NORD gratefully acknowledges Andrew A. Bremer, MD, PhD, Department of Pediatrics, Division of Endocrinology, Vanderbilt University School of Medicine, for assistance in the preparation of this report.
ACTH deficiency arises as a result of decreased or absent production of adrenocorticotropic hormone (ACTH) by the pituitary gland. A decline in the concentration of ACTH in the blood leads to a reduction in the secretion of adrenal hormones, resulting in adrenal insufficiency (hypoadrenalism). Adrenal insufficiency leads to weight loss, lack of appetite (anorexia), weakness, nausea, vomiting, and low blood pressure (hypotension). Because these symptoms are so general, the diagnosis is sometimes delayed or missed entirely. For that reason, some clinicians believe the disorder to be more common than previously thought.
ACTH deficiency can either be congenital or acquired, and its manifestations are clinically indistinguishable from those of glucocorticoid deficiency. Symptoms include weight loss, lack of appetite (anorexia), muscle weakness, nausea and vomiting, and low blood pressure (hypotension). Low blood levels of sugar and dilutional hyponatremia (low blood sodium levels) may occur; however, blood potassium levels are typically normal as affected patients are deficient in glucocorticoids and not mineralocorticoids due to their intact renin-angiotensin-aldosterone system. The pituitary hormone ACTH may be undetectable in blood tests, and the level of the adrenal hormone cortisol is abnormally low. Concentrations of 17-hydroxycorticosteroids and 17-ketosteroids, produced from the adrenal cortex, are also abnormally low in the urine. Some adrenal hormones that are decreased are precursors of male sex hormones and are also known as “pre-androgens”.
Although males with this disorder usually have a normal hair pattern, females may have very little pubic and underarm (axillary) hair. In contrast to Addison’s disease, skin pigmentation usually remains normal. Emotional symptoms may range from depression to psychosis.
The exact cause(s) of ACTH deficiency remain unknown. A defect in the brain’s hypothalamus or in the pituitary gland may cause the deficiency. Also, there is a congenital (present at birth) form of ACTH deficiency that has been tracked to mutations of the T-box 19 (TBX19) gene (also referred to as TPIT) on the long arm of chromosome one (1q23-q24) and the corticotropin releasing hormone (CRH) gene on the long arm of chromosome eight (8q13). The inheritance pattern is thought to be autosomal recessive.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, chromosome 1q23-q24 refers to a region on the long arm of chromosome 1 between bands 23 and 24. Similarly chromosome 8q13 refers to the band numbered 13 on the long arm of chromosome 8. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms.
The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Symptoms of ACTH deficiency most often occur in adults, but the disorder may also be diagnosed in infancy. The disorder affects males and females in equal numbers.
When ACTH deficiency is suspected, blood samples are taken for analysis, especially of the level of cortisol in the blood. Cortisol is the name of one of the hormones produced by the outer portion (cortex) of the adrenal glands. If the concentration of cortisol is low, it typically indicates a low concentration of ACTH. On occasion, an ACTH stimulation test may be administered.
Hormone replacement therapy with cortisol is the treatment of choice for this disorder. With such therapy, patients can lead a normal life.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Contact for additional information about ACTH deficiency:
Andrew A Bremer, MD, PhD
Department of Pediatrics
Division of Endocrinology
Vanderbilt University School of Medicine
11134-A DOT 9170
2200 Children’s Way
Nashville, TN 37232-9170
Email: [email protected]
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