Congenital Anomalies and Congenital Adrenal Hyperplasia

Among 74 patients with congenital adrenal hyperplasia observed at Childrens Hospital, Los Angeles, in a 25-year period, 36 had the simple virilizing type and 38 the salt-losing type. During the same time, seven children with virilizing adrenal tumors were observed at the hospital.While virilization and dehydration were the most common presenting symptoms, some of the children first came to medical attention because of other symptoms, and 11 of them died before adrenal hyperplasia had been diagnosed. Twenty-eight additional congenital cardiovascular, genitourinary, and gastrointestinal anomalies were found in 16 of these 74 children.With proper management, the patients tolerated such stresses as surgical operation and infections without difficulty.     

A 30-Year,Single-Center Experience of Unilateral Adrenalectomy for Primary Bilateral Macronodular Adrenal Hyperplasia

ObjectiveThe aim was to assess the short- and long-term outcomes of unilateral adrenalectomy (UA) in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH).MethodsWe conducted a retrospective study of 124 patients with PBMAH who underwent UA.ResultsOne hundred sixteen patients were available for follow-up (median, 28.5 months). Cushingoid features remitted in 43 of 65 patients (70.8%) with overt Cushing syndrome (CS). Hypertension and diabetes mellitus improved in 79 of 96 (82.3%) and 29 of 42 patients (69.0%), respectively. Glucocorticoid insufficiency developed in 7 of 116 patients (6.0%) after the surgery, and it resolved in all the patients during follow-up. The mean 24-hour urinary free cortisol level decreased gradually from 456.02 ± 422.33 mg/24 h at baseline to 84.47 ± 70.06 mg/24 h within 3 months and then increased progressively in some patients. Sixty-four of the 116 patients (55.2%) had biochemical recurrence and 43 patients (67.2%) underwent contralateral adrenalectomy. The median time interval between the second operation and the first UA was 24 months. Patients with overt CS had a larger surgical-side or contralateral adrenal volume than patients without overt CS. Patients with a contralateral adrenal volume of >33.54 mL or with a preoperative urinary free cortisol level of >216.08 mg/24 h were more likely to have recurrence.ConclusionThe efficiency of UA is transient for the majority of patients, and the indications should be strictly limited to those with subclinical or milder CS. Patients who undergo successful UA still require close life-time follow-up for the recurrence of hypercortisolism.     

Prenatal Dexamethasone for Congenital Adrenal Hyperplasia

Following extensive examination of published and unpublished materials, we provide a history of the use of dexamethasone in pregnant women at risk of carrying a female fetus affected by congenital adrenal hyperplasia (CAH). This intervention has been aimed at preventing development of ambiguous genitalia, the urogenital sinus, tomboyism, and lesbianism. We map out ethical problems in this history, including: misleading promotion to physicians and CAH-affected families; de facto experimentation without the necessary protections of approved research; troubling parallels to the history of prenatal use of diethylstilbestrol (DES); and the use of medicine and public monies to attempt prevention of benign behavioral sex variations. Critical attention is directed at recent investigations by the U.S. Food and Drug Administration (FDA) and Office of Human Research Protections (OHRP); we argue that the weak and unsupported conclusions of these investigations indicate major gaps in the systems meant to protect subjects of high-risk medical research.     

Corticotropin-Independent Cushing Syndrome in a Child With an Ovarian Tumor Misdiagnosed as Nonclassic Congenital Adrenal Hyperplasia

ObjectiveTo describe a patient with corticotropinindependent Cushing syndrome previously diagnosed and treated as congenital adrenal hyperplasia (CAH).MethodsWe describe the initial manifestations, clinical investigations, and postoperative follow-up of the patient and review similar cases in the literature.ResultsA 5 and 9/12-year-old girl who was initially diagnosed and treated as having CAH and was noncompliant with glucocorticoid therapy presented with weight gain, hypertension, and a mass in the lower abdomen. On physical examination, she was a cushingoid-appearing girl with proximal muscle weakness and notable facial acne. Laboratory findings included elevated serum testosterone, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione, estradiol, and cortisol, as well as elevated urinary cortisol and cortisone. Serum corticotropin was undetectable. She had normal serum electrolytes and plasma renin activity. Computed tomography scan of the abdomen and pelvis showed a cystic mass with a focal enhancing solid component arising from the right ovary, which was subsequently determined to be a steroid cell tumor not otherwise specified.ConclusionAlthough ovarian steroid cell tumors typically secrete gonadal steroids, the rare steroid cell tumors not otherwise specified can secrete both glucocorticoids and gonadal steroids and are an unusual cause of Cushing syndrome. (Endocr Pract. 2008;14:875-879)     

Polycystic Ovaries Associated with Congenital Adrenal Hyperplasia

Polycystic ovaries were found in a 16-year-old female with congenital absence of vagina, male-like external genitalia, and congenital adrenal hyperplasia. Masculinization was sufficiently severe to cause the patient to be reared as a male. Biochemical studies of ovarian tissue revealed hyperactivity and an imbalance of enzyme systems concerned with steroid-hormone biosynthesis, which led to production of large amounts of androgens. The pathway towards estrogens was preserved but less efficient than normal. Urinary steroid metabolites before and after hysterectomy and bilateral salpingo-oophorectomy revealed an absence of Porter-Silber chromogens and tetrahydrocortisone. Excretion of aldosterone was normal and that of corticosterone slightly higher than normal. The patterns of urinary 17-ketosteroids, pregnanediol, pregnanetriol and pregnanetriolone were similar to those commonly seen in congenital adrenal hyperplasia with steroid 21-hydroxylase deficiency. Urinary estrogens after panhysterectomy were low, being in the post-menopausal range. The pathogenesis of polycystic ovaries and their possible contribution to masculinization are discussed.     

Psychosexual Development of Women with Congenital Adrenal Hyperplasia

Women with congenital adrenal hyperplasia (CAH) (N= 31) and their unaffected sisters or female cousins (N= 15) participated in a study of psychosexual development. All participants were ≥18 years of age (mean age, 25 years; range, 18–40). Comparisons were also made between the CAH women with the salt-wasting (SW) form of the disorder and those with simple virilization (SV). A psychosexual assessment protocol examined six variables: (1) sex assignment at birth (probands only); (2) recalled sex-typed behavior during childhood; (3) gender identity and gender role identification in adulthood; (4) relationship status; (5) sexual orientation in fantasy; and (6) sexual orientation in behavior. Salt-wasting status and sex assignment at birth were also ascertained for the CAH women who either refused to participate in the study (N= 10) or could not be traced (N= 13). Compared to the controls, the women with CAH recalled more cross-gender role behavior and less comfort with their sense of “femininity” during childhood. The two groups did not differ in degree of gender dysphoria in adulthood, although the probands showed more cross-gender role identification. Three of the nonparticipant probands were living, as adults, in the male social role (2 reared from birth as boys and 1 who changed from the female to the male social role during adolescence). The CAH women and the controls did not differ in relationship status (married/cohabiting vs. single). The CAH women had lower rates of exclusive heterosexual fantasy and fewer sexual experiences with men than the controls; however, the CAH women did not have more sexual experiences with women than the controls. Comparisons between the SW and SV revealed several differences: the SW were less likely to be assigned to the female sex at birth, recalled more cross-gender role behavior during childhood, were less likely to be married or cohabiting, and had lower rates of sexual experiences with men. The results were discussed in relation to the effects of prenatal androgens on psychosexual differentiation.     

Gender Change from Female to Male in Classical Congenital Adrenal Hyperplasia

The psychoendocrinology of the development of normal gender identity and its variations is poorly understood. Studies of gender development in individuals born with endocrinologically well-characterized intersex conditions are heuristically valuable for the disaggregation of factors that are acting in concert during normal development. Four 46,XX individuals with classical congenital adrenal hyperplasia (CAH) and atypical gender identity entered a comprehensive research protocol including systematic interviews and self-report inventories on gender role behavior and identity, sexual history, and psychiatric history. Some of the data on gender variables were compared to data from 12 CAH women with the salt-wasting variant (CAH-SW) with female gender identity. The four patients (ages 28, 35, 38, and 30 years) represented three different subtypes of classical early-onset CAH: 21-OH deficiency, simple virilizing (CAH-SV); 21-OH deficiency, salt-wasting (CAH-SW); and 11-β-OH deficiency. Their medical histories were characterized by delay beyond infancy or lack of surgical feminization of the external genitalia and progressive virilization with inconsistent or absent glucocorticoid replacement therapy. Although three patients had undergone one or more genital surgeries, all had retained at least some orgasmic capacity. In regard to childhood gender-role behavior, the four gender-change patients tended to be more masculine or less feminine than (behaviorally masculinized) CAH-SW controls. All patients were sexually attracted to females only. The process of gender change was gradual and extended well into adulthood. The most plausible factors contributing to cross-gender identity development in these patients to be neither a particular genotype or endocrinotype nor a sex-typing bias on the part of the parents but a combination of a genderatypical behavioral self-image, a gender-atypical body image, and the development of erotic attraction to women. Implications for psychosocial management are also discussed.     

Modeling Congenital Adrenal Hyperplasia and Testing Interventions for Adrenal Insufficiency Using Donor-Specific Reprogrammed Cells

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Transition Readiness in Adolescents and Young Adults Living With Congenital Adrenal Hyperplasia

ObjectiveCongenital adrenal hyperplasia (CAH) refers to a group of genetic disorders that affect cortisol biosynthesis and the need for glucocorticoid treatment is lifelong. The complexities of CAH can greatly affect teenage life and the transition from pediatric to adult care. The aim was to assess transition readiness and the impact on quality of life (QoL) as well as medication adherence rates in adolescents and young adults with CAH.MethodsProspective assessment of transition readiness was conducted through standardized questionnaires for adolescents and young adults (aged 16-35 years). Four open-ended questions on self-care were summarized in adolescents (aged 18-19 years) and their parents. Transition readiness was assessed using a modified CAH specific questionnaire: “Transition preparation and readiness to transfer from pediatric to adult care” with a cutoff level of >25 defined as good transition readiness. Measurement of QoL was performed using Rand 36. Medication adherence rate was measured using the self-reported questionnaire Adherence Starts with Knowledge.ResultsThirty-eight adolescents and young adults with CAH were included in the study. Transition readiness was classified as good in 26 (68%) of the participants. Good transition readiness was more frequent in participants with good medication adherence rates. A general linear model analysis showed a good transition readiness affected QoL by increasing QoL scores.ConclusionSelf-reported transition readiness was found in the majority of adolescents and young adults with CAH. A good medication adherence rate was associated with a better transition readiness and a good transition readiness was associated with increased QoL scores.     

Adrenal Myelolipomas in Patients with Congenital Adrenal Hyperplasia: Review of the Literature and A Case Report

ObjectiveTo review the association between congenital adrenal hyperplasia (CAH) and adrenal myelolipomas and report a case of bilateral, giant adrenal myelolipomas in a patient with untreated CAH due to 21-hydroxylase deficiency.MethodsWe describe the patient’s clinical presentation, imaging findings, and laboratory test results and review the relevant English-language literature concerning patients with both CAH and myelolipomas.ResultsA 45-year-old man with untreated CAH due to 21-hydroxylase deficiency presented with increasing abdominal girth and abdominal pain. Computed tomography of the abdomen demonstrated very low-density adrenal masses (22 × 11 cm on the left side and 6 × 5.5-cm on the right side) consistent with adrenal myelolipomas. The left adrenal myelolipoma was resected (24.4 × 19.0 × 9.5 cm; 2557 g). The mass was composed of mature adipose tissue with areas of hematopoietic cells of myeloid, erythroid, and megakaryocytic cell lines. Islands of adrenal cortical cells were scattered between the adipose and hematopoietic tissue. Including the present case, we identified 31 patients with both CAH and myelolipomas who have been described in the English-language literature. The details of these cases were reviewed.ConclusionsPersons with CAH may be at increased risk of developing adrenal myelolipomas, particularly if their CAH is poorly controlled. How and whether chronic exposure of the adrenal glands to high corticotropin levels increases the risk of developing myelolipomas remains a matter of speculation. (Endocr Pract. 2011;17:441-447)     

Health-Related Quality of Life in Children and Adolescents with Nonclassic Congenital Adrenal Hyperplasia

Objective: Nonclassic congenital adrenal hyperplasia (NCCAH) is a late-onset milder form of congenital adrenal hyperplasia that differs dramatically from the classic form. Health-related quality of life (HRQOL) in pediatric patients with the sole diagnosis of NCCAH has not been determined; therefore, in this study, we aimed to determine whether HRQOL is compromised in comparison to the general population.Methods: Single-center, cross-sectional, case-control study. Twenty-three hydrocortisone-treated children and adolescents (7 males) diagnosed with NCCAH by cosyntropin stimulation test and CYP21A2 gene mutation analysis were recruited to this study; 6 healthy siblings were also recruited. HRQOL was assessed by the child and parent-proxy PedsQL Inventory and compared between NCCAH subjects and healthy siblings. HRQOL scores of NCCAH subjects were compared with known standards from the U.S. and Israeli general healthy populations. Anthropometric measurements of children and parents were performed and compared between NCCAH subjects and healthy siblings. Pearson correlation coefficients were calculated.Results: HRQOL scores of the participants and parents did not differ between NCCAH subjects and healthy siblings. The HRQOL emotional domain scores of the NCCAH patients and parent were significantly lower than the healthy U.S. pediatric population (P = .046) but not different from established standards of the healthy Israeli population (P = .583). Anthropometric measurements were within the normal range and did not differ between NCCAH subjects and their siblings. Total, school functioning, and psychosocial HRQOL domain scores were positively correlated with body mass index–standard deviation score in NCCAH subjects.Conclusion: HRQOL was not adversely affected by NCCAH among adequately treated children and adolescents.Abbreviations: BMI = body mass index; CAH = congenital adrenal hyperplasia; HRQOL = health-related quality of life; NCCAH = nonclassic congenital adrenal hyperplasia; PedsQL = Pediatric Quality of Life Inventory; SDS = standard deviation score     

Prevalence and Characteristics of Adrenal Tumors and Myelolipomas in Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis

Objective: The prevalence of adrenal tumors in congenital adrenal hyperplasia (CAH) is uncertain. Our objective was to estimate the prevalence and characteristics of adrenal tumors and myelolipoma in CAH, and investigate clinical features of this population.Methods: We carried out systematic searches in Medline Ovid and Embase for articles published until January, 2020. Studies with confirmed CAH, biochemically and/or genetically, were included. The two authors independently extracted data from each study.Results: Six cohort studies were included in the prevalence calculation. In addition, 32 case reports on adrenal myelolipomas and CAH were included. The prevalence of adrenal tumors in CAH was 29.3%. When only studies with genetically verified cytochrome P450, Family 21, subfamily A, polypeptide 2 gene (CYP21A2) mutations were included the prevalence was 23.6%. The prevalence of myelolipoma in CAH was 7.4% (verified CYP21A2 mutations 8.6%). The proportion of myelolipoma in the adrenal tumors was 25.4% (genetically verified 36.6%). The median (range) age at tumor diagnosis was 36.0 (12 to 60) years and there were more tumors in males than in females (37.9% versus 22.1%; P<.05). In patients with myelolipomas, 93.5% had an undiagnosed or poorly managed CAH.Conclusion: Patients with CAH had a high prevalence of adrenal tumors, particularly myelolipomas. Those with myelolipomas had a high frequency of late-diagnosed or poorly controlled CAH. Adrenal imaging may be considered in patients with CAH, especially if abdominal pain is present.     

Energy Expenditure in 21-Hydroxylase Congenital Adrenal Hyperplasia Patients and Comparison with Predictive Equations

Objective: To characterize resting energy expenditure (REE) in patients with classic 21-hydroxylase congenital adrenal hyperplasia (21-OH CAH) using indirect calorimetry and compare it to the most commonly used REE predictive equations.Methods: This case-control study comprised 29 post-pubertal 21-OH CAH patients regularly followed at the University of Campinas. Elevated serum 17-hydroxyprogesterone and CYP21 gene molecular analysis confirmed the diagnosis. A healthy control group paired by age, gender, and body mass index was examined. Dual-energy X-ray absorptiometry (DEXA) measured body compositions. A bioimpedance analyzer determined fat-free mass, and indirect calorimetry using a metabolic cart measured REE.Results: Unlike our initial hypothesis, REE was similar between the groups (18.7 ± 3.1 kcal/kg/day in CAH vs. 20.3 ± 3.5 kcal/kg/day in controls; P = .728). No predictive equations reached the stipulated accuracy criteria, thus lacking validity in REE assessment in adults with the characteristics of the group studied. DEXA analysis revealed higher body fat and diminished nonbone lean mass in 21-OH CAH. Anthropometric and bioelectrical impedance parameters were not significantly different.Conclusion: Classic 21-OH CAH is generally followed in reference centers, which may facilitate indirect calorimetry use for REE measurement. Alternatively, considering our REE findings in adult 21-OH CAH patients, nutrition management based on 25 kcal/body weight/day (measured REE × activity factor 1.2 to 1.3) may be reasonable for current body weight maintenance in these patients.Abbreviations: 17-OHP = 17-hydroxyprogesterone; 21-OH CAH = classic 21-hydroxylase deficiency congenital adrenal hyperplasia; BMI = body mass index; REE = resting energy expenditure; VO2 = volume of oxygen; VCO₂ = volume of carbon dioxide     

Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency Presenting as Adrenal Incidentaloma: A Systematic Review and Meta-Analysis

Objective: Adrenal incidentalomas (AIs) may be due to congenital adrenal hyperplasia (CAH) due to homozygous CYP21A2 mutations, or perhaps from heterozygous carrier status. It is unclear if genetic or biochemical testing of CYP21A2 status in AI is justified, despite its potential for avoiding adrenal crises in those referred for adrenalectomy.Methods: We systematically searched PubMed/MEDLINE for articles published up to October 19, 2015 containing all terms associated with adrenal tumors and CAH. Meta-analyses were used to estimate the CAH or carrier prevalence in AI and assess clinical factors that may guide testing.Results: Thirty-six publications were included. Of AI patients biochemically screened for CAH, 58/990 (5.9%) were diagnosed with CAH. Genetic screening of all AIs revealed only 2/252 (0.8%) with clear CAH. The carrier prevalence was 10.2% (36/352). The rate of 0.8% (8/1,000) genetically confirmed CAH is higher than the 1/15,000 affected by classic CAH or 1/1,000 by nonclassic CAH in the Caucasian population. The rate of heterozygous CYP21A2 mutation frequency is similar to those in reported in population studies. Levels of both basal and stimulated 17-hydroxyprogesterone positively correlated with AI diameter. Although bilateral incidentalomata were frequent in CAH, their presence did not predict CYP21A2 status.Conclusion: The presence of an AI does not increase the probability of detection of CAH or CYP21A2 carrier status to the extent routine genetic testing is justified. Screening with 17-hydroxyprogesterone levels appears to lack specificity in the setting of an AI. CYP21A2 mutation analysis is probably the only reliable method for CAH diagnosis in AIs.Abbreviations:ACC = adrenocortical carcinomaACTH = adrenocorticotropic hormoneAI = adrenal incidentalomaCAH = congenital adrenal hyperplasiaNCAH = nonclassic congenital adrenal hyperplasia17OHP = 17-hydroxyprogesteroneSV = simple virilizing     

HLA Typing of Patients with 21-Hydroxylase Deficiency in Iranian Children with Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a group of potentially life-threatening disorders, most often caused by deficiency of steroid 21-hydroxylase. Children with ambiguous genitalia, hermaphroditism, or signs and symptoms of CAH admitted to Children's Medical Center were enrolled in the survey, and 101 patients were found. Karyotyping, clinical examination, and paraclinical tests were done. HLA typing was done in patients with proven classical CAH and their parents. HLA antigens were typed in children with CAH-type 21-hydroxylase deficiency. The antigen frequencies were compared with those of the control population. The studies revealed that two HLA antigens, HLA-B18 and HLA-B21, showed a significant increase in frequency. The calculated relative risk value was high, distinguishing the population of patients and their parents. The relative risk among patients was 11.82 for HLA-B18 and 1.75 for HLA-B21 antigens. There was no relationship between HLA-DR antigens and CAH. Studies on the correlation between HLA and CAH indicate an association with HLA-B18 and HLA-B21 antigens, and they can be used as genetic markers of the disorder in the Iranian population, if they are restricted to Iranian patients.