Current Advances in the Management of Congenital Adrenal Hyperplasia.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic condition caused by various enzyme deficiencies that result in disruptions of pathways of adrenal steroidogenesis. 21-hydroxylase deficiency is the most common form of CAH and has a variable phenotype which ranges a spectrum, from the most severe salt-wasting type to the simple-virilizing type and the least severe nonclassical form. Patients with CAH are at risk for various comorbidities due to the underlying adrenal hormone production imbalance as well as the treatment of the condition, which typically includes supraphysiologic glucocorticoid dosing. Children and adults require frequent monitoring and careful medication dosing adjustment. However, there are multiple novel therapies on the horizon that offer promise to patients with CAH in optimizing their treatment regimens and reducing the risk of comorbidities.

Screening for Anxiety and Depression in Children with Congenital Adrenal Hyperplasia

Objective: Congenital adrenal hyperplasia (CAH) is an inherited condition in which individuals require multiple daily doses of medication and are at risk for life-threatening adrenal crisis. The chronic nature and severity of CAH place children at risk for psychiatric morbidity. The aim was to assess the degree of anxiety and depressive symptoms in children with CAH. Methods: A cross-sectional cohort study of children (7-17 years) with CAH and their caregivers were recruited between May and December 2021. Children with hypothyroidism (HT) and their caregivers served as unaffected controls. Validated mental health questionnaires [Children's Depression Inventory 2 Self Report-Short (CDI-2), Screen for Child Anxiety Related Disorders (SCARED), Patient Health Questionnaire modified for Adolescents (PHQ-A); self and proxy] were completed by participants at one clinic visit. Higher scores indicated greater symptoms of anxiety and depression. Results: A total of 60 children and 56 parents participated. Among the children 34 had CAH (68% female, mean age 11.41±2.5, CAH duration 8.5±4.1) and 26 had HT (73% female, mean age 12.7±2.9 years, HT duration 6.0±4.2 years). There was no increase in anxiety and depression symptoms in children with CAH compared to controls. In sub-analyses, children with CAH and controls reported a greater number of anxiety and depression symptoms than their caregivers on the SCARED and CDI-2, respectively. There was no association between adrenal control and the degree of anxiety or depression symptoms. Conclusion: Children with CAH do not have more symptoms of anxiety or depression compared to controls. Child and caregiver-proxy responses lack agreement, suggesting that children with CAH may continue to benefit from routine mental health evaluation, regardless of voiced caregiver concern.

A 12-Day-Old Female with Hypothermia, Hypoglycemia and Hyperbilirubinemia.

A 12-day-old, full-term female, born small for gestational age, presented to the emergency department with a 1-week history of worsening hyperbilirubinemia, intermittent hypoglycemia, and episodic hypothermia. The baby's emergency department evaluation revealed transaminitis, pneumatosis intestinalis, indirect hyperbilirubinemia, and hypoglycemia. She was admitted to the ICU and received intravenous glucose, bowel rest, and phototherapy. Thyroid-stimulating hormone, thyroxine, and cortisol levels were low, and growth hormone was undetectable. The patient was hospitalized for a total of 19 days and was discharged from the hospital.

Twice Daily Compared to Three Times Daily Hydrocortisone in Prepubertal Children with Congenital Adrenal Hyperplasia.

INTRODUCTION: Glucocorticoid therapy in children with congenital adrenal hyperplasia (CAH) must be finely balanced between optimizing adrenal control and minimizing side effects. Twice (BID) rather than three times daily (TID) hydrocortisone may provide similar adrenal control and reduce metabolic risk. We compared BID and TID regimens with respect to adrenal control, growth, and metabolic effects. METHODS: A retrospective chart review (n = 128 visits, 36 individual patients) of prepubertal children with classical CAH was conducted at a tertiary care center between March 2007 and February 2020. Adrenal control, growth, and metabolic data were extracted in those taking hydrocortisone BID versus TID. Univariate generalized estimating equations models were performed to analyze the effect of dose frequency on outcomes of interest. RESULTS: Overall, we found no difference in adrenal control (8% vs. 18% poor control) or testosterone levels (9.65 ng/dL vs. 7.62 ng/dL) between the BID versus TID groups. We detected no difference in growth velocity (6.86 vs. 6.32 cm/year) or bone age advancement (11.3 vs. 5.91 months) between the groups. There was no difference in daily steroid dose (12.1 vs. 11.7 mg/m2/day), BMI Z-score (0.43 vs. 0.31), or systolic blood pressure percentile (65.5 vs. 61.7). CONCLUSION: BID dosing provides similar adrenal control and does not appear to impact growth or bone age advancement. On the other hand, TID dosing does not appear to increase the metabolic side effect profile in this age-group. Dosing should be patient-centered with individualized consideration.

Perioperative stress dose steroid management of children with classical congenital adrenal hyperplasia: Too much or too little?

BACKGROUND: Children with congenital adrenal hyperplasia (CAH) are at risk for adrenal crises in the perioperative period and require higher doses of glucocorticoids. However, there are no specific protocols detailing the appropriate stress dosing required for children with CAH undergoing surgery with anesthesia. OBJECTIVE: To evaluate CAH patients using our current hydrocortisone stress dose surgical protocol. We hypothesized that current clinical protocols may overestimate the endogenous response to perioperative stress. STUDY DESIGN: 14 children with CAH scheduled to have genital surgery and a control group of 10 unaffected children scheduled to have cardiac or urologic surgery (of a similar duration) were evaluated in a prospective observational study. Urinary free cortisol (UFC) and urinary 17-hydroxycorticosteroids (17-OHCS) per body surface area were measured in the postoperative period. RESULTS: UFC levels were significantly higher in CAH patients (115.8 ± 24.6 nmol/m2) than in controls (26.5 ± 12.2 nmol/m2), P < 0.05.17-OHCS levels were also higher in CAH patients than in controls (6.5 ± 0.5 nmol/m2 vs. 3.4 ± 0.5 nmol/m2), P < 0.05). CONCLUSION: In the immediate postoperative period, urinary cortisol and its metabolites are significantly higher in pediatric CAH patients receiving stress dose corticosteroids compared to controls. Results suggest that the amount of hydrocortisone given during our stress dose protocol may be higher than physiologic needs. Future dynamic studies are needed to determine appropriate perioperative and postoperative cortisol requirements in pediatric CAH patients in order to develop optimal stress dose regimens.

Infertility and Reproductive Function in Patients with Congenital Adrenal Hyperplasia: Pathophysiology, Advances in Management, and Recent Outcomes.

Individuals with congenital adrenal hyperplasia have reduced fertility. However, reproductive outcomes have improved over the years. This review provides an update on the multiple pathologic processes that contribute to reduced fertility in both sexes, from alterations of the hypothalamic-pituitary-gonadal axis to the direct effect on gonadal function by elevated circulating adrenal androgens. In addition, elevated serum progesterone concentrations may hinder ovulation and embryo implantation in women, whereas in men testicular adrenal rest tumors can be a major cause of infertility. Suppression of adrenal androgen secretion represents the first line of therapy toward spontaneous conception in both sexes.

Congenital adrenal hyperplasia patient perception of 'disorders of sex development' nomenclature.

BACKGROUND: As the benefits of patient-centered care have become more widely recognized, it is important to understand patients' sentiments regarding aspects affecting their care. In an effort to display more sensitivity to patient concerns, the term "disorders of sex development" (DSD) was proposed in 2006 as new nomenclature to replace older terms that were considered to have negative connotations. METHODS: The objective of the study was to examine the views of congenital adrenal hyperplasia (CAH) patients and their caregivers regarding the new nomenclature. The study was observational to evaluate the views of the CAH community, and the primary endpoint was perception of the term DSD. The study was conducted as a survey about views regarding DSD nomenclature. The survey was sent via email to eligible subjects. Along with a short introduction explaining the term DSD, the survey was sent to eligible CAH patients and their caregivers. 589 CAH patients or family members participated in the survey. RESULTS: A total of 589 responses were received (255 classical females, 104 non-classical females, 174 males, 56 not specified) (547 U.S., 42 international) (128 CAH patients, 408 parents or other family members). 70.6% had never heard the term DSD. 71.0% disliked or strongly disliked the term DSD. 83.6% stated they did not identify with the term DSD. 76.0% felt that the term DSD has a negative effect on the CAH community. There was no significant difference in opinion of DSD between classical females and other CAH patients, between US and international, between surgical and non-surgical patients, or between patients and parents. There was no correlation with patient age. CONCLUSIONS: Our results indicate that the majority of parents and patients with CAH are dissatisfied with the term DSD. Our results highlight the challenges within the field of DSD to reach a consensus regarding a sensitive topic and to bridge the gap between current medical practice and patient satisfaction. It is the authors' belief that reconsideration of the current nomenclature and ongoing dialogue between the medical community and patients will eventually lead to removal of stigmatization, better management protocols, and improved outcomes.

An update on prenatal diagnosis and treatment of congenital adrenal hyperplasia.

Congenital adrenal hyperplasia causes genital ambiguity in females affected with the severe form of the disease; yet the abnormality is preventable with prenatal dexamethasone treatment that must be given to the mother before the ninth week of gestation. In the period from 1978 to March 2011 we have made prenatal diagnosis in 719 pregnancies. Our results indicate that the average Prader score of those fetuses treated with dexamethasone was 1.7, which is much lower than the average Prader score of 3.73 in those not treated. While our data demonstrate no significant abnormalities in the long-range medical and cognitive outcomes in patients prenatally treated with dexamethasone, the current protocol involves invasive procedures such as chorionic villus sampling or amniocentesis, and all fetuses are treated unnecessarily for several weeks before the sex and the affection status of the fetus is known. We are collaborating with Dr. Dennis Lo in Hong Kong to develop a noninvasive protocol, whereby at the sixth to seventh week of gestation we can determine the sex and the affection status of the fetus by harvesting fetal DNA from the maternal plasma. The method will eliminate invasive procedures and unnecessary prenatal treatment and bring noninvasive prenatal diagnosis to underdeveloped areas where amniocentesis and chorionic villus sampling are not available.

Congenital lipoid adrenal hyperplasia (a rare form of adrenal insufficiency and ambiguous genitalia) caused by a novel mutation of the steroidogenic acute regulatory protein gene.

UNLABELLED: Congenital lipoid adrenal hyperplasia (lipoid CAH) is a rare autosomal recessive disorder of adrenal and gonadal steroidogenesis. It is most frequently caused by mutations in the steroidogenic acute regulatory protein (StAR) gene. Patients with lipoid CAH typically present with adrenal crisis in early infancy, and those with a 46,XY karyotype have female genitalia. However, it has been recently recognized that the phenotype can be quite variable, in that adrenal insufficiency is detected later in life and patients may have partially masculinized or even normal male genitalia. We report a patient assigned and reared as a female with a 46,XY karyotype and with a homozygous intron 2 (c.178+1G>C) splice site mutation of the StAR gene, which is a novel mutation that causes lipoid CAH. Her clinical presentation was somewhat atypical for a patient with classic lipoid CAH, marked by mild masculinization of the genitalia, detectable adrenal steroids at baseline, and ability to tolerate the stress of a surgical procedure with anesthesia without receiving glucocorticoid treatment. CONCLUSION: There is significant phenotypic variability among patients with lipoid CAH. While splice site mutations in the StAR gene lead to premature translational termination, resulting in truncated and non-functional proteins, there is phenotypic variability among patients with such mutations. Our patient appears to have the more atypical phenotype compared to reported patients with similar mutations. The molecular mechanism underlying this heterogeneity remains unclear.

Adrenal disease in pregnancy.

Adrenal disorders in pregnancy are relatively rare, yet can lead to significant maternal and fetal morbidity. Making a diagnosis is challenging as pregnancy may alter the manifestation of disease, many signs and symptoms associated with pregnancy are also seen in adrenal disease, and the fetal-placental unit alters the maternal endocrine metabolism and hormonal feedback mechanisms. The most common cause of Cushing's syndrome in pregnancy is an adrenal adenoma, followed by pituitary etiology, adrenal carcinoma, and other exceedingly rare causes. Medical therapy of Cushing's syndrome includes metyrapone and ketoconazole, but generally surgical treatment is more effective. Exogenous corticosteroid administration is the most common cause of adrenal insufficiency, followed by the endogenous causes of ACTH or CRH secretion. Primary adrenal insufficiency is least common. A low early morning cortisol <3 mcg/dL (83 mmol/L) in the non-stressed state and in the setting of typical clinical symptoms confirms the diagnosis. In the second and third trimester cortisol rises to levels 2-3 fold above those in the non-pregnant state, therefore a baseline level of <30 mcg/dL (823 mmol/L) warrants further evaluation. ACTH stimulated normal cortisol values have been established for each trimester. Hydrocortisone, which does not cross the placenta, is the glucocorticoid treatment of choice, and fludrocortisone is used as mineralocorticoid replacement in patients with primary disease. Congenital adrenal hyperplasia is an autosomal recessive disorder; 21-hydroxylase deficiency (21OHD) is the most common form of the disease. Non-classical 21OHD is most common, followed by the salt-wasting and simple virilizing forms. The treatment of choice for pregnant women affected with CAH is hydrocortisone, and fludrocortisones is added for those with the salt-wasting form of the disease. If the fetus is at risk for classical CAH, dexamethasone treatment can be used prenatally to prevent masculinization of the genitalia in a female infant. Because dexamethasone crosses the placenta, it should not be used to treat pregnant women with CAH if the fetus is not at risk for the disease.

Final adult height in children with congenital adrenal hyperplasia treated with growth hormone.

CONTEXT: Patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency typically reach a final adult height well below their mid-parental target height. OBJECTIVE: The objective of this study was to examine whether GH alone or in combination with an LHRH analog (LHRHa) improved the final adult height in patients with CAH. DESIGN: The study was a nonrandomized prospective study. SETTING: The study was conducted at two university hospitals in New York City, NY. PARTICIPANTS: Thirty-four patients with CAH treated with GH participated in this study. Nineteen males and 15 females who were predicted to be more than 2 SD below their mid-parental target height or more than 2 SD below the population mean received GH until reaching final adult height. In addition to GH, 27 patients (16 males, 11 females) were also treated with an LHRHa. INTERVENTION: The mean duration of GH treatment was 5.6 ± 1.8 yr in males and 4.5 ± 1.6 yr in females. The mean duration of LHRHa therapy was 3.7 ± 1.7 yr for both sexes. MAIN OUTCOME MEASURES: The primary endpoint variables were final adult height, final height discrepancy, and gain in height. RESULTS: Males reached a significantly higher final adult height (172.0 ± 4.8 cm) than their initial predicted height (162.8 ± 7.7 cm) (P < 0.00001). Females also reached a significantly higher final adult height (162.2 ± 5.3 cm) than initially predicted (151.7 ± 5.2 cm) (P < 0.0000001). Mean gain in height was 9.2 ± 6.7 cm in males and 10.5 ± 3.7 cm in females. CONCLUSION: Our results indicate that GH alone or in combination with LHRHa improves final adult height in patients with CAH.