Congenital Adrenal Hyperplasia

Congenital Congenital Chorioretinitis adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation (CAH) consists of a group of autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance disorders that cause a deficiency of an enzyme needed in cortisol Cortisol Glucocorticoids, aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia, and androgen synthesis Synthesis Polymerase Chain Reaction (PCR). The most common subform of CAH is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Clinical manifestations depend on the specific enzyme affected. Notably, CAH is the most common cause of ambiguous genitalia Ambiguous Genitalia Primary Amenorrhea in genotypic female individuals. All forms of CAH cause low levels of cortisol Cortisol Glucocorticoids, high levels of adrenocorticotropic hormone Adrenocorticotropic hormone An anterior pituitary hormone that stimulates the adrenal cortex and its production of corticosteroids. Acth is a 39-amino acid polypeptide of which the n-terminal 24-amino acid segment is identical in all species and contains the adrenocorticotropic activity. Upon further tissue-specific processing, acth can yield alpha-msh and corticotropin-like intermediate lobe peptide (clip). Adrenal Hormones (ACTH), and adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation. Laboratory studies help confirm the diagnosis. Lifelong glucocorticoid replacement is needed, and surgical correction of ambiguous genitalia Ambiguous Genitalia Primary Amenorrhea is often performed.

Last updated: 23 May, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Epidemiology and Genetics

Epidemiology

  • Most common cause of 46,XX genotypic female individuals with ambiguous or undetermined genitalia
  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency of classical congenital Congenital Chorioretinitis adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation (CAH) worldwide: 1 in 15,000 live births
  • Genetic predisposition varies depending on ethnicity and geographic location.
  • Classical CAH predisposition:
    • In the United States, prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency greater for whites (1 in 15,000 live births) than African Americans (1 in 42,000 live births)
    • Yupik in Alaska: 1 in 280 live births
    • White Europeans: 1 in 5,000–23,0000 live births
  • Non-classical CAH predisposition
    • Whites: 1 in 100–1,000 live births
    • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency amongst Ashkenazi Jews, Mediterraneans, and Hispanics

Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics

Congenital Congenital Chorioretinitis adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation comprises a spectrum of disorders in which different gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations cause different enzyme deficiencies affecting steroid biogenesis, which is carried out by the adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands: Anatomy.

  • Inheritance pattern: autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance for all types
  • 21-hydroxylase deficiency
    • Caused by mutations in the CYP21A2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
    • Most common cause of CAH (> 90% of cases)
    • Severity of mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations and resulting 21-hydroxylase function or lack thereof causes 2 different clinical forms of the disorder:
      • Classical CAH (severe)
      • Non-classical CAH (milder, more common)
  • 11β-hydroxylase deficiency
    • Caused by mutations in CYP11B1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
    • Causes up to 5% of cases
  • 17α-hydroxylase 17α-hydroxylase A microsomal cytochrome p450 enzyme that catalyzes the 17-alpha-hydroxylation of progesterone or pregnenolone and subsequent cleavage of the residual two carbons at C17 in the presence of molecular oxygen and NADPH-ferrihemoprotein reductase. This enzyme, encoded by cyp17 gene, generates precursors for glucocorticoid, androgen, and estrogen synthesis. Defects in cyp17 gene cause congenital adrenal hyperplasia and abnormal sexual differentiation. Gonadal Hormones deficiency: caused by mutations in CYP17A1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
  • P450 oxidoreductase deficiency (PORD): caused by mutations in POR gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
  • 3β-hydroxysteroid-dehydrogenase (3BHSD) deficiency: caused by mutations in HSD3B2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
  • Aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia synthase deficiency: caused by mutations in CYP11B2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
  • Steroidogenic acute regulatory protein (StAR) deficiency: caused by mutations in STAR gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics

Pathophysiology

Normal adrenal hormone synthesis Synthesis Polymerase Chain Reaction (PCR)

  • The adrenal cortex Adrenal Cortex The outer layer of the adrenal gland. It is derived from mesoderm and comprised of three zones (outer zona glomerulosa, middle zona fasciculata, and inner zona reticularis) with each producing various steroids preferentially, such as aldosterone; hydrocortisone; dehydroepiandrosterone; and androstenedione. Adrenal cortex function is regulated by pituitary adrenocorticotropin. Adrenal Glands: Anatomy, which is made up of 3 layers, is the major site of steroid synthesis Synthesis Polymerase Chain Reaction (PCR).
    • Zona glomerulosa Zona Glomerulosa The narrow subcapsular outer zone of the adrenal cortex. This zone produces a series of enzymes that convert pregnenolone to aldosterone. The final steps involve three successive oxidations by cytochrome p-450 cyp11b2. Adrenal Glands: Anatomy (outer layer): site of synthesis Synthesis Polymerase Chain Reaction (PCR) of the mineralocorticoid aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia
    • Zona fasciculata Zona Fasciculata The wide middle zone of the adrenal cortex. This zone produces a series of enzymes that convert pregnenolone to cortisol (hydrocortisone) via 17-alpha-hydroxyprogesterone. Adrenal Glands: Anatomy (middle layer): site of synthesis Synthesis Polymerase Chain Reaction (PCR) of the glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids, including cortisol Cortisol Glucocorticoids
    • Zona reticularis Zona Reticularis The inner zone of the adrenal cortex. This zone produces the enzymes that convert pregnenolone, a 21-carbon steroid, to 19-carbon steroids (dehydroepiandrosterone; and androstenedione) via 17-alpha-hydroxypregnenolone. Adrenal Glands: Anatomy (inner layer): site of adrenal androgen synthesis Synthesis Polymerase Chain Reaction (PCR), including dehydroepiandrosterone Dehydroepiandrosterone A major C19 steroid produced by the adrenal cortex. It is also produced in small quantities in the testis and the ovary. Dehydroepiandrosterone (DHEA) can be converted to testosterone; androstenedione; estradiol; and estrone. Androgens and Antiandrogens ( DHEA DHEA A major C19 steroid produced by the adrenal cortex. It is also produced in small quantities in the testis and the ovary. Dehydroepiandrosterone (dhea) can be converted to testosterone; androstenedione; estradiol; and estrone. Androgens and Antiandrogens)
  • Adrenocorticotropic hormone Adrenocorticotropic hormone An anterior pituitary hormone that stimulates the adrenal cortex and its production of corticosteroids. Acth is a 39-amino acid polypeptide of which the n-terminal 24-amino acid segment is identical in all species and contains the adrenocorticotropic activity. Upon further tissue-specific processing, acth can yield alpha-msh and corticotropin-like intermediate lobe peptide (clip). Adrenal Hormones (ACTH) is secreted by the anterior pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types.
  • ACTH stimulates the adrenal cortex Adrenal Cortex The outer layer of the adrenal gland. It is derived from mesoderm and comprised of three zones (outer zona glomerulosa, middle zona fasciculata, and inner zona reticularis) with each producing various steroids preferentially, such as aldosterone; hydrocortisone; dehydroepiandrosterone; and androstenedione. Adrenal cortex function is regulated by pituitary adrenocorticotropin. Adrenal Glands: Anatomy ( zona fasciculata Zona Fasciculata The wide middle zone of the adrenal cortex. This zone produces a series of enzymes that convert pregnenolone to cortisol (hydrocortisone) via 17-alpha-hydroxyprogesterone. Adrenal Glands: Anatomy) to produce cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism.
  • Cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism is converted into pregnenolone Pregnenolone A 21-carbon steroid, derived from cholesterol and found in steroid hormone-producing tissues. Pregnenolone is the precursor to gonadal steroid hormones and the adrenal corticosteroids. Gonadal Hormones.
  • Pregnenolone Pregnenolone A 21-carbon steroid, derived from cholesterol and found in steroid hormone-producing tissues. Pregnenolone is the precursor to gonadal steroid hormones and the adrenal corticosteroids. Gonadal Hormones is a substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes for both the mineralocorticoids Mineralocorticoids Mineralocorticoids are a drug class within the corticosteroid family and fludrocortisone is the primary medication within this class. Fludrocortisone is a fluorinated analog of cortisone. The fluorine moiety protects the drug from isoenzyme inactivation in the kidney, allowing it to exert its mineralocorticoid effect. Mineralocorticoids and glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids pathways, which produce aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia and cortisol Cortisol Glucocorticoids, respectively.
    • Aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia helps regulate salt and water levels in the body by increasing sodium reabsorption Sodium reabsorption Tubular System and potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia excretion through the urine.
    • Cortisol Cortisol Glucocorticoids affects energy levels, blood pressure levels, blood sugar levels, and the body’s response to stress, illness, and injury.
  • Metabolic intermediates from these 2 pathways are also used as substrates for the androgen pathway in the production of testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens.

Impaired hormone synthesis Synthesis Polymerase Chain Reaction (PCR) in CAH

  • Deficient enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes in steroidogenesis pathway cause: 
    • Low levels of cortisol Cortisol Glucocorticoids
    • Low levels of aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia
    • Overproduction of androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens such as testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens
  • Low levels of cortisol Cortisol Glucocorticoids produce a lack of negative feedback Negative feedback Hypothalamic and Pituitary Hormones to the pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types, which then excessively secretes ACTH.
  • This secretion Secretion Coagulation Studies results in adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation and increased synthesis Synthesis Polymerase Chain Reaction (PCR) of adrenal precursor steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors.

21-hydroxylase deficiency

  • 2 subforms:
    • Salt wasting (approximately 75% of cases): no enzyme activity
    • Simple virilizing/non-salt wasting (approximately 25% of cases): very low, but detectable enzyme activity allowing for some aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia production
  • Causes inability to convert 17-hydroxyprogesterone to 11-deoxycortisol
  • Only affects adrenal steroidogenesis
  • Does not affect Affect The feeling-tone accompaniment of an idea or mental representation. It is the most direct psychic derivative of instinct and the psychic representative of the various bodily changes by means of which instincts manifest themselves. Psychiatric Assessment gonadal/ sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria hormone synthesis Synthesis Polymerase Chain Reaction (PCR)
  • Cortisol Cortisol Glucocorticoids is not or only partially produced.
  • Result is a deficiency of cortisol Cortisol Glucocorticoids and aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia with an accumulation of intermediate products that are used for androgenic synthesis Synthesis Polymerase Chain Reaction (PCR).
21-hydroxylase deficiency

21-hydroxylase deficiency: diagram of the pathophysiology of congenital Congenital Chorioretinitis adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation due to 21-hydroxylase deficiency

Image by Lecturio.

11β-hydroxylase deficiency

  • Enzyme mediates the final step of cortisol Cortisol Glucocorticoids synthesis Synthesis Polymerase Chain Reaction (PCR).
  • Impairs ability to convert 11-deoxycorticosterone (DOC) and 11-deoxycortisol to corticosterone Corticosterone An adrenocortical steroid that has modest but significant activities as a mineralocorticoid and a glucocorticoid. Adrenal Hormones and cortisol Cortisol Glucocorticoids, respectively
  • Only affects adrenal steroidogenesis
  • No effects on gonadal hormone synthesis Synthesis Polymerase Chain Reaction (PCR)
  • DOC has aldosterone-like activity and in increased amounts inhibits renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation and aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia production.
  • Results in deficiency of cortisol Cortisol Glucocorticoids and aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia but an excess of androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens and mineralcorticoids (DOC)
11β-hydroxylase deficiency

11β-hydroxylase deficiency: diagram of the pathophysiology of congenital Congenital Chorioretinitis adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation due to 11β-hydroxylase deficiency

Image by Lecturio.

17α-hydroxylase 17α-hydroxylase A microsomal cytochrome p450 enzyme that catalyzes the 17-alpha-hydroxylation of progesterone or pregnenolone and subsequent cleavage of the residual two carbons at C17 in the presence of molecular oxygen and NADPH-ferrihemoprotein reductase. This enzyme, encoded by cyp17 gene, generates precursors for glucocorticoid, androgen, and estrogen synthesis. Defects in cyp17 gene cause congenital adrenal hyperplasia and abnormal sexual differentiation. Gonadal Hormones deficiency

  • Rare
  • Inhibits metabolization of pregnenolone Pregnenolone A 21-carbon steroid, derived from cholesterol and found in steroid hormone-producing tissues. Pregnenolone is the precursor to gonadal steroid hormones and the adrenal corticosteroids. Gonadal Hormones, progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones, and their 17-hydroxy derivatives, thereby limiting steroidogenesis to only progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones, DOC, corticosterone Corticosterone An adrenocortical steroid that has modest but significant activities as a mineralocorticoid and a glucocorticoid. Adrenal Hormones, and 18-oxygenated derivatives
  • Affects adrenal ( cortisol Cortisol Glucocorticoids and aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia) synthesis Synthesis Polymerase Chain Reaction (PCR) and gonadal ( sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria hormone) synthesis Synthesis Polymerase Chain Reaction (PCR), resulting in decreased synthesis Synthesis Polymerase Chain Reaction (PCR) of both cortisol Cortisol Glucocorticoids and sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors
  • Increase in DOC production results in a decrease in renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation and aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia production.
17α-hydroxylase deficiency

17α-hydroxylase 17α-hydroxylase A microsomal cytochrome p450 enzyme that catalyzes the 17-alpha-hydroxylation of progesterone or pregnenolone and subsequent cleavage of the residual two carbons at C17 in the presence of molecular oxygen and NADPH-ferrihemoprotein reductase. This enzyme, encoded by cyp17 gene, generates precursors for glucocorticoid, androgen, and estrogen synthesis. Defects in cyp17 gene cause congenital adrenal hyperplasia and abnormal sexual differentiation. Gonadal Hormones deficiency: diagram of the pathophysiology of congenital Congenital Chorioretinitis adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation due to 17α-hydroxylase 17α-hydroxylase A microsomal cytochrome p450 enzyme that catalyzes the 17-alpha-hydroxylation of progesterone or pregnenolone and subsequent cleavage of the residual two carbons at C17 in the presence of molecular oxygen and NADPH-ferrihemoprotein reductase. This enzyme, encoded by cyp17 gene, generates precursors for glucocorticoid, androgen, and estrogen synthesis. Defects in cyp17 gene cause congenital adrenal hyperplasia and abnormal sexual differentiation. Gonadal Hormones deficiency

Image by Lecturio.

P450 oxidoreductase deficiency

  • Rare
  • Abnormal electron transport causes deficiency and decreased function of 21-hydroxylase, 17α-hydroxylase 17α-hydroxylase A microsomal cytochrome p450 enzyme that catalyzes the 17-alpha-hydroxylation of progesterone or pregnenolone and subsequent cleavage of the residual two carbons at C17 in the presence of molecular oxygen and NADPH-ferrihemoprotein reductase. This enzyme, encoded by cyp17 gene, generates precursors for glucocorticoid, androgen, and estrogen synthesis. Defects in cyp17 gene cause congenital adrenal hyperplasia and abnormal sexual differentiation. Gonadal Hormones, and aromatase Aromatase An enzyme that catalyzes the desaturation (aromatization) of the ring a of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues. Aromatase is encoded by the cyp19 gene, and functions in complex with NADPH-ferrihemoprotein reductase in the cytochrome p450 system. Adipose Tissue: Histology enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes.
  • Increased androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens before birth
  • Decreased androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens after birth
  • Decreased glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids
  • Equivocal mineralcorticoids
  • Impairs production of cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism and normal bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types formation

3β-hydroxysteroid dehydrogenase deficiency

3β-hydroxysteroid dehydrogenase deficiency (3bhsd)

3β-hydroxysteroid dehydrogenase deficiency: diagram of the pathophysiology of congenital Congenital Chorioretinitis adrenal hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation due to 3β-hydroxysteroid dehydrogenase deficiency

Image by Lecturio.

Aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia synthase deficiency

  • Very rare
  • Enzyme is involved in the final 3 steps of aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia synthesis Synthesis Polymerase Chain Reaction (PCR).
  • Deficiency results in decreased or no aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia synthesis Synthesis Polymerase Chain Reaction (PCR).
  • Sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia excretion and potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia retention

Steroidogenic acute regulatory protein deficiency

Table: Enzyme deficiencies
Enzyme deficiency Gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutated Cortisol Cortisol Glucocorticoids Aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia 11-deoxycorticosterone Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens
21-hydroxylase CYP21A2 Decreased Decreased Decreased Increased
11β-hydroxylase CYP11B1 Increased
17α-hydroxylase 17α-hydroxylase A microsomal cytochrome p450 enzyme that catalyzes the 17-alpha-hydroxylation of progesterone or pregnenolone and subsequent cleavage of the residual two carbons at C17 in the presence of molecular oxygen and NADPH-ferrihemoprotein reductase. This enzyme, encoded by cyp17 gene, generates precursors for glucocorticoid, androgen, and estrogen synthesis. Defects in cyp17 gene cause congenital adrenal hyperplasia and abnormal sexual differentiation. Gonadal Hormones CYP17A1 Decreased
3BHSD HSD3B2 Decreased

Clinical Presentation

General clinical features

  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia 
  • Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive 
  • Hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi in areas not exposed to sunlight

21-hydroxylase deficiency

There is a classic form of CAH due to 21-hydroxylase deficiency and a non-classic form. The classic form has 2 different types: simple virilizing and salt wasting.

Classical CAH is the most severe form of 21-hydroxylase deficiency.

  • Presents in neonatal period/infancy
  • Ambiguous genitalia Ambiguous Genitalia Primary Amenorrhea/pseudohermaphroditism noted at birth in girls
  • Normal external genitalia in genotypic boys but may have hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi of the scrotum Scrotum A cutaneous pouch of skin containing the testicles and spermatic cords. Testicles: Anatomy and/or increased penile size
  • Boys with salt-wasting type often become symptomatic at 7–14 days of life. 
    • Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive
    • Severe dehydration Dehydration The condition that results from excessive loss of water from a living organism. Volume Depletion and Dehydration
    • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia
    • Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia
    • Salt-wasting crisis ( adrenal crisis Adrenal crisis Adrenal crisis is the acute decompensation of adrenal function that can be triggered by another disease, surgery, stress, or increased glucocorticoid inactivation. Adrenal Insufficiency and Addison’s Disease) may occur:
      • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
      • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
      • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
      • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
      • Metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
      • Hypovolemic shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock
  • Boys with simple virilizing form often present with symptoms at 2–4 years of age with early virilization (pubic hair, growth spurt Growth spurt Puberty, adult body odor).
  • Precocious puberty Precocious puberty Precocious puberty (PP) is the appearance of secondary sexual characteristics due to elevated sex hormones before the age of 6-8 in girls and 9 in boys. Excess hormone secretion may occur only at the level of the sex hormone or may involve the whole hypothalamic-pituitary-gonadal axis. Precocious Puberty ( premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis onset of puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty occurs < 8 years of age in girls and < 9 years of age in boys)
  • Infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility in both genders
  • Adrenal rest tumors (mostly testicular, rarely ovarian)
    • Noted in childhood or adolescence
    • Present as testicular masses with adrenal-like tissue
    • Typically bilateral
    • Increases likelihood of infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility
    • More common in those with salt-wasting type versus simple virilizing type

Nonclassic CAH is the milder, more common form of 21-hydroxylase deficiency.

  • Onset of symptoms occurs during late childhood, adolescence, or adulthood
  • Normal genitalia at birth
  • Precocious puberty Precocious puberty Precocious puberty (PP) is the appearance of secondary sexual characteristics due to elevated sex hormones before the age of 6-8 in girls and 9 in boys. Excess hormone secretion may occur only at the level of the sex hormone or may involve the whole hypothalamic-pituitary-gonadal axis. Precocious Puberty
  • Accelerated bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types age
  • Irregular menstrual cycles
  • Hirsutism Hirsutism A condition observed in women and children when there is excess coarse body hair of an adult male distribution pattern, such as facial and chest areas. It is the result of elevated androgens from the ovaries, the adrenal glands, or exogenous sources. The concept does not include hypertrichosis, which is an androgen-independent excessive hair growth. Polycystic Ovarian Syndrome
  • Acne
  • Possible fertility issues
  • Post-pubertal boys typically asymptomatic

11β-hydroxylase deficiency

  • Ambiguous genitalia Ambiguous Genitalia Primary Amenorrhea noted at birth in girls
  • Normal external genitalia in genotypic boys but may have increased penile size
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension (due to mineralocorticoid DOC accumulation)
  • Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia
  • Premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis adrenarche (axillary and pubic hair development and body odor)
  • Accelerated growth and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types age
  • Precocious pseudopuberty
  • Acne in men
  • Hirsutism Hirsutism A condition observed in women and children when there is excess coarse body hair of an adult male distribution pattern, such as facial and chest areas. It is the result of elevated androgens from the ovaries, the adrenal glands, or exogenous sources. The concept does not include hypertrichosis, which is an androgen-independent excessive hair growth. Polycystic Ovarian Syndrome and irregular menstrual cycles in women
  • Vulnerable to adrenal crisis Adrenal crisis Adrenal crisis is the acute decompensation of adrenal function that can be triggered by another disease, surgery, stress, or increased glucocorticoid inactivation. Adrenal Insufficiency and Addison’s Disease
  • Boys may have adrenal rest tumors.

17α-hydroxylase 17α-hydroxylase A microsomal cytochrome p450 enzyme that catalyzes the 17-alpha-hydroxylation of progesterone or pregnenolone and subsequent cleavage of the residual two carbons at C17 in the presence of molecular oxygen and NADPH-ferrihemoprotein reductase. This enzyme, encoded by cyp17 gene, generates precursors for glucocorticoid, androgen, and estrogen synthesis. Defects in cyp17 gene cause congenital adrenal hyperplasia and abnormal sexual differentiation. Gonadal Hormones deficiency

  • Genotypic female individuals with normal female external genitalia
  • Genotypic male individuals with pseudohermaphroditism
    • Female external genitalia with blind-ending vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor: Anatomy 
    • Intra-abdominal testes Testes Gonadal Hormones present
  • Primary amenorrhea Primary Amenorrhea Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic-pituitary-ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Primary Amenorrhea
  • Delayed puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty or failure to develop secondary sexual characteristics Secondary Sexual Characteristics Precocious Puberty seen in both genders
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia

P450 oxidoreductase deficiency

  • Mild maternal virilization during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
  • Undervirilization of genitalia in boys 
  • Hypospadias Hypospadias A birth defect due to malformation of the urethra in which the urethral opening is below its normal location. In the male, the malformed urethra generally opens on the ventral surface of the penis or on the perineum. In the female, the malformed urethral opening is in the vagina. Penile Anomalies and Conditions
  • Virilized/ ambiguous genitalia Ambiguous Genitalia Primary Amenorrhea in girls
  • Cystic Cystic Fibrocystic Change ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries: Anatomy
  • Pattern of craniofacial and limb abnormalities (Antley-Bixler syndrome)
  • Vulnerable to adrenal crisis Adrenal crisis Adrenal crisis is the acute decompensation of adrenal function that can be triggered by another disease, surgery, stress, or increased glucocorticoid inactivation. Adrenal Insufficiency and Addison’s Disease

3β-hydroxysteroid dehydrogenase deficiency

  • Salt wasting in infancy
  • Ambiguous genitalia Ambiguous Genitalia Primary Amenorrhea in both boy and girls 
    • Virilization in girls
    • Undervirilization in boys
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia
  • Girls may have precocious puberty Precocious puberty Precocious puberty (PP) is the appearance of secondary sexual characteristics due to elevated sex hormones before the age of 6-8 in girls and 9 in boys. Excess hormone secretion may occur only at the level of the sex hormone or may involve the whole hypothalamic-pituitary-gonadal axis. Precocious Puberty, hirsutism Hirsutism A condition observed in women and children when there is excess coarse body hair of an adult male distribution pattern, such as facial and chest areas. It is the result of elevated androgens from the ovaries, the adrenal glands, or exogenous sources. The concept does not include hypertrichosis, which is an androgen-independent excessive hair growth. Polycystic Ovarian Syndrome, acne, and menstrual irregularities
  • Fertility may be impaired.

Aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia synthase deficiency

  • Salt wasting in infancy
  • Normal external genitalia in both sexes
  • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia
  • Stress-induced hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia
  • Metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
  • Postural hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension in adults

Steroidogenic acute regulatory protein deficiency

  • Severe adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison’s Disease/crisis in infancy
    • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Volume depletion Volume depletion Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Volume depletion can be caused by GI losses, renal losses, bleeding, poor oral Na intake, or third spacing of fluids. Volume Depletion and Dehydration/ dehydration Dehydration The condition that results from excessive loss of water from a living organism. Volume Depletion and Dehydration
    • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia
    • Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia
  • All are phenotypically female individuals.
  • Boys (46,XY karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System) have female external genitalia (male pseudohermaphroditism).
  • Girls have normal-appearing genitalia.
  • Girls may have impaired pubertal development.

Diagnosis

  • History and clinical examination
  • Newborn screening Newborn Screening The identification of selected parameters in newborn infants by various tests, examinations, or other procedures. Screening may be performed by clinical or laboratory measures. A screening test is designed to sort out healthy neonates from those not well, but the screening test is not intended as a diagnostic device, rather instead as epidemiologic. Severe Combined Immunodeficiency (SCID): In the United States, every infant is screened for 21-hydroxylase deficiency by the detection of elevated levels of 17α-hydroxyprogesterone 17α-hydroxyprogesterone A metabolite of progesterone with a hydroxyl group at the 17-alpha position. It serves as an intermediate in the biosynthesis of hydrocortisone and gonadal steroid hormones. Gonadal Hormones.
  • Postnatal diagnosis: 
    • Electrolyte abnormalities
    • Hormone analysis 
      • Hypocortisolism (seen in all types of CAH)
      • Increase in specific steroid precursors in blood/urine (according to type of CAH; see table below)
    • Cosyntropin (ACTH) stimulation test: gold standard to diagnose all forms of CAH
    • Magnetic resonance imaging (MRI) or ultrasound of genitalia to look for Müllerian duct Müllerian duct A pair of ducts near the wolffian ducts in a developing embryo. In the male embryo, they degenerate with the appearance of testicular anti-mullerian hormone. In the absence of anti-mullerian hormone, mullerian ducts give rise to the female reproductive tract, including the oviducts; uterus; cervix; and vagina. Uterus, Cervix, and Fallopian Tubes: Anatomy malformations
    • Adrenal ultrasound may show bilateral enlarged adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands: Anatomy.
    • Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies is considered if diagnosis is still uncertain and hormonal analysis is equivocal, or for purposes of genetic counseling Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies.

The following table outlines important findings in the 3 most common types of CAH.

Table: Important findings in the 3 most common types of CAH
Type of CAH Steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors/precursors Electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes
21-hydroxylase
  • ↑↑ 17-hydroxyprogesterone
  • ↓ DOC and corticosterone Corticosterone An adrenocortical steroid that has modest but significant activities as a mineralocorticoid and a glucocorticoid. Adrenal Hormones
  • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia
  • Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia
  • Metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
11β-hydroxylase
  • ↑ 17-hydroxyprogesterone
  • ↑ 11-deoxycortisol and DOC
  • Corticosterone Corticosterone An adrenocortical steroid that has modest but significant activities as a mineralocorticoid and a glucocorticoid. Adrenal Hormones
  • Cortisol Cortisol Glucocorticoids and aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia
  • Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens
  • Hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia
  • Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia
  • Metabolic alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis
17α-hydroxylase 17α-hydroxylase A microsomal cytochrome p450 enzyme that catalyzes the 17-alpha-hydroxylation of progesterone or pregnenolone and subsequent cleavage of the residual two carbons at C17 in the presence of molecular oxygen and NADPH-ferrihemoprotein reductase. This enzyme, encoded by cyp17 gene, generates precursors for glucocorticoid, androgen, and estrogen synthesis. Defects in cyp17 gene cause congenital adrenal hyperplasia and abnormal sexual differentiation. Gonadal Hormones
  • ↓ 17-hydroxyprogesterone
  • Progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones
  • ↑ DOC and corticosterone Corticosterone An adrenocortical steroid that has modest but significant activities as a mineralocorticoid and a glucocorticoid. Adrenal Hormones
  • Cortisol Cortisol Glucocorticoids, aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia, renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation
  • Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens and estrogens

Management

Prenatal prevention

General management

The general treatment goals are to mitigate the effects of respective steroid deficiencies and excessive amounts of steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors and to aid secondary sexual development Secondary Sexual Development Delayed Puberty.

  • Often require lifelong glucocorticoid ( hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants) replacement therapy
  • Extra steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors may be needed when sick or hospitalized.
  • Genital reconstruction surgery may be considered in children with ambiguous genitalia Ambiguous Genitalia Primary Amenorrhea according to gender identity Gender identity A person’s concept of self as being male and masculine or female and feminine, or ambivalent, based in part on physical characteristics, parental responses, and psychological and social pressures. It is the internal experience of gender role. Sexual Physiology.
  • Genetic counseling Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies

21-hydroxylase deficiency

  • Lifelong fludrocortisone Fludrocortisone A synthetic mineralocorticoid with anti-inflammatory activity. Mineralocorticoids therapy to substitute aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia
  • High-salt diet and/or sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia chloride Chloride Inorganic compounds derived from hydrochloric acid that contain the Cl- ion. Electrolytes supplements
  • Glucocorticoid therapy and/or surgery for adrenal rest tumors
  • Glucocorticoid therapy may also help with infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility and gonadal dysfunction.

11β-hydroxylase deficiency

  • Children typically treated only with glucocorticoid ( hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants) to lower ACTH secretion Secretion Coagulation Studies
  • Spironolactone Spironolactone A potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. Potassium-sparing Diuretics (blocks mineralocorticoid receptors Mineralocorticoid Receptors Mineralocorticoids) may be added in women to treat hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia, and androgen excess.
  • Spironolactone Spironolactone A potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. Potassium-sparing Diuretics should be avoided in male individuals as it can cause gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia and sexual dysfunction Sexual dysfunction Physiological disturbances in normal sexual performance in either the male or the female. Sexual Physiology; alternatives are eplerenone Eplerenone A spironolactone derivative and selective aldosterone receptor antagonist that is used in the management of hypertension and congestive heart failure, post-myocardial infarction. Potassium-sparing Diuretics or triamterene Triamterene A pteridinetriamine compound that inhibits sodium reabsorption through sodium channels in renal epithelial cells. Potassium-sparing Diuretics.
  • Low-sodium diet

17α-hydroxylase 17α-hydroxylase A microsomal cytochrome p450 enzyme that catalyzes the 17-alpha-hydroxylation of progesterone or pregnenolone and subsequent cleavage of the residual two carbons at C17 in the presence of molecular oxygen and NADPH-ferrihemoprotein reductase. This enzyme, encoded by cyp17 gene, generates precursors for glucocorticoid, androgen, and estrogen synthesis. Defects in cyp17 gene cause congenital adrenal hyperplasia and abnormal sexual differentiation. Gonadal Hormones deficiency

  • Spironolactone Spironolactone A potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. Potassium-sparing Diuretics may be used in women to block mineralocorticoid receptors Mineralocorticoid Receptors Mineralocorticoids.
  • Low-sodium diet
  • Estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy replacement therapy in early puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty for girls
  • Testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens replacement may be given to boys.

P450 oxidoreductase deficiency

  • Management depends on degree of glucocorticoid deficiency and degree of cortisol Cortisol Glucocorticoids response to ACTH.
  • Ranges from no need for glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids to lifelong replacement with hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants
  • Appropriate sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria hormone replacement therapy Hormone Replacement Therapy Hormone replacement therapy (HRT) is used to treat symptoms associated with female menopause and in combination to suppress ovulation. Risks and side effects include uterine bleeding, predisposition to cancer, breast tenderness, hyperpigmentation, migraine headaches, hypertension, bloating, and mood changes. Noncontraceptive Estrogen and Progestins at pubertal age
  • Spironolactone Spironolactone A potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. Potassium-sparing Diuretics/ eplerenone Eplerenone A spironolactone derivative and selective aldosterone receptor antagonist that is used in the management of hypertension and congestive heart failure, post-myocardial infarction. Potassium-sparing Diuretics to treat hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension if needed
  • Surgery may be needed for craniofacial and limb abnormalities.

3β-hydroxysteroid-dehydrogenase

  • Glucocorticoid replacement therapy with hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants
  • Mineralocorticoid replacement therapy with fludrocortisone Fludrocortisone A synthetic mineralocorticoid with anti-inflammatory activity. Mineralocorticoids
  • Appropriate sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria hormone replacement therapy Hormone Replacement Therapy Hormone replacement therapy (HRT) is used to treat symptoms associated with female menopause and in combination to suppress ovulation. Risks and side effects include uterine bleeding, predisposition to cancer, breast tenderness, hyperpigmentation, migraine headaches, hypertension, bloating, and mood changes. Noncontraceptive Estrogen and Progestins at pubertal age

Aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia synthase deficiency

  • Fludrocortisone Fludrocortisone A synthetic mineralocorticoid with anti-inflammatory activity. Mineralocorticoids therapy to substitute aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia
  • Low-sodium diet
  • Clinical severity improves with age; adults may not need replacement therapy.

StAR deficiency

  • Approximately 2⁄3 of infants with classical (complete) form of this condition die during infancy.
  • Glucocorticoid and mineralocorticoid replacement needed for survivors
  • Estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy replacement therapy in puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty to induce secondary sexual characteristics Secondary Sexual Characteristics Precocious Puberty

Differential Diagnosis

  • Androgen insensitivity syndrome Androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is an X-linked recessive condition in which a genetic mutation affects the function of androgen receptors, resulting in complete (CAIS), partial (PAIS), or mild (MAIS) resistance to testosterone. All individuals with AIS have a 46,XY karyotype; however, phenotypes vary and include phenotypic female, virilized female, undervirilized male, and phenotypic male individuals. Androgen Insensitivity Syndrome: an X-linked recessive X-Linked Recessive Duchenne Muscular Dystrophy condition affecting individuals with a 46,XY karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System in which the function of androgen receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors is impaired, with resulting resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing to testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens. Phenotypes vary and include phenotypic female, virilized female, undervirilized male, or phenotypic male individuals. Hormonal analysis, imaging, and genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies help make the diagnosis. Management varies depending on the degree of androgen sensitivity and gender identity Gender identity A person’s concept of self as being male and masculine or female and feminine, or ambivalent, based in part on physical characteristics, parental responses, and psychological and social pressures. It is the internal experience of gender role. Sexual Physiology, and may involve hormone replacement and surgery.
  • Steroid 5-alpha reductase deficiency: an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance genetic condition affecting individuals with a 46,XY karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System. External genitalia most often appear female, but may also appear male or ambiguous. Affected individuals have testes Testes Gonadal Hormones and normal testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens production. However, there is impairment in the ability to convert testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens to dihydrotestosterone Dihydrotestosterone A potent androgenic metabolite of testosterone. It is produced by the action of the enzyme 3-oxo-5-alpha-steroid 4-dehydrogenase. Gonadal Hormones ( DHT DHT A potent androgenic metabolite of testosterone. It is produced by the action of the enzyme 3-oxo-5-alpha-steroid 4-dehydrogenase. Gonadal Hormones), causing undervirilization. Hormonal and genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies help make the diagnosis. Management depends on phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics and gender identity Gender identity A person’s concept of self as being male and masculine or female and feminine, or ambivalent, based in part on physical characteristics, parental responses, and psychological and social pressures. It is the internal experience of gender role. Sexual Physiology and may involve hormone replacement and surgery.
  • Polycystic ovarian syndrome Polycystic ovarian syndrome Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women, affecting nearly 5%-10% of women in the age group. It is characterized by hyperandrogenism, chronic anovulation leading to oligomenorrhea (or amenorrhea), and metabolic dysfunction. Polycystic Ovarian Syndrome: a common ovarian disorder affecting women associated with excess androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens and difficulty conceiving. Individuals are born with normal female genitalia and may develop irregular menstrual cycles, hirsutism Hirsutism A condition observed in women and children when there is excess coarse body hair of an adult male distribution pattern, such as facial and chest areas. It is the result of elevated androgens from the ovaries, the adrenal glands, or exogenous sources. The concept does not include hypertrichosis, which is an androgen-independent excessive hair growth. Polycystic Ovarian Syndrome, and acne. Laboratories and pelvic ultrasound aid in diagnosis. Treatment involves lifestyle changes and medications such as oral contraceptives, metformin Metformin A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. Non-insulinotropic Diabetes Drugs, and spironolactone Spironolactone A potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. Potassium-sparing Diuretics to manage symptoms.

References

  1. Podgórski R, Aebisher D, Stompor M, Podgórska D, Mazur A. (2018). Congenital adrenal hyperplasia: clinical symptoms and diagnostic methods. Acta Biochim Pol. 65(1):25-33. Epub 2018 Mar 15. PMID: 29543924. https://doi.org/10.18388/abp.2017_2343
  2. White, P.C., & Speiser, P.W. (2000). Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency. Endocrine Reviews. 21(3): 245–291. https://doi.org/10.1210/edrv.21.3.0398
  3. Hui, E., Yeung, M.C., Cheung, P.T. et al. (2014). The clinical significance of aldosterone synthase deficiency: report of a novel mutation in the CYP11B2 gene. BMC Endocr Disord 14 (29). https://doi.org/10.1186/1472-6823-14-29
  4. Merke, D. P. (2020). Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. UpToDate. Retrieved January 21, 2020, from https://www.uptodate.com/contents/genetics-and-clinical-presentation-of-classic-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency
  5. Nieman, L. K. (2020). Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency. UpToDate. Retrieved January 21, 2021, from https://www.uptodate.com/contents/genetics-and-clinical-presentation-of-nonclassic-late-onset-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency
  6. Merke, D.P. & Auchus, R.J. (2020). Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children. UpToDate. Retrieved January 21, 2020, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-classic-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency-in-infants-and-children
  7. Hannah-Shmouni, F., Morissette, R., Sinali, N., et al. (2017). Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians. Genet Med.  19(11): 1276–1279. doi: 10.1038/gim.2017.46
  8. Auchus, R. J. (2020). Uncommon congenital adrenal hyperplasias. UpToDate. Retrieved January 21, 2020, from https://www.uptodate.com/contents/uncommon-congenital-adrenal-hyperplasias
  9. Chan, Y. & Levitsky, L.L. (2020). Causes of differences of sex development. UpToDate. Retrieved January 22, 2021, from https://www.uptodate.com/contents/causes-of-differences-of-sex-development

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