MedGen

Multiple endocrine neoplasia is a group of disorders that affect the body's network of hormone-producing glands called the endocrine system. Hormones are chemical messengers that travel through the bloodstream and regulate the function of cells and tissues throughout the body. Multiple endocrine neoplasia typically involves tumors (neoplasia) in at least two endocrine glands; tumors can also develop in other organs and tissues. These growths can be noncancerous (benign) or cancerous (malignant). If the tumors become cancerous, the condition can be life-threatening.

The major forms of multiple endocrine neoplasia are called type 1, type 2, and type 4. These types are distinguished by the genes involved, the types of hormones made, and the characteristic signs and symptoms.

The most common sign of multiple endocrine neoplasia type 2 is a form of thyroid cancer called medullary thyroid carcinoma. Some people with this disorder also develop a pheochromocytoma, which is an adrenal gland tumor that can cause dangerously high blood pressure. Multiple endocrine neoplasia type 2 is divided into three subtypes: type 2A, type 2B (formerly called type 3), and familial medullary thyroid carcinoma (FMTC). These subtypes differ in their characteristic signs and symptoms and risk of specific tumors; for example, hyperparathyroidism occurs only in type 2A, and medullary thyroid carcinoma is the only feature of FMTC. The signs and symptoms of multiple endocrine neoplasia type 2 are relatively consistent within any one family.

Multiple endocrine neoplasia type 4 appears to have signs and symptoms similar to those of type 1, although it is caused by mutations in a different gene. Hyperparathyroidism is the most common feature, followed by tumors of the pituitary gland, additional endocrine glands, and other organs.

Many different types of tumors are associated with multiple endocrine neoplasia. Type 1 frequently involves tumors of the parathyroid glands, the pituitary gland, and the pancreas. Tumors in these glands can lead to the overproduction of hormones. The most common sign of multiple endocrine neoplasia type 1 is overactivity of the parathyroid glands (hyperparathyroidism). Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of bones, nausea and vomiting, high blood pressure (hypertension), weakness, and fatigue. [from MedlinePlus Genetics]

Hashimoto's disease is a condition that affects the function of the thyroid, which is a butterfly-shaped gland in the lower neck. The thyroid makes hormones that help regulate a wide variety of critical body functions. For example, thyroid hormones influence growth and development, body temperature, heart rate, menstrual cycles, and weight. Hashimoto's disease is a form of chronic inflammation that can damage the thyroid, reducing its ability to produce hormones.

One of the first signs of Hashimoto's disease is an enlargement of the thyroid called a goiter. Depending on its size, the enlarged thyroid can cause the neck to look swollen and may interfere with breathing and swallowing. As damage to the thyroid continues, the gland can shrink over a period of years and the goiter may eventually disappear.

Other signs and symptoms resulting from an underactive thyroid can include excessive tiredness (fatigue), weight gain or difficulty losing weight, hair that is thin and dry, a slow heart rate, joint or muscle pain, and constipation. People with Hashimoto's disease may also have a pale, puffy face and feel cold even when others around them are warm. Affected women can have heavy or irregular menstrual periods and difficulty conceiving a child (impaired fertility). Difficulty concentrating and depression can also be signs of a shortage of thyroid hormones.

Hashimoto's disease usually appears in mid-adulthood, although it can occur earlier or later in life. Its signs and symptoms tend to develop gradually over months or years. [from MedlinePlus Genetics]

Adenosine deaminase 2 deficiency (DADA2) is a complex systemic autoinflammatory disorder in which vasculopathy/vasculitis, dysregulated immune function, and/or hematologic abnormalities may predominate. Inflammatory features include intermittent fevers, rash (often livedo racemosa/reticularis), and musculoskeletal involvement (myalgia/arthralgia, arthritis, myositis). Vasculitis, which usually begins before age ten years, may manifest as early-onset ischemic (lacunar) and/or hemorrhagic strokes, or as cutaneous or systemic polyarteritis nodosa. Hypertension and hepatosplenomegaly are often found. More severe involvement may lead to progressive central neurologic deficits (dysarthria, ataxia, cranial nerve palsies, cognitive impairment) or to ischemic injury to the kidney, intestine, and/or digits. Dysregulation of immune function can lead to immunodeficiency or autoimmunity of varying severity; lymphadenopathy may be present and some affected individuals have had lymphoproliferative disease. Hematologic disorders may begin early in life or in late adulthood, and can include lymphopenia, neutropenia, pure red cell aplasia, thrombocytopenia, or pancytopenia. Of note, both interfamilial and intrafamilial phenotypic variability (e.g., in age of onset, frequency and severity of manifestations) can be observed; also, individuals with biallelic ADA2 pathogenic variants may remain asymptomatic until adulthood or may never develop clinical manifestations of DADA2. [from GeneReviews]

Familial cold autoinflammatory syndrome-3 is an autosomal dominant immune disorder characterized by the development of cutaneous urticaria, erythema, and pruritus in response to cold exposure. Affected individuals have variable additional immunologic defects, including antibody deficiency, decreased numbers of B cells, defective B cells, increased susceptibility to infection, and increased risk of autoimmune disorders (summary by Ombrello et al., 2012). For a discussion of genetic heterogeneity of FCAS, see FCAS1 (120100). [from OMIM]

Any autoimmune disease in which the cause of the disease is a mutation in the FOXD3 gene. [from MONDO]

A rare defect resulting in C1 deficiency and impaired activation of the complement classical pathway. C1 deficiency generally leads to severe immune complex disease with features of systemic lupus erythematosus and glomerulonephritis. [from MONDO]

Syndromic multisystem autoimmune disease due to Itch deficiency is a rare, genetic, systemic autoimmune disease characterized by failure to thrive, global developmental delay, distinctive craniofacial dysmorphism (relative macrocephaly, dolichocephaly, frontal bossing, orbital proptosis, flattened midface with a prominent occiput, low, posteriorly rotated ears, micrognatia), hepato- and/or splenomegaly, and multisystemic autoimmune disease involving the lungs, liver, gut and/or thyroid gland. [from ORDO]

Cowden syndrome is a genetic disorder characterized by multiple noncancerous, tumor-like growths called hamartomas and an increased risk of developing certain cancers.

Almost everyone with Cowden syndrome develops hamartomas. These growths are most commonly found on the skin and mucous membranes (such as the lining of the mouth and nose), but they can also occur in the intestine and other parts of the body. The growth of hamartomas on the skin and mucous membranes typically becomes apparent by a person's late twenties.

Cowden syndrome is associated with an increased risk of developing several types of cancer, particularly cancers of the breast, a gland in the lower neck called the thyroid, and the lining of the uterus (the endometrium). Other cancers that have been identified in people with Cowden syndrome include kidney cancer, colorectal cancer, and an agressive form of skin cancer called melanoma. Compared with the general population, people with Cowden syndrome develop these cancers at younger ages, often beginning in their thirties or forties. People with Cowden syndrome are also more likely to develop more than one cancer during their lifetimes compared to the general population. Other diseases of the breast, thyroid, and endometrium are also common in Cowden syndrome. Additional signs and symptoms can include an enlarged head (macrocephaly) and a rare, noncancerous brain tumor called Lhermitte-Duclos disease. A small percentage of affected individuals have delayed development, intellectual disability, or autism spectrum disorder, which can affect communication and social interaction.

Some people do not meet the strict criteria for a clinical diagnosis of Cowden syndrome, but they have some of the characteristic features of the condition, particularly the cancers. These individuals are often described as having Cowden-like syndrome. Both Cowden syndrome and Cowden-like syndrome are caused by mutations in the same genes.

The features of Cowden syndrome overlap with those of another disorder called Bannayan-Riley-Ruvalcaba syndrome. People with Bannayan-Riley-Ruvalcaba syndrome also develop hamartomas and other noncancerous tumors.  Some people with Cowden syndrome have relatives diagnosed with Bannayan-Riley-Ruvalcaba syndrome, and other affected individuals have the characteristic features of both conditions. Based on these similarities, researchers have proposed that Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome represent a spectrum of overlapping features known as PTEN hamartoma tumor syndrome (named for the genetic cause of the conditions) instead of two distinct conditions.

 [from MedlinePlus Genetics]

Vertebral anomalies and variable endocrine and T-cell dysfunction is a syndrome characterized by an overlapping spectrum of features. Skeletal malformations primarily involve the vertebrae, and endocrine abnormalities involving parathyroid hormone (PTH; 168450), growth hormone (GH1; 139250), and the thyroid gland have been reported. T-cell abnormalities have been observed, with some patients showing thymus gland aplasia or hypoplasia. Patients have mild craniofacial dysmorphism, and some show developmental delay or behavioral problems. Cardiac defects may be present (Liu et al., 2018). [from OMIM]