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??Congenital adrenal hyperplasia??CAH??is mainly caused by 21-hydroxylase deficiency??21-OHD??. Nationwide neonatal screening for CAH caused by 21-OHD in China is based on measurement of 17-hydroxyprogesterone ??17-OHP?? levels from heel-stick blood samples on filter paper. The situation and methods of neonatal screening??confirmed diagnosis and therapeutic rule for CAH in China and other countries are described for the standardization of screening.     

Infant with classic congenital adrenal hyperplasia (CAH) born to a mother with classic CAH

We report a female infant with classic congenital adrenal hyperplasia (CAH), secondary to 21-hydroxylase deficiency, who was born to a mother with salt-wasting CAH.     

Twenty years experience in rapid identification of congenital adrenal hyperplasia in Hungary

The aim of this study was to assess the effectivity of the identification of patients with congenital adrenal hyperplasia (CAH) in Hungary in the absence of systematic neonatal screening and to estimate the incidence. Dried blood-spot samples of patients clinically suspected at any age to have CAH were collected between 1978 and 1998 throughout the whole country. 17-Hydroxyprogesterone (17-OHP) was measured by radioimmunoassay. Age-specific cut-offs were used. The effectivity of the system was retrospectively assessed. Additional cases were sought to assess the overall incidence of CAH in Hungary. Among the 1,837 patients investigated, 185 cases of CAH were identified. The overall effectivity was 94.7%. The sensitivity and the specificity were 98.9% and 94.2%, respectively. Salt-wasting (SW) boys were, on average, diagnosed 2 weeks later than SW girls, while both boys and girls with the simple virilising (SV) form were diagnosed at similar ages (2 versus 2.5 years). An additional 19 cases were diagnosed during the study period using other methods (plasma and urinary steroid profiles without blood-spot 17-OHP measurements). The incidence of classical CAH in Hungary was 1:14,300 (CI 95% between 1:12,450 and 1:16,795). Presuming that the incidence of CAH is the same among boys and girls, one can calculate that the diagnosis was missed in 24 boys (2 SW, 22 SV). Conclusion: it is possible to identify the vast majority of classical cases of congenital adrenal hyperplasia without a neonatal mass screening programme. However, a significant number of boys with the simple virilising form missed whereas both salt-wasting boys and girls are diagnosed safely.Abbreviations CAH congenital adrenal hyperplasia - 11-OHD 11-hydroxylase deficiency - 21-OHD 21-hydroxylase deficiency - 17-OHP 17-hydroxyprogesterone - NCAH non-classical congenital adrenal hyperplasia - RIA radioimmunoassay - SV simple virilising - SW salt-wasting     

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.     

Prevalence of congenital adrenal hyperplasia in Kuwait

Between 1978 and 1988 congenital adrenal hyperplasia (CAH) was diagnosed in 60 children in Kuwait with an estimated prevalence of 19,000 livebirths, which is higher than that reported from Europe and Canada. In addition, there was presumptive evidence of CAH resulting in the death of 20 other children, giving a prevalence figure of 17000. There were 41 girls (68%) and 19 boys (32%). Thirty-one of the girls (75.6%) and 11 of the boys (57.9%) were saltlosers. Fifty-four patients (90%) were diagnosed as 21-hydroxylase deficient, 3 patients (5%) had a deficiency of the 3-hydroxysteroid dehydrogenase enzyme, and 3 patients (5%) showed a deficiency of 11-hydroxylase.     

Prednisolone in the treatment of adrenal insufficiency: a re-evaluation of relative potency

Prednisolone has unknown growth-suppressing effects relative to other steroids. We retrospectively studied 9 children (6 with congenital adrenal hyperplasia, CAH) receiving hydrocortisone replacement after switching to prednisolone (dose ratio, 1:5). Growth velocity and, in patients with CAH, 17-OHP decreased significantly. Dose reduction reversed these effects. Roughly, growth suppression relative potency for prednisolone:hydrocortisone was 15:1.     

Psychological adjustment in children and adults with congenital adrenal hyperplasia

OBJECTIVE: To determine psychological health in individuals with one form of intersexuality, congenital adrenal hyperplasia (CAH), and its relation to characteristics of the disease and treatment. STUDY DESIGN: Participants (ages 3-31 years) included 72 females and 42 males with CAH, and unaffected relatives (44 females and 69 males). Psychological adjustment was assessed with parent-reports on the Child Behavior Checklist (CBCL) and subject self-reports on the Self-Image Questionnaire for Young Adolescents (SIQYA) or the Multidimensional Personality Questionnaire (MPQ). Information about disease characteristics and genital surgery was obtained from medical records. RESULTS: There were no significant differences between females with CAH and unaffected females on any measure. Psychological adjustment was not significantly associated with genital virilization or age at genital surgery. Males with CAH were not significantly different from unaffected males in childhood, but they showed more negative affect at older ages. CONCLUSIONS: Psychological adjustment is not compromised in females with virilized genitalia who are treated early in life and reared as females. Adjustment does not appear to depend on the characteristics of the disease or its treatment, but sample size and restricted range limit generalizability about adjustment-disease associations.     

17-Hydroxyprogesterone rhythms and growth velocity in congenital adrenal hyperplasia

Six patients on steroid replacement therapy for congenital adrenal hyperplasia provided capillary blood samples collected at 0800, 1200, 1700, and 2200h, on to filter paper for 17-hydroxyprogesterone analysis. There was a strong correlation between 17-hydroxyprogesterone day profiles and height velocity over a 4 year period of study. Steroid over-replacement, identified by significantly decreased height velocity (Standard Deviation Score [SDS] 1.92), caused suppression of 17-hydroxyprogesterone concentrations to below 10 nmol/L throughout the day. Near average height velocity (Standard Deviation Score 0.245) was accompanied by suppression of 17-hydroxyprogesterone concentrations below 40 nmol/L but with significant diurnal variation. Under-replacement with rapid height velocity and bone maturation was accompanied by non-suppression of 17-hydroxyprogesterone concentrations (i.e. > 40 nmol/L). These results suggest that serial blood spot 17-hydroxyprogesterone measurements are a convenient and helpful supplement to measurements of height velocity and bone age maturation to monitor steroid replacement therapy in congenital adrenal hyperplasia. These measurements may be useful particularly in differentiating between over-replacement and appropriate replacement, and should allow adjustments in dose before abnormal growth patterns are established.     

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...     

False negative 17-hydroxyprogesterone screening in children with classical congenital adrenal hyperplasia

We report 5 out of 214 children with classical congenital adrenal hyperplasia (CAH) that was not detected by neonatal 17-Hydroxyprogesterone screening. Therefore, diagnosis was only based on a suspect clinical picture and subsequent re-evaluation. In addition to 3 patients suffering from the simple virilizing form of CAH and not reported so far, the remaining 2 children whose CAH was missed by the screening suffered from the severe salt-wasting form. This report underlines the importance of a careful clinical investigation of newborns to detect signs of genital virilization. The differential diagnosis of classical CAH should be kept in mind even if neonatal screening is reported to be normal.     

Congenital adrenal hyperplasia: Experience at intersex clinic,AIIMS

During 1981–88, 63 cases of female pseudohermaphroditism (FPH) were seen at the Intersex clinic at AIIMS, of whom 34 (54%) were diagnosed as due to congenital adrenal hyperplasia (CAH). Though ambiguity was present at birth in most cases, only one child was brought immediately after birth, while 14 presented after one year. Family history of affected siblings and fetal wast-age was present in 10. Salt wasting symptoms were present in 13 (38.2%), evidence of early virilization in 10 (29.4%) and generalised hyperpigmentation in 7 (20.6%). Clitoromegaly was present in 30 children with labial fusion in 10 and scrotalisation of labia in 6. The urogenital opening was single in 25 (73.5%). Buccal smear was positive for sex chromatin in 19. Chromosomal pattern showed 46 XX in 33. Dyselectrolytemia was present in 16 children. Bone age was advanced in all. Adrenal hyperplasia could be documented in 3 on CT scan. All the girls were put on hydrocortisone or prednisolone, and fluodrocortisone was given only to children with salt wasting CAH. Children with CAH are being broght to medical attention much too late and investigative and therapeutic facilities are grossly inadequate. There is a need to educate primary care physicians for early case detection and provide minimum diagnostic and therapeutic facilities in regional centres. This article is based on the presentation in the “International Workshop on Recent Advances in Neonatal Surgery and Intersex Disorders” held at All India Institute of Medical Sciences, New Delhi from March 1–4, 1989. It was accepted for publication in 1991.     

Steroid 21 hydroxylase deficiency congenital adrenal hyperplasia

Steroid 21 hydroxylase deficiency is the most common form of congenital adrenal hyperplasia (CAH). The severity of this disorder depends on the extent of impaired enzymatic activity, which is caused by various mutations of the 21 hydroxylase gene. This article reviews adrenal steroidogenesis and the pathophysiology of 21 hydroxylase deficiency. The three forms of CAH are then discussed in terms of clinical presentation, diagnosis and treatment, and genetic basis. Prenatal diagnosis and treatment are also reviewed. The goal of therapy is to correct the deficiency in cortisol secretion and suppress androgen overproduction. Glucocorticoid replacement has been the mainstay of treatment for CAH, but new treatment strategies continue to be developed and studied.     

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.     

Growth in congenital adrenal hyperplasia

Individuals with congenital adrenal hyperplasia (CAH) are shorter, on an average, than the general population. A recent meta analysis of final height in CAH indicated that the height deficit is typically 1 to 2 standard deviations below the mean in both males and females. Growth in CAH due to 21-hydroxylase deficiency is influenced by a number of factors, related both to the underlying disease and its treatment. In general, males with the simple virilising form have the poorest height prognosis. This relates in part to late diagnosis and treatment and the bone age advancement seen in individuals with untreated postnatal androgen excess. Obesity in CAH patients also appears to be correlated with reduced height potential. Glucocorticoid treatment which is vital for cortisol replacement, prevention of adrenal crises and androgen suppression, results in growth inhibition when administered in larger doses. Current evidence suggests that infancy and peripubertal periods are the time periods where heights outcome is most sensitive to glucocorticoid dose. More recent estimates of physiological cortisol secretion rates indicate that standard cortisol replacement schedules may result in overtreatment. In addition, dose titration to achieve complete androgen suppression and normalization of 17-hydroxyprogesterone is likely to result in overtreatment and consequent growth impairment. Optimization of current treatment may lead to further improvements in height prognosis. The potential benefits of more complex treatment regimes, using aromatase inhibitors and antiandrogens, in combination with a reduced glucocorticoid dose remain uncertain.     

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.     

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.     

先天性肾上腺皮质增生症合并中枢性性早熟临床分析

目的分析先天性肾上腺皮质增生症(CAH)患儿合并中枢性性早熟的临床表现。方法通过回顾性分析和临床随访,在12例21羟化酶缺乏患儿中发现20例合并中枢性性早熟。根据治疗和非治疗情况分为A组(9例)和B组(11例),分析其发生的年龄、骨龄以及与激素替代治疗的关系。结果A组中发生中枢性性早熟的实际年龄平均为(5.6±2.1)岁,骨龄平均为(12.0±3.2)岁;B组中诊断中枢性性早熟平均年龄在(6.8±1.1)岁;骨龄平均值在(11.7±2.0)岁,两组在统计学上差异无显著性。B组应用氢化可的松治疗后平均2.3年出现中枢性性早熟。结论CAH患儿骨龄发育提前是发生性早熟的主要原因,早诊断和早治疗可改善预后。