Congenital adrenal hyperplasia
Congenital adrenal hyperplasia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
primary or secondary sex characteristics in some affected infants, children, or adults.[5] It is one of the most common autosomal recessive disorders in humans.[6][7][8]
TypesCAH can occur in various forms. The clinical presentation of each form is different and depends to a large extent on the underlying enzyme defect, its precursor retention, and deficient products.[9] Classical forms appear in infancy, and nonclassical forms appear in late childhood. The presentation in patients with classic CAH can be further subdivided into three forms: salt-wasting, simple-virilizing, and non-classic (NC) depending on whether mineralocorticoid deficiency presents or absents, respectively.[10][11][12] This subtyping is often not clinically meaningful, though, because all patients lose salt to some degree, and clinical presentations may overlap.[13] ClassicSalt-wastingIn 75% of cases of severe enzyme deficiency, insufficient neonatal morbidity and death.[2]
Simple-virilizingThe main feature of CAH in newborn females is the abnormal development of the external genitalia, which has varying degrees of virilization. According to clinical practice guidelines, for newborns found to have bilateral inaccessible gonads, CAH evaluation should be considered. If virilizing CAH cannot be identified and treated, both boys and girls may undergo rapid postnatal growth and virilization.[2] NonclassicIn addition to the salt-wasting and simple-virilizing forms of CAH diagnosed in infancy, a mild or "nonclassic" form exists, which is characterized by varying degrees of postnatal androgen excess, but is sometimes asymptomatic.[14] The nonclassic form may be noticed in late childhood and may lead to signs of hyperandrogenism such as accelerated growth, acne, hirsutism, premature pubarche, menstrual irregularities,[14] and secondary polycystic ovary syndrome.[15] In adult males, early balding[14] and infertility may suggest the diagnosis. The nonclassic form is characterized by mild subclinical impairment of cortisol synthesis[14] serum cortisol concentration is usually normal.[14] Signs and symptomsThe symptoms of CAH vary depending upon the form of CAH and the sex of the patient. Symptoms can include: Due to inadequate mineralocorticoids:[citation needed]
Due to excess androgens:
Due to insufficient androgens and estrogens:[citation needed]
GeneticsCAH results from steroidogenesis).[20]
Each form of CAH is associated with a specific defective gene. The most common type (95% of cases) ExpressivityFurther variability is introduced by the degree of enzyme inefficiency produced by the specific sex hormone effects in childhood or adolescence, while the mildest forms of CAH interfere with ovulation and fertility in adults.[citation needed ]
Diagnosis
Clinical evaluationFemale infants with classic CAH have ambiguous genitalia due to exposure to high concentrations of androgens in utero. Males with classic CAH generally have no signs of CAH at birth. Some may present with hyperpigmentation, due to co-secretion with melanocyte-stimulating hormone, and possible penile enlargement. Age of diagnosis of males with CAH varies and depends on the severity of aldosterone deficiency. Boys with salt-wasting disease present early with symptoms of hyponatremia and hypovolemia. Boys with non-salt-wasting disease present later with signs of virilization.[24] In rarer forms of CAH, males are undermasculinized[27] and females generally have no signs or symptoms at birth.[medical citation needed] Laboratory studiesGenetic analysis can be helpful to confirm a diagnosis of CAH, but it is not necessary if classic clinical and laboratory findings are present. In classic 21-hydroxylase deficiency, laboratory studies will show:
Classic 21-hydroxylase deficiency typically causes 17α-hydroxyprogesterone blood levels >242 nmol/L.[medical citation needed] (For comparison, a full-term infant at three days of age should have <3 nmol/L. Many neonatal screening programs have specific reference ranges by weight and gestational age because high levels may be seen in premature infants without CAH.) Salt-wasting patients tend to have higher 17α-hydroxyprogesterone levels than non-salt-wasting patients. In mild cases, 17α-hydroxyprogesterone may not be elevated in a particular random blood sample, but it will rise during a corticotropin stimulation test. ClassificationCortisol is an adrenal steroid hormone required for normal endocrine function. Production begins in the second month of fetal life. Poor cortisol production is a hallmark of most forms of CAH. Inefficient cortisol production results in rising levels of ACTH, because cortisol feeds back to inhibit ACTH production, so loss of cortisol results in increased ACTH.[28] This increased ACTH stimulation induces overgrowth (hyperplasia) and overactivity of the steroid-producing cells of the adrenal cortex. The defects causing adrenal hyperplasia are congenital (i.e. present at birth). Cortisol deficiency in CAH is usually partial, and not the most serious problem for an affected person. Synthesis of cortisol shares steps with synthesis of mineralocorticoids such as aldosterone, androgens such as testosterone, and estrogens such as estradiol. The resulting excessive or deficient production of these three classes of hormones produce the most important problems for people with CAH. Specific enzyme inefficiencies are associated with characteristic patterns of over- or underproduction of mineralocorticoids or sex steroids. Since the 1960s, most endocrinologists have referred to the forms of CAH by the traditional names in the left column, which generally correspond to the deficient enzyme activity. As exact structures and genes for the enzymes were identified in the 1980s, most of the enzymes were found to be cytochrome P450 oxidases and were renamed to reflect this. In some cases, more than one enzyme was found to participate in a reaction, and in other cases, a single enzyme mediated in more than one reaction. Variation in different tissues and mammalian species also was found.
In all its forms, congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for about 95% of diagnosed cases of CAH.[2] Unless another specific enzyme is mentioned, "CAH" in nearly all contexts refers to 21-hydroxylase deficiency. (The terms "salt-wasting CAH", and "simple virilizing CAH" usually refer to subtypes of this condition.) CAH due to deficiencies of enzymes other than 21-hydroxylase present many of the same management challenges, as 21-hydroxylase deficiency, but some involve mineralocorticoid excess or sex steroid deficiency.
ScreeningCurrently, in the United States and over 40 other countries, every child born is screened for 21-hydroxylase CAH at birth. This test detects elevated levels of 17α-hydroxyprogesterone (17-OHP). Detecting high levels of 17-OHP enables early detection of CAH. Newborns detected early enough can be placed on medication and live relatively normal lives.[citation needed ]
The screening process, however, is characterized by a high false-positive rate. In one study, In 2020, Wael AbdAlmageed from USC Information Sciences Institute and Mimi Kim from USC Keck School Of Medicine led a joint study in which they used deep learning technology to analyze the facial morphology and features of CAH patients compared to control. In this cross-sectional study[31] of 102 patients with CAH and 144 control participants, deep learning methods achieved a mean area under the receiver operating characteristic curve of 92% for predicting CAH from facial images. Facial features distinguished patients with CAH from controls, and analyses of facial regions found that the nose and upper face were most contributory. The findings suggest that facial morphologic features, as analyzed by deep neural network techniques, can be used as a phenotypic biomarker to predict CAH. TreatmentSince the clinical manifestations of each form of CAH are unique and depend to a large extent on the underlying enzyme defects, their precursor retention and defective products, the therapeutic goal of CAH is to replenish insufficient adrenal hormones and suppress excess of precursors.[9] Treatment of all forms of CAH may include any of:
If CAH is caused by the deficiency of the 21-hydroxylase enzyme, then treatment aims to normalize levels of androstenedione, but normalization of 17α-hydroxyprogesterone is a sign of overtreatment.[32] Treatment can be monitored by measuring androstenedione and 17α-hydroxyprogesterone levels in blood or saliva[32]. EpidemiologyThe incidence varies ethnically. In the United States, congenital adrenal hyperplasia in its classic form is particularly common in Native Americans and Yupik Inuit (incidence 1⁄280). Among American Caucasians, the incidence of the classic form is about 1⁄15,000).[24]
Continued treatment and wellness are enhanced by education and follow up.[33] HistoryBefore 20th centuryAn Italian anatomist, Luigi De Crecchio (1832-1894) provided the earliest known description of a case of probable CAH.
De Crecchio then described the internal organs, which included a normal vagina, uterus, fallopian tubes, and ovaries.
He interviewed many people and satisfied himself that Joseph Marzo "conducted himself within the sexual area exclusively as a male", even to the point of contracting the "French disease" on two occasions. The cause of death was another in a series of episodes of vomiting and diarrhea.[34] This account was translated by Alfred Bongiovanni from De Crecchio ("Sopra un caso di apparenzi virili in una donna". Morgagni 7:154–188, 1865) in 1963 for an article in The New England Journal of Medicine. 20th and 21st centuriesThe association of excessive sex steroid effects with diseases of the adrenal cortex have been recognized for over a century. The term "adrenogenital syndrome" was applied to both sex-steroid producing tumors and severe forms of CAH for much of the 20th century, before some of the forms of CAH were understood. Congenital adrenal hyperplasia, which also dates to the first half of the century, has become the preferred term to reduce ambiguity and to emphasize the underlying pathophysiology of the disorders. Much modern understanding and treatment of CAH comes from research conducted at Johns Hopkins Medical School in Baltimore in the middle of the 20th century. Lawson Wilkins, "founder" of pediatric endocrinology, worked out the apparently paradoxical pathophysiology: that hyperplasia and overproduction of adrenal androgens resulted from impaired capacity for making cortisol. He reported use of adrenal cortical extracts to treat children with CAH in 1950. Genital reconstructive surgery was also pioneered at Hopkins. After application of karyotyping to CAH and other intersex disorders in the 1950s, John Money, JL Hampson, and JG Hampson persuaded both the scientific community and the public [citation needed] that sex assignment should not be based on any single biological criterion, and gender identity was largely learned and has no simple relationship with chromosomes or hormones. See Intersex for a fuller history, including recent controversies over reconstructive surgery.
Hydrocortisone, fludrocortisone, and prednisone were available by the late 1950s. By 1980, all of the relevant steroids could be measured in blood by reference laboratories for patient care. By 1990, nearly all specific genes and enzymes had been identified. The last decade, though, has seen a number of new developments, discussed more extensively in congenital adrenal hyperplasia due to 21-hydroxylase deficiency:
Society and culturePeople with CAHNotable people with CAH include:
See also
References
Further reading
External linksWikimedia Commons has media related to Congenital adrenal hyperplasia.
|