Mulibrey nanism is an extremely rare autosomal recessive genetic disorder characterized by profound growth delays and distinctive abnormalities of the muscles, liver, brain, and eyes. The acronym MULIBREY stands for (MU)scle, (LI)ver, (BR)ain, and (EY)e. Nanism is another word for dwarfism. A characteristic feature not included in the original acronym is the overgrowth of the fibrous sac that surrounds the heart restricting normal filling of the heart (constrictive pericarditis). Characteristic symptoms may include low birth weight, short stature, and severe progressive growth delays. Muscles are usually underdeveloped and lack normal tone (hypotonia). Some infants with this disorder may have an abnormally large liver (hepatomegaly). Infants typically have yellow discoloration in their eyes.
Mulibrey nanism is characterized by progressive growth failure that begins prenatally. Muscle hypotonia is frequently seen and newborns often have characteristic abnormalities of the head and face including a triangularly shaped face. Yellow discoloration deep within the eyes (ocular fundi) and other ocular abnormalities may be present but vision is usually normal. The voice is characteristically high-pitched. More than 90 percent of affected individuals have a J-shaped sella turcica, which is a depression in the sphenoid bone at the base of the skull.
Infants with mulibrey nanism may also exhibit symptoms related to overgrowth of the fibrous sac surrounding the heart (constrictive pericarditis). When constrictive pericarditis is present at birth, affected infants may have a bluish discoloration of the skin (cyanosis), especially on the lips and fingertips.
Other symptoms may include abnormally prominent veins in the neck, congestion in the lungs, abnormal fluid accumulation in the abdomen (ascites), swelling of the arms and/or legs (peripheral edema), and/or enlargement of the heart (cardiac hypertrophy) and/or liver (hepatomegaly). There may also be elevated pressure in the veins, congestion or blockage in the main artery serving the lungs (pulmonary artery), and/or a build-up of fibrous tissue in the walls of the lungs (pulmonary fibrosis). Associated complications of these conditions may lead to congestive heart failure.
In some cases, individuals with mulibrey nanism may have additional physical abnormalities, such as an unusually thin shinbone (fibrous tibia dysplasia). Large cerebral ventricles in the brain and delayed motor development are uncommon findings. Most affected individuals have normal intelligence.
Individuals with mulibrey nanism often have underdevelopment of various endocrine glands that leads to hormone deficiencies. Delayed puberty sometimes occurs accompanied by infrequent or very light menstrual periods. Females have an increased risk for premature ovarian failure and ovarian tumors.
Mulibrey nanism is caused by an abnormality in the TRIM37 gene located on chromosome 17 at 17q22-q23 and is inherited as an autosomal recessive genetic disorder.
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 17q22-23″ refers to bands 22-23 on the short arm of chromosome 17. 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 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. 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.
Mulibrey nanism is an extremely rare disorder that affects males and females in equal numbers. Approximately 110 patients have been reported worldwide with this condition. Most of the reported cases are from Finland but this condition has also occurred in North America, South America, Central America, Spain, France and Egypt.
Mulibrey nanism may be diagnosed at birth by a thorough clinical evaluation, characteristic physical findings, and specialized tests. Such tests may include x-ray studies, which may show abnormal calcium deposits in the sac surrounding the heart (pericardium); studies measuring the electrical activity of the heart (electrocardiograms or EKGs); and/or examination with a device that visualizes the interior of the eye which may detect ocular abnormalities. Molecular genetic testing for the TRIM37 gene is available to confirm the diagnosis.
Constrictive pericarditis may be treated with surgery. Diuretics and digoxin may be prescribed for progressive heart failure. Hormone replacement therapy should be offered to children with growth hormone deficiency, delayed puberty, infrequent or very light menstrual periods, hypothyroidism, hypoadrenocorticism and abnormal ovaries or testes. Females with mulibrey nanism should be monitored closely for ovarian tumors.
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Avela K, Lipsanen-Nyman M, Idanheimo N, et al. Gene encoding a new RING-B-box-coil protein is mutated in mulibrey nanism. Nat Genet 2000;25:298-301.
Jagiello P, Hammans C, Wieczorek S, et al. A novel splice site mutation in the TRIM37 gne causes mulibrey nanism in a Turkish amily with phenotypic heterogeneity. Hum Mutat 2003;21:630-635.
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Karlberg S, Tiitinen A and Lipsanen-Nyman M. Failure of sexual maturation in mulibrey nanism (letter) New Engl J Med 2004;351:2559-2560.
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McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University:Entry No. 253250; Last Update:1/11/05.