Last updated:
November 29, 2022
Years published: 1996, 1998, 2006, 2022
NORD gratefully acknowledges Santina Conte, MDCM Candidate, McGill University School of Medicine, Savannah Castaneda and Julia Smith, NORD Editorial Interns from the University of Notre Dame, and Taisto Sarkola, MD, PhD, Docent in Pediatrics, Specialist in Pediatrics and Pediatric Cardiology, New Children’s Hospital, Helsinki University Hospital, Helsinki, Finland, for assistance in the preparation of this report.
Mulibrey nanism (MN) is an extremely rare genetic disorder characterized by severe progressive growth delays and abnormalities in multiple organs. Mulibrey is an acronym for MUscles, LIver, BRain, and EYes relating to the original clinical description of the disease. Nanism refers to the short stature (dwarfism) often observed in patients with this disorder. The growth delay usually begins before birth. Non-inflammatory constrictive pericarditis involving fibrotic overgrowth of the sac surrounding the heart is a common feature with a major impact on prognosis. Overgrowth of heart muscle walls (hypertrophy) may add to circulatory problems (congestive heart failure) in these patients as they get older. Short height and facial abnormalities are commonly present. Radiologic findings include slender long bones with thick cortex, narrow medullary channel and fibrous dysplasia, J-shaped sella turcica and a small thoracic cage. The liver is usually enlarged. Additionally, fibrous tissue may build up on the interior of the lungs (pulmonary fibrosis) causing difficulty breathing. Weak muscle tone (hypotonia) is another symptom. The clinical presentation is very variable.
Early recognition and management of feeding, respiratory or cardiac problems are of major importance. Treatment involves addressing organ related problems including the heart through medications or surgery. In addition, hormone replacement therapy is offered, and abdominal ultrasound screening is warranted in all patients to detect Wilms’ tumor and to detect ovarian tumors in females.
Mulibrey nanism is caused by mutations in the TRIM37 gene and is inherited in an autosomal recessive pattern (gene inherited from both parents for disease to occur).
Mulibrey nanism is characterized by progressive growth failure that begins before birth. Infants often have characteristic abnormalities of the head and face including a triangularly shaped face. Yellow discoloration deep within the eyes and other ocular abnormalities may be present but vision is usually normal. Most patients have an enlarged skull (macrocephaly) and a J-shaped sella turcica, which is a depression in the sphenoid bone at the base of the skull. Because this is where the pituitary gland is located, individuals with MN often have underdevelopment of various endocrine glands that leads to hormone deficiencies. The voice of patients with MN is characteristically high pitched.
Patients may also have symptoms related to overgrowth of the fibrous sac surrounding the heart (non-inflammatory constrictive pericarditis). When constrictive pericarditis presents early (affecting a minority of patients), infants may have a mildly bluish discoloration of the skin (cyanosis). Congestive heart failure of the right heart can also cause abnormal fluid accumulation in the abdomen (ascites) and swelling of the arms and/or legs (peripheral edema). Circulatory problems can progress and lead to failure-to-thrive. Prominent veins in the neck indicate an elevated pressure in the systemic veins that is commonly related to a lack of space in the sac surrounding the heart (pericardial constriction) limiting the filling phase of the heart cycle, and thus leading to fluid accumulation (congestion) in the body. Fibrous tissue in the walls of the lungs (pulmonary fibrosis) decreases the total volume capacity of the lungs.
Enlargement of the liver (hepatomegaly) is another common symptom. In addition, patients often struggle to regulate the breakdown (metabolism) of sugars and fats, potentially resulting in type 2 diabetes, fatty liver and high blood pressure (hypertension). Structural abnormalities of the kidney and urinary tract such as non-cancerous pockets of membranous tissue (cysts) are also observed. However, most patients have normal kidney function. Another persistent kidney complication is a mildly decreased ability to filter the blood (glomerular filtration). Wilms’ tumor, the most common type of cancer originating in the kidney in children, is relatively common (about 8%) and screening is mandatory.
Delayed puberty sometimes occurs accompanied by infrequent or very light menstrual periods. Females have an increased risk for premature ovarian failure and tumors. Both male and female patients show failure of sexual maturation and inability of the sex organs to function properly (hypogonadism) leading to infertility.
Some individuals with MN may have additional physical abnormalities such as an unusually thin shinbone (fibrous tibia dysplasia).
Some children suffer from airway obstruction related to infections or exercise but asthma in adulthood is rare. Large cerebral ventricles in the brain and delayed motor development are uncommon findings. Most affected individuals have normal intelligence.
Mulibrey nanism is caused by harmful changes (pathogenic variants) in the TRIM37 gene located on chromosome 17 (17q22-q23). This gene codes for a protein present in the peroxisome, the part of cell responsible for metabolism. Loss of function of the TRIM37 protein results in a defect in the proper separation of genetic material during cell division. Normal loss of TRIM37 protein activity leads to cell death to prevent mutations in the DNA from multiplying. However, if cell death does not occur, cells with these mutations have a higher likelihood of becoming cancerous. In addition, pathogenetic variants in the TRIM37 gene can impact the number and function of immune cells, leading to an increased risk of severe infections.
Mulibrey nanism is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working 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 non-working 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 working genes from both parents is 25%. The risk is the same for males and females.
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 been diagnosed 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. The disease can be misdiagnosed as other similar syndromes such as Silver-Russell syndrome, especially in geographic areas where mulibrey nanism is less common.
Molecular genetic testing for the TRIM37 gene is available to confirm the diagnosis. It is especially important to consider the possibility of genetic rearrangements when testing for TRIM37 gene variants due to frequent repeated sequences that are more prone to mutations. Early diagnosis of this disorder is important due to the risk of respiratory failure associated with congestive heart failure which can lead to premature death.
Constrictive pericarditis may be treated with surgery (pericardiectomy) in symptomatic patients. Constriction-restriction assessments can be useful in determining the underlying cause of congestive heart failure and when to intervene. Diuretics may be prescribed for progressive heart failure. Difficulty breathing due to infection and/or exercise associated with abnormalities of the lungs can be treated with inhaled therapies and asthma medication. 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, and all patients should be monitored for Wilms’ tumor. Patients who develop cancer can be treated with chemotherapy, surgery and multi-specialty care.
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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Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Grimberg A. Mulibrey Nanism. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins. 2003:224.
JOURNAL ARTICLES
Domínguez-Calvo A, Gönczy P, Holland AJ, Balestra FR. TRIM37: a critical orchestrator of centrosome function. Cell Cycle. 2021;20(23):2443-2451. doi:10.1080/15384101.2021.1988289 [doi].
Sarkola T, Lipsanen-Nyman M, Jalanko H, Jokinen E. Pericardial constriction and myocardial restriction in pediatric mulibrey nanism: a complex disease with diastolic dysfunction. CJC Open. 2021;4(1):28-36. doi:10.1016/j.cjco.2021.08.012 [doi].
Upasana K, Thakkar D, Gautam D, et al. Wilms tumor with mulibrey nanism: A case report and review of literature. Cancer Rep (Hoboken). 2021:e1512. doi:10.1002/cnr2.1512 [doi].
Bruzzaniti S, Cirillo E, Prencipe R, et al. CD4(+) T cell defects in a mulibrey patient with specific TRIM37 mutations. Front Immunol. 2020;11:1742. doi:10.3389/fimmu.2020.01742 [doi].
Anwer M, Bin Mahmood SU, Stawiarski K, Elder R, Ali A, Jacoby D. Mulibrey nanism syndrome: a case for heart transplantation. Ann Thorac Surg. 2020;109(2):e115-e117. doi:S0003-4975(19)30906-3 [pii].
Sivunen J, Piirilä P, Karlberg S, et al. Restriction of lung volumes but normal function of pulmonary tissue in mulibrey nanism. Pediatr Pulmonol. 2020;55(1):122-129. doi:10.1002/ppul.24518 [doi].
Brigant B, Metzinger-Le Meuth V, Rochette J, Metzinger L. TRIMming down to TRIM37: relevance to inflammation, cardiovascular disorders, and cancer in MULIBREY nanism. Int J Mol Sci. 2018;20(1):67. doi: 10.3390/ijms20010067. doi:10.3390/ijms20010067 [doi].
Karlberg S, Tiitinen A, Alfthan H, Lipsanen-Nyman M. Premature ovarian insufficiency and early depletion of the ovarian reserve in the monogenic mulibrey nanism disorder. Hum Reprod. 2018;33(7):1254-1261. doi:10.1093/humrep/dey103 [doi].
Wang W, Xia Z, Farré JC, Subramani S. TRIM37 deficiency induces autophagy through deregulating the MTORC1-TFEB axis. Autophagy. 2018;14(9):1574-1585. doi:10.1080/15548627.2018.1463120 [doi].
Jobic F, Morin G, Vincent-Delorme C, et al. New intragenic rearrangements in non-Finnish mulibrey nanism. Am J Med Genet A. 2017;173(10):2782-2788. doi:10.1002/ajmg.a.38381 [doi].
Sivunen J, Karlberg S, Lohi J, Karlberg N, Lipsanen-Nyman M, Jalanko H. Renal findings in patients with mulibrey nanism. Pediatr Nephrol. 2017;32(9):1531-1536. doi:10.1007/s00467-017-3669-5 [doi].
Karlberg N, Karlberg S, Karikoski R, Mikkola S, Lipsanen-Nyman M, Jalanko H. High frequency of tumours in Mulibrey nanism. J Pathol. 2009;218:163-71.
Karlberg N Jalanko H, Perheentupa J, et al. Mulbrey nanism:clinical features and diagnostic criteria. J Med Genet 2004;41:92-98.
Karlberg S, Tiitinen A and Lipsanen-Nyman M. Failure of sexual maturation in mulibrey nanism (letter) New Engl J Med 2004;351:2559-2560.
Jagiello P, Hammans C, Wieczorek S, et al. A novel splice site mutation in the TRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity. Hum Mutat 2003;21:630-635.
Lipsanen-Nyman M, Perheentupa J, Rapola J, Sovijärvi A, Kupari M. Mulibrey heart disease: clinical manifestations, long-term course, and results of pericardiectomy in a series of 49 patients born before 1985. Circulation. 2003;107:2810-5.
Avela K, Lipsanen-Nyman M, Idänheimo N, et al. Gene encoding a new RING-B-box-coil protein is mutated in mulibrey nanism. Nat Genet 2000;25:298-301.
Perheentupa J, Autio S, Leisti S, et al. Mulibrey nanism, an autosomal recessive syndrome with pericardial constriction. Lancet. 1973;2:351–355.
INTERNET
Mulibrey Nanism. Genetic and Rare Diseases Information Center (GARD). Last Updated: Nov. 8, 2021. https://rarediseases.info.nih.gov/diseases/95/mulibrey-nanism Accessed June 8, 2022.
Mulibrey Nanism McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University: Entry No. 253250; Last Update: 05/17/2021. https://www.omim.org/entry/253250 Accessed June 8, 2022.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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