Nonclassic CAH Research Articles

8665 Female Fertility In Patients With Classic And Non-Classic Congenital Adrenal Hyperplasia Under Modified-Release Hydrocortisone (MR-HC)

Abstract Disclosure: L. Tschaidse: None. H.F. Nowotny: None. M. Auer: None. C. Lottspeich: None. M. Bidlingmaier: None. J. Hawley: None. B.G. Keevil: None. N. Reisch: None. Background: Female patients with classic and non-classic (NC) CAH struggle with fertility, due to androgen excess, elevated progesterone and 17-hydroxyprogesterone (17OHP) levels, causing anovulation, impairment of endometrial development and menstrual irregularities. The typical approach to treating infertility often includes an increase in glucocorticoid (GC) dose. However, this poses a potential risk of side effects. Limited observational data on modified-release hydrocortisone (MR-HC), which better mimics the physiological diurnal rhythm of cortisol secretion, indicates improved fertility in female and male patients with classic CAH. Therefore, the aim of this study was to investigate fertility in women with classic and non-classic CAH before and after switching to MR-HC. Methods: 21 adult female patients with CAH (14 classic; 5 NC) with a median (range) age of 33.0 (30.0) years, premenopausal and without hormonal contraception, were enrolled in this prospective, observational, single-centre study. The data collection took place before (conventional GC preparation) and after dose-equivalent switching the medication to MR-HC. In addition to clinical parameters such as menstrual cycle and desire to conceive, the collection of morning serum and daily saliva profiles was conducted, measuring progesterone, 17OHP, androstenedione (A4), testosterone, 11-ketotestosterone (11KT) as well as 11-hydroxyandrostenedione (11OHA4). Results: Before study inclusion, 4/21 patients had an irregular cycle, 5/21 were amenorrhoeic and 10/21 patients had a desire to have children. There was no difference in median (range) hydrocortisone dose equivalent before and after switching to MR-HC (25.0 (50.0) vs. 25.0 (30.0), p=.441). Median (range) morning serum concentrations between 8-10 am were not different before and after switch to MR-HC for progesterone (5.9 (55.5) vs. 5.0 (58.8), p=.823), 17OHP (5.9 (362.1) vs. 5.7 (73.7), p=.280), A4 (2.9 (25.6) vs. 2.5 (6.9), p=.106), testosterone (0.8 (3.5) vs. 0.7 (1.5), p=.063), 11KT (0.4 (7.4) vs. 0.2 (2.6), p=.242) and 11OHA4 (0.8 (12.9) vs. 0.9 (10.4), p=.231). Concerning saliva day profiles, we found a significantly lower median (range) 17OHP level in early morning saliva (43.0 (526.9) vs. 19.4 (264.3), p=.049). 5/9 patients with menstrual irregularities reported menstrual regularisation within and 5/10 patients with a desire to have children became pregnant after switching to MR-HC. Conclusion: Our preliminary data show clinical improvement in fecundity and fertility under MR-HC in both women with classic and NC CAH without a dose increase of glucocorticoids. Under MR-HC replacement lower 17OHP concentrations in early morning saliva reflect better hormonal control over night contributing to ovulatory cycle regulation and improved fertility. Presentation: 6/1/2024

FRI247 Case Of Metabolic Resolution Of Non-classic Congenital Adrenal Hyperplasia Post Roux-En-Y Gastric Bypass

Abstract Disclosure: K.G. Romo: None. S. Shu: None. M. Gabriel: None. S. Bhamre: None. Q.Z. Iqbal: None. A.A. Noor: None. G.I. Uwaifo: None. Background: Non-classic congenital adrenal hyperplasia (NCCAH) is an autosomal recessive disorder resulting from loss of function mutations of the 21-hydroxylase gene. It is characterized by mild cortisol deficiency, excess ACTH production, and androgen excess, often with various features of dysmetabolic syndrome. Elective bariatric surgery is one of the most effective long-term management strategies for morbid and complicated obesity. This case presents a woman with NCCAH and complicated morbid obesity who s/p Roux-en-Y Gastric Bypass (RYGB) had metabolic resolution of NCCAH and no longer required glucocorticoid (GC) therapy. Clinical Case: A 34-year-old G1P1 woman with NCCAH on glucocorticoid therapy, treated hypothyroidism with thyroid nodular disease, dyslipidemia, and morbid obesity (pre-RYGB BMI 60-69.9) initially presented to endocrinology on account of hirsutism and secondary amenorrhea attributed to PCOS. Work-up then confirmed diagnosis of NCCAH with 21-hydroxylase genetic testing showing deletion of one copy of CYP21A2 and the pathogenic variant p.V282L in the remaining copy. Outside the peripartum period, she was managed with OCP therapy, spironolactone, and metformin. She was additionally prescribed GC therapy of hydrocortisone 10mg TID following her diagnosis of NCCAH. She subsequently became pregnant unexpectedly. Post-partum course was complicated by significant weight gain, which led her to seek elective bariatric surgery for long-term weight management. At 5 months post-op, she had a weight deficit of ∼100lbs. Although she self-discontinued GC therapy due to fear of weight gain, her amenorrhea resolved, her hirsutism significantly improved, and lab testing revealed normalization of all NCCAH markers, including ACTH, 17-OHP, and androstenedione. Thus, GC therapy was not restarted. At 11 months post-op and still off GC therapy, she had a total weight deficit of ∼160lbs and continued metabolic resolution of NCCAH markers. Conclusions: This case presents a patient with NCCAH and morbid obesity who no longer required GC therapy post-RYGB. Presently, GC therapy remains the only available treatment for CAH; however, long-term GC therapy has the potential for myriad possible complications and side effects. Our case presents elective bariatric surgery as a potential and unique treatment option for patients with classic or non-classic CAH who have associated morbid obesity. The exact pathophysiologic basis for this effect and its potential role in long-term management of appropriate CAH patients requires further in-depth study. Presentation: Friday, June 16, 2023

PSAT047 Dual Heterozygous Mutations in CYP21A2 and CYP11B1 in a Case of Nonclassic Congenital Adrenal Hyperplasia

Abstract Background Congenital Adrenal Hyperplasia (CAH) is classically attributed to defective 21-hydroxylase, caused by mutations in CYP21A2, impairing the production of mineralocorticoids and glucocorticoids and subsequently shifting steroidogenesis towards androgen production. This produces a classic constellation of neonatal symptoms, including genital virilization, salt-wasting, and adrenal crisis. A rare cause of CAH is a defect in 11β-hydroxylase from a mutation in CYP11B1, preventing production of cortisol and corticosterone, resulting in hypertension, hypokalemia, and androgen excess. Reports of combined mutations in CYP21A2 and CYP11B1 in the literature and the clinical manifestations of such a case are not well described. Here we present a case report wherein a pair of heterogenous mutations in CYP2A12 and CYP11B1 were detected in a new diagnosis of nonclassic Congenital Adrenal Hyperplasia, including a previously undescribed mutation in CYP11B1. Clinical Case The patient is a 30-year-old female who presented to her primary care clinic with teenage-onset irregular menses occurring every 2-3 months. She also reported hirsutism, but never had acne, changes in thirst or urination, or breast discharge. Primary evaluation revealed prolactin of 34.7 ng/mL, prompting a pituitary MRI which revealed a 2×3mm lesion. At this point, referral was made to endocrinology for endocrinological. PCOS was felt to be the top differential for her hirsutism and irregular menses but further workup to rule out CAH revealed a 17-OH-Progesterone of 554 ng/dL and a Testosterone of 83 ng/dL. Subsequently, a 250 mcg cosyntropin test increased 17-OH progesterone to 837 ng/dL and resulted in a cortisol of 24.7 mCg/dL after 60 minutes. Subsequent CAH gene sequencing was performed and revealed a heterogeneous pathogenic CYP21A2 variant (c.332_339 del; p.Gly111Valfs*21) and a heterogeneous previously undescribed variant of undetermined significance in CYP11B1 (c.1123C>T; p.Leu375Phe). Conclusion At least 100 mutations of CYP11B1 have been found to cause CAH due to 11β-Hydroxylase deficiency. Our case adds to the growing database of described mutations in CY11B1 and suggests that heterogenous mutations in two different genes may present phenotypically as nonclassic CAH in a potentially epistatic fashion. This enriches earlier conclusions that broader genetic analysis beyond CYP21A2 deletions is needed to identify the genotypes of those with CAH due to the complex diversity of genetic mutations, and ought to remind clinicians to consider it as a diagnosis, particularly in young women whose hyperandrogenism or menstrual irregularities cannot be explained by common endocrinological abnormalities or do not have an appropriate response to traditional treatment. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Experience with Congenital Adrenal Hyperplasia in Tripoli Children's Hospital, Libya

AbstractCongenital adrenal hyperplasia (CAH) denotes a group of autosomal recessive disorders. Its clinical spectrum varies from classical CAH (CCAH) to nonclassic CAH. It may be a simple virilizing form or salt-wasting type. The study described the clinical presentation, treatment modalities, and sequelae of CAH, including its effect on patient growth during long-term follow-up. A case series study was conducted on patients with CAH who attended and followed up in the Endocrine Clinic in Tripoli Children's Hospital from January 1, 2000 to December 31, 2018. The presentation and the last visit captured demographic and clinical features at the time of diagnosis, types of CAH (classical vs. nonclassical), investigations, treatment details, and height. All patients underwent biochemical testing and hormonal assay, including adrenocorticotropin hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and plasma renin activity (PRA) levels before and after treatment. Fifty-eight patients were included; 38 (65.5.2%) were female, age at presentation in 94.8% ranged between 1 day and 10 years, with a mean age of 2.3 ± 1.1 years. Ambiguous genitalia was the presenting feature in 55.2 and 84% of total and female patients, respectively. Salt wasting was present in 37.9%. Of 32 female patients with ambiguous genitalia, only 11 (34.4%) out of them and 19% of all patients had a surgical correction. The mean and standard deviation of height at diagnosis was 78.327 + 31.070, and the last visit after treatment was 108.345 + 31.781. The relation between the date of birth and height throughout follow-up for those at last visit with age ranges from 13 to 18 years old, their mean and standard deviation of height was 135.650 + 29.286, and for patients who were less than13 years at last visit, the mean and standard deviation of height was 101.079 + 32.121; p-value = 0.003. The Z-scores were calculated and showed that about eight patients were positively above the average mean of the population. Biochemical disturbances were improved after treatment, including sodium, potassium, and glucose in CCAH type; p-value < 0.001. Hormonal findings included levels of ACTH, 17-OHP, and PRA; all levels were reduced with treatment; p-value < 0.001. In this single-center series, most of our patients with biochemical and hormonal abnormalities were normalized with hormonal replacement and limited surgical correction of females with ambiguous genitalia.

Taking it with a Grain of Salt: A Woman with ‘PCOS’ and Infertility Diagnosed with Nonclassic Congenital Adrenal Hyperplasia and a Large Renal Mass

Background: Clinical manifestations of Nonclassic CAH (NCCAH) in women may range from asymptomatic to hirsutism, oligo-menorrhea, or infertility. Testicular adrenal rest tumors are common in men with classic CAH though uncommon in NCCAH. In women with classic CAH, ovarian adrenal rest tumors are even rarer. 11–58% of patients with classic CAH will have at least one adrenal nodule but the prevalence is unknown in NCCAH (1).Clinical Case: A 34-year-old Hispanic woman was seen by reproductive endocrinology for evaluation of infertility. She had been unable to conceive for the past 7 years. She was diagnosed with PCOS by her PCP. She was referred to our clinic for further workup. The patient denied galactorrhea. Laboratory evaluation revealed prolactin 49.3 (< 20.0 ng/ml), TSH 2.290 (0.5–5.0 μU/mL), fT4 1.14 (0.9–2.3 ng/dL), total testosterone 92 (15 -70 ng/dL for women), DHEAS 361 (45 -270 µg/dL), 8 AM cortisol 20.0 (5–23 μg/dL), ACTH 59.0 (6–76 pg/ml), 17-hydroxyprogesterone (17OHP) >2000 ng/dL, and A1c 5%. 24-hour urinary free cortisol was 26.4 (3.5–45 mcg/day). MRI of the pituitary did not show any adenoma. Pelvic ultrasound did not reveal any ovarian cysts.Cosyntropin stimulation test showed baseline 17OHP 1076 ng/dL, 30 minutes 8812 ng/dL, and 60 minutes 9452 ng/dL. She was begun on hydrocortisone and cabergoline. CT of the abdomen did not reveal any adrenal masses but showed mildly thickened adrenal limbs suggesting adrenal hyperplasia. A 4.5 cm exophytic enhancing mass on the left kidney was noted representing an adrenal rest tumor versus angiomyolipoma.Given the exophytic nature of the mass and increased risk of hemorrhage with angiomyolipomas greater than 4 cm, the patient was referred to urology and interventional radiology for radioembolization and possible biopsy of the mass. We are unsure if this renal mass is an angiomyolipoma or an adrenal rest tumor, which are uncommon in the kidneys. The patient was also referred for genetic counseling. Patients with CAH typically have CYP21A2 gene mutations, and the chance that a patient with NCCAH will have a child with classic CAH is reported to be 1 to 2% in two large cohort studies (2).Conclusion: This case is a reminder that evaluation of infertility/subfertility includes less common diagnoses, such as NCCAH. This genetic disorder is seen more frequently in certain ethnic groups, including Hispanics; and after diagnosis, patients should be referred to a genetic specialist. Additional abdominopelvic imaging should be considered in both men and women with a new diagnosis of NCCAH to evaluate for rare but clinically significant tumors.Reference: 1. Nordenström, A., Falhammar H. Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency Eur J Endocrinol. 2019 Mar;180(3):R127-R145.2. Merke, D, Auchus, R Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. NEJM 2020;383:1248–61.

Double Trouble: Co-Occurrence of Aromatase Deficiency and Non-Classic CAH in Three Siblings

Introduction: Aromatase deficiency (AD), an exceedingly rare autosomal recessive condition, causes virilization in females and tall stature with metabolic derangements in males. Clinical manifestations result from decreased estrogen production and androgen excess, but presentation varies based on residual aromatase activity. Non-classic CAH (NCCAH) is a relatively common disorder. Males are often asymptomatic or present with premature adrenarche (PA). Females are typically diagnosed during childhood/adolescence with PA, acne, hirsutism, or menstrual irregularities. We present three siblings with both conditions and describe their long-term follow-up. Cases: Identical twin sisters presented at birth with virilized genitalia. Evaluation revealed 46XX karyotype, transiently elevated testosterone (unchanged with hCG stimulation), normal 17OHP and normal ovarian tissue on gonadal biopsy. Due to sporadic follow-up, their diagnosis and care were delayed until age 15y when AD was confirmed with genetic testing (compound heterozygous: whole gene deletion on one allele and c.242A>G (p.tyr81cys) mutation on the other). Both girls had acne, hirsutism and clitoromegaly, but reached spontaneous menarche at 11y and height within mid-parental height (MPH). Given the genetic nature of AD, younger brother was assessed and diagnosed with AD with the same mutation in CYP19A1. He had normal height-corrected BMD, lipids and glucose. His testosterone level was high-normal with undetectable estradiol. He had height below MPH with slow growth velocity, low IGF-1 and bone age (BA) within 2SD for age (BA 14y at CA 15y). GH stimulation test with estrogen priming revealed GH peak of 4.1 ng/ml, consistent with GH deficiency. All three siblings had high baseline and stimulated 17OHP which prompted genetic testing for CAH and confirmed NCCAH due to homozygous pVal282Leu substitution in CYP21A2. Treatment for both AD and NCCAH in females is combined estrogen+progesterone (usually given as an oral contraceptive pill), to replace estrogen and suppress androgen overproduction. The twin sisters elected clitoral reduction at age 19y with a satisfactory outcome. Their brother is not on any treatment at this time. At age 18y, his BA is still 14y-14.5y, as expected in AD, but atypical for NCCAH. Conclusion: Virilized genitalia in the newborn period prompted extensive evaluation of twin sisters that led to diagnosis of AD but also prompted assessment and diagnosis of their asymptomatic brother. Elevation of 17OHP, previously not described in AD patients, prompted testing for CAH and confirmed the unique finding of both AD and NCCAH in these three siblings. We postulate that the combined AD/NCCAH caused exacerbation of androgen excess in all three siblings. The short stature in our male patient is presumably due to GH deficiency.

Late diagnosis of classic congenital adrenal hyperplasia: long-term consequences during adulthood.

SummaryCongenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders related to enzyme deficiencies in the adrenal steroidogenesis pathway leading to impaired corticosteroid biosynthesis. Depending on the extension of enzyme defect, there may be variable severities of CAH – classic and non-classic. We report the case of a 37-year-old male patient with a previously unknown diagnosis of classic CAH referred to Endocrinology evaluation due to class III obesity and insulin resistance. A high diagnostic suspicion was raised at the first Endocrinology consultation after careful past medical history analysis especially related to the presence of bilateral adrenal myelolipomas and primary infertility. A genetic test confirmed the presence of a variant of the CYP21A2 in homozygous with an enzymatic activity of 0–1%, corresponding to a classic and severe CAH form. Our case represents an unusually late definitive diagnose of classic CAH since the definition was established only during adulthood in the fourth decade of life. The missing diagnosis of classic 21 hydroxylase deficiency during infancy led to important morbidity, with a high impact on patients’ quality of life. Learning pointsCongenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive enzyme disorders responsible for an impaired cortical adrenal hormonal synthesis.CAH may be divided into two major forms: classic and non-classic CAH. If untreated, CAH may be fatal or may be responsible for important multi-organ long-term consequences that can be undervalued during adulthood. Adrenal myelolipomas are associated with chronic exposure to high ACTH levels and continuous androgen hyperstimulation typically found in undertreated CAH patients.Testicular adrenal rest tumours (TART) and primary infertility can be the first manifestation of the disease during adulthood.

Novel non-classic CYP21A2 variants, including combined alleles, identified in patients with congenital adrenal hyperplasia

ObjectiveCongenital adrenal hyperplasia (CAH) is an inborn error of metabolism and a common disorder of sex development where >90% of all cases are due to 21-hydroxylase deficiency. Novel and rare pathogenic variants account for 5% of all clinical cases. Here, we sought to investigate the functional and structural effects of four novel (p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro) and three combinations of CYP21A2 variants (i.e. one allele containing two variants p.[Ile172Asn;Val358Ile], p.[Val281Leu;Arg369Gln], or p.[Asp377Tyr;Leu461Pro]) identified in patients with CAH. MethodsAll variants were reconstructed by in vitro site-directed mutagenesis, the proteins were transiently expressed in COS-1 cells and enzyme activities directed toward the two natural substrates (17-hydroxyprogesterone and progesterone) were determined. In parallel, in silico prediction of the pathogenicity of the variants based on the human CYP21 X-ray structure was performed. ResultsThe novel variants, p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro exhibited residual enzymatic activities within the range of non-classic (NC) CAH variants (40–82%). An additive effect on the reduction of enzymatic activity (1–17%) was observed when two variants were expressed together, as identified in several patients, resulting in either NC or more severe phenotypes. In silico predictions were in line with the in vitro data except for p.Leu461Pro. ConclusionsAltogether, the combination of clinical data, in silico prediction, and data from in vitro studies are important for establishing a correct genotype and phenotype correlation in patients with CAH.

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency.

Non-classic congenital adrenal hyperplasia (NCAH) is a relatively common disorder regardless of ethnicity, but most cases are never diagnosed, especially in males. A baseline 17-hydroxyprogesterone measurement may be used for screening, but 17-hydroxyprogesterone measurement after ACTH stimulation is the gold standard. We advocate a CYP21A2 mutation analysis to verify the diagnosis, for genetic counselling and for better prognostic and treatment guidance. Most patients are diagnosed in adolescence and adult life with hirsutism, acne, a PCOS-like picture and fertility issues. Many men with NCAH never seek medical attention and escape diagnosis. Although treatment is somewhat controversial, an early diagnosis and start of treatment may have positive implications on growth and be relevant for preventing and ameliorating the symptoms and consequences of androgen excess that develop over time, including fertility issues. Long-term treatment with glucocorticoids will improve the androgen symptoms but may result in long-term complications, such as obesity, insulin resistance, hypertension, osteoporosis and fractures. The glucocorticoid doses should be kept low. However, complications seen in NCAH, assumed to be caused by the glucocorticoid treatment, may also be associated with long-term androgen exposure. Oral contraceptive pills are a common treatment option for young females with NCAH. Regular clinical monitoring to improve the clinical outcome is recommended. It is important to acknowledge that glucocorticoid treatment will lead to secondary cortisol insufficiency and the need for stress dosing. Studies focusing on the specific difficulties patients with NCAH face, both those with a late clinical diagnosis and those with a neonatal diagnosis obtained by screening, are warranted.

Functional and Structural Consequences of Nine CYP21A2 Mutations Ranging from Very Mild to Severe Effects.

We present the functional and structural effects of seven novel (p.Leu12Met, p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, p.Gln389_Ala391del, and p.Thr450Met) and two previously reported but not studied (p.Ser113Phe and p.Thr450Pro) CYP21A2 mutations. Functional analyses were complemented with in silico prediction of mutation pathogenicity based on the recently crystallized human CYP21A2 structure. Mutated proteins were transiently expressed in COS-1 cells and enzyme activities towards 17-hydroxyprogesterone and progesterone were determined. Residual enzyme activities between 43% and 97% were obtained for p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, and p.Thr450Met, similar to the activities of the well-known nonclassic mutations p.Pro453Ser and p.Pro482Ser, whereas the p.Leu12Met variant showed an activity of 100%. Conversely, the novel p.Ser113Phe, p.Gln389_Ala391del, and p.Thr450Pro mutations drastically reduced the enzyme function below 4%. The K m values for all novel variants were in the same order of magnitude as for the wild-type protein except for p.The450Met. The maximum velocity was decreased for all mutants except for p.Leu12Met. We conclude that p.Leu12Met is a normal variant; the mutations p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, and p.Thr450Met could be associated with very mild nonclassic CAH, and the mutations p.Ser113Phe, p.Gln389_Ala391del, and p.Thr450Pro are associated with classic CAH. The obtained residual activities indicated a good genotype-phenotype correlation.

Clinical and mutational spectrum of patients with congenital lipoid adrenal hyperplasia in Southeast Asia

Aims Mutations in Steroidogenic Acute Regulatory protein (StAR) cause congenital lipoid adrenal hyperplasia (lipoid CAH), characterized by absent steroidogenesis, potentially lethal salt loss, 46,XY sex reversal and massively enlarged adrenals engorged with cholesterol esters. Nonclassic lipoid CAH is a recently recognized disorder caused by StAR mutations that retain partial function. We aim to delineate the clinical and mutational spectrum of StAR mutations in patients with lipoid CAH.

Genetic and functional study of StAR (steroidogenic acute regulatory protein) deficiency

Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH, impairing adrenal and gonadal steroidogenesis. Most cases of lipoid CAH are caused by recessive mutations in the gene encoding steroidogenic acute regulatory protein (StAR), a protein that plays an essential role in cholesterol transfer from the outer to inner mitochondrial membrane, thus providing the substrate for steroid hormone biosynthesis. Affected children typically present with life-threatening adrenal insufficiency in early infancy due to a failure of glucocorticoid (cortisol) and mineralocorticoid (aldosterone) biosynthesis, and 46,XY genetic males have complete lack of androgenization and appear phenotypically female due to impaired testicular androgen secretion in utero. Previously, the Q258X mutation of StAR was shown to account for about 70% of affected alleles in most patients of Japanese and Korean ancestry. However, it is more prevalent (92.3%) in the Korean population. These results suggest that the genetic defect in the StAR gene in Korean patients with lipoid CAH is highly homogeneous, probably reflecting a founder effect. Recently, some patients have been reported that they showed late and mild clinical presentation. These cases and studies establish a new entity of ‘non-classic lipoid CAH’ showing that the phenotypic spectrum of StAR mutations is substantially broader than previously appreciated.

Congenital lipoid adrenal hyperplasia.

Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most fatal form of CAH, as it disrupts adrenal and gonadal steroidogenesis. Most cases of lipoid CAH are caused by recessive mutations in the gene encoding steroidogenic acute regulatory protein (StAR). Affected patients typically present with signs of severe adrenal failure in early infancy and 46,XY genetic males are phenotypic females due to disrupted testicular androgen secretion. The StAR p.Q258X mutation accounts for about 70% of affected alleles in most patients of Japanese and Korean ancestry. However, it is more prevalent (92.3%) in the Korean population. Recently, some patients have been showed that they had late and mild clinical findings. These cases and studies constitute a new entity of 'nonclassic lipoid CAH'. The cholesterol side-chain cleavage enzyme, P450scc (CYP11A1), plays an essential role converting cholesterol to pregnenolone. Although progesterone production from the fetally derived placenta is necessary to maintain a pregnancy to term, some patients with P450scc mutations have recently been reported. P450scc mutations can also cause lipoid CAH and establish a recently recognized human endocrine disorder.

Prise en charge à l’âge adulte des patients avec un bloc en 21 hydroxylase

A unit taking care of adults with congenital 21 hydroxylase deficiency (CAH) includes patients with classic CAH, comprising the salt-wasting and the simple-virilizing forms as well as patients with non-classic form. Classic CAH is a rare disease with an incidence of 1/10,000 to 1/15,000, patients have usually been followed in pediatric units and transition represents an important step. Non-classic CAH are more frequent with an incidence of 1/1000. The diagnosis is made at puberty or even when patients are adults. In all cases, genetic counselling is needed. The main issues in patients with CAH are sexuality, fertility, bone health and cardiovascular risk. In classic CAH, fertility is decreased both in women and men; risk of osteoporosis is increased as well as cardiovascular risk. The main problem is to replace the missing glucocorticoids without overtreating patients. Undertreatment induces hyperandrogenism in women, and testicular adrenal rests tumors in men. On the opposite, overtreatment increases body mass index, blood pressure, decreases insulin sensitivity, modifies adipose tissue, increases cardiovascular risk and osteoporosis. In non-classic CAH, fertility is subnormal.

Characterization of Novel StAR (Steroidogenic Acute Regulatory Protein) Mutations Causing Non-Classic Lipoid Adrenal Hyperplasia

ContextSteroidogenic acute regulatory protein (StAR) is crucial for transport of cholesterol to mitochondria where biosynthesis of steroids is initiated. Loss of StAR function causes lipoid congenital adrenal hyperplasia (LCAH).ObjectiveStAR gene mutations causing partial loss of function manifest atypical and may be mistaken as familial glucocorticoid deficiency. Only a few mutations have been reported.DesignTo report clinical, biochemical, genetic, protein structure and functional data on two novel StAR mutations, and to compare them with published literature.SettingCollaboration between the University Children's Hospital Bern, Switzerland, and the CIBERER, Hospital Vall d'Hebron, Autonomous University, Barcelona, Spain.PatientsTwo subjects of a non-consanguineous Caucasian family were studied. The 46,XX phenotypic normal female was diagnosed with adrenal insufficiency at the age of 10 months, had normal pubertal development and still has no signs of hypergonodatropic hypogonadism at 32 years of age. Her 46,XY brother was born with normal male external genitalia and was diagnosed with adrenal insufficiency at 14 months. Puberty was normal and no signs of hypergonadotropic hypogonadism are present at 29 years of age.ResultsStAR gene analysis revealed two novel compound heterozygote mutations T44HfsX3 and G221S. T44HfsX3 is a loss-of-function StAR mutation. G221S retains partial activity (∼30%) and is therefore responsible for a milder, non-classic phenotype. G221S is located in the cholesterol binding pocket and seems to alter binding/release of cholesterol.ConclusionsStAR mutations located in the cholesterol binding pocket (V187M, R188C, R192C, G221D/S) seem to cause non-classic lipoid CAH. Accuracy of genotype-phenotype prediction by in vitro testing may vary with the assays employed.

Premature Moustache As Presenting Symptom of Nonclassic Congenital Adrenal Hyperplasia due to 2 Uncommon Mutations of theCYP21A2Gene

A Turkish boy was referred at the age of 3 6/12 years for the evaluation of a premature moustache. No other signs of virilisation were present. The endocrine evaluation led to the diagnosis of nonclassic congenital adrenal hyperplasia. Genetic analysis revealed 2 rare mutations of the CYP21A2 gene, the gene encoding for the 21-hydroxylase enzyme: a recently reported R132C mutation in exon 3 and a R339H mutation in exon 8, both reported in the nonclassic CAH. An early moustache, for which the term premature moustache can be coined, can be the presenting symptom of nonclassic CAH. In all children presenting with a sex or age inappropriate development of a moustache, an endocrine evaluation is indicated.

Partial Defect in the Cholesterol Side-Chain Cleavage Enzyme P450scc (CYP11A1) Resembling Nonclassic Congenital Lipoid Adrenal Hyperplasia

The cholesterol side-chain cleavage enzyme (P450scc), encoded by the CYP11A1 gene, converts cholesterol to pregnenolone to initiate steroidogenesis. Genetic defects in P450scc cause a rare autosomal recessive disorder that is clinically indistinguishable from congenital lipoid adrenal hyperplasia (lipoid CAH). Nonclassic lipoid CAH is a recently recognized disorder caused by mutations in the steroidogenic acute regulatory protein (StAR) that retain partial function. We describe two siblings with hormonal findings suggesting nonclassic lipoid CAH, who had a P450scc mutation that retains partial function. A 46,XY male presented with underdeveloped genitalia and partial adrenal insufficiency; his 46,XX sister presented with adrenal insufficiency. Hormonal studies suggested nonclassic lipoid CAH. Sequencing of the StAR gene was normal, but compound heterozygous mutations were found in the CYP11A1 gene. Mutations were recreated in the F2 plasmid expressing a fusion protein of the cholesterol side-chain cleavage system. P450scc activity was measured as Vmax/Km for pregnenolone production in transfected COS-1 cells. The patients were compound heterozygous for the previously described frameshift mutation 835delA and the novel missense mutation A269V. When expressed in the P450scc moiety of F2, the A269V mutant retained 11% activity of the wild-type F2 protein. There is a broad clinical spectrum of P450scc deficiency. Partial loss-of-function CYP11A1 mutation can present with a hormonal phenotype indistinguishable from nonclassic lipoid CAH.

Nonclassic congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency

Nonclassic CAH, also termed as late onset of CAH, is a very mild form of 21-hydroxylase deficiency. The incidence of disease is estimated at 0.1% of population. Nonclassic CAH is usually diagnosed in the childhood before the age of 6 to 8 years as premature pubarche. The disease is not common in the infants and usually not before 6 to 8 months. This is a case report of 7-month female infant who was suspected of mild hyperandrogenism because of premature pubarche. The diagnosis was confirmed by mild basal elevation of 17-OHP (5.55 ng/ml) and characteristic hyper-response to ACTH, reaching values of 21 ng/ml, as well as accelerated bone maturation. The conventional treatment of NCAH was initiated, with glucocorticoid therapy (hydrocortisone) for one year and a half. After that period, our decision was to discontinue the hormonal therapy because of the impression that hyperandrogenism was mild (mild deficiency of the enzymes for steroid hormone synthesis). Child's growth, development and maturation are under constant control.

Nonclassic 21-hydroxylase deficiency in Croatia.

This is the first report of nonclassic congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency in Croatia in which the patients have been evaluated clinically, hormonally, and by molecular genetic analysis. Genetic analysis was performed on 18 Croatian patients with nonclassic CAH due to 21-OH deficiency using allele-specific PCR. ACTH stimulation testing and HLA typing were used to evaluate patients hormonally. Molecular genetic analysis revealed a variety of mutations in individuals with different clinical symptoms, including precocious pubarche, hirsutism, (dysmenorrhea, subfertility and clitoromegaly. Serum stimulated 17-hydroxyprogesterone (17-OHP) levels indicated that all patients fell within the acceptable range for nonclassic congenital adrenal hyperplasia. Clinical and genetic analysis confirmed nonclassic 21-OH deficiency in our Croatian sample of ten males and eight females. This study shows that genotype does not necessarily predict fertility status in our group of affected patients.