Lipoid congenital adrenal hyperplasia
Encyclopedia
Lipoid congenital adrenal hyperplasia is an endocrine disorder that is an uncommon and potentially lethal form of congenital adrenal hyperplasia
(CAH). It arises from defects in the earliest stages of adrenal
cortisol
synthesis: the transport of cholesterol
into the mitochondria
of the cells of the adrenal cortex
and the conversion of cholesterol to pregnenolone
-- the first step in the synthesis of all steroid hormone
s. Lipoid CAH causes mineralocorticoid
deficiency in affected infants and children. Male infants are severely undervirilized
causing their external genitalia to look feminine. Consequently, they are usually raised as girls. The adrenals are large and filled with lipid
globules derived from cholesterol.
s are a family of autosomal recessive diseases resulting from defects in steps of the synthesis
of cortisol
from cholesterol
by the adrenal gland
. All forms of CAH involve excessive or defective production of sex steroid
s and can prevent or impair development of primary or secondary sex characteristic
s in affected infants, children, and adults. Many also involve excessive or defective production of mineralocorticoid
s, which can cause hypertension
or salt-wasting.
Lipoid CAH is one of the rarer forms of CAH and results from defects in the steps from cholesterol to pregnenolone. This results in the catastrophic loss of most or all steroid hormones in the body. It is caused by mutations in either of two protein
s: cytochrome
P450scc and steroidogenic acute regulatory protein
(StAR).
P450scc (cholesterol side chain
cleavage enzyme). However, few cases of lipoid CAH due to a mutation and defect of P450scc have been identified. Although the disorder is considered autosomal recessive, a single mutation in P450scc can be sufficient to cause the condition. All other cases of lipoid adrenal hyperplasia that have been studied have been found to be due to mutations of the gene
for the primary protein that transports cholesterol into the mitochondria, StAR, encoded by a gene on chromosome
8p11.2 in the human.
Lipoid CAH is quite rare in European and North American populations. Most cases occur in Japan and Korea (where the incidence is 1 in 300,000 births) and Palestinian Arabs. Despite autosomal inheritance, there has been an unexplained preponderance of genetic females in reported cases.
(ACTH). A low level of steroid synthesis proceeds even without efficient transport, but is rarely enough to prevent the consequences of deficiency. While severe loss of steroid production results in manifestation of the disease within a few weeks of birth, milder forms (late onset) can present years after birth. Unlike in models of the disease in mice, patients with lipoid CAH do not always have enlarged adrenals due to lipid accumulation. This may in part be due to hormone replacement
used to keep them alive preventing hyperstimulation of the gland by the pituitary.
ACTH stimulates growth of the adrenal cells and increases LDL
receptors to amplify transport of cholesterol into the cells of the adrenal cortex which make adrenal steroids, where it accumulates since little can enter the mitochondria for conversion to steroid. Normally, adrenal steroids then signal their presence to the brain to moderate ACTH levels (feedback
inhibition). However, in the absence of this, ACTH levels are elevated and cholesterol uptake by the cortical cells continues unabated. The adrenals become markedly enlarged (hyperplastic) by the accumulated lipid. Lipid accumulation is thought to damage the cells further (“second hit hypothesis”).
Because P450scc and StAR are also essential for sex steroid synthesis in the testis and ovary
, the production of testosterone
by Leydig cell
s in the testis and androgen
(which leads to estrogen
production by granulosa cells) and progesterone
by ovarian theca cells and luteal cells, respectively, can also be impaired. Similar to the adrenal gland, cholesterol accumulation damages the Leydig cell
s of the testes. In the ovary, the damage begins after puberty
, the time when the ovary starts making steroid with follicle
development. The placenta
also makes steroid to help maintain pregnancy
. However, since StAR is not required for placental steroid production, pregnancy goes to term. When the mutation in P450scc that causes lipoid CAH is either heterozygous or its presence on both allele
s does not completely destroy all function, affected babies can survive to birth as well. Also of note, enlargement of the adrenal gland is not always found in the patient, especially in cases where a mutation in the gene for P450scc is the cause.
The pathophysiology of lipoid CAH differs from other forms of CAH in certain aspects. First, the affected gene in most cases is that for a transport protein (StAR) rather than a steroidogenic enzyme. Second, because the defect compromises all steroid synthesis. Thus, there are no problems due to excessive mineralocorticoids or androgens. Third, lipid accumulation damages the testes and ovaries so that even with appropriate adrenal hormone replacement (and in the absence of other intervention), gonadal function and fertility cannot be preserved.
is undifferentiated and inactive before delivery, it is undamaged at birth and can make aldosterone
for a while, so the eventual salt-wasting crisis develops more gradually and variably than with severe 21-hydroxylase-deficient CAH
.
Most come to medical attention between 2 weeks and 3 months of age, when after a period of poor weight gain and vomiting, they were found to be dehydrated, with severe hyponatremia
, hyperkalemia
, and metabolic acidosis
("Addisonian or adrenal crisis"). Renin
but not aldosterone
is elevated. Many infants born with this condition died before a method for diagnosis was recognized for proper treatment to begin. In some cases, the condition is more mild with signs and symptoms of mineralocorticoid and glucocorticoid deficiency appearing after months or even years (late onset).
synthesis has several consequences. Elevated ACTH is accompanied by and contributes to marked hyperpigmentation
even in the newborn period. An inadequate cortisol response to stress undoubtedly hastens the deterioration as dehydration develops, can cause hypoglycemia
, and contributes to the high mortality rate in infancy.
by the fetal adrenal glands is impaired, resulting in abnormally low maternal estriol
levels by the middle of pregnancy. The effects of impaired progesterone production from placental cells that originate from the affected baby (trophoblasts) in the case of lipoid CAH due to P450scc deficiency are still unclear, but are thought to result in miscarriage when the deficit in the enzyme's activity are severe enough. The results of reduced or absent testosterone output by fetal Leydig cells in the male is detailed below.
.
With glucocorticoid and mineralocorticoid replacement, these girls will reach the age of puberty. Because the ovaries are relatively inactive in fetal life and childhood, they sustain little damage from lipid accumulation during childhood. In the case of lipoid CAH due to StAR deficiency, when rising gonadotropin
levels initiate puberty
, despite the inefficiency of sex steroid
synthesis, the ovaries
will usually make enough estradiol
to produce breast development, and in some cases even menarche
, with menses continuing for some years. Ovarian and adrenal androgen production is minimal and produces little pubic or other body hair.
However insufficient estradiol and progesterone
are produced to induce maturation of an egg and ovulation
. Although prepubertal ovaries are inactive enough that no lipid accumulates to cause damage, once they have begun to produce estrogen, lipid damage begins to accrue and the ability to produce estrogen, as well as ovulate, is slowly degraded. Cysts also form in the ovaries. Women with lipoid CAH have been infertile presumably due to anovulation
.
, the testes are usually remain in the abdomen or lodge in the inguinal canal
s (undescended testes) and are nonfunctional. Consequently, XY patients do not undergo puberty and remain infertile.
In addition to the testes remaining inside, formation of the penis
, also dependent on testosterone, is compromised. Hence, the external genitalia in most of infants resemble that of normal females (though the vagina is a short, blind pouch), or is slightly ambiguous (more female than male). Nearly all reported XY cases have been assumed to be girls and raised as such with no reports of later gender identity problems.
These nonclassic forms of the disorder are sometimes diagnosed as familial glucocorticoid deficiency type 3.
.
Glucocorticoids can be provided at minimal replacement doses because there is no need for suppression of excessive adrenal androgens or mineralocorticoids. As with other forms of adrenal insufficiency, extra glucocorticoid is needed for stress coverage.
in combination with an assisted fertility technique, intracytoplasmic sperm injection
. This led to ovulation and with implantation of the in vitro
fertilized egg, a successful birth.
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands ....
(CAH). It arises from defects in the earliest stages of adrenal
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
synthesis: the transport of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
into the mitochondria
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
of the cells of the adrenal cortex
Adrenal cortex
Situated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
and the conversion of cholesterol to pregnenolone
Pregnenolone
Pregnenolone is a steroid hormone involved in the steroidogenesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. As such it is a prohormone. Pregnenolone sulfate is a GABAA antagonist and increases neurogenesis in the hippocampus.-Chemistry:Like other steroids,...
-- the first step in the synthesis of all steroid hormone
Steroid hormone
A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens...
s. Lipoid CAH causes mineralocorticoid
Mineralocorticoid
Mineralocorticoids are a class of steroid hormones characterised by their similarity to aldosterone and their influence on salt and water balances.-Physiology:...
deficiency in affected infants and children. Male infants are severely undervirilized
Virilization
In biology and medicine, virilization refers to the biological development of sex differences, changes that make a male body different from a female body. Most of the changes of virilization are produced by androgens...
causing their external genitalia to look feminine. Consequently, they are usually raised as girls. The adrenals are large and filled with lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
globules derived from cholesterol.
Introduction
Congenital adrenal hyperplasiaCongenital adrenal hyperplasia
Congenital adrenal hyperplasia refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands ....
s are a family of autosomal recessive diseases resulting from defects in steps of the synthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
of cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
from cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
by the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
. All forms of CAH involve excessive or defective production of sex steroid
Sex steroid
Sex steroids, also known as gonadal steroids, are steroid hormones that interact with vertebrate androgen or estrogen receptors. Their effects are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and...
s and can prevent or impair development of primary or secondary sex characteristic
Secondary sex characteristic
Secondary sex characteristics are features that distinguish the two sexes of a species, but that are not directly part of the reproductive system. They are believed to be the product of sexual selection for traits which give an individual an advantage over its rivals in courtship and aggressive...
s in affected infants, children, and adults. Many also involve excessive or defective production of mineralocorticoid
Mineralocorticoid
Mineralocorticoids are a class of steroid hormones characterised by their similarity to aldosterone and their influence on salt and water balances.-Physiology:...
s, which can cause hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
or salt-wasting.
Lipoid CAH is one of the rarer forms of CAH and results from defects in the steps from cholesterol to pregnenolone. This results in the catastrophic loss of most or all steroid hormones in the body. It is caused by mutations in either of two protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s: cytochrome
Cytochrome
Cytochromes are, in general, membrane-bound hemoproteins that contain heme groups and carry out electron transport.They are found either as monomeric proteins or as subunits of bigger enzymatic complexes that catalyze redox reactions....
P450scc and steroidogenic acute regulatory protein
Steroidogenic acute regulatory protein
The steroidogenic acute regulatory protein, commonly referred to as StAR , is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones...
(StAR).
Genetics and epidemiology
This inherited disease is autosomal recessive. Understanding of the molecular basis for it has been advanced in the last decade by better understanding of adrenal steroidogenesis as well as genetic studies of affected patients. It used to be assumed that lipoid CAH resulted from a defect of the enzyme that converted cholesterol to pregnenolone. The conversion reactions are mediated by a single enzyme, formerly referred to as 20,22-desmolase, but now identified as cytochromeCytochrome
Cytochromes are, in general, membrane-bound hemoproteins that contain heme groups and carry out electron transport.They are found either as monomeric proteins or as subunits of bigger enzymatic complexes that catalyze redox reactions....
P450scc (cholesterol side chain
Side chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...
cleavage enzyme). However, few cases of lipoid CAH due to a mutation and defect of P450scc have been identified. Although the disorder is considered autosomal recessive, a single mutation in P450scc can be sufficient to cause the condition. All other cases of lipoid adrenal hyperplasia that have been studied have been found to be due to mutations of the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
for the primary protein that transports cholesterol into the mitochondria, StAR, encoded by a gene on chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
8p11.2 in the human.
Lipoid CAH is quite rare in European and North American populations. Most cases occur in Japan and Korea (where the incidence is 1 in 300,000 births) and Palestinian Arabs. Despite autosomal inheritance, there has been an unexplained preponderance of genetic females in reported cases.
Pathophysiology
The deficiency results in impaired synthesis of all three categories of adrenal steroids (cortisol, mineralocorticoids, sex steroids) and high levels of adrenocorticotropic hormoneAdrenocorticotropic hormone
Adrenocorticotropic hormone , also known as 'corticotropin', 'Adrenocorticotrophic hormone', is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological...
(ACTH). A low level of steroid synthesis proceeds even without efficient transport, but is rarely enough to prevent the consequences of deficiency. While severe loss of steroid production results in manifestation of the disease within a few weeks of birth, milder forms (late onset) can present years after birth. Unlike in models of the disease in mice, patients with lipoid CAH do not always have enlarged adrenals due to lipid accumulation. This may in part be due to hormone replacement
Hormone therapy
Hormone therapy, or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also referred to as hormonal therapy...
used to keep them alive preventing hyperstimulation of the gland by the pituitary.
ACTH stimulates growth of the adrenal cells and increases LDL
Low density lipoprotein
Low-density lipoprotein is one of the five major groups of lipoproteins, which in order of size, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, that enable transport of cholesterol within the water-based bloodstream...
receptors to amplify transport of cholesterol into the cells of the adrenal cortex which make adrenal steroids, where it accumulates since little can enter the mitochondria for conversion to steroid. Normally, adrenal steroids then signal their presence to the brain to moderate ACTH levels (feedback
Feedback
Feedback describes the situation when output from an event or phenomenon in the past will influence an occurrence or occurrences of the same Feedback describes the situation when output from (or information about the result of) an event or phenomenon in the past will influence an occurrence or...
inhibition). However, in the absence of this, ACTH levels are elevated and cholesterol uptake by the cortical cells continues unabated. The adrenals become markedly enlarged (hyperplastic) by the accumulated lipid. Lipid accumulation is thought to damage the cells further (“second hit hypothesis”).
Because P450scc and StAR are also essential for sex steroid synthesis in the testis and ovary
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
, the production of testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
by Leydig cell
Leydig cell
Leydig cells, also known as interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle. They produce testosterone in the presence of luteinizing hormone...
s in the testis and androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
(which leads to estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
production by granulosa cells) and progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
by ovarian theca cells and luteal cells, respectively, can also be impaired. Similar to the adrenal gland, cholesterol accumulation damages the Leydig cell
Leydig cell
Leydig cells, also known as interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle. They produce testosterone in the presence of luteinizing hormone...
s of the testes. In the ovary, the damage begins after puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
, the time when the ovary starts making steroid with follicle
Ovarian follicle
Ovarian follicles are the basic units of female reproductive biology, each of which is composed of roughly spherical aggregations of cells found in the ovary. They contain a single oocyte . These structures are periodically initiated to grow and develop, culminating in ovulation of usually a single...
development. The placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
also makes steroid to help maintain pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
. However, since StAR is not required for placental steroid production, pregnancy goes to term. When the mutation in P450scc that causes lipoid CAH is either heterozygous or its presence on both allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s does not completely destroy all function, affected babies can survive to birth as well. Also of note, enlargement of the adrenal gland is not always found in the patient, especially in cases where a mutation in the gene for P450scc is the cause.
The pathophysiology of lipoid CAH differs from other forms of CAH in certain aspects. First, the affected gene in most cases is that for a transport protein (StAR) rather than a steroidogenic enzyme. Second, because the defect compromises all steroid synthesis. Thus, there are no problems due to excessive mineralocorticoids or androgens. Third, lipid accumulation damages the testes and ovaries so that even with appropriate adrenal hormone replacement (and in the absence of other intervention), gonadal function and fertility cannot be preserved.
Clinical manifestations
Problems that emerge in persons with lipoid CAH can be divided into:- mineralocorticoid deficiency,
- glucocorticoid deficiency,
- sex steroid deficiency, and
- damage to gonads caused by lipid accumulation.
Mineralocorticoid deficiency
Most infants born with lipoid CAH have had genitalia female enough that no disease was suspected at birth. Because the adrenal zona glomerulosaZona glomerulosa
The zona glomerulosa of the adrenal gland is the most superficial layer of the adrenal cortex, lying directly beneath the adrenal gland's capsule...
is undifferentiated and inactive before delivery, it is undamaged at birth and can make aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
for a while, so the eventual salt-wasting crisis develops more gradually and variably than with severe 21-hydroxylase-deficient CAH
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency , in all its forms, accounts for over 95% of diagnosed cases of congenital adrenal hyperplasia, and "CAH" in most contexts refers to 21-hydroxylase deficiency...
.
Most come to medical attention between 2 weeks and 3 months of age, when after a period of poor weight gain and vomiting, they were found to be dehydrated, with severe hyponatremia
Hyponatremia
Hyponatremia is an electrolyte disturbance in which the sodium concentration in the serum is lower than normal. In the vast majority of cases, hyponatremia occurs as a result of excess body water diluting the serum sodium and is not due to sodium deficiency. Sodium is the dominant extracellular...
, hyperkalemia
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...
, and metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
("Addisonian or adrenal crisis"). Renin
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
but not aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
is elevated. Many infants born with this condition died before a method for diagnosis was recognized for proper treatment to begin. In some cases, the condition is more mild with signs and symptoms of mineralocorticoid and glucocorticoid deficiency appearing after months or even years (late onset).
Glucocorticoid deficiency
Insufficiency of cortisolCortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
synthesis has several consequences. Elevated ACTH is accompanied by and contributes to marked hyperpigmentation
Hyperpigmentation
In dermatology, hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.-Causes:Hyperpigmentation may be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris...
even in the newborn period. An inadequate cortisol response to stress undoubtedly hastens the deterioration as dehydration develops, can cause hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
, and contributes to the high mortality rate in infancy.
In development
Prenatal production of DHEADehydroepiandrosterone
5-Dehydroepiandrosterone is a 19-carbon endogenous steroid hormone. It is the major secretory steroidal product of the adrenal glands and is also produced by the gonads and the brain. DHEA is the most abundant circulating steroid in humans....
by the fetal adrenal glands is impaired, resulting in abnormally low maternal estriol
Estriol
Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...
levels by the middle of pregnancy. The effects of impaired progesterone production from placental cells that originate from the affected baby (trophoblasts) in the case of lipoid CAH due to P450scc deficiency are still unclear, but are thought to result in miscarriage when the deficit in the enzyme's activity are severe enough. The results of reduced or absent testosterone output by fetal Leydig cells in the male is detailed below.
Female patients
Genetic XX females with lipoid CAH are born with normal external and internal pelvic anatomy. They come to medical attention when they develop a salt-wasting adrenal crisis or other signs of progressive adrenal insufficiencyAdrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...
.
With glucocorticoid and mineralocorticoid replacement, these girls will reach the age of puberty. Because the ovaries are relatively inactive in fetal life and childhood, they sustain little damage from lipid accumulation during childhood. In the case of lipoid CAH due to StAR deficiency, when rising gonadotropin
Gonadotropin
Gonadotropins are protein hormones secreted by gonadotrope cells of the pituitary gland of vertebrates. This is a family of proteins, which include the mammalian hormones follitropin , lutropin , placental chorionic gonadotropins hCG and eCG and chorionic gonadotropin , as well as at least two...
levels initiate puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
, despite the inefficiency of sex steroid
Sex steroid
Sex steroids, also known as gonadal steroids, are steroid hormones that interact with vertebrate androgen or estrogen receptors. Their effects are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and...
synthesis, the ovaries
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
will usually make enough estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
to produce breast development, and in some cases even menarche
Menarche
Menarche is the first menstrual cycle, or first menstrual bleeding, in female human beings. From both social and medical perspectives it is often considered the central event of female puberty, as it signals the possibility of fertility....
, with menses continuing for some years. Ovarian and adrenal androgen production is minimal and produces little pubic or other body hair.
However insufficient estradiol and progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
are produced to induce maturation of an egg and ovulation
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...
. Although prepubertal ovaries are inactive enough that no lipid accumulates to cause damage, once they have begun to produce estrogen, lipid damage begins to accrue and the ability to produce estrogen, as well as ovulate, is slowly degraded. Cysts also form in the ovaries. Women with lipoid CAH have been infertile presumably due to anovulation
Anovulation
An anovulatory cycle is a menstrual cycle during which the ovaries do not release an oocyte. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause...
.
Male patients
The genitalia of XY fetuses with lipoid CAH are severely undervirilized due to impairment of steroid hormone synthesis. The fetal testes make AMH, which prevents a uterus and inner vagina from forming, but since the Leydig cells fail to make testosterone during development even in response to hCGHuman chorionic gonadotropin
Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
, the testes are usually remain in the abdomen or lodge in the inguinal canal
Inguinal canal
The inguinal canal is a passage in the anterior abdominal wall which in men conveys the spermatic cord and in women the round ligament. The inguinal canal is larger and more prominent in men.-Site:...
s (undescended testes) and are nonfunctional. Consequently, XY patients do not undergo puberty and remain infertile.
In addition to the testes remaining inside, formation of the penis
Penis
The penis is a biological feature of male animals including both vertebrates and invertebrates...
, also dependent on testosterone, is compromised. Hence, the external genitalia in most of infants resemble that of normal females (though the vagina is a short, blind pouch), or is slightly ambiguous (more female than male). Nearly all reported XY cases have been assumed to be girls and raised as such with no reports of later gender identity problems.
Late onset forms of the disease
Milder cases of lipoid CAH have been described that arise from less severe mutations that compromise but do not eliminate the ability of StAR to instigate steroid production. In these cases, mineralocorticoid deficiency emerges up to several years after birth. Sex steroid production may be sufficient to allow for normal sexual development as well and even fertility.These nonclassic forms of the disorder are sometimes diagnosed as familial glucocorticoid deficiency type 3.
Management
Management of salt-wasting crises and mineralocorticoid treatment are as for other forms of salt-wasting congenital adrenal hyperplasias: saline and fludrocortisoneFludrocortisone
Fludrocortisone is a synthetic corticosteroid with moderate glucocorticoid potency and much greater mineralocorticoid potency. The brand name in the U.S. and Canada is Florinef.-Uses:...
.
Glucocorticoids can be provided at minimal replacement doses because there is no need for suppression of excessive adrenal androgens or mineralocorticoids. As with other forms of adrenal insufficiency, extra glucocorticoid is needed for stress coverage.
Female patients
XX females with lipoid CAH may need estrogen replacement at or after puberty. Active intervention has been used to preserve the possibility of fertility and conception in lipoid CAH females. In a case report in 2009, a woman with late onset lipoid CAH due to StAR deficiency underwent hormone replacement therapyHormone therapy
Hormone therapy, or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also referred to as hormonal therapy...
in combination with an assisted fertility technique, intracytoplasmic sperm injection
Intracytoplasmic sperm injection
Intracytoplasmic sperm injection is an in vitro fertilization procedure in which a single sperm is injected directly into an egg.-Indications:...
. This led to ovulation and with implantation of the in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
fertilized egg, a successful birth.
Male patients
Most XY children are so undervirilized that they are raised as girls. The testes are uniformly nonfunctional and undescended; they are removed when the diagnosis is made due to the risk of cancer development in these tissues.See also
- Congenital adrenal hyperplasiaCongenital adrenal hyperplasiaCongenital adrenal hyperplasia refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands ....
for an overview of CAH - Congenital adrenal hyperplasia due to 17α-hydroxylase deficiencyCongenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiencyCongenital adrenal hyperplasia due to 17α-hydroxylase deficiency is an uncommon form of congenital adrenal hyperplasia resulting from a defect in the gene for the enzyme CYP17A1. It produces decreased synthesis of both cortisol and sex steroids, with resulting increase in mineralocorticoid production...
- Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiencyCongenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency3β-Hydroxysteroid dehydrogenase II deficient congenital adrenal hyperplasia is an uncommon form of CAH resulting from a mutation in the gene for one of the key enzymes in cortisol synthesis by the adrenal gland, 3β-hydroxysteroid dehydrogenase type II...
- Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency
- IntersexIntersexIntersex, in humans and other animals, is the presence of intermediate or atypical combinations of physical features that usually distinguish female from male...
and ambiguous genitalia - Adrenal insufficiencyAdrenal insufficiencyAdrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...