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1.  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.
PMCID: PMC3830282  PMID: 24251136
Bone health; cardio-metabolic risk; congenital adrenal hyperplasia; fertility; final height; glucocorticoids; neurocognitive outcome; quality-of-life
2.  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.
PMCID: PMC3894515  PMID: 24459514
Congenital adrenal hyperplasia; 21-hydroxylase deficiency; Hyponatremia; Adrenal tumor
3.  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.
PMCID: PMC2929598  PMID: 17336344
development; corticosteroid; androgen; affective processing; fMRI; stress hormones
4.  A Case of Congenital Adrenal Hyperplasia Mimicking Cushing's Syndrome 
Journal of Korean Medical Science  2012;27(11):1439-1443.
Congenital adrenal hyperplasia (CAH) is characterized by decreased adrenal hormone production due to enzymatic defects and subsequent rise of adrenocorticotrophic hormone that stimulates the adrenal cortex to become hyperplastic, and sometimes tumorous. As the pathophysiology is basically a defect in the biosynthesis of cortisol, one may not consider CAH in patients with hypercortisolism. We report a case of a 41-yr-old man with a 4 cm-sized left adrenal tumorous lesion mimicking Cushing's syndrome who was diagnosed with CAH. He had central obesity and acanthosis nigricans involving the axillae together with elevated 24-hr urine cortisol level, supporting the diagnosis of Cushing's syndrome. However, the 24-hr urine cortisol was suppressed by 95% with the low dose dexamethasone suppression test. CAH was suspected based on the history of precocious puberty, short stature and a profound suppression of cortisol production by dexamethasone. CAH was confirmed by a remarkably increased level of serum 17-hydroxyprogesterone level. Gene mutation analysis revealed a compound heterozygote mutation of CYP21A2 (I173N and R357W).
PMCID: PMC3492685  PMID: 23166432
Congenital Adrenal Hyperplasia; 21-Hydroxylase Deficiency; Hypercortisolism
5.  Phenotypic profiling of parents with cryptic nonclassic congenital adrenal hyperplasia: findings in 145 unrelated families 
To comprehensively phenotype parents identified with nonclassic congenital adrenal hyperplasia (NCCAH) by family genetic studies, termed here as cryptic NCCAH and to define the incidence of cryptic NCCAH in the parents of a large cohort of patients with 21-hydroxylase deficiency.
Genotyping was performed on 249 parents of 145 unrelated congenital adrenal hyperplasia CAH) patients. Parents with two CYP21A2 mutations underwent extensive evaluation.
Of the 249 parents, ten (4%; seven females and three males) were identified as having cryptic NCCAH. The majority was of ethnicities previously reported to have a higher incidence of NCCAH. Cosyntropin stimulation performed in eight parents provided biochemical confirmation (17-hydroxyprogesterone range 56–364 nmol/l) and cortisol response was % 500 nmol/l in three parents (38%). Of the seven women (27–54 years) with cryptic NCCAH, four had prior infertility, two reported irregular menses, two had treatment for hirsutism, one had androgenic alopecia. Men were asymptomatic. All cryptic NCCAH parents reported normal puberty and had normal height. Adrenal hypertrophy and a small adrenal myelolipoma were observed in two parents; testicular adrenal rest tissue was not found.
Parents diagnosed with NCCAH by genetic testing are mostly asymptomatic. Temporary female infertility and suboptimal cortisol response were commonly observed. Ongoing glucocorticoid therapy is not indicated in adults with CAH identified by family genotype studies unless symptomatic, but glucocorticoid stress coverage should be considered in select cases. Parents of a child with CAH have a 1:25 risk of having NCCAH; if the mother of a child with CAH has infertility, evaluation for NCCAH is indicated.
PMCID: PMC3470911  PMID: 21444649
6.  Prostate gland development and adrenal tumor in a female with congenital adrenal hyperplasia: A case report and review from radiology perspective 
We describe a case of a female with simple virilizing congenital adrenal hyperplasia (CAH) reared as a male diagnosed at the late age of 64. Computed Tomography (CT) demonstrated a large adrenal mass, bilateral diffuse adrenal enlargement, female pelvic organs as well as a clearly visualized prostate gland. This is to the best of our knowledge the first case of such a sizable prostate gland in a female CAH patient documented on CT. We review the literature regarding aspects where radiologists may encounter CAH and the finding of presence of a prostate gland in female CAH patients.
PMCID: PMC3888328
Congenital adrenal hyperplasia; adrenogenital syndrome; radiology; imaging; prostate; CT; computed tomography; sonography; ultrasound; MRI; magnetic resonance imaging
7.  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
8.  A Case of Congenital Lipoid Adrenal Hyperplasia 
Lipoid congenital adrenal hyperplasia (lipoid CAH), a rare disorder of steroid biosynthesis, is the most severe form of CAH. In this disorder the synthesis of glucocorticoids, mineralocorticoids and sex steroids is impaired which result in adrenal failure, severe salt wasting crisis and hyperpigmentation in phenotypical female infants irrespective of genetic sex. In this report, we presented a 28-day-old phenotypic female infant, which referred with lethargy, failure to thrive and electrolyte abnormalities. Considering the clinical and biochemical findings, lipoid CAH was diagnosed and replacement therapy with standard doses of glucocorticoid and mineralocorticoid and sodium chloride was initiated. During follow-up, she had good clinical condition, but at 6 years of age, she refers with hypertension and adrenal insufficiency because of arbitrary drug discontinuation by mother. In ultrasonography an abdominal mass (the testicles) was reported. Chromosome study showed 46XY pattern. Orchiectomy was performed. We recommended that in cases with clinical presentation of adrenal insufficiency if there is not the facility to determine the karyotype, repeated ultrasonography perform during follow-up. In addition, investigating the genetic bases of the disorder would help us to determine the pathogenesis of lipoid CAH in our community. It would be helpful in prenatal diagnosis and treatment of the disorder to prevent its related comorbidities.
PMCID: PMC3415193  PMID: 22891154
46XY; failure to thrive; lipoid congenital adrenal hyperplasia
9.  Hypoglycemia during acute illness in children with classic congenital adrenal hyperplasia 
Congenital adrenal hyperplasia (CAH) describes a group of genetic, autosomal recessive conditions, where there is a block in cortisol biosynthesis. Approximately 95 percent of cases are due to 21-hydroxylase deficiency, which is discussed in this article. Patients with the severe or classic form of CAH have epinephrine deficiency in addition to cortisol deficiency. Both epinephrine and cortisol are important counterregulatory hormones and help prevent hypoglycemia during physical stress. This is the first prospective study to evaluate the incidence of hypoglycemia during acute illness in children with classic CAH. Our objective was to examine blood glucose levels and symptoms of these children during the physical stressor of a typical acute illness managed at home.
Twenty patients, ages 3 to 10 years with classic CAH participated. Parents were instructed regarding management of illnesses, home blood glucose monitoring and questionnaire completion. Over 29 months, 20 patients completed questionnaires and 6 patients performed home blood glucose monitoring. A blood glucose of <60mg/dL was documented in 3 out of 8 monitored acute illness episodes, and in 2 out of 6 of monitored children. The acute illness episodes with documented blood glucose <60mg/dL were not associated with vomiting.
Our data suggest that children with classic CAH may experience lowering of blood glucose during illnesses, and patient education regarding the management of common childhood illness should include glucose supplementation.
PMCID: PMC2819226  PMID: 20117671
10.  A Success Story in Congenital Adrenal Hyperplasia 
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by enzyme defects in adrenal steroidogenic pathways. CAH due to 21-hydroxylase deficiency accounts for 95 % of cases. This case was diagnosed to have simple virilizing type of CAH and started on dexamethasone, and underwent genitoplasty and clitoroplasty at 25 years of age, then was married 3 years after surgery and conceived spontaneously 2 years after marriage, to deliver a healthy male baby. Thus, proper diagnosis and treatment with steroids and genitoplasty can give females with CAH a normal sexual, normal menstrual, and reproductive function.
PMCID: PMC3632694  PMID: 24293885
11.  Long-term outcome of genital reconstruction of Middle Eastern women with congenital adrenal hyperplasia 
Urology Annals  2013;5(4):277-282.
There is a paucity of data on the long-term outcome of genital reconstruction of female children with congenital adrenal hyperplasia (CAH) as they become adult women. We report on the surgical outcome general condition and marriage status.
Materials and Methods:
We reviewed the medical records of women 20 years or older with CAH who had genital reconstruction. We interviewed married patients utilizing the female sexual function index (FSFI-6) questionnaire and compared them to age-matched controls.
We identified 43 women with CAH with a median age of 24.2 ± 3.9 years and a median follow-up of 23.4 ± 4.6 years. Salt wasting and the severity of virilization affected most patients, parents were commonly cousins, children were reared as boys for a protracted period and surgical reconstruction was usually complex. Only five women had married. Compared with single women, married women had significantly more frequent normal menses, emergency hospital admissions and number of repeated reconstructive surgery. There was no significant difference in FSFI score between patients and controls. Four women conceived and three gave birth to one healthy child. There was no significant difference in the number of children between patients and controls.
CAH has a significant impact on adult women in our region. Most of the patients remain single. Few women get married and these are able to lead a nearly normal sexual life and give birth to healthy children.
PMCID: PMC3835989  PMID: 24311911
Adrenal hyperplasia; congenital; female urogenital diseases; fertility; follow-up studies; reconstructive surgical procedures
12.  A Giant Ovarian Cyst in a Neonate with Classical 21-Hydroxylase Deficiency with Very High Testosterone Levels Demonstrating a High-Dose Hook Effect 
Congenital adrenal hyperplasia (CAH) is a group of disorders affecting the adrenal steroid synthesis. The most common form, 21-hydroxylase deficiency (21-OHD), leads to decreased production of cortisol and aldosterone with increased androgen secretion. In classic CAH, glucocorticoid treatment can be life-saving and serves to bring the symptoms under control. However, the treatment challenge is to effectively control the excess androgen effect by using the lowest possible glucocorticoid dose. Previous studies suggested a relationship between ovarian cyst formation and adrenal androgen excess, but neonatal large ovarian cysts have been very rarely reported in newborns with CAH. Here, we present the unique case of a neonate with classical 21-OHD who underwent surgery for a giant (10x8x7 cm) unilateral solitary ovarian follicular cyst on the 2nd postnatal day. Hormonal evaluation of the patient revealed high-dose hook effect for serum testosterone levels for the first time by a two-site immunoradiometric assay. Possible mechanisms by which androgen excess may cause ovarian cyst formation are discussed.
Conflict of interest:None declared.
PMCID: PMC3459164  PMID: 22664361
21-hydroxylase deficiency; Ovarian cyst; testosterone; ambiguous genitalia; hook effect; Neonate
13.  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.
PMCID: PMC3329455  PMID: 22523607
acne; congenital adrenal hyperplasia; hirsutism
14.  Male genitoplasty for 46 XX congenital adrenal hyperplasia patients presenting late and reared as males 
To evaluate the clinical profile and management of 46 XX Congenital Adrenal Hyperplasia (CAH) patients presenting with severe virilization and assigned a male gender.
Materials and Methods:
Of 173 children diagnosed with CAH at the Pediatric Intersex Clinic since 1980, seven children with CAH presented late with severe virilization and were reared as males. All of them were assigned the male sex with removal of the female adnexa. Six were treated with male genitoplasty. Appropriate hormonal supplementation was offered after puberty.
The mean age at presentation was 14.2 years (7 – 21). Six patients had presented after puberty, only one at seven years of age. Staged male genitoplasty comprising of chordee correction, male urethroplasty, and bilateral testicular prosthesis was performed. The female adnexa (uterus, ovaries, most of the upper vagina, and the fallopian tubes) were removed. The mental makeup was masculine in six and bigender in one. Bilateral mastectomy was performed at puberty in all. Hormonal treatment comprised of glucocorticoids and testosterone. Six patients were comfortable with the outcome of the masculinizing genitoplasty. One had a short-sized phallus. One had repeated attacks of urinary tract infection arising from the retained lower vaginal pouch. Social adjustments were good in all, except in one who had a bigender mental makeup.
CAH patients with severe virilization presenting late and reared as males are extremely rare. However, the assigned gender can be retained adequately as males, meeting the socioeconomic compulsions of the society. The results are satisfactory following appropriate surgical procedures and hormonal supplementation.
PMCID: PMC3510963  PMID: 23226638
46XX male; congenital adrenal hyperplasia; masculinizing genitoplasty
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.
PMCID: PMC3809185  PMID: 24353545
Congenital adrenal hyperplasia; Clitoromegaly; Virilization; Clitoroplasty; Ambiguous genitalia
16.  Ethnic disparity in 21-hydroxylase gene mutations identified in Pakistani congenital adrenal hyperplasia patients 
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by defects in the steroid 21 hydroxylase gene (CYP21A2). We studied the spectrum of mutations in CYP21A2 gene in a multi-ethnic population in Pakistan to explore the genetics of CAH.
A cross sectional study was conducted for the identification of mutations CYP21A2 and their phenotypic associations in CAH using ARMS-PCR assay.
Overall, 29 patients were analyzed for nine different mutations. The group consisted of two major forms of CAH including 17 salt wasters and 12 simple virilizers. There were 14 phenotypic males and 15 females representing all the major ethnic groups of Pakistan. Parental consanguinity was reported in 65% cases and was equally distributed in the major ethnic groups. Among 58 chromosomes analyzed, mutations were identified in 45 (78.6%) chromosomes. The most frequent mutation was I2 splice (27%) followed by Ile173Asn (26%), Arg 357 Trp (19%), Gln319stop, 16% and Leu308InsT (12%), whereas Val282Leu was not observed in this study. Homozygosity was seen in 44% and heterozygosity in 34% cases. I2 splice mutation was found to be associated with SW in the homozygous. The Ile173Asn mutation was identified in both SW and SV forms. Moreover, Arg357Trp manifested SW in compound heterozygous state.
Our study showed that CAH exists in our population with ethnic difference in the prevalence of mutations examined.
PMCID: PMC3050769  PMID: 21329531
17.  Bone Health Should Be an Important Concern in the Care of Patients Affected by 21 Hydroxylase Deficiency 
Osteoporosis has been an understandable concern for children and adult patients with congenital adrenal hyperplasia (CAH) who may receive or have received supraphysiological doses of glucocorticoids. Some previous reports on bone mineral density (BMD) in adult CAH patients showed no significant differences in BMD between patients with CAH and controls, but others have found lower BMD in CAH patients. In reports documenting the BMD reduction, this outcome has been attributed to an accumulated effect of prolonged exposure to excess glucocorticoids during infancy and childhood. We recently conducted a trial to establish the role of the total cumulative glucocorticoid dose on BMD. We established for the first time that there was a negative relationship between total cumulative glucocorticoid dose and lumbar and femoral BMD. Women might benefit from the preserving effect of estrogens compared to men. BMI (Body Mass Index) also appeared to protect patients from bone loss. In light of this, physicians should bear in mind the potential consequences of glucocorticoids on bone and therefore adjust the treatment and improve clinical and biological surveillance from infancy. Furthermore, preventive measures against corticosteroid-induced osteoporosis should be discussed right from the beginning of glucocorticoid therapy.
PMCID: PMC2948879  PMID: 20936142
18.  Reproductive outcomes of female patients with congenital adrenal hyperplasia due to 21-hydroxylase defi ciency 
Fertility in women with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) appears to be reduced, especially in women with the classic salt-wasting type. Several factors have been suggested to contribute to this subfertility such as androgen excess, adrenal progesterone hypersecretion, consequences of genital reconstructive surgery, secondary polycystic ovaries syndrome, and psychosexual factors. In contrast to this subfertility, pregnancies are commonly normal and uneventful. Adequate glucocorticoid therapy and improvement of surgical and psychological management could contribute to optimize fertility in CAH female patients, even among women with the classic variant. This review provides current information regarding the reproductive outcomes of women with CAH due to 21-OHD and the fertility and pregnancy issues in this population.
PMCID: PMC3784860  PMID: 24083158
Congenital adrenal hyperplasia; fertility; 21-hydroxylase deficiency; pregnancy
19.  Leydig Cell Tumor Associated with Testicular Adrenal Rest Tumors in a Patient with Congenital Adrenal Hyperplasia due to 11β-Hydroxylase Deficiency 
Case Reports in Urology  2012;2012:648643.
Congenital adrenal hyperplasia (CAH) describes a group of inherited autosomal recessive disorders characterized by enzyme defects in the steroidogenic pathways that lead to the biosynthesis of cortisol, aldosterone, and androgens. Chronic excessive adrenocorticotropic hormone (ACTH) stimulation may result in hyperplasia of ACTH-sensitive tissues in adrenal glands and other sites such as the testes, causing testicular masses known as testicular adrenal rest tumors (TARTs). Leydig cell tumors (LCTs) are make up a very small number of all testicular tumors and can be difficult to distinguish from TARTs. This distinction is interesting because LCTs and TARTs require different therapeutic approaches. Hereby, we present an unusual case of a 19-year-old patient with CAH due to 11β-hydroxylase deficiency, who presented with TARTs and an epididymal Leydig cell tumor.
PMCID: PMC3350130  PMID: 22606635
20.  Gendered Occupational Interests: Prenatal Androgen Effects on Psychological Orientation to Things Versus People 
Hormones and behavior  2011;60(4):313-317.
There is considerable interest in understanding women’s underrepresentation in science, technology, engineering, and mathematics careers. Career choices have been shown to be driven in part by interests, and gender differences in those interests have generally been considered to result from socialization. We explored the contribution of sex hormones to career-related interests, in particular studying whether prenatal androgens affect interests through psychological orientation to Things versus People. We examined this question in individuals with congenital adrenal hyperplasia (CAH), who have atypical exposure to androgens early in development, and their unaffected siblings (total N = 125 aged 9 to 26 years). Females with CAH had more interest in Things versus People than did unaffected females, and variations among females with CAH reflected variations in their degree of androgen exposure. Results provide strong support for hormonal influences on interest in occupations characterized by working with Things versus People.
PMCID: PMC3166361  PMID: 21689657
androgens; interests; occupations; sex differences; congenital adrenal hyperplasia; STEM careers
21.  Steroid Analysis in Saliva: An overview 
Clinical Biochemist Reviews  2006;27(3):139-146.
The first report of steroid analysis in saliva was more than thirty years ago. Since that time its popularity has increased due to the attractiveness of non-invasive, repeated and simple stress-free sampling. It has proved a popular sampling fluid for psychobiology, sports medicine, pharmacology and paediatric studies as well as in the area of complementary medicine. In the diagnostic laboratory, salivary progesterone and oestradiol have been used for assessing ovarian function and 17α-OH progesterone for the diagnosis of congenital adrenal hyperplasia (CAH). Salivary cortisol is used for investigating adrenal function and recently there has been considerable interest in the use of bedtime salivary cortisol levels as a screening test for Cushing’s disease. However, there are several caveats on the use of saliva including collection techniques, the variable matrix of saliva, sensitivity, steroid stability, the presence of binding proteins and reference range anomalies. This brief review will attempt to address these issues and provide a balanced approach to steroid analysis in saliva.
PMCID: PMC1579286  PMID: 17268582
22.  The Clinical and Biochemical Spectrum of Congenital Adrenal Hyperplasia Secondary to 21-Hydroxylase Deficiency 
21-Hydroxylase Deficiency (21-OH Deficiency) represents the most common form of Congenital Adrenal Hyperplasia (CAH), a complex and heterogenous group of conditions, characterised by defects in one of the five enzymes involved in adrenal steroidogenesis. Defects in this steroidogenic enzyme, the product of the CYP21A2 gene, cause disruption in the pathway involved in cortisol and aldosterone production and consequently, the accumulation of their steroid precursors as well as a resulting adrenocorticotrophic hormone (ACTH)-driven overproduction of adrenal androgens. Treatment with glucocorticoid, with or without mineralocorticoid and salt replacement, is directed at preventing adrenal crises and ensuring normal childhood growth by alleviating hyperandrogenism. Conventionally, two clinical forms of 21-OH Deficiency are described - the classical form, separated into salt-wasting and simple-virilising phenotypes, and the non-classical form. They are differentiated by their hormonal profile, predominant clinical features and age of presentation. A greater understanding of the genotype-phenotype correlation supports the view that 21-OH Deficiency is a continuum of phenotypes as opposed to a number of distinct phenotypical entities. Significant advancements in technologies such as Tandem Mass Spectrometry (TMS) and improvements in gene analysis, such as complete PCR-based sequencing of the involved gene, have resulted in remarkable developments in the areas of diagnosis, treatment and treatment monitoring, neonatal screening, prenatal diagnosis and prenatal therapy.
PMCID: PMC2702216  PMID: 19565027
23.  Does Pseudohypoaldosteronism Mask the Diagnosis of Congenital Adrenal Hyperplasia?  
Hyponatremia and hyperpotassemia occurring in the first few weeks of life primarily indicate aldosterone deficiency due to salt-losing congenital adrenal hyperplasia (SL-CAH), while mineralocorticoid deficiency and insensitivity are the main causes of hyponatremia and hyperpotassemia in older infants. Some patients who present with vomiting and poor sucking, who have hyponatremia and hyperpotassemia and are initially diagnosed as CAH, during follow-up, are found to suffer from pseudohypoaldosteronism (PHA). This situation has been reported several times before. The cases described here represent the opposite situation: they presented with hyponatremia and hyperpotassemia, thus PHA was considered as aldosterone levels were very high, but subsequent investigation and genetic analysis led to the diagnosis of SL-CAH.
Conflict of interest:None declared.
PMCID: PMC3245498  PMID: 22155467
Pseudohypoaldosteronism; congenital adrenal hyperplasia
24.  Direct molecular diagnosis of CYP21 mutations in congenital adrenal hyperplasia. 
Journal of Medical Genetics  1996;33(5):371-375.
The majority of congenital adrenal hyperplasia (CAH) cases arise from mutations in the steroid 21-hydroxylase (CYP21) gene. Without reliance on HLA gene linkage analysis, we have developed primers for differential polymerase chain reaction (PCR) amplification of the CYP21 gene and the non-functional CYP21P gene. Using the amplification created restriction site (ACRS) approach for direct mutational detection, a secondary PCR was then performed using a panel of primers specific for each of the 11 known mutations associated with CAH. Subsequent restriction analysis allowed not only the detection but also the determination of the zygosity of the mutations analysed. Existing deletion of the CYP21 gene could also be detected. In the analysis of 20 independent chromosomes in 11 families of CAH patients in Taiwan, four CYP21 mutation types, besides deletion, were detected. Interestingly, in five different alleles, the CYP21P pseudogene contained some polymorphisms generally associated with the CYP21 gene. These results suggest gene conversion events that are occurring in both CYP21P and CYP21 genes. Our combined differential PCR-ACRS protocol is simple and direct and is applicable for prenatal diagnosis of CAH using chorionic villi or amniotic cells.
PMCID: PMC1050604  PMID: 8733045
25.  A rare case report of 46XY mixed gonadal dysgenesis 
A 16-year-old person, reared as female presented with complaints of genital ambiguity and primary amenorrhoea along with lack of secondary sexual characters, but without short stature and Turner's stigmata. She was taking steroids after being misdiagnosed as congenital adrenal hyperplasia (CAH). Karyotype analysis revealed 46XY karyotype. There was no evidence of hypocortisolemia (cortisol 9.08 μg/dl, adrenocorticotropic hormone [ACTH] 82.5 pg/ml) or elevated level of 17-OH-progesterone (0.16 ng/ml). Pooled luteinizing hormone (LH) was 11.79 mIU/ml and follicle-stimulating hormone (FSH) was 66.37 mIU/ml. Serum estradiol level was 25 pg/ml (21-251). Basal and 72 h post beta-human chorionic gonadotropin (hCG) levels of androstenedione and testosterone levels were done (basal testosterone of 652 ng/dl and basal androstenedione of 1.17 ng/ml; 72 h post hCG testosterone of 896 ng/dl and androstenedione of 1.34 ng/ml). Magnetic resonance imaging (MRI) pelvis (with ultrasonogrphy [USG] correlation) revealed uterus didelphys with obstructed right moiety and bilateral ovarian-like structures. Right sided gonads and adjacent tubal structures were visualized laparoscopically and removed. Left sided gonads were not visualized and Mullerian remnants were adhered to sigmoid colon. Histopathological examination revealed presence of testicular tissue showing atrophic seminiferous tubules with hyperplasia of Leydig cells. No ovarian tissue was seen. Based on these results a diagnosis of 46XY mixed gonadal dysgenesis (MGD) was made, which is rare and is difficult to distinguish from 46XY ovotesticular disorder of sexual differentiation (OT-DSD). The patient was managed with a multidisciplinary approach and fertility issues discussed with the patient's caregivers.
PMCID: PMC3830329  PMID: 24251183
46XY; disorders of sexual differentiation; mixed gonadal dysgenesis

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