Congenital Adrenal Hyperplasia Children Research Articles

Hospital Admission Patterns in Children with CAH: Admission Rates and Adrenal Crises Decline with Age.

Objective. To examine patterns of hospitalisation for acute medical conditions in children with congenital adrenal hyperplasia (CAH). Design. A retrospective study of hospitalisation using administrative data. Setting. All hospitals in NSW, Australia. Patients. All patients admitted with CAH and a random sample of admissions in patients aged 0 to 18 years without adrenal insufficiency (AI). Main Outcome Measures. Admissions and comorbidities by age and sex. Results. Of 573 admissions for medical problems in CAH children, 286 (49.9%) were in males, and 236 (41.2%) had a principal diagnosis of CAH or had an adrenal crisis (AC). 37 (6.5%) ACs were recorded. An infection was found in 43.5% (n = 249) of the CAH patient admissions and 51.7% (n = 1613) of the non-AI group, p < 0.001. Children aged up to one year had the highest number of admissions (n = 149) and six ACs (four in males). There were 21 ACs recorded for children aged 1–5 years. Older CAH children had fewer admissions and fewer ACs. No in-hospital deaths were recorded. Conclusions. Admission for medical problems in CAH children declines with age. An AC was recorded in 6.5% of the admissions, with the majority of ACs occurring in the 1 to 5 years age group and there were no deaths.

Correlation of Bone Mineral Parameters with Anthropometric Measurements and the Effect of Glucocorticoids on Bone Mineral Parameters in Congenital Adrenal Hyperplasia.

To correlate the bone mineral parameters [bone mineral content (BMC) and bone mineral density (BMD)] using Dual energy X ray Absorptiometry (DXA) scan with anthropometric measurements and to study the effect of glucocorticoid therapy on BMC/BMD in children with Congenital adrenal hyperplasia (CAH). A cross-sectional study was carried out in the Pediatric Endocrinology unit from January 2012 through March 2013 at Kanchi Kamakoti CHILDS Trust hospital, Chennai. Thirteen CAH children aged 0-132 mo with classic salt wasting due to 21 hydroxylase deficiency were included in the study. All children were treated with T.hydrocortisone @10-15 mg/m(2)/d twice daily and T. fludrocortisone 50 μg once daily orally at the time of enrollment into the study. The duration of glucocorticoid (hydrocortisone) treatment from the date of diagnosis till the time of enrollment into the study was noted and categorized as children receiving < 5 and > 5 y of glucocorticoid therapy. None received Vitamin D/calcium supplementation at the time of enrollment. BMC and areal BMD for the lumbar spine and total body less head (TBLH) were measured with Lunar DXA machine. The mean height, weight and BMI of children were 87.3 ± 33 cm, 13.49 ± 11.2 kg and 14 ± 4.07 kg/m(2) respectively. TBLH BMC was 369.14 ± 312.18 g and TBLH BMD was 0.63 ± 0.11 g/cm(2). There was a significant correlation between height and total body less head BMC/BMD in the index series [P < 0.05, significant]. The TBLH and spine BMD were also assessed with regards to the duration of glucocorticoid therapy and it has been observed that TBLH and spine BMD decreased with increased duration of steroid therapy (p < 0.05, significant). In the absence of normative data or z scores, BMC/BMD correlates well with height for age. Children who received more than 5 y of glucocorticoid treatment had lower TBLH and spine BMD scores and hence, calcium and Vitamin D supplementation should be considered.

Use of Automated Bone Age for Critical Growth Assessment.

We compared the variability of bone age (BA) rating between clinicians and an automated system in children with congenital adrenal hyperplasia (CAH). A total of 126 radiographs assessed by 3 clinicians blinded to patient details using Greulich and Pyle (GP) (readers 1, 2, and 3) and BoneXpert (BX). Comparing BA rating with each other, the mean of the absolute differences varied from 0.42 ± 0.53 years (reader 1 and BX) to 0.57 ± 0.58 years (reader 2 and reader 3), P = .368. Comparing ratings that were consistent with all 4 methods (within 1 year of each other, 93/126, 74%) and the remaining, "outliers" (33/126, 26%), the outliers were younger (P = .003), smaller (height, P = .011, weight, P = .000), and prepubertal (P = .001). The variability of BA rating in CAH children is similar whether performed by clinicians or an automated system. The greatest variability was in prepubertal children.

Congenital adrenal hyperplasia in children--a survey on the current practice in the UK.

Congenital adrenal hyperplasia (CAH) in children varies in presentation and progression with several challenges in optimal management. Effective treatment is to achieve normal growth and development while avoiding adrenal crisis and hyperandrogenisation. Our aim was to ascertain the current practice in the UK on CAH management in children in comparison with the recommendations made by the Endocrine Society. An online survey was emailed to the British Society of Paediatric Endocrinology (BSPED) members requesting a response from each centre regarding CAH management. The survey was completed by 35 out of 92 centres (38% response rate). Tertiary centres constituted 22/35, while 8/35 were district general hospitals providing tertiary services. Treatment varied among centres with 25/35 using 10-15 mg/m2/day of hydrocortisone and 21/35 of centres using 50-150 μg/day of fludrocortisone. The frequency of clinical reviews was contentious and varied depending on the child's age and clinical status. Reviews were done 3-4 monthly in 68% and 6 monthly in 31% of centres. The frequency of investigations including 17-hydroxyprogesterone (66% 3-6 monthly; 34% yearly), testosterone/dehydroepiandrosterone sulphate (37% 6 monthly; 51% yearly), renin/aldosterone (31% 6 monthly; 69% yearly) and bone age (83% yearly, 6% 2 yearly) varied significantly among centres. Genetic counselling was provided at diagnosis in 69% of the centres while surgical (66%) and psychology (80%) input were provided on an as required basis. Our survey highlights the diversity in managing children with CAH in the UK as compared with the recommendations of the Endocrine Society. It also demonstrates inconsistent involvement of essential specialist services, which are essential for optimal management of this condition.

Clinical profile and inheritance pattern of CYP21A2 gene mutations in patients with classical congenital adrenal hyperplasia from 10 families.

Context:Congenital adrenal hyperplasia (CAH) is an autosomal recessive metabolic disorder caused by mutations in the CYP21A2 gene. Genetic diagnosis of 21-OH deficiency causing CAH is more complicated than any other monogenic disorder due to high variability of the locus. The disease has a wide spectrum of clinical variants making it difficult to establish a genotyp–phenotype correlation. Therefore, family studies are necessary to ascertain parental genotype and segregation of the mutant allele among the offspring.Aim:The present study aimed to identify CYP21A2 gene mutations and analyze the segregation pattern in CAH trios (patients and their parents).Materials and Methods:A total of ten families having at least one CAH child were recruited.Results:Out of 31 children from ten families, 15 were affected with CAH and 13 of/them (12 females and 1 male) were available for genetic testing. One family had all the children affected with CAH. Compound heterozygous mutations were identified in seven patients (53.8%) whereas p.P30L, In2 and Δ8 bp mutations were present in homozygous state in three (23.1%), two (15.3 %) and one (7.6%) patient respectively.Conclusions:In majority of the families, mutant alleles observed in the patients were inherited from the parents whereas three families showed sporadic mutations without any paternal or maternal origin. This indicated their novel occurrence due to misalignment of the parental genes and/or large deletion of the gene. Female preponderance was noted in the CAH families and also among the patients raising the possibility of survival advantage among females.

Congenital Adrenal Hyperplasia: Issues in Diagnosis and Treatment in Children

Congenital adrenal hyperplasia (CAH) is a common disorder of impaired adrenal cortisol biosynthesis with associated androgen excess. The clinical presentation of 21-hydroxylase deficiency, the commonest cause of CAH, forms a spectrum and can be divided into classic and non-classic types. The former consists of life threatening salt wasting and non-life threatening simple virilizing phenotypes. Patients with the non-classic form are asymptomatic or have mild features of androgen excess. Most developed countries have newborn screening facilities for CAH. In the absence of newborn screening, the diagnosis of CAH may be missed or delayed. This can result in neonatal mortality in salt wasting forms and incorrect sex of rearing in females with simple virilizing form. The diagnosis is reached by demonstrating high serum 17-hydroxyprogesterone (17OHP) levels. Preterm birth and neonatal illness can cause physiological elevation of 17OHP, thus complicating the diagnosis of CAH in the newborn period. Prenatal diagnosis and treatment with dexamethasone to prevent virilization of affected female fetuses is another area of controversy. The management of CAH is complicated by the need to use supraphysiologic doses of glucocorticoids to suppress adrenal androgen synthesis. In this review, the authors address pertinent issues related to the diagnosis and management of CAH in children.

Behavioral aggressiveness in boys with sexual precocity

Background:Some boys with sexual precocity are known to have behavioral problems like increased physical and verbal aggression and school and social maladjustments. It is believed to be due to premature androgen exposure. However, it is not clear why only some develop this problem, difference in etiology could be one explanation.Aim:The aim of the study is to assess behavioral aggression in boys with sexual precocity due to different disorders.Materials and Methods:Seven children, ages three to seven years, were enrolled for this study. Two were diagnosed to have congenital adrenal hyperplasia (CAH), three had testotoxicosis, while two had central precocious puberty. Parents of children with precocious puberty underwent the (CASP) questionnaire (children's aggression scale-parent version).Results:Testosterone levels were high in all patients. Parents denied any history of physical or verbal aggression in the two boys with CAH. Their CASP rating was 0. In contrast, the CASP ratings in the two boys with testotoxicosis and the two with precocious puberty for five domains ranged from 3.1 – 24.2, 2.6 – 8.3,1-5.6,0 – 7.1, and 0 – 1, respectively. In the present study, increased aggression was seen among all the patients with testotoxicosis and both with precocious puberty. In contrast, there were no symptoms of either increased verbal or physical aggression in either of the two patients with CAH.Conclusions:The hormonal milieu in the boys with CAH versus those with sexual precocity due to other causes differed in terms of cortisol and androgen precursors. The androgen excess in CAH children was a consequence of cortisol deficiency. It is possible that cortisol sufficiency is required for androgen-mediated behavioral effects.

Clinical and MRI characteristics of acute encephalopathy in congenital adrenal hyperplasia

Acute encephalopathy in childhood is frequently associated with common infections, especially in East Asia. Various types have been identified although many cases remain unclassified. Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease presenting impairment of cortisol biosynthesis. We report three CAH children with acute infection-related encephalopathy. They exhibited disturbed consciousness or seizures, which did not improve after glucocorticoid administration, accompanied by clinical and laboratory findings of adrenal insufficiency. Brain MRI disclosed various patterns of white matter lesions, suggesting different types of acute encephalopathy such as clinically mild encephalitis/encephalopathy with a reversible splenial lesion or hemiconvulsion-hemiplegia syndrome. Acute encephalopathy should be considered and brain MRI immediately performed when impairment of consciousness does not improve after intravenous glucocorticoid administration in CAH patients. Further research is required to elucidate the epidemiology and pathogenic mechanisms of acute encephalopathy in CAH.

Growth Pattern of Untreated Boys with Simple Virilizing Congenital Adrenal Hyperplasia Indicates Relative Androgen Insensitivity during the First Six Months of Life

Context: Mild forms of simple virilizing congenital adrenal hyperplasia (CAH) may be missed in newborn screening. In the pre-newborn-screening era, missed diagnosis of simple virilizing CAH was not infrequent in boys. Elevated adrenal androgens lead to accelerated growth and bone maturation. Traditional treatment of CAH consists of the suppression of ACTH through glucocorticoid replacement, in an attempt to reduce excessive androgen production. Objective: To retrospectively analyze early growth pattern and bone maturation in untreated boys with simple virilizing CAH. Patients: In the pre-newborn screening era, 13 boys had a late diagnosis of simple virilizing classical CAH. Diagnosis of 21-hydroxylase deficiency was confirmed by mutation analysis of the CYP21A2 gene in all patients. Growth data were retrospectively collected from standarized preventive medical checkups at the regular pediatrician until the time of diagnosis of CAH. Results: Length was 0.1 ± 0.8 SDS (mean ± SD) at birth, 0.2 ± 1 SDS at 3 months, 0.2 ± 0.9 SDS at 6 months, 0.7 ± 1 SDS at 1 year, +1.1 ± 0.9 SDS at 2 years and +1.8 ± 1.2 SDS at 4 years. At diagnosis, mean chronological age was 4.4 ± 1.6 years and height SDS was 2 ± 1.7. Bone age was accelerated (9.4 ± 4 years) at diagnosis. Signs that had led to diagnosis were pubic hair (n = 11), accelerated growth rate (n = 6) and birth of an affected sister (n = 3). Despite late start of hydrocortisone treatment, mean final height was –1 ± 0.9 SDS. Seven of 18 patients had a final height within 1 SD of target height. Conclusion: Height velocity is not markedly increased in untreated boys with simple virilizing CAH in the first 6 months of life, indicating that infants are relatively androgen insensitive during that period. After the first 6 months of life, growth velocity increases significantly and elevated androgens lead to advanced skeletal maturation. This observation has implications for lower hydrocortisone doses to be used in CAH children during the first 6 months of life. In addition, staying alert for clinical symptoms and signs of simple virilizing CAH is still warranted, since mild forms may be missed in newborn screening.

Growth Impairment in a Boy with Late-Onset Congenital Adrenal Hyperplasia and Anorexia Nervosa

Treatment of congenital adrenal hyperplasia (CAH) in its salt-wasting form with appropriate doses of glucocorticoids and mineralocorticoids should promote growth, puberty and final height in a similar to normal pattern. However, the individual requirements for these drugs to normalize the hormonal profile and to achieve a physiologic growth pattern may differ. Moreover, the time of onset of puberty is also unpredictable since the course of the disease may predispose for precocity. The aim of this study was to explain the unexpected arrest of growth during puberty in a boy with late-onset CAH, who had been treated with glucocorticoid from early childhood. A short course of GnRH agonist treatment was also introduced in later years. The growth chart reflects two periods of impaired growth velocity preceded by weight loss. The reason for the first decline is difficult to prove retrospectively, but during the second episode the boy became both clinically and hormonally hypogonadal. At that time the anorexia nervosa (AN) was diagnosed according to APA DSM-IV criteria. We conclude that there were several reasons for the discontinued growth spurt and reduced final height in this boy with CAH: (a) early variant of puberty and subsequent late treatment with GnRH agonist, (b) AN possibly occurring during mid-childhood and clearly during puberty and (c) the repeated use of high doses of glucocorticoids. AN, a relatively rare disorder in boys, appears to have had a significant negative effect on this patient's growth and should be considered in the differential diagnosis in CAH children with impaired growth.

Insulin sensitivity and body composition in children with classical and nonclassical congenital adrenal hyperplasia

Reduced insulin sensitivity and increased fat mass have been reported in children and adults with congenital adrenal hyperplasia (CAH). To understand the potential mechanisms underlying these differences, we assessed insulin sensitivity and body composition in children with classical or nonclassical (late-presenting) CAH compared with normal controls. Thirty-seven children with CAH (26 classical and 11 nonclassical) median (range) age 9.4 year (0.5-15.8) were compared with 41 healthy control children age 11.0 year (3.2-17.1). All children had an overnight fasting blood sample and body composition assessed by DEXA. Pubertal children (14 CAH and 19 controls) also had an oral glucose tolerance test. Classical and nonclassical CAH groups were each compared with controls, adjusting for age, gender and pubertal status. Results Classical CAH children had more fat mass than controls (P = 0.03), while nonclassical CAH children had more lean mass (P = 0.006) and higher systolic blood pressure (P = 0.003) than control children. Among pubertal children, nonclassical CAH children had higher mean insulin (0-120 min; P = 0.04), stimulated insulin (0-30 min; P = 0.02), 120 min insulin (P = 0.004) and 120 min glucose levels (P = 0.03) than controls, but no difference in disposition index. Greater body fat in classical (early-presenting) CAH children could reflect the effects of lifetime glucocorticoid therapy. In contrast, the greater lean mass and parameters of insulin resistance in nonclassical (late-presenting) CAH children likely indicate the adverse metabolic effects of prolonged postnatal androgen excess.

Molecular analysis of CYP21A2 can optimize the follow‐up of positive results in newborn screening for congenital adrenal hyperplasia

Neonatal screening for congenital adrenal hyperplasia (CAH) is useful in diagnosing salt wasting form (SW). However, there are difficulties in interpreting positive results in asymptomatic newborns. The main objective is to analyze genotyping as a confirmatory test in children with neonatal positive results. Patients comprised 23 CAH children and 19 asymptomatic infants with persistently elevated 17-hydroxyprogesterone (17OHP) levels. CYP21A2 gene was sequenced and genotypes were grouped according to the enzymatic activity of the less severe allele: A1 null, A2 < 2%, B 3-7%, C > 20%. Twenty-one children with neonatal symptoms and/or 17OHP levels > 80 ng/ml carried A genotypes, except two virilized girls (17OHP < 50 ng/ml) without CAH genotypes. Patients carrying SW genotypes (A1, A2) and low serum sodium levels presented with neonatal 17OHP > 200 ng/ml. Three asymptomatic boys carried simple virilizing genotypes (A2 and B): in two, the symptoms began at 18 months; another two asymptomatic boys had nonclassical genotypes (C). The remaining 14 patients did not present CAH genotypes, and their 17OHP levels were normalized by 14 months of age. Molecular analysis is useful as a confirmatory test of CAH, mainly in boys. It can predict clinical course, identify false-positives and help distinguish between clinical forms of CAH.

Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Testicular adrenal rest tumours (TART) are a well-known complication in adult male patients with congenital adrenal hyperplasia (CAH), with a reported prevalence of up to 94%. In adulthood, the tumours are associated with gonadal dysfunction most probably due to longstanding obstruction of the seminiferous tubules. The aim of our study was to determine the presence of TART and their influence on gonadal function in childhood. Retrospective study. Scrotal ultrasound was performed in 34 children with CAH due to 21-hydroxylase deficiency who were between 2 and 18 years old. FSH, LH, testosterone and inhibin B concentrations were measured in serum of 27 patients. TART were detected by ultrasound in 8 out of 34 (24%) children. In two of them, bilateral tumours were found. All lesions were located in the rete testis. Seven patients had the salt-wasting type of CAH; one patient had the simple virilising type of CAH. Mean tumour size was 4.1 mm (range 2-8 mm). In none of the patients were the tumours palpable. Two children with TART were between 5 and 10 years old, the other six children were above 10 years old. In all children with TART, LH, FSH, testosterone and inhibin B levels were similar to the patients without TART. TART can be found in CAH children before the age of 10 years. The absence of gonadal dysfunction in our group of children suggests that gonadal dysfunction as frequently reported in adult CAH patients with TART develops after childhood.

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

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. To assess how children with CAH are treated in Canada. 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. 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.

Growth Patterns and Final Height in Congenital Adrenal Hyperplasia due to Classical 21-Hydroxylase Deficiency

Background: Longitudinal growth and bone age (BA) development are the most important clinical parameters for monitoring adequate glucocorticoid replacement in children with congenital adrenal hyperplasia (CAH). Aim of the Study: To analyze the growth pattern of patients treated for CAH of the salt wasting (SW) and simple virilizing (SV) clinical forms; to evaluate final height as compared to reference data and individual target height; to evaluate the course of BA development. Patients and Methods: A large database of 598 patients with CAH was created in 5 Central European countries and growth data of 341 treated patients with 21-hydroxylase deficiency were analyzed retrospectively. The patients were of Caucasian origin. Centiles were constructed in a cross-sectional manner and an additional longitudinal analysis was performed in order to evaluate the pubertal growth spurt by applying particular statistical methods (Preece-Baines model). Results: The growth of SW CAH patients was impaired in infancy and early childhood (0–3 years of age), but followed normal patterns in childhood until puberty. In contrast, children with SV CAH had normal patterns of growth in infancy and early childhood and were considerably taller than healthy references during childhood. In the longitudinal study, peak height velocity in both boys and girls was normal, but it occurred at an earlier age than in the standard population. The final height of patients with CAH was reduced in comparison to both the reference and the individual target height. No correlations were found between final height and age at the start of the therapy in SV patients or between final height and year of birth. BA was advanced in both types of CAH, but more accelerated in SV patients. Conclusion: Characteristic growth patterns for treated SV and SW CAH children were identified, with a normal pubertal growth spurt and reduced final height being observed.

DEXAMETHASONE TREATMENT OF CONGENITAL ADRENAL HYPERPLASIA IN UTERO: AN EXPERIMENTAL THERAPY OF UNPROVEN SAFETY

Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency is a common cause of genital virilization in female infants resulting from inappropriate fetal adrenal androgen secretion. Some investigators have advocated treating pregnant women who are at risk for carrying a CAH fetus with dexamethasone to suppress fetal adrenal androgen synthesis. Experience to date shows that this treatment can be effective in ameliorating the genital virilization in female fetuses. However, the doses used are supraphysiological, the mechanism of dexamethasone action in the fetus is unclear and no long-term followup studies have been done. To be effective the treatment would need to be started by week 6 of gestation but the genetic diagnosis cannot be made until week 12. If the mother has had a previous CAH child, only 1 in 4 pregnancies will be affected and only the female fetuses stand to benefit from treatment, thus, 7 of 8 fetuses will be treated needlessly. In view of these and other concerns, the prenatal treatment of CAH remains an experimental therapy and, hence, must only be done with fully informed consent in controlled prospective trials approved by human experimentation committees at centers that see enough of these patients to collect meaningful data.