mostly population-specific mutations have been characterized among the remaining 5%. The mutations can be divided into different groups according to severity. This makes it possible to predict clinical outcome in affected subjects based on genotyping. The risk of salt-wasting and prenatal virilization can be estimated, and over-treatment can be avoided in mildly affected cases.     

Elevation of serum luteinizing hormone levels during hydrocortisone treatment in infant girls with 21-hydroxylase deficiency

During the first months of postnatal life serum luteinizing hormone (LH) levels in girls are lower than in boys. The mechanism of this sex difference is not known. In order to study the possible influence of high levels of androgens and other adrenal steroids on serum gonadotropins during the first months of life, nine girls with salt-losing congenital adrenal hyperplasia (CAH), mean ± SD age 17.1 ± 7.52 days at diagnosis, were studied before and during oral hydrocortisone replacement therapy for 45.7 ± 29.8 days. A control group of 16 girls (C1) and 15 boys (C2), mean ages 41.7 ± 33.6 and 59.3 ± 43.3 days, respectively, was also studied. Serum LH and follicle stimulating hormone (FSH) were determined by enzymoimmunoassay in the presence of one monoclonal and one polyclonal antibody. In treated girls with CAH, mean ± SD serum LH (3.49 ± 82 IU1^?1) was significantly higher than in C1 (0.47 ± 0.38) p < 0.02, and similar to C2 (2.52 ± 1.74), while mean ± SD serum FSH (3.72 ± 1.78 IU1^?1) was not different from C1 (6.57 ± 5.23). The mean ± SD serum FSH/serum LH ratio (2.53 ± 1.44) was lower than in C1 (14.9 ± 13.6) and similar to C2 (1.60 ± 1.69). These data suggest that high levels of foetal and/or perinatal adrenal steroids, probably androgens, might modulate gonadotropin secretion after the neonatal period. The fact that, after adrenal steroid suppression, serum LH and the serum FSH/serum LH ratio in these infant girls with CAH were similar to that of control boys suggests that foetal or perinatal androgenic steroids have an effect on the control of LH secretion that persists after androgen withdrawal.     

Salt-wasting 21-hydroxylase deficiency congenital adrenal hyperplasia and pyloric stenosis in two Hispanic brothers

The differential diagnosis of vomiting and dehydration in the first month of life includes congenital adrenal hyperplasia (CAH) and pyloric stenosis (PS). Each diagnosis may mask the presence of the other, requiring careful evaluation and follow-up. We document the occurrence of CAH and PS in two Hispanic siblings.     

Urinary excretion of 17-hydroxypregnanolones in patients with different forms of congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency

To improve diagnostic criteria in different (classical salt-wasting (SW), classical simple virilizing (SV) and non classical late onset (LO)) forms of congential adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency, we investigated the urinary excretion of 17-hydroxypregnanolones (17OH-PO(5) and (5), 15-hydroxypregnanolone(15OH-PO), pregnanetriol(PT) and 11-oxo-pregnanetriol (11-O-PT) compared to hydrocortisone metabolities During the 1st month of life newborn infants with CAH-SW excreted from barely detectable to very large amounts of 17OH-PO(5), 15OH-PO and PT, and, in 12 of 14 cases, also 11-O-PT in their urines. From the 1st to the 28th day of life, cortisol metabolites were virtually absent in urines of CAH-SW infants. This was in contrast of 36 healthy newborn infants. We measured the excretion of 17OH-PO(5) in children with CAH of whom 19 patients with CAH-SV had a median 17OH-PO(5) excretion of 1110 g/day (range: 152–5515). In 21patients with CAH-LO, median excretion of 17OH-PO(5) was 294g/day (range: 66–1273). Besides the conventional metabolites of 17-hydroxyprogesterone (17OH-PO(5), PT and 11-O-PT),no 17OH-PO(5) was detected in the urines of 14 patients with precocious pubarche, in 14 patients with virilization of unknown origin and in 94 healthy children of comparable age. The ratio of 17OH-PO(5) to tetrahydrocortisone (THE) discriminated between CAH-SV and CAH-LO from the 1st to the 18th year of age. The determination of urinary 17OH-PO(5) is an excellent diagnostic method in CAH-SV as well as CAH-LO.