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1.  Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene. 
Journal of Clinical Investigation  1997;99(6):1265-1271.
Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH in which the synthesis of all gonadal and adrenal cortical steroids is markedly impaired. We report here the clinical, endocrinological, and molecular analyses of two unrelated Japanese kindreds of 46,XX subjects affected with lipoid CAH who manifested spontaneous puberty. Phenotypic female infants with 46,XX karyotypes were diagnosed with lipoid CAH as newborns based on a clinical history of failure to thrive, hyperpigmentation, hyponatremia, hyperkalemia, and low basal values of serum cortisol and urinary 17-hydroxycorticosteroid and 17-ketosteroid. These patients responded to treatment with glucocorticoid and 9alpha-fludrocortisone. Spontaneous thelarche occurred in association with increased serum estradiol levels at the age of 10 and 11 yr, respectively. Pubic hair developed at the age of 12 yr 11 mo in one subject and menarche was at the age of 12 yr in both cases. Both subjects reported periodic menstrual bleeding and subsequently developed polycystic ovaries. To investigate the molecular basis of the steroidogenic lesion in these patients, the StAR gene was characterized by PCR and direct DNA sequence analyses. DNA sequence analysis revealed that one patient is homozygous for the Gln 258 Stop mutation in exon 7 and that the other patient is a compound heterozygote with the Gln 258 Stop mutation and a single A deletion at codon 238 in the other allele causing a frame-shift, which renders the StAR protein nonfunctional. These findings demonstrate that ovarian steroidogenesis can be spared to some extent through puberty when the StAR gene product is inactive. This is in marked contrast to the early onset of severe defects in testicular and adrenocortical steroidogenesis which are characteristics of this disease.
PMCID: PMC507941  PMID: 9077535
2.  Non-Classic Congenital Lipoid Adrenal Hyperplasia: A New Disorder of the Steroidogenic Acute Regulatory Protein With Very Late Presentation and Normal Male Genitalia 
Context
Congenital lipoid adrenal hyperplasia (lipoid CAH) is a severe disorder of adrenal and gonadal steroidogenesis caused by mutations in the steroidogenic acute regulatory protein (StAR). 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.
Objective
The objective of this study was to investigate whether non-classic forms of this condition exist.
Patients & Methods
Sequence analysis of the gene encoding StAR was undertaken in three children from two families who presented with primary adrenal insufficiency at 2-4 years of age; the males had normal genital development. Identified mutants were tested in a series of biochemical assays.
Results
DNA sequencing identified homozygous StAR mutations Val187Met and Arg188Cys in these two families. Functional studies of StAR activity in cells and in vitro, and cholesterol-binding assays showed these mutants retained ∼20% of wild type activity.
Conclusions
These patients define a new disorder, “non-classic lipoid CAH”, and represent a new cause of non-autoimmune Addison disease (primary adrenal failure).
doi:10.1210/jc.2006-1565
PMCID: PMC1865081  PMID: 16968793
3.  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.
doi:10.6065/apem.2014.19.4.179
PMCID: PMC4316413  PMID: 25654062
Steroidogenic acute regulatory protein; Lipoid congenital adrenal hyperplasia; Cholesterol side-chain cleavage enzyme
4.  Characterization of Novel StAR (Steroidogenic Acute Regulatory Protein) Mutations Causing Non-Classic Lipoid Adrenal Hyperplasia 
PLoS ONE  2011;6(5):e20178.
Context
Steroidogenic 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).
Objective
StAR gene mutations causing partial loss of function manifest atypical and may be mistaken as familial glucocorticoid deficiency. Only a few mutations have been reported.
Design
To report clinical, biochemical, genetic, protein structure and functional data on two novel StAR mutations, and to compare them with published literature.
Setting
Collaboration between the University Children's Hospital Bern, Switzerland, and the CIBERER, Hospital Vall d'Hebron, Autonomous University, Barcelona, Spain.
Patients
Two 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.
Results
StAR 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.
Conclusions
StAR 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.
doi:10.1371/journal.pone.0020178
PMCID: PMC3103540  PMID: 21647419
5.  Normal genes for the cholesterol side chain cleavage enzyme, P450scc, in congenital lipoid adrenal hyperplasia. 
Journal of Clinical Investigation  1991;88(6):1955-1962.
Congenital lipoid adrenal hyperplasia is the most severe form of congenital adrenal hyperplasia. Affected individuals can synthesize no steroid hormones, and hence are all phenotypic females with a severe salt-losing syndrome that is fatal if not treated in early infancy. All previous studies have suggested that the disorder is in the cholesterol side chain cleavage enzyme (P450scc), which converts cholesterol to pregnenolone. A newborn patient was diagnosed by the lack of significant concentrations of adrenal or gonadal steroids either before or after stimulation with corticotropin (ACTH) or gonadotropin (hCG). The P450scc gene in this patient and in a previously described patient were grossly intact, as evidenced by Southern blotting patterns. Enzymatic (polymerase chain reaction) amplification and sequencing of the coding regions of their P450scc genes showed these were identical to the previously cloned human P450scc cDNA and gene sequences. Undetected compound heterozygosity was ruled out in the new patient by sequencing P450scc cDNA enzymatically amplified from gonadal RNA. Northern blots of gonadal RNA from this patient contained normal sized mRNAs for P450scc and also for adrenodoxin reductase, adrenodoxin, sterol carrier protein 2, endozepine, and GRP-78 (the precursor to steroidogenesis activator peptide). These studies show that lipoid CAH is not caused by lesions in the P450scc gene, and suggest that another unidentified factor is required for the conversion of cholesterol to pregnenolone, and is disordered in congenital lipoid adrenal hyperplasia.
Images
PMCID: PMC295776  PMID: 1661294
6.  Congenital Adrenal Hyperplasia due to 17-alpha-hydoxylase/17,20-lyase Deficiency Presenting with Hypertension and Pseudohermaphroditism: First Case Report from Oman 
Oman Medical Journal  2014;29(1):55-59.
This is the first report of congenital adrenal hyperplasia (CAH) due to combined 17α-hydroxylase/17,20 lyase deficiency in an Omani patient who was initially treated for many years as a case of hypertension. CAH is an uncommon disorder that results from a defect in steroid hormones biosynthesis in the adrenal cortex. The clinical presentation depends on the site of enzymatic mutations and the types of accumulated steroid precursors. A 22-year-old woman who was diagnosed to have hypertension since the age of 10 years who was treated with anti-hypertensive therapy was referred to the National Diabetes and Endocrine Centre, Royal Hospital, Oman. The patient also had primary amenorrhea and features of sexual infantilism. Full laboratory and radio-imaging investigations were done. Adrenal steroids, pituitary function and karyotyping study were performed and the diagnosis was confirmed by molecular mutation study. Laboratory investigations revealed adrenal steroids and pituitary hormones profile in addition to 46XY karyotype that are consistent with the diagnosis of CAH due to 17α-hydroxylase deficiency. Extensive laboratory workup revealed low levels of serum cortisol (and its precursors 17α-hydroxyprogesterone and 11-deoxycortisol), adrenal androgens (dehydroepiandrosterone sulfate and androstenedione), and estrogen (estradiol); and high levels of mineralocorticoids precursors (11-deoxycorticosterone and corticosterone) with high levels of ACTH, FSH and LH. Mutation analysis revealed CYP17A1-homozygous mutation (c.287G>A p.Arg96Gln) resulting in the complete absence of 17α-hydroxylase/17,20-lyase activity. The patient was treated with dexamethasone and ethinyl estradiol with cessation of anti-hypertensive therapy. A review of the literature was conducted to identify previous studies related to this subtype of CAH. This is the first biochemically and genetically proven case of CAH due to 17α-hydroxylase/17,20-lyase deficiency in Oman and in the Arab World described in the literature.
doi:10.5001/omj.2014.12
PMCID: PMC3910417  PMID: 24498484
Congenital adrenal hyperplasia; 17 α-hydroxylase; 17,20-lyase; Hypertension; Pseudohermaphroditism; Adrenal cortex; Oman
7.  Congenital adrenal hyperplasia: Treatment and outcomes 
Congenital adrenal hyperplasia (CAH) describes a group of autosomal recessive disorders where there is impairment of cortisol biosynthesis. CAH due to 21-hydroxylase deficiency accounts for 95% of cases and shows a wide range of clinical severity. Glucocorticoid and mineralocorticoid replacement therapies are the mainstays of treatment of CAH. The optimal treatment for adults with CAH continues to be a challenge. Important long-term health issues for adults with CAH affect both men and women. These issues may either be due to the disease or to steroid treatment and may affect final height, fertility, cardiometabolic risk, bone metabolism, neuro-cognitive development and the quality-of-life. Patients with CAH should be regularly followed-up from childhood to adulthood by multidisciplinary teams who have knowledge of CAH. Optimal replacement therapy, close clinical and laboratory monitoring, early life-style interventions, early and regular fertility assessment and continuous psychological management are needed to improve outcome.
doi:10.4103/2230-8210.119491
PMCID: PMC3830282  PMID: 24251136
Bone health; cardio-metabolic risk; congenital adrenal hyperplasia; fertility; final height; glucocorticoids; neurocognitive outcome; quality-of-life
8.  Adrenal Hypoplasia Congenita Presenting as Congenital Adrenal Hyperplasia 
Case Reports in Endocrinology  2013;2013:393584.
We report on a patient with genetically confirmed adrenal hypoplasia congenita (AHC) whose presentation and laboratory abnormalities were consistent with the more common condition, congenital adrenal hyperplasia (CAH). The patient presented with failure to thrive and salt wasting. General appearance showed marked hyperpigmentation and normal male genitalia. He displayed mildly elevated 17-hydroxyprogesterone and markedly elevated 11-deoxycortisol levels at baseline and with ACTH stimulation testing. Results were consistent with 11β-hydroxylase deficiency. He required glucocorticoids and high doses of mineralocorticoids. The marked elevation in 11-deoxycortisol directed our clinical reasoning away from a hypoplastic condition and towards a hyperplasic adrenal condition. Sequencing of the DAX1 gene (named for dosage-sensitive sex reversal (DSS) locus and the AHC locus on the X chromosome) revealed a missense mutation. A review of the literature revealed that elevated 11-deoxycortisol levels have been noted in kindreds with DAX1 mutations, but only when measured very early in life. A mouse model has recently been described that displays elevated 11-deoxycorticosterone levels and evidence for hyperplasia of the zona glomerulosa of the adrenal gland. We conclude that DAX1 testing may be considered in patients with laboratory evidence of 11β-hydroxylase deficiency, especially in those with severe salt wasting.
doi:10.1155/2013/393584
PMCID: PMC3583052  PMID: 23476826
9.  Amygdala Function In Adolescents With Congenital Adrenal Hyperplasia: A Model For The Study Of Early Steroid Abnormalities 
Neuropsychologia  2007;45(9):2104-2113.
Early disruption of steroids affects the development of mammalian neural circuits underlying affective processes. In humans, patients with classic Congenital Adrenal Hyperplasia (CAH) can serve as a natural model to study early hormonal alterations on functional brain development. CAH is characterized by congenital glucocorticoid insufficiency, leading to altered hypothalamic-pituitary-adrenal (HPA) function, and hyperandrogenism. Using fMRI, we compared fourteen adolescents with CAH to 14 healthy controls on amygdala response to a face viewing task. In response to negative facial emotions, CAH females activated the amygdala significantly more than healthy females, whereas CAH males did not differ from control males. Furthermore, females with CAH showed a similar pattern of amygdala activation to control males, suggesting virilized amygdala function in females with CAH. These findings suggest a prominent effect of early hyperandrogenism on the development and function of the amygdala in females with CAH, whereas no effects were detected in males with CAH. This study provides data that can be further tested in a model of the neurobiological mechanisms underlying early androgen organizational effect on amygdala function.
doi:10.1016/j.neuropsychologia.2007.01.019
PMCID: PMC2929598  PMID: 17336344
development; corticosteroid; androgen; affective processing; fMRI; stress hormones
10.  Clinical Features of Congenital Adrenal Insufficiency Including Growth Patterns and Significance of ACTH Stimulation Test 
Journal of Korean Medical Science  2013;28(11):1650-1656.
Congenital adrenal insufficiency is caused by specific genetic mutations. Early suspicion and definite diagnosis are crucial because the disease can precipitate a life-threatening hypovolemic shock without prompt treatment. This study was designed to understand the clinical manifestations including growth patterns and to find the usefulness of ACTH stimulation test. Sixteen patients with confirmed genotyping were subdivided into three groups according to the genetic study results: congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH, n=11), congenital lipoid adrenal hyperplasia (n=3) and X-linked adrenal hypoplasia congenita (n=2). Bone age advancement was prominent in patients with CAH especially after 60 months of chronologic age (n=6, 67%). They were diagnosed in older ages in group with bone age advancement (P<0.05). Comorbid conditions such as obesity, mental retardation, and central precocious puberty were also prominent in this group. In conclusion, this study showed the importance of understanding the clinical symptoms as well as genetic analysis for early diagnosis and management of congenital adrenal insufficiency. ACTH stimulation test played an important role to support the diagnosis and serum 17-hydroxyprogesterone levels were significantly elevated in all of the CAH patients. The test will be important for monitoring growth and puberty during follow up of patients with congenital adrenal insufficiency.
doi:10.3346/jkms.2013.28.11.1650
PMCID: PMC3835509  PMID: 24265530
Adrenal Insufficiency, Congenital; Adrenal Hyperplasia; Lipoid Congenital Adrenal Hyperplasia; X-Linked Adrenal Hypoplasia Congenita; Growth; Puberty
11.  Review of Outcome Information in 46,XX Patients with Congenital Adrenal Hyperplasia Assigned/Reared Male: What Does It Say about Gender Assignment? 
There is ample historical verification of 46,XX congenital adrenal hyperplasia (CAH) patients being born with essentially male genitaliawhile outcome information is scant. Prior to glucocorticoid therapy, most patients died very young from adrenal insufficiency. Most available reports from laterchildhood, contain little information concerning sexual identity. Reports on older individuals lack adequate information about sexual identity and quality of life. The difficulty in assessing the relative impact of multiple dynamic environmental factors on the development of sexual identity, self- and body esteem and overall adjustment to life is clear. Nevertheless, it remains unclear whether those infants whose masculine genitalia at birth resulted in an initial male assignment would have enjoyed a better adult outcome had they been allowed to remain male rather than the female reassignment that most received. Further, one could ask whether a male sex of rearing should be considered in 46,XX CAH infants with male external genitalia. After reviewing available literature, we conclude that because those extremely virlized 46,XX CAH patients who were reared male with healthy social support demonstrated satisfactory levels of social and sexual function as adults a male sex assignment should be considered in these types of infants when social and cultural environment are supportive.
doi:10.1155/2010/982025
PMCID: PMC3010645  PMID: 21197442
12.  Health Status of Adults with Congenital Adrenal Hyperplasia: A Cohort Study of 203 Patients 
Context: No consensus exists for management of adults with congenital adrenal hyperplasia (CAH) due to a paucity of data from cohorts of meaningful size.
Objective: Our objective was to establish the health status of adults with CAH.
Design and Setting: We conducted a prospective cross-sectional study of adults with CAH attending specialized endocrine centers across the United Kingdom.
Patients: Participants included 203 CAH patients (199 with 21-hydroxylase deficiency): 138 women, 65 men, median age 34 (range 18–69) years.
Main Outcome Measures: Anthropometric, metabolic, and subjective health status was evaluated. Anthropometric measurements were compared with Health Survey for England data, and psychometric data were compared with appropriate reference cohorts.
Results: Glucocorticoid treatment consisted of hydrocortisone (26%), prednisolone (43%), dexamethasone (19%), or a combination (10%), with reverse circadian administration in 41% of patients. Control of androgens was highly variable with a normal serum androstenedione found in only 36% of patients, whereas 38% had suppressed levels suggesting glucocorticoid overtreatment. In comparison with Health Survey for England participants, CAH patients were significantly shorter and had a higher body mass index, and women with classic CAH had increased diastolic blood pressure. Metabolic abnormalities were common, including obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised.
Conclusions: Currently, a minority of adult United Kingdom CAH patients appear to be under endocrine specialist care. In the patients studied, glucocorticoid replacement was generally nonphysiological, and androgen levels were poorly controlled. This was associated with an adverse metabolic profile and impaired fertility and quality of life. Improvements in the clinical management of adults with CAH are required.
Adult patients with congenital adrenal hyperplasia (CAH) have poor subjective health status and only a minority of CAH adults receives regular review by endocrine specialists.
doi:10.1210/jc.2010-0917
PMCID: PMC3066446  PMID: 20719839
13.  Long-term Follow up of Congenital Adrenal Hyperplasia Patients with Hyponatremia 
Congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency is an autosomal recessive disease, which leads to cortisol and aldosterone deficiency and hyperandrogenism. Typical medical treatment includes oral glucocorticoid and mineralocorticoid administration to suppress adrenal androgens and to compensate for adrenal steroid deficiencies. However, some patients stopped taking medicine without the doctor's consent. Among these patients, four cases of CAH patients showing the presence of hyponatremia as an initial electrolyte disorder were found with adrenal adenoma. Hypersecretion of adrenocorticotrophic hormone and chronic poor compliance to therapy appears to be associated with the development of the adrenal tumor. Two cases were managed with adrenalectomy because of increasing adrenal tumor size and virilization. Whereas the other two cases did not increase in size and were observed without adrenalectomy. Therefore, it is important that patients with CAH maintain steroid medication to avoid the appearance of adrenal tumor.
doi:10.5049/EBP.2007.5.2.140
PMCID: PMC3894515  PMID: 24459514
Congenital adrenal hyperplasia; 21-hydroxylase deficiency; Hyponatremia; Adrenal tumor
14.  Severe Combined Adrenal and Gonadal Deficiency Caused by Novel Mutations in the Cholesterol Side Chain Cleavage Enzyme, P450scc 
Context:
Mitochondrial cytochrome P450scc converts cholesterol to pregnenolone in all steroidogenic tissues. Although progesterone production from the fetally-derived placenta is necessary to maintain pregnancy to term, four patients with mutations in the gene encoding P450scc (CYP11A1) have been described, one in a 46,XX female and three in under-androgenized 46,XY individuals, all with primary adrenal failure.
Objective:
To determine whether P450scc mutations might be found in other children, and to explore genotype/phenotype correlations.
Methods & Patients:
Mutational analysis of CYP11A1 in individuals with 46,XY disorders of sex development and primary adrenal failure, followed by functional studies of P450scc activity and of P450scc RNA splicing.
Results:
Among 9 46,XY infants with adrenal failure and disordered sexual differentiation, two infants had compound heterozygous mutations in CYP11A1. One patient harbored the novel P450scc missense mutations L141W and V415E, which retained 38% and 0% activity, respectively. The other carried a CYP11A1 frameshift mutation c835delA (0% activity) and a splice site mutation (IVS3+(2-3)insT) that prevented correct splicing of P450scc mRNA.
Conclusions:
P450scc deficiency is a recently-recognized disorder that may be more frequent than originally thought. The phenotypic spectrum ranges from severe loss-of-function mutations associated with prematurity, complete underandrogenization and severe, early-onset adrenal failure, to partial deficiencies found in children born at term with clitoromegaly and later-onset adrenal failure. In contradistinction to congenital lipoid adrenal hyperplasia caused by StAR mutations, adrenal hyperplasia has not been reported in any of the six patients with P450scc deficiency.
doi:10.1210/jc.2007-2330
PMCID: PMC2266942  PMID: 18182448
Cholesterol; adrenal; Addison disease; adrenal hypoplasia; CYP11A1; steroidogenesis
15.  Classic congenital adrenal hyperplasia: A delayed presentation 
Congenital adrenal hyperplasia (CAH) is a rare congenital disorder, which in cases of female genotype may result in virilization. Specific enzyme deficiencies in adrenocorticoid hormones biosynthetic pathway lead to excess androgen production causing virilization. Classic type presents early in infant life as salt losing or simple virilizing type, whereas non classic form presents late at puberty or in adult life. Depending on the type of classic CAH, type of adrenocorticoid deficiency, extent of virilization & genotype, surgical corrective procedures, glucocorticoid & mineralocorticoid replacement therapy are the mainstay of management. We present here a case of classic congenital adrenal hyperplasia of simple virilizing type, which presented later in childhood.
doi:10.12669/pjms.291.2830
PMCID: PMC3809185  PMID: 24353545
Congenital adrenal hyperplasia; Clitoromegaly; Virilization; Clitoroplasty; Ambiguous genitalia
16.  Congenital Adrenal Hyperplasia in an Elite Female Soccer Player; What Sports Medicine Clinicians Should Know about This? 
Asian Journal of Sports Medicine  2012;3(3):209-213.
Background
Congenital Adrenal Hyperplasia (CAH) refers to a group of congenital conditions characterized by disordered cortisol synthesis. The correlation between CAH and sports performance has been less studied before and there is very limited information regarding the impacts of this congenital disease on sports performance. Probably, there are some limitations for patients who suffer from CAH in sports, but at the same time, they may enjoy some advantage due to the probable effect of endogenous hyperandrogenism on their exercise performance.
Case Presentation
The case is a 14 - year old girl with male phenotype who is a known case of congenital adrenal hyperplasia. She plays in the women's national soccer team of under 16. She has been in the first division league of indoor soccer for 4 years and was also selected in the preparation training camp of women's football team for Singapore's youth Olympic Games. Her illness and dependence on corticosteroid have caused some concerns for her participation in the international competitions of women. However, following consultations with the Therapeutic Use Exemption (TUE) Committee of games organization, she received TUE to use corticosteroid only within the games period. Despite all her problems, she is now playing in the Second Division League of indoor soccer.
Conclusions
A female adolescent with CAH may compete at the high level of outdoor and indoor soccer. However, there are many questions regarding the advantages and disadvantages of this congenital disorder and its treatment on sports related issues.
PMCID: PMC3445650  PMID: 23012642
Congenital Adrenal Hyperplasia; Doping; Gender Identity; Sports; Soccer; Therapeutic Use Exemption
17.  Adult Patients with Congenital Adrenal Hyperplasia Have Elevated Blood Pressure but Otherwise a Normal Cardiovascular Risk Profile 
PLoS ONE  2011;6(9):e24204.
Objective
Treatment with glucocorticoids and mineralocorticoids has changed congenital adrenal hyperplasia (CAH) from a fatal to a chronic lifelong disease. Long-term treatment, in particular the chronic (over-)treatment with glucocorticoids, may have an adverse effect on the cardiovascular risk profile in adult CAH patients. The objective of this study was to evaluate the cardiovascular risk profile of adult CAH patients.
Design
Case-control study.
Patients and Measurements
In this case-control study the cardiovascular risk profile of 27 adult CAH patients and 27 controls, matched for age, sex and body mass index was evaluated by measuring ambulatory 24-hour blood pressure, insulin sensitivity (HOMA-IR), lipid profiles, albuminuria and circulating cardiovascular risk markers (PAI-1, tPA, uPA, tPA/PAI-1 complex, hsCRP, adiponectin, IL-6, IL-18 and leptin).
Results
24-Hour systolic (126.3 mmHg±15.5 vs 124.8 mmHg±15.1 in controls, P = 0.019) and diastolic (76.4 mmHg±12.7 vs 73.5 mmHg±12.4 in controls, P<0.001) blood pressure was significantly elevated in CAH patients compared to the control population. CAH patients had higher HDL cholesterol levels (P<0.01), lower hsCRP levels (P = 0.03) and there was a trend toward elevated adiponectin levels compared to controls. Other cardiovascular risk factors were similar in both groups.
Conclusion
Adult CAH patients have higher ambulatory blood pressure compared to healthy matched controls. Other cardiovascular risk markers did not differ, while HDL-cholesterol, hsCRP and adiponectin levels tended to be more favorable.
doi:10.1371/journal.pone.0024204
PMCID: PMC3164719  PMID: 21909422
18.  Molecular genetic analysis of CYP21A2 gene in patients with congenital adrenal hyperplasia 
Context:
Congenital adrenal hyperplasia (CAH) is one of the inborn errors of metabolic disorder inherited in an autosomal recessive manner caused by the defects in the steroid 21 hydroxylase CYP21A2 gene. We analyzed the genotype of 62 patients with classic CAH.
Aims:
To find out the underlying mutations of CYP21A2 gene.
Settings and Design:
Cohort of CAH patients.
Materials and Methods:
Sixty-two patients with CAH were recruited from the endocrine clinic at AIIMS. Electrochemiluminiscence method was used for estimating the levels of cortisol. Radioimmunoassay kit-based method was used for estimating the 17 OHP levels. Polymerase chain reaction amplification was done using specific primers to amply the CYP21A2 gene.
Statistical Analysis Used:
Statistical analysis was done by using Epi Info Version 3.5.1.2008.
Results:
Out of 62 patients, 50 were simple virilizers (SV) and 12 were salt wasters (SW). Fifty-six were females and six were males. Five 46, XX children were reared as males. Age at presentation varied from 8 months to 38 years. Molecular genetic analysis revealed that the highest number of patients harboured (In 2) IVS2-13 A/C > G (48%), followed by p.P30L (46%), p.Q318X (35%), (D 8 bp) deletion 8 bp (26%), p.I172N (26%), and p. R356W (20%) mutations.
Conclusion:
This is among the few studies to analyze the mutational spectrum of CYP21A2 gene in a large CAH cohort from India. Molecular diagnosis of CYP21A2 gene should be considered as part of the CAH evaluation to assess the risk of the patients/parents/siblings and to offer genetic counseling.
doi:10.4103/2230-8210.95679
PMCID: PMC3354845  PMID: 22629504
Ambiguous genitalia; CYP21A2 gene; phenotype; salt wasting; simple virilizing
19.  Motor development in individuals with congenital adrenal hyperplasia: Strength, targeting, and fine motor skill 
Psychoneuroendocrinology  2008;34(2):249-258.
Summary
This study investigated early androgen influence on the development of human motor and visuomotor characteristics. Participants, ages 12 to 45 years, were individuals with congenital adrenal hyperplasia (CAH), a disorder causing increased adrenal androgen production before birth (40 females, 29 males) and their unaffected relatives (29 females, 30 males). We investigated grip strength and visuomotor targeting tasks on which males generally outperform females, and fine motor pegboard tasks on which females generally outperform males. Physical characteristics (height and weight) were measured to explore whether body parameters could explain differences in motor skills. Females with CAH were stronger and showed better targeting than unaffected females and showed reduced fine visuomotor skill on one pegboard measure, with no difference on the other. Males with CAH were weaker than unaffected males in grip strength but did not differ on the targeting or pegboard measures. Correction for body size could not explain the findings for females, but suggests that the reduced strength of males with CAH may relate to their smaller stature. Further, the targeting advantage in females with CAH persisted following adjustment for their greater strength. Results in females support the hypothesis that androgen may masculinize, or promote, certain motor characteristics at which males excel, and contribute to defeminization of certain fine motor characteristics at which females excel. Thus, these data suggest that organizational effects of androgens on behavior during prenatal life may extend to motor characteristics and may contribute to general sex differences in motor-related behaviors; however, alternative explanations based on activational influences of androgen or altered experiential factors cannot be excluded without further study. KEYWORDS: congenital adrenal hyperplasia (CAH), androgen, sex, motor, strength, targeting
doi:10.1016/j.psyneuen.2008.09.007
PMCID: PMC3287956  PMID: 18938041
20.  Genotype-Phenotype Correlation in 153 Adult Patients With Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: Analysis of the United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE) Cohort 
Context:
In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a strong genotype-phenotype correlation exists in childhood. However, similar data in adults are lacking.
Objective:
The objective of the study was to test whether the severity of disease-causing CYP21A2 mutations influences the treatment and health status in adults with CAH.
Research Design and Methods:
We analyzed the genotype in correlation with treatment and health status in 153 adults with CAH from the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive cohort.
Results:
CYP21A2 mutations were distributed similarly to previously reported case series. In 7 patients a mutation was identified on only 1 allele. Novel mutations were detected on 1.7% of alleles (5 of 306). Rare mutations were found on 2.3% of alleles (7 of 306). For further analysis, patients were categorized into CYP21A2 mutation groups according to predicted residual enzyme function: null (n = 34), A (n = 42), B (n = 36), C (n = 34), and D (n = 7). Daily glucocorticoid dose was highest in group null and lowest in group C. Fludrocortisone was used more frequently in patients with more severe genotypes. Except for lower female height in group B, no statistically significant associations between genotype and clinical parameters were found. Androgens, blood pressure, lipids, blood glucose, and homeostasis model assessment of insulin resistance were not different between groups. Subjective health status was similarly impaired across groups.
Conclusions:
In adults with classic CAH and women with nonclassic CAH, there was a weak association between genotype and treatment, but health outcomes were not associated with genotype. The underrepresentation of males with nonclassic CAH may reflect that milder genotypes result in a milder condition that is neither diagnosed nor followed up in adulthood. Overall, our results suggest that the impaired health status of adults with CAH coming to medical attention is acquired rather than genetically determined and therefore could potentially be improved through modification of treatment.
doi:10.1210/jc.2012-3343
PMCID: PMC3651585  PMID: 23337727
21.  Congenital adrenal hyperplasia 
Dermato-endocrinology  2009;1(2):87-91.
Congenital adrenal hyperplasia consists of a heterogenous group of inherited disorders due to enzymatic defects in the biosynthetic pathway of cortisol and/or aldosterone. This results in glucocorticoid deficiency, mineralocorticoid deficiency, and androgen excess. 95% of CAH cases are due to 21-hydroxylase deficiency. Clinical forms range from the severe, classical CAH associated with complete loss of enzyme function, to milder, non-classical forms (NCAH). Androgen excess affects the pilosebaceous unit, causing cutaneous manifestations such as acne, androgenetic alopecia and hirsutism. Clinical differential diagnosis between NCAH and polycystic ovary syndrome may be difficult. In this review, the evaluation of patients with suspected CAH, the clinical presentation of CAH forms, with emphasis on the cutaneous manifestations of the disease, and available treatment options, will be discussed.
doi:10.4161/derm.1.2.7818
PMCID: PMC3329455  PMID: 22523607
acne; congenital adrenal hyperplasia; hirsutism
22.  Incentive processing in Congenital Adrenal Hyperplasia (CAH): a reward-based antisaccade study 
Psychoneuroendocrinology  2012;38(5):716-721.
Little is known about how steroid hormones contribute to the beneficial effect of incentives on cognitive control during adolescent development. In this study, 27 adolescents with Congenital Adrenal Hyperplasia (CAH, mean age 15.6 years, 12 female), a disorder of cortisol deficiency and androgen excess, and 36 healthy participants (mean age 16.3 years, 18 female) completed a reward-based antisaccade task. In this mixed-saccade task, participants performed eye movements towards (prosaccades) or away (antisaccades) from a peripherally occuring stimulus. On incentive trials, monetary reward was provided for correct performance, while no such reward was provided on no-incentive trials. Consistent with the hypothesis, the results showed that healthy, but not CAH adolescents, significantly improved their inhibitory control (antisaccade accuracy) during incentive trials relative to noincentive trials. These findings were not driven by severity of CAH (salt wasters vs. simple virilizers), individual hormone levels, sex, age-at-diagnosis, or medication type (dexamethasone vs. hydrocortisone). In addition, no significant differences between groups were found on orienting responses (prosaccades). Additional analyses revealed an impact of glucocorticoid (GC) dosage, such that higher GC dose predicted better antisaccade performance. However, this effect did not impact incentive processing. The data are discussed within the context of steroid hormone mediated effects on cognitive control and reward processing.
doi:10.1016/j.psyneuen.2012.08.001
PMCID: PMC3522784  PMID: 22917623
inhibitory control; androgen; development; adolescence; sex steroids; testosterone; cortisol
23.  A Rare Combination: Congenital Adrenal Hyperplasia Due To 21 Hydroxylase Deficiency and Turner Syndrome 
A combination of Turner syndrome (TS) and classical congenital adrenal hyperplasia (CAH) is rare. A one-day-old newborn was referred to our hospital with ambiguous genitalia. The parents were third-degree relatives. The infant’s weight was 3350g (50-75p), and the head circumference was 34.5cm (50p). The gonads were nonpalpable. Presence of a 3 cm phallus, one urogenital opening into the perineum, and incomplete labial fusion were identified. Laboratory tests revealed a classical type of CAH due to 21-hydroxylase deficiency. Karyotyping revealed a 45X0(35)/46XX(22) pattern with negative sex-determining region Y (SRY) on gene analysis. At the most recent follow-up visit, the patient appeared to be in good health - her height was 70.4 cm [-1.5 standard deviation (SD)] and her weight was 9.8 kg (0.3 SD). She was receiving hydrocortisone in a dose of 10 mg/m2/day, fludrocortisone acetate in a dose of 0.075 mg/day, and oral salt of 1 g/day. System examinations were normal. The patient’s electrolyte levels were found to be normal and she was in good metabolic control. The findings of this patient demonstrate that routine karyotyping during investigation of patients with sexual differentiation disorders can reveal TS. Additionally, signs of virilism should always be investigated at diagnosis or during physical examinations for follow-up of TS cases. [i][/i]SRY analysis should be performed primarily when signs of virilism are observed. CAH should also be considered in patients with negative [i]SRY[/i].
Conflict of interest:None declared.
doi:10.4274/Jcrpe.767
PMCID: PMC3537289  PMID: 23261864
Turner syndrome; congenital adrenal hyperplasia; sex differentiation disorder; karyotyping
24.  Health related quality of life of children and adolescents with congenital adrenal hyperplasia in Brazil 
Background
Congenital Adrenal Hyperplasia (CAH) is an endocrine disorder characterized by enzymatic deficiency in adrenal steroidogenesis, leading to adrenal insufficiency and hyperandrogenism. Patients need continuous hormone replacement therapy, but adequate control has proven challenging, exposing patients to undesirable consequences of both disease and treatment.
Objective
To evaluate the health related quality of life (HRQoL) of children and adolescents with CAH due to 21-hydroxylase deficiency.
Methods
In an analytical study, generic questionnaires, validated and translated versions, Pediatric Quality of Life Inventory 4.0 (for self-assessment of patients) and Child Health Questionnaire - PF50 (for parents) were applied and mean scores were analyzed with Student’s t-test.
Results
We included 25 patients (19 female) with classical CAH (14 salt wasting/11 simple virilizing), mean age ± standard deviation (SD) of 11.4 ± 3.6 years (5–17.9), and their parents. Self-assessment of HRQOL showed decrease in mean scores: overall (67.8 ± 15.5 vs. 88.9 ± 7.4, p value = 0.015) and in the physical (75.2 ± 15.0 vs. 95.9 ± 5.8, p value = 0.014) and psychosocial (63.9 ± 17.8 vs. 85.0 ± 9.6, p value = 0.023) dimensions of patients, compared to healthy controls (previously published national data on children and adolescents). The assessment of the parent’s view was concordant, also showing losses in the physical (43.7 ± 8.0 vs. 55.1 ± 3.6, p value = 0.013) and psychosocial (41.9 ± 9.7 vs. 53.0 ± 7.0, p value = 0.025) dimensions. The comparison of HRQOL between subgroups 1) males versus females and 2) salt-wasting versus simple virilizing showed no significant differences.
Conclusion
There seems to be a loss of HRQOL in children and adolescents with classical CAH. The self-assessment was concordant in key areas with the assessment made by their parents. No differences were observed between genders or clinical presentation of the disease.
doi:10.1186/s12955-014-0107-2
PMCID: PMC4243953  PMID: 25115634
Congenital adrenal hyperplasia; Quality of life; Glucocorticoid; Children and adolescents
25.  Identification of Novel Mutations in STAR Gene in Patients with Lipoid Congenital Adrenal Hyperplasia: A First Report from India 
Lipoid congenital adrenal hyperplasia (LCAH), a rare disorder of steroid biosynthesis, is the most severe form of CAH. We report novel molecular findings of three unrelated infants with LCAH diagnosed at our center. A known missense mutation c.653C>T (p.A218V) and two novel mutations [premature termination c.441G>A (or p.W147X) and frameshift deletion c.del815G (or p.R272PfsX35)] were identified after complete sequencing of the STAR gene. Prenatal diagnosis was carried out for the family with mutation c.815delG by molecular testing wherein the fetus was found to be homozygous for the mutation. This is the first report of molecular diagnosis and prenatal testing for LCAH from India.
Conflict of interest:None declared.
doi:10.4274/Jcrpe.927
PMCID: PMC3701918  PMID: 23748066
Lipoid congenital adrenal hyperplasia; STAR gene; mutation; XY sex reversal

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