Última actualización:
May 29, 2012
Años publicados: 1997, 1998, 1999, 2006, 2007, 2009, 2012, 2016
NORD gratefully acknowledges Robert C. Olney, MD, Director, Pediatric Endocrinology Training Program; Assistant Professor of Pediatrics, Mayo Medical School, for assistance in the preparation of this report.
Acromesomelic dysplasia is an extremely rare, inherited, progressive skeletal disorder that results in a particular form of short stature known as short-limb dwarfism. The disorder is characterized by acromelia and mesomelia. Mesomelia describes the shortening of the bones of the forearms and lower legs relative to the upper parts of those limbs. Acromelia is the shortening of the bones of the hands and feet. Thus, the short stature of affected individuals is the result of unusually short forearms and abnormal shortening of bones of the lower legs. The very short hands, fingers, feet, and toes are characteristic. These findings are apparent during the first years of life.
Acromesomelic dysplasia (AMD) is characterized by inhibition of growth of certain long bones (i.e. bones of the forearms and lower legs). As a result, affected individuals exhibit unusually short forearms and lower legs and short stature (short-limbed dwarfism). These findings typically become apparent during the first years of life. Abnormal cartilage and bone development also affect other bones, particularly those of the hands and feet (i.e. metacarpals, phalanges, metatarsals).
Infants with acromesomelic dysplasia often have a normal birth weight. In most cases, in addition to having unusually short, broad hands and feet, affected infants often have characteristic facial abnormalities that are apparent at birth. Such features may include a relatively enlarged head (macrocephaly), unusually prominent forehead (frontal bossing), and pronounced back portion of the head (occipital prominence); a slightly flattened midface; and/or an abnormally small, pug nose.
During the first years of life, as the forearms, lower legs, hands, and feet do not grow proportionally with the rest of the body, short stature (short-limbed dwarfism) begins to become apparent. Due to abnormal development and premature fusion (ossification) of the growth portions and the shafts of the long bones of the arm, the bones on the outer aspect and the thumb side of the forearm (ulna and radius, respectively) may be markedly shortened (hypoplastic) and abnormally curved. In addition, the end portion of the radius (that normally meets with the bone of the upper arm [humerus] to form part of the elbow joint) may be completely or partially dislocated (subluxation). This is known as Madelung deformity. As a result, affected individuals may be unable to fully extend their arms, rotate the arms so the palms face down (pronation), or rotate their arms so the palms face upward (supination). Some affected individuals may also experience progressive degeneration, stiffness, tenderness, and pain of the elbows (osteoarthritis).
The hands and feet appear unusually short and broad at birth. Because the abnormalities of cartilage and bone development in the hands and feet are also progressive, the bones within the fingers and toes (phalanges), as well as in the body of the hands (metacarpals) and feet (metatarsals), become increasingly shorter and broader during the first years of life. During the second year of life, the growing ends of these bones (epiphyses) may begin to appear abnormally shaped like a cone or a square and may fuse prematurely. Thus, the fingers and toes appear short and stubby (brachydactyly); the hands and feet may seem unusually short, broad, and square; and the feet may appear abnormally flat. In many individuals, the great toes may appear relatively large in comparison to the other toes. In addition, the fingernails and toenails may also appear abnormally short and broad, though they are otherwise normal. In early childhood, extra, loose (redundant) skin may develop over the fingers.
During early childhood, individuals with AMD may also begin to demonstrate abnormalities of bones of the spinal column (vertebrae) and to experience progressive, abnormal curvature of the spine. Affected children may demonstrate unusual front-to-back curvature of the central portion of the spine (low thoracic kyphosis) and/or abnormally exaggerated inward curvature of the lower spine (lumbar hyperlordosis).
In rare cases, additional abnormalities may be present. For example, some individuals with AMD experience delayed puberty and, in a few reported cases, affected children have demonstrated corneal clouding.
There are thought to be five types of acromesomelic dysplasia. Each is extremely rare, and each is inherited as an autosomal recessive genetic trait, except for AMD Osebold-Remondini type, which appears to be autosomal dominant. The Maroteaux type has been traced to chromosome 9 at gene map locus 9p13-12. Grebe dysplasia (including AMD Hunter-Thompson type) and Du Pan syndrome all have each been mapped to chromosome 20 at gene map locus 20q11.2. Acromesomelic dysplasia with genital anomalies maps to 4q23-24. Osebold-Remondini type has not been genetically mapped yet.
Genetic studies indicate that the change (mutation) at chromosome 9p13-12 (AMD Maroteaux type) is in a gene that codes for a protein the affects bone development, natriuretic peptide receptor B (NPR-B). This is a receptor (a protein that binds another protein) for a hormone called C-type natriuretic peptide, a hormone that is very important for bone growth. The gene located at chromosome 20q11.2 (Grebe dysplasia) codes for a protein known as growth and development factor-5 (GDF5, previously named cartilage-derived morphogenetic protein-1, CDMP1). The gene located at chromosome 4q23-24 (AMD with genital anomalies) codes for a protein known as bone morphogenetic protein receptor, type 1B (BMPR1B). This is a receptor for GDF5.
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 9p13-12” refers to a region on the short arm of chromosome 9 between bands 13 and 12. 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 two copies of an abnormal gene for the same trait, one 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 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 to cause a particular 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. The risk is the same for males and females.
As of 2005, there were about 10 affected individuals of Hunter-Thompson type ADM and about 40 to 50 patients of Maroteaux type AMD reported in the medical literature. The number of cases of Grebe type ADM is not known, but that type is believed to be almost entirely limited to persons living in Brazil.
In most patients, acromesomelic dysplasia is diagnosed within the first few years of life based upon a thorough clinical evaluation, detailed patient history, identification of characteristic findings, and advanced imaging techniques. Although the hands and feet may appear unusually short and broad at birth, the progressive abnormalities associated with the disorder (e.g. abnormal shortening of bones in the forearms and lower legs and short stature, further shortening and broadening of bones of the hands and feet, progressive vertebral abnormalities, limited elbow and arm extension, etc.) typically do not become apparent until late infancy or early childhood.
Specialized x-ray studies may confirm the abnormal development and premature fusion of the regions where the shafts (diaphyses) of certain long bones (i.e. bones of the arms and legs) meet their growing ends (epiphyses). In addition, they may reveal abnormal fusion of the growing ends of bones within the fingers, toes, hands, and feet (i.e. phalanges, metacarpals, metatarsals). Such studies may also confirm the presence and/or extent of resulting bone abnormalities (e.g. short, bowed ulna and radius, dislocated or subluxated radial head, short, malformed phalanges, etc.) as well as other skeletal abnormalities that may be associated with acromesomelic dysplasia (e.g. vertebral abnormalities and resulting low thoracic kyphosis and/or lumbar hyperlordosis; hypoplastic ilia; etc.).
Treatment
The treatment of acromesomelic dysplasia is directed toward the specific symptoms and physical characteristics that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who assess and treat skeletal abnormalities (orthopedists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.
Specific therapies for the treatment of acromesomelic dysplasia are symptomatic and supportive. Abnormal curvature of the spine (i.e. low thoracic kyphosis and/or lumbar hyperlordosis) may be treated with a combination of exercises and physical therapy, other supportive techniques, braces, casts, and/or, in severe cases, corrective surgery. Physical therapy, other supportive techniques, and/or orthopedic surgery may help correct certain specific findings associated with acromesomelic dysplasia.
Early intervention is important to ensure that children with acromesomelic dysplasia reach their potential. Special services that may be beneficial to affected children may include social support and other medical, social, and/or vocational services.
Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
Recombinant human growth hormone (rhGH) has been used in a very small number of patients with AMD Maroteaux Type and none showed an improvement in height velocity. Hence, rhGH is not recommended for treatment of these disorders.
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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
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/
The Center for the Study of Genetic Skeletal Disorders at Boston Children’s Hospital/Harvard Medical School is conducting research on acromesomelic dysplasia and is also assisting families to communicate with one another. For additional information, visit the following website:
https://www.childrenshospital.org/research-and-innovation/research/centers/center-for-the-study-of-genetic-skeletal-disorders/research-focus-areas/acromesomelic-dysplasia
Contact for additional information about acromesomelic dysplasia:
Robert Olney, MD
Director, Pediatric Endocrinology Training Program
Nemours Children’s Clinic
807 Children’s Way
Jacksonville, FL 32207
(904) 697-3674 fax: (904) 697-3948
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., skeletal dysplasia, short stature,etc.].)
TEXTBOOKS
Warman ML,Olney RC. NPR2 and acromesomelic dysplasia, type Maroteaux. In: Epstein CJ, Erikson RP, Wynshaw-Boris AJ, eds. Inborn Errors of Development (Oxford Monographs on Medical Genetics), 2nd ed. New York, NY: Oxford University Press; 2008.
Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds. Emory and Rimoin’s Principles and Practice of Medical Genetics. 5th ed. New York, NY: Churchill Livingstone; 2006.
Jones KL, ed. Smith’s Recognizable Patterns of Human Malformation. 6th ed. Philadelphia, PA: W. B. Saunders Co.; 2005:404-406.
JOURNAL ARTICLES
Khan S, Basit S, Khan MA, Muhammad N, Ahmad W. Genetics of human isolated acromesomelic dysplasia. Eur J Med Genet. 2016 Apr;59(4):198-203.
Olney RC. C-type natriuretic peptide in growth: A new paradigm. Growth Horm IGF Res. 2006;16S:6-14.
Olney RC, Bukulmez H, Bartels CF, Prickett TC, Espiner EA, Potter LR, Warman ML. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature. J Clin Endocrinol Metab. 2006;91:1229-32.
Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev. 2006;27:47-72.
Szczaluba K, Hilbert K, Obersztyn E, Zabel B, Mazurczak T, Kozlowski K. Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in CDMP1 gene. Am J Med Genet A. 2005;138(4):379-83.
Bartels CF, Bukulmez H, Padayatti P, et al. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia type Maroteaux. Am J Hum Genet. 2004;75:27-34.
Al-Yahyaee SA, Al-Kindi MN, Habbal O, Kumar DS. Clinical and molecular analysis of Grebe acromesomelic dysplasia in an Omani family. Am J Med Genet A. 2003;121:9-14.
Savarirayan R, White SM, Goodman FR, et al. Broad phenotypic spectrum caused by an identical heterozygous CDMP-1 mutation in three unrelated families. Am J Med Genet A. 2003;117:136-42.
INTERNET
Chen H. Skeletal Dysplasia.Medscape. https://emedicine.medscape.com/article/943343-overview. Last Updated March 2, 2015. Accessed July 28, 2016.
Faivre L, Cormier-Daire V. Acromesomelic dysplasia Hunter-Thompson type. https://www.orpha.net/data/patho/GB/uk-hunter05.pdf . Updated February 2005. Accessed July 28, 2016.
Faivre L, Cormier-Daire V. Acromesomelic dysplasia Grebe type. https://www.orpha.net/data/patho/Pro/en/AcromesomelicDysplasiaGrebe-FRenPro2010.pdf . Updated February 2005. Accessed July 28, 2016.
Acromesomelic Dysplasia. Little People of America. https://lpamrs.memberclicks.net/index.php?option=com_content&view=article&id=20 Accessed July 28, 2016.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Chondrodysplasia, Grebe Type. Entry No: 200700. Last Update 10/02/2015.. Available at: https://omim.org/entry/200700. Accessed July 28, 2016.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Acromesomelic Dysplasia, Hunter-Thompson Type. Entry No: 201250. Last Update 10/02/2015.. Available at: https://omim.org/entry/201250. Accessed July 28, 2016.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Acromesomelic Dysplasia, Maroteaux Type; AMDM. Entry No: 602875. Last Update 01/14/2016. Available at: https://omim.org/entry/602875. Accessed July 28, 2016.
NORD y la Fundación MedicAlert se han asociado en un nuevo programa para brindar protección a pacientes con enfermedades raras en situaciones de emergencia.
Aprende más https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Asegurarse de que los pacientes y los cuidadores estén equipados con las herramientas que necesitan para vivir su mejor vida mientras manejan su condición rara es una parte vital de la misión de NORD.
Aprende más https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/Este programa de asistencia, primero en su tipo, está diseñado para los cuidadores de un niño o adulto diagnosticado con un trastorno raro.
Aprende más https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
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 report