Maffucci syndrome is a disorder that primarily affects the bones and skin. It is characterized by multiple enchondromas, which are noncancerous (benign) growths of cartilage that develop within the bones. These growths most commonly occur in the limb bones, especially in the bones of the hands and feet; however, they may also occur in the skull, ribs, and bones of the spine (vertebrae). Enchondromas may result in severe bone deformities, shortening of the limbs, and fractures.

The signs and symptoms of Maffucci syndrome may be detectable at birth, although they generally do not become apparent until around the age of 5. Enchondromas develop near the ends of bones, where normal growth occurs, and they frequently stop forming after affected individuals stop growing in early adulthood. As a result of the bone deformities associated with Maffucci syndrome, people with this disorder generally have short stature and underdeveloped muscles.

Maffucci syndrome is distinguished from a similar disorder that involves enchondromas (Ollier disease) by the presence of red or purplish growths in the skin consisting of tangles of abnormal blood vessels (hemangiomas). In addition to hemangiomas, individuals with Maffucci syndrome occasionally also have lymphangiomas, which are masses made up of the thin tubes that carry lymph fluid (lymphatic vessels). These growths may appear anywhere on the body.

Although the enchondromas associated with Maffucci syndrome start out as benign, they may become cancerous (malignant). In particular, affected individuals may develop bone cancers called chondrosarcomas, especially in the skull. People with Maffucci syndrome also have an increased risk of other cancers, such as ovarian or liver cancer.

People with Maffucci syndrome usually have a normal lifespan, and intelligence is unaffected. The extent of their physical impairment depends on their individual skeletal deformities, but in most cases they have no major limitations in their activities.

Maffucci syndrome is very rare. Since it was first described in 1881, fewer than 200 cases have been reported worldwide.

In most people with Maffucci syndrome, the disorder is caused by mutations in the IDH1 or IDH2 gene. These genes provide instructions for making enzymes called isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2, respectively. These enzymes convert a compound called isocitrate to another compound called 2-ketoglutarate. This reaction also produces a molecule called NADPH, which is necessary for many cellular processes. IDH1 or IDH2 gene mutations cause the enzyme produced from the respective gene to take on a new, abnormal function. Although these mutations have been found in some cells of enchondromas and hemangiomas in people with Maffucci syndrome, the relationship between the mutations and the signs and symptoms of the disorder is not well understood.

Mutations in other genes may also account for some cases of Maffucci syndrome.

Normal Function

The IDH1 gene provides instructions for making an enzyme called isocitrate dehydrogenase 1. This enzyme is primarily found in the fluid-filled space inside cells (the cytoplasm). It is also found in cellular structures called peroxisomes, which are small sacs within cells that process many types of molecules. In both the cytoplasm and in peroxisomes, isocitrate dehydrogenase 1 converts a compound called isocitrate to another compound called 2-ketoglutarate. This reaction also produces a molecule called NADPH, which is necessary for many cellular processes. The NADPH produced from isocitrate dehydrogenase 1 is involved in the breakdown of fats for energy, and it also protects cells from potentially harmful molecules called reactive oxygen species.

Health Conditions Related to Genetic Changes

Maffucci syndrome

Mutations in the IDH1 gene can cause Maffucci syndrome, a disorder that primarily affects the bones and skin. It is characterized by multiple enchondromas, which are noncancerous (benign) growths of cartilage that develop in the bones, and red or purplish growths in the skin consisting of tangles of abnormal blood vessels (hemangiomas).

The IDH1 gene mutations that cause Maffucci syndrome are somatic, which means they occur during a person's lifetime and are not inherited. A somatic mutation occurs in a single cell. As that cell continues to grow and divide, the cells derived from it also have the same mutation. In Maffucci syndrome, the mutation is thought to occur in a cell during early development before birth; cells that arise from that abnormal cell have the mutation, while the body's other cells do not. This situation is called mosaicism.

IDH1 gene mutations have been found in some cells of enchondromas and hemangiomas in people with Maffucci syndrome, as well as in the bone marrow or blood of a few affected individuals. These mutations prevent isocitrate dehydrogenase 1 from carrying out its usual activity, the conversion of isocitrate to 2-ketoglutarate. Instead, the altered enzyme takes on a new, abnormal function: the production of a compound called D-2-hydroxyglutarate. Because the genetic changes lead to an enzyme with a new function, they are classified as "gain-of-function" mutations. The relationship between the mutations and the signs and symptoms of the disorder is not well understood.

Ollier disease

Mutations in the IDH1 gene also cause Ollier disease, a disorder similar to Maffucci syndrome (described above) but without the blood vessel abnormalities.

As in Maffucci syndrome, the IDH1 gene mutations that cause Ollier disease are somatic gain-of-function mutations and are thought to occur early in development, resulting in mosaicism. IDH1 gene mutations have been found in enchondroma cells in most people with Ollier disease, but the relationship between the mutations and the signs and symptoms of the disorder is not well understood.

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Cytogenetically normal acute myeloid leukemia

Mutations in the IDH1 gene have been identified in some people with a form of blood cancer known as cytogenetically normal acute myeloid leukemia (CN-AML). While large chromosomal abnormalities can be involved in the development of acute myeloid leukemia, about half of cases do not have these abnormalities; these are classified as CN-AML. IDH1 gene mutations occur in about 16 percent of people with CN-AML.

The IDH1 gene mutations involved in CN-AML are somatic mutations, found only in cells that become cancerous. They change a single protein building block (amino acid) in the isocitrate dehydrogenase 1 enzyme, replacing the amino acid arginine at position 132 with another amino acid. As in Maffucci syndrome and Ollier disease (described above), the IDH1 gene mutations found in CN-AML are gain-of-function mutations that result in the production of D-2-hydroxyglutarate. Studies suggest that an increase in D-2-hydroxyglutarate may interfere with the process that determines the type of cell an immature cell will ultimately become (cell fate determination). Instead of becoming normal mature cells, immature blood cells with somatic IDH1 gene mutations divide uncontrollably, leading to CN-AML. It is unknown why somatic IDH1 gene mutations can result in these various disorders.

Primary myelofibrosis

MedlinePlus Genetics provides information about Primary myelofibrosis

Other cancers

Somatic mutations in the IDH1 gene have been associated with several other forms of cancer, including brain tumors called gliomas and bone tumors known as chondrosarcomas. Like the genetic changes that cause CN-AML (described above), the IDH1 gene mutations found in these cancers are gain-of-function mutations. These mutations alter the function of isocitrate dehydrogenase 1 such that it abnormally produces D-2-hydroxyglutarate. As in CN-AML, D-2-hydroxyglutarate likely blocks the maturation of cells, resulting in overproduction of immature cells and tumor formation. It is unclear why IDH1 gene mutations have been found in only these few types of cancer.

Other Names for This Gene

• IDCD
• IDH
• IDHC_HUMAN
• IDP
• IDPC
• isocitrate dehydrogenase 1 (NADP+)
• isocitrate dehydrogenase 1 (NADP+), soluble
• isocitrate dehydrogenase [NADP] cytoplasmic
• NADP(+)-specific ICDH
• NADP-dependent isocitrate dehydrogenase, cytosolic
• NADP-dependent isocitrate dehydrogenase, peroxisomal
• oxalosuccinate decarboxylase
• PICD

Genomic Location

Normal Function

The IDH2 gene provides instructions for making an enzyme called isocitrate dehydrogenase 2. This enzyme is found in mitochondria, which are the energy-producing centers within cells. Within mitochondria, the enzyme participates in reactions that produce energy for cell activities. Specifically, isocitrate dehydrogenase 2 normally converts a compound called isocitrate to another compound called 2-ketoglutarate. A series of additional enzymes further process 2-ketoglutarate to produce energy. The conversion reaction also produces a molecule called NADPH, which is necessary for many cellular processes and helps protect cells from potentially harmful molecules called reactive oxygen species.

Health Conditions Related to Genetic Changes

2-hydroxyglutaric aciduria

At least two mutations in the IDH2 gene have been found to cause a type of 2-hydroxyglutaric aciduria known as D-2-hydroxyglutaric aciduria (D-2-HGA) type II. This condition has a variety of signs and symptoms that result primarily from progressive damage to the brain beginning early in life.

The mutations that cause D-2-HGA type II are present in all of an affected person's cells. These mutations prevent isocitrate dehydrogenase 2 from carrying out its usual activity, the conversion of isocitrate to 2-ketoglutarate. Instead, the altered enzyme takes on a new, abnormal function: the production of a compound called D-2-hydroxyglutarate. Because the genetic changes lead to an enzyme with a new function, they are classified as "gain-of-function" mutations.

In people with D-2-HGA type II, D-2-hydroxyglutarate builds up abnormally in cells. At high levels, this compound can damage cells and lead to cell death. Brain cells appear to be the most vulnerable to the toxic effects of this compound, which may explain why the signs and symptoms of D-2-HGA type II primarily involve the brain. However, some people with this form of the disorder also have a weakened and enlarged heart (cardiomyopathy). It is unclear why an accumulation of D-2-hydroxyglutarate may be associated with cardiomyopathy.

Maffucci syndrome

Mutations in the IDH2 gene can cause Maffucci syndrome, a disorder that primarily affects the bones and skin. It is characterized by multiple enchondromas, which are noncancerous (benign) growths of cartilage that develop in the bones, and red or purplish growths in the skin consisting of tangles of abnormal blood vessels (hemangiomas).

The mutations associated with Maffucci syndrome are somatic, which means they occur during a person's lifetime and are not inherited. A somatic mutation occurs in a single cell. As that cell continues to grow and divide, the cells derived from it also have the same mutation. In Maffucci syndrome, the mutation is thought to occur in a cell during early development before birth; cells that arise from that abnormal cell have the mutation, while the body's other cells do not. This situation is called mosaicism. IDH2 gene mutations have been found in some enchondroma cells, and like other IDH2 gene mutations discussed previously, they appear to be gain-of-function mutations that result in the production of D-2-hydroxyglutarate, but the relationship between the abnormal buildup of this substance and the signs and symptoms of the disorder is not well understood.

Ollier disease

Mutations in the IDH2 gene can also cause Ollier disease, a disorder similar to Maffucci syndrome (described above) but without the blood vessel abnormalities.

As in Maffucci syndrome, the IDH2 gene mutations that cause Ollier disease are somatic gain-of-function mutations and are thought to occur early in development, resulting in mosaicism. IDH2 gene mutations have been found in enchondroma cells in a few people with Ollier disease, but the relationship between the mutations and the signs and symptoms of the disorder is not well understood, and it is not clear why IDH2 mutations can cause these various disorders.

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Cytogenetically normal acute myeloid leukemia

Mutations in the IDH2 gene have been identified in some people with a form of blood cancer known as cytogenetically normal acute myeloid leukemia (CN-AML). While large chromosomal abnormalities can be involved in the development of acute myeloid leukemia, about half of cases do not have these abnormalities; these are classified as CN-AML. Nearly 20 percent of people with CN-AML have a mutation in the IDH2 gene.

The IDH2 gene mutations involved in CN-AML are called somatic mutations; they are found only in cells that become cancerous and are not inherited. These mutations change single protein building blocks (amino acids) in the isocitrate dehydrogenase 2 enzyme. Like the genetic changes that cause the conditions described above, the IDH2 gene mutations found in CN-AML are gain-of-function mutations. These mutations alter the function of isocitrate dehydrogenase 2 such that it abnormally produces D-2-hydroxyglutarate. Studies suggest that an increase in D-2-hydroxyglutarate may interfere with the process that determines the type of cell an immature cell will ultimately become (cell fate determination). Instead of becoming normal mature cells, immature blood cells with somatic IDH2 gene mutations become cancerous and divide uncontrollably, which plays a role in the development of CN-AML.

Primary myelofibrosis

MedlinePlus Genetics provides information about Primary myelofibrosis

Other cancers

Somatic mutations in the IDH2 gene have been associated with other forms of cancer, including primary myelofibrosis (linked above) and brain tumors called gliomas. Like the genetic changes that cause the conditions described above, the IDH2 gene mutations found in gliomas are gain-of-function mutations that lead to the abnormal production of D-2-hydroxyglutarate. As in CN-AML, D-2-hydroxyglutarate likely blocks the maturation of cells, resulting in overproduction of immature cells and formation of tumors. It is unclear why IDH2 gene mutations have been found in only these few types of cancer.

Other Names for This Gene

• D2HGA2
• ICD-M
• IDH
• IDHM
• IDHP_HUMAN
• IDP
• IDPM
• isocitrate dehydrogenase 2 (NADP+), mitochondrial
• isocitrate dehydrogenase [NADP], mitochondrial
• mNADP-IDH
• NADP(+)-specific ICDH
• oxalosuccinate decarboxylase

Genomic Location

Maffucci syndrome is not inherited. The mutations that cause this disorder are somatic, which means they occur during a person's lifetime. A somatic mutation occurs in a single cell. As that cell continues to grow and divide, the cells derived from it also have the same mutation. In Maffucci syndrome, the mutation is thought to occur in a cell during early development before birth; cells that arise from that abnormal cell have the mutation, while the body's other cells do not. This situation is called mosaicism.

Management aims at relief of symptoms and early detection of malignancies.

Individuals with Maffucci syndrome may benefit from consultations with the following specialists:

• Radiologist: Radiography or CT scanning performed periodically to evaluate bone changes.
• Orthopedic surgeon: An orthopedic surgeon may be consulted to evaluate bone changes and skeletal neoplasms and to help in treatment of fractures associated with the disease.
• Dermatologist: A dermatologist may be consulted to evaluate hemangiomas associated with the condition and to identify any new lesions on the skin.