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47-624: The MAGIC Foundation (short for Major Aspects of Growth in Children ) is an American non-profit organization which helps families of children diagnosed with a wide variety of different growth impacting medical conditions through education, networking, physician referrals and numerous other services. It was founded in 1989. It is maintained through a network of volunteers and a full-time staff of five people. Their services include public education and awareness, quarterly newsletters, national networking, an annual convention, disorder specific brochures, and

94-499: A Kids Program. The foundation has a membership network in excess of 25,000 families. The disorders MAGIC families have are grouped into primary categories. They include: congenital adrenal hyperplasia , precocious puberty , growth hormone deficiency (both adults and children), panhypopituitarism , McCune–Albright syndrome , Turner syndrome , Russell–Silver syndrome , thyroid disorders (both congenital and acquired), optic nerve hypoplasia , and other rare disorders. MAGIC offers

141-460: A case of probable CAH. I propose in this narrative that it is sometimes extremely difficult and even impossible to determine sex during life. In one of the anatomical theaters of the hospital..., there arrived toward the end of January a cadaver which in life was the body of a certain Joseph Marzo... The general physiognomy was decidedly male in all respects. There were no feminine curves to

188-582: 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

235-472: 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 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

282-541: A longer period than adults, but deteriorate rapidly and severely once they are unable to compensate ( decompensate ). Consequently, any possibility of internal bleeding in children should be treated aggressively. Signs of external bleeding should be assessed, noting that individuals can bleed internally without external blood loss or otherwise apparent signs. There should be considered possible mechanisms of injury that may have caused internal bleeding, such as ruptured or bruised internal organs. If trained to do so and if

329-431: A mild or "nonclassic" form exists, which is characterized by varying degrees of postnatal androgen excess, but is sometimes asymptomatic. 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, and secondary polycystic ovary syndrome . In adult males, early balding and infertility may suggest

376-696: A national educational program every year for the families of affected children and another for affected adults. Physicians specialising in these disorders, from all over the world, volunteer to speak to and assist the children and affected adults. They also offer a weekly email with links to recently published medical information to parents of children impacted by Small for Gestational Age babies, Congenital Adrenal Hyperplasia, McCune-Albright Syndrome, Russell–Silver Syndrome (also known as Silver–Russell Syndrome), Optic Nerve Hypoplasia , Septo Optic Dysplasia , Hypophosphatasia , and others. The MAGIC Foundation received significant funding from Genentech and Eli Lilly . It

423-418: A number of other systems exist with as many as 6 stages. The 4 stages are sometimes known as the "Tennis" staging of hypovolemic shock, as the stages of blood loss (under 15% of volume, 15–30% of volume, 30–40% of volume and above 40% of volume) mimic the scores in a game of tennis : 15, 15–30, 30–40 and 40. It is basically the same as used in classifying bleeding by blood loss. The signs and symptoms of

470-547: A particular random blood sample, but it will rise during a corticotropin stimulation test . Cortisol 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. This increased ACTH stimulation induces overgrowth ( hyperplasia ) and overactivity of

517-470: A point where it "blows off" clots that have formed. Fluid replacement is beneficial in hypovolemia of stage 2, and is necessary in stage 3 and 4. See also the discussion of shock and the importance of treating reversible shock while it can still be countered. The following interventions are carried out: Vasopressors (such as dopamine and noradrenaline ) should generally be avoided, as they may result in further tissue ischemia and don't correct

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564-755: Is caused by a variety of events, but these can be simplified into two categories: those that are associated with kidney function and those that are not. The signs and symptoms of hypovolemia worsen as the amount of fluid lost increases. Immediately or shortly after mild fluid loss (from blood donation , diarrhea , vomiting , bleeding from trauma, etc.), one may experience headache , fatigue , weakness , dizziness , or thirst . Untreated hypovolemia or excessive and rapid losses of volume may lead to hypovolemic shock . Signs and symptoms of hypovolemic shock include increased heart rate , low blood pressure , pale or cold skin , and altered mental status . When these signs are seen, immediate action should be taken to restore

611-425: Is introduced by the degree of enzyme inefficiency produced by the specific alleles each patient has. Some alleles result in more severe degrees of enzyme inefficiency. In general, severe degrees of inefficiency produce changes in the fetus and problems in prenatal or perinatal life. Milder degrees of inefficiency are usually associated with excessive or deficient sex hormone effects in childhood or adolescence, while

658-408: 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. Currently, in

705-661: 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. (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

752-464: Is often not clinically meaningful, though, because all patients lose salt to some degree, and clinical presentations may overlap. In 75% of cases of severe enzyme deficiency, insufficient aldosterone production can lead to salt wasting, failure to thrive, and potentially fatal hypovolemia and shock. A missed diagnosis of salt-loss CAH is related to the increased risk of early neonatal morbidity and death. The main feature of CAH in newborn females

799-599: Is one of the most common autosomal recessive disorders in humans. CAH 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. 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. This subtyping

846-454: 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. In addition to the salt-wasting and simple-virilizing forms of CAH diagnosed in infancy,

893-737: Is to replenish insufficient adrenal hormones and suppress excess of precursors. 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. Treatment can be monitored by measuring androstenedione and 17α-hydroxyprogesterone levels in blood or saliva. Crinecerfont , an oral corticotropin-releasing factor type 1 receptor (CRF1) antagonist that reduces ACTH secretion, may allow reduction of daily glucocorticoid dosing to physiologic ranges with adequate maintenance of androstenedione control. The incidence varies ethnically . In

940-467: The carotid sinuses and aortic arch ) sense the reduction of circulating fluid and send signals to the brain to increase sympathetic response ( see also: baroreflex ). This sympathetic response is to release epinephrine and norepinephrine , which results in peripheral vasoconstriction (reducing size of blood vessels) in order to conserve the circulating fluids for organs vital to survival (i.e. brain and heart). Peripheral vasoconstriction accounts for

987-457: The 1950s, John Money , JL Hampson, and JG Hampson persuaded both the scientific community and the public 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

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1034-519: 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. The screening process, however, is characterized by a high false-positive rate. In one study, CAH screening had

1081-497: 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 ). Continued treatment and wellness are enhanced by education and follow up. Italian anatomist, Luigi De Crecchio (1832-1894), provided the earliest known description of

1128-571: The active and pseudogenes (gene conversion). About 5% of cases of CAH are due to defects in the gene encoding 11β-hydroxylase and consequent 11β-hydroxylase deficiency . Other, more rare forms of CAH are caused by mutations in genes, including HSD3B2 (3β-hydroxysteroid dehydrogenase 2), CYP17A1 (17α-hydroxylase/17,20-lyase), CYP11A1 (P450scc; cholesterol side-chain cleavage enzyme), STAR ( steroidogenic acute regulatory protein ; StAR), CYB5A ( cytochrome b 5 ), and CYPOR ( cytochrome P450 oxidoreductase ; POR). Further variability

1175-649: The biochemical steps of production of mineralocorticoids , glucocorticoids , or sex steroids from cholesterol by the adrenal glands ( steroidogenesis ). Each form of CAH is associated with a specific defective gene. The most common type (95% of cases) involves the gene for 21-hydroxylase , which is found on 6p21.3 as part of the HLA complex; 21-hydroxylase deficiency results from a unique mutation with two highly homologous near-copies in series consisting of an active gene ( CYP21A2 ) and an inactive pseudogene ( CYP21A1P ). Mutant alleles result from recombination between

1222-447: The body. There was a heavy beard. There was some delicacy of structure with muscles that were not very well developed... The distribution of pubic hair was typical of the male. Perhaps the lower extremities were somewhat delicate, resembling the female, and were covered with hair... The penis was curved posteriorly and measured 6 cm, or with stretching, 10 cm. The corona was 3 cm long and 8 cm in circumference. There

1269-780: The cold extremities (hands and feet), increased heart rate, increased cardiac output (and associated chest pain). Eventually, there will be less perfusion to the kidneys, resulting in decreased urine output. Hypovolemia can be recognized by a fast heart rate , low blood pressure , and the absence of perfusion as assessed by skin signs (skin turning pale) and/or capillary refill on forehead , lips and nail beds . The patient may feel dizzy, faint, nauseated, or very thirsty. These signs are also characteristic of most types of shock . In children, compensation can result in an artificially high blood pressure despite hypovolemia (a decrease in blood volume). Children typically are able to compensate (maintain blood pressure despite hypovolemia) for

1316-412: The consequences of decreased circulating volume and a subsequent reduction in the amount of blood reaching the tissues of the body. In order to properly perform their functions, tissues require the oxygen transported in the blood. A decrease in circulating volume can lead to a decrease in bloodflow to the brain, resulting in headache and dizziness. Baroreceptors in the body (primarily those located in

1363-450: The diagnosis. The nonclassic form is characterized by mild subclinical impairment of cortisol synthesis and serum cortisol concentration is usually normal. The symptoms of CAH vary depending upon the form of CAH and the sex of the patient. Symptoms can include: Due to inadequate mineralocorticoids : Due to excess androgens: Due to insufficient androgens and estrogens: CAH results from mutations of genes for enzymes mediating

1410-598: The effect of this loss of blood pressure on stroke volume by increasing venous return. The use of intravenous fluids (IVs) may help compensate for lost fluid volume, but IV fluids cannot carry oxygen the way blood does—however, researchers are developing blood substitutes that can. Infusing colloid or crystalloid IV fluids also dilutes clotting factors in the blood, increasing the risk of bleeding. Current best practice allow permissive hypotension in patients with hypovolemic shock, both avoid overly diluting clotting factors and avoid artificially raising blood pressure to

1457-522: 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. Unless another specific enzyme

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1504-424: 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 : Notable people with CAH include: Hypovolemia Hypovolemia

1551-562: The lost volume . Signs and symptoms of hypovolemia progress with increased loss of fluid volume. Early symptoms of hypovolemia include headache, fatigue, weakness, thirst, and dizziness. The more severe signs and symptoms are often associated with hypovolemic shock. These include oliguria , cyanosis , abdominal and chest pain, hypotension , tachycardia , cold hands and feet, and progressively altering mental status. The causes of hypovolemia can be characterized into two categories: The signs and symptoms of hypovolemia are primarily due to

1598-530: The lowest positive predictive value (111 true-positive cases among 20,647 abnormal screening results in a 2-year period, or 0.53%, compared with 6.36% for biotinidase deficiency, 1.84% for congenital hypo-thyroidism, 0.56% for classic galactosemia, and 2.9% for phenylketonuria). According to this estimate, 200 unaffected newborns required clinical and laboratory follow-up for every true case of CAH. In 2020, Wael AbdAlmageed from USC Information Sciences Institute and Mimi Kim from USC Keck School Of Medicine led

1645-439: The major stages of hypovolemic shock include: The most important step in treatment of hypovolemic shock is to identify and control the source of bleeding. Medical personnel should immediately supply emergency oxygen to increase efficiency of the patient's remaining blood supply. This intervention can be life-saving. Also, the respiratory pump is especially important during hypovolemia as spontaneous breathing may help reduce

1692-473: 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

1739-780: The mildest forms of CAH interfere with ovulation and fertility in adults. Female infants with classic CAH have ambiguous genitalia due to exposure to high concentrations of androgens in utero . CAH due to 21-hydroxylase deficiency is the most common cause of ambiguous genitalia in genotypically normal female infants (46XX). Less severely affected females may present with early pubarche . Young women may present with symptoms of polycystic ovarian syndrome ( oligomenorrhea , polycystic ovaries, hirsutism ). 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

1786-673: The money was to be utilized. The donations were support funds for the patients affected. Congenital adrenal hyperplasia Congenital adrenal hyperplasia ( CAH ) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex . Most of these disorders involve excessive or deficient production of hormones such as glucocorticoids , mineralocorticoids , or sex steroids , and can alter development of primary or secondary sex characteristics in some affected infants , children, or adults. It

1833-405: 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

1880-414: 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. Since 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

1927-400: 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. In rarer forms of CAH, males are undermasculinized and females generally have no signs or symptoms at birth. Genetic analysis can be helpful to confirm a diagnosis of CAH, but it

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1974-597: The situation permits, there should be conducted a secondary survey and checked the chest and abdomen for pain, deformity, guarding, discoloration or swelling. Bleeding into the abdominal cavity can cause the classical bruising patterns of Grey Turner's sign (bruising along the sides) or Cullen's sign (around the navel). In a hospital, physicians respond to a case of hypovolemic shock by conducting these examinations: Untreated hypovolemia can lead to shock (see also: hypovolemic shock ). Most sources state that there are 4 stages of hypovolemia and subsequent shock; however,

2021-542: 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

2068-472: Was an ample prepuce . There was a first grade hypospadias ... There were two folds of skin coming from the top of the penis and encircling it on either side. These were somewhat loose and resembled labia majora . De Crecchio then described the internal organs, which included a normal vagina , uterus , fallopian tubes , and ovaries . It was of the greatest importance to determine the habits, tendencies, passions, and general character of this individual... I

2115-473: Was another in a series of episodes of vomiting and diarrhea. 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 . The association of excessive sex steroid effects with diseases of the adrenal cortex have been recognized for over

2162-467: Was determined to get as complete a story as possible, determined to get at the base of the facts and to avoid undue exaggeration which was rampant in the conversation of many of the people present at the time of the dissection. 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" ( syphilis ) on two occasions. The cause of death

2209-512: Was thought that the money was to undertake case finding of children with short stature who might benefit from their human growth hormone treatments. The US Food and Drug Administration investigated Genentech in 1992 and 1994 for using numerous charities to improperly advertise this medication. None of the monies donated to either the Human Growth Foundation nor The Magic foundation were donated with any stipulations as to how

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