CONGENITAL ADRENAL HYPERPLASIA-NEJM PDF

NCBI Bookshelf. Endotext [Internet]. Congenital adrenal hyperplasia CAH refers to a group of disorders that arise from defective steroidogenesis. In general, all forms of CAH are transmitted in autosomal recessive mode of inheritance as a monogenic disorder. The other forms of CAH are considered rare diseases and the incidence is unknown in the general population. Prenatal androgen exposure in females affected with the classic forms of 21OHD CAH not only has a masculinizing effect on the development of the external genitalia, but also on childhood brain and behavior.

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An important goal in treating children with congenital adrenal hyperplasia CAH is to achieve a normal final adult height FH. The aim of this study was to describe the clinical presentations and evaluate linear growth and possible factors affecting it in children with CAH. This is a retrospective study of 56 patients with CAH followed up in a tertiary center for 11 years. Patient's data including demographics, clinical, anthropometric, and laboratory information at presentation and during follow-up period were collected from medical records.

Of these, Positive family history was documented in Males had significantly decreased HtSDS versus females and females had significantly higher body mass index. The HtSDS of children who had had higher 17OHP or salt-losing crisis during treatment was significantly lower than those who had normal 17OHP and those who did not have salt-losing crisis, respectively. The final height outcome in our patients with CAH treated with glucocorticoids is lower than the population norm.

Proper control of the disease clinically and biochemically through strict compliance to medical therapy as well as close clinical and laboratory monitoring is an important key to achieve normal final adult height in these patients. Side effects, including overweight, obesity, and hypertension are true risk associations and need timely diagnosis and early management. Congenital adrenal hyperplasia CAH occurs due to an autosomal recessive mutation in one of the five enzymatic steps necessary in the conversion of cholesterol to cortisol.

Incidence differs significantly among different populations. It ranges from 1 in live births in Yupik Eskimos of Alaska, to 1 in 5, live births in Saudi Arabia, to 1 in 23, live births in New Zealand. This allows transfer of genetic material between them, or loss on one chromosome and duplication on the other of the genetic material in the loop. The resulting mutations involving the CYP21A2 gene are associated with variable degrees of impairment in hydroxylase OH activity, ranging from complete inactivation to partially functioning enzymes, translating into a diverse range of disease severity and phenotypes.

However, the prediction of phenotype in relation to genotype is not always accurate. One study verified a genotype—phenotype concordance in Replacement glucocorticoid therapy remains the customary treatment for patients with CAH. The growth-suppressing effects of glucocorticoids, however, combined with early epiphyseal fusion from the high androgens in CAH, limit the height potential of patients affected with CAH.

Although quite often tall as children, many patients with CAH complete growth prematurely and are ultimately short as adults. Many other factors may contribute in the production of this short final adult height. These include the severity of the phenotype at presentation, the degree of control of hyperandrogenemia, the dose of corticosteroids and mineralocorticoids given and compliance with this medication.

Many factors could affect FH in these patients including, the age at diagnosis, severity of the disease, long-term glucocorticoid intake and their doses, degree of suppression of androgens, and compliance with medications and onset and progression of puberty.

Current information about the clinical presentation and linear growth of patients with CAH in Saudi Arabia is limited. The data of 56 patients were studied. The diagnosis was based on clinical features, endocrine data, and molecular genetic analysis. The children were treated with replacement doses of hydrocortisone and fludrocortisone as required.

Data were collected retrospectively in this study and no signed consent forms were obtained from parents as personal information was anonymous and data were kept confidential. Patients' data including demographics, clinical presentations, laboratory data, management, and clinical progress during their follow-up, were collected from medical records.

These included anthropometric data age, weight, and height , clinical data including the state of virilization in females and slat-losing manifestations, and laboratory data at diagnosis and follow-up including testosterone and hydroxy progesterone OHP. The anthropometric data at the last visit were recorded. The WHO growth standard references were used. Doses of hydrocortisone per square meter and fludrocortisone were recorded.

Serum OHP and testosterone concentrations were measured by standard radioimmunoassay method. All our classic CAH patients were treated with fludrocortisone at the time of diagnosis in the newborn period and treatment is lifelong; but the requirement decreases with growing age. Mineralocorticoid replacement is monitored by plasma renin activity and electrolytes as well as by blood pressure BP readings at clinic visits.

The bone age BA analysis was based on the left hand and wrist plain x -ray films, using the method of Greulich and Pyle. Student t -test was used to compare variables among the selected groups. Wilcoxon test was used to compare variables when the data were not normally distributed.

Linear regression equation was used to investigate possible correlation between variables. Initial Lab data at diagnosis showed that males had higher 17OHP and testosterone levels compared with females. Serum Na was significantly lower in females. At the last visit, the levels of 17 OHP, testosterone, and renin did not differ between males and females [ Table 2 ]. Comparison of anthropometric data between males and females showed that female group was significantly older than males in our cohort.

Neither hydrocortisone nor fludrocortisone doses differed among the two groups [ Table 3 ]. The doses refer to an average dose calculated for these patients during their follow-up. Comparison between patients who presented before versus after 1 month of age did not show significant difference in the electrolytes' levels or hormone concentrations among the two groups.

Treatment progress at the last visit showed that Physicians reported compliance in HtSDS did not differ between those who required versus those who did not require surgical correction. Patients who had salt-losing manifestations at presentation had HtSDS lower than those who did not have salt losing at diagnosis.

The HtSDS of children who had salt-losing crisis during treatment was significantly lower than those who did not have salt-losing crisis during treatment.

HtSDS of children who had higher 17OHP during treatment was significantly lower than those who did not have high levels during treatment. The compliance in the last column was based on the assessment of the clinician following the patient interview subjective. Recently introduced universal screening for CAH reported an incidence of 1 in 6, live births.

Fifty-one These results were comparable with other results obtained at different Saudi studies [ Table 5 ] and indicated that salt-losing manifestations became less frequent due to early diagnosis of these patients and stressed the importance of physicians' awareness and the need for a neonatal screening program for early detection and appropriate. The pediatric endocrinologist has the tough task of judiciously adjusting medications in actively growing children with CAH so as to avoid overtreatment as well as under treatment.

Glucocorticoid excess may result in poor linear growth, weight gain, hypertension, and other side effects. Under treatment may results in excess androgen production and advanced skeletal maturation. Patients with CAH due to hydroxylase deficiency OHD often reach a final height significantly below their parentally determined target height. In a meta-analysis, studies between and detected a short final height outcome in patients with CAH. It was generally perceived that children with CAH would eventually be short adults and consistently below their genetic potential.

Thirty patients had final adult height Age This confirmed that the height SDS was significantly decreased in adults compared with the childhood period. This effect on stature can be explained by excess androgens not suppressed well during therapy. Subsequently, these children develop fast linear growth during childhood associated with early epiphyseal fusion leading to short adult height. This conforms with other studies reporting decreased FH with males tending to have a slightly inferior outcome than females.

In a longitudinal study by Eugster et al. The early loss of prepubertal growth and relatively low PHV might have important implications for further growth and final height in these children. In addition, the growth of salt-wasting patients with CAH was impaired in infancy and early childhood 0—3 years of age ,[ 12 ] with normal patterns in childhood until puberty suggesting a great loss of stature occurring early in life.

However, all our patients were diagnosed during early infancy 0—6 months of age that did not allow studying this effect. Although clinical parameters such as growth velocity and BA remain the gold standard for monitoring the adequacy of therapy in CAH, the proper measuring of serum OHP level can offer a good tool in monitoring their control. There is now substantial evidence that with appropriate clinical management, most children with CAH can obtain a final height that is within their genetic potential.

A final adult height nearly equal to target height can be attained following strict compliance and regular clinic visits every three months has also been reported. This documented that the degree of control played an important role in stature growth.

Severity of disease may also have some deleterious effect on the final adult height in these patients. Depending on the severity of the mutation, OHD ultimately leads to variable degrees of glucocorticoid and mineralocorticoid deficiency due to the inability to produce cortisol and aldosterone.

In our cohort, the HtSDS of children who had salt losing crisis at presentation and during treatment suggesting a severe form of disease was significantly lower than those who did not have salt losing crisis during treatment. However, the HtSDS of those with high OHP and testosterone levels at presentation was not different than those with relatively lower levels. In addition, the HtSDS of females with ambiguous genitalia who required surgical correction more severe form of virilization did not differ than those with less genital ambiguity.

A comparison between patients with salt wasting SW versus those without salt losing SV showed no significant differences in height between the SW and SV groups. Besides the importance of excess adrenal androgen, other factors can negatively affect the attainment of optimal adult height in these patients. Central precocious puberty may develop in patients with CAH due to androgen activation of the hypothalamic-pituitary-gonadal axis, thus exacerbating premature epiphyseal fusion.

This supported the view that precocious puberty may compromise the final adult height. Chronic glucocorticoid therapy, even at replacement doses, has been linked with a higher risk for poor growth. It has been shown that long-term glucocorticoid treatment during childhood, particularly during the pubertal growth spurt, can adversely affect final height.

In addition to the judicious use of standard glucocorticoid, other therapies may help patients to achieve normal adult height. In a 2-year randomized parallel study of 28 children, patients receiving the experimental four-drug regimen had normal growth and bone maturation, despite elevated adrenal steroids.

Children with CAH are at an increased risk of developing obesity. Females had higher BMI versus males. It is generally believed that excess glucocorticoid treatment in children with CAH results in weight gain.

Hypertension is an additional risk factor associated with CAH. Their dose of hydrocortisone Our findings support the study of Nebesio et al. An elevated BMI was not a determining factor in the development of hypertension in their patients. The average BMI was not statistically different between those without hypertension Increased insulin and leptin levels correlated well with BMI and age, but the laboratory markers of CAH control, glucocorticoid dose, and fludrocortisone dose did not correlate with blood pressure.

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This is performed for the investigation of congenital adrenal hyperplasia CAH in children and adults. Adrenal glucocorticoid secretion is controlled by adrenocorticotrophic hormone ACTH released by the anterior pituitary. In subjects with enzyme deficiency in the steroid synthetic pathway, cortisol may, or may not, be adequately secreted. However, there is excessive secretion of the precursor steroids before the defective enzyme. The commonest form of CAH is due to deficiency of hydroxylase and in these subjects increased secretion of 17 OH-progesterone can be detected. There are rare reports of hypersensitivity reactions to Synacthen particularly in children with history of allergic disorders.

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