Last updated:
11/17/2023
Years published: 1989, 1997, 1998, 2000, 2004, 2018, 2023
NORD gratefully acknowledges Brianna McDaniels, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program, Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, and Svetlana Vakkilainen, MD, PhD, Children’s Hospital, Helsinki University Hospital and University of Helsinki, and Outi Mäkitie, MD, Professor of Pediatric Endocrinology, Children’s Hospital, University of Helsinki, Finland, for assistance in the preparation of this report.
Summary
McKusick type metaphyseal chondrodysplasia, also known as cartilage-hair hypoplasia (CHH), is a rare inherited disorder marked by unevenly short arms and legs (short-limbed dwarfism), increased joint mobility (hypermobility) and fine silky hair. Cartilage forms improperly at the large (bulbous) end portions (metaphyses) of the long bones in the arms and legs (metaphyseal chondrodysplasia). In addition, most affected individuals have impaired function of the immune system (immunodeficiency) which causes them to get more infections. Individuals with McKusick type metaphyseal chondrodysplasia can have low levels of red blood cells (anemia). Some individuals also experience difficulties in the absorption of nutrients from their food (intestinal malabsorption) and have increased risks for cancer. The most common types of cancer seen in people with this condition are non-Hodgkin lymphoma, basal cell carcinoma and leukemia. The symptoms of McKusick type metaphyseal chondrodysplasia vary between affected individuals, even within the same family. McKusick type metaphyseal chondrodysplasia is inherited in an autosomal recessive pattern.
Introduction
McKusick type metaphyseal chondrodysplasia was first described in 1965 in the Old Order Amish population. Originally, the syndrome was believed to be characterized by unevenly short arms and legs (short limbed dwarfism), fine and light-colored hair (hypotrichosis), low levels of red blood cells (anemia) and problems with the immune system (immunodeficiency). Now, this condition is considered to be a spectrum of disorders that includes metaphyseal dysplasia without hypotrichosis (MDWH), cartilage hair hypoplasia (CHH) with metaphyseal dysplasia and hypotrichosis and a more severe form called anauxetic dysplasia (AD). McKusick type metaphyseal chondrodysplasia has been reported in approximately 700 individuals and has been extensively studied in the Finnish population. The symptoms are highly variable, even among individuals of the same family. The variability in symptoms seen among affected individuals is not well understood at this time.
Unevenly short arms and legs (short limbed dwarfism) are the most common features in McKusick type metaphyseal chondrodysplasia and are seen in almost all affected individuals. Increased inward curvature of the lower spine (lumbar lordosis) and increased side curvature of the rest of the spine (scoliosis) also cause a shorter height in affected individuals. Median height is estimated to be around 4 feet 3 inches in males and 4 feet 0 inches in females. In individuals with the more severe form, anauxetic dysplasia (AD), the median height is less than 2 feet 10 inches.
Increased joint mobility (hypermobility) has been reported in 87% of affected individuals. The joints in the hands and feet are most commonly affected. However, increased joint mobility can also be present in the knees, which can lead to a bowlegged appearance (varus leg deformity) in around 77% of affected individuals.
Fine, sparse and silky hair (hypotrichosis) is seen in around 90% of individuals with McKusick type metaphyseal chondrodysplasia. In most people, the hair also tends to be blonde or light colored. About 15% of affected individuals have complete hair loss (alopecia) which includes the scalp, eyelashes, eyebrows and body hair.
Decreased red blood cell production (anemia) has been reported in about 80% of affected individuals. The decreased red blood cell production ranges from mild to severe, and usually goes away on its own by childhood. Persistent severe decreased red cell production has only been reported in 6% of individuals.
Decreased white blood cell production (lymphopenia) leads to decreased immunity (immunodeficiency) in around 88% of affected individuals. Decreased immunity leads to an increased rate of infections in approximately 35-65% of affected individuals. Most infections occur during infancy or childhood, and ear and lung infections appear to be the most common. Also, chickenpox can be severe.
The risk for cancer in is estimated to be around 11%. Most cancers tend to be diagnosed when patients are under 44 years old. The most common cancers are non-Hodgkin lymphoma, basal cell carcinoma, leukemia and Hodgkin lymphoma. The reason why individuals with McKusick type metaphyseal chondrodysplasia have increased risks for cancer is unclear at this time.
In about 8% of individuals, the intestines do not absorb nutrients from food properly (intestinal malabsorption). Intestinal malabsorption presents as diarrhea and decreased ability to gain weight (failure to thrive) in the newborn period. Most of the intestinal symptoms appear within the first two years of life. Some individuals have Hirschsprung’s disease, an absence of nerve cells in the intestine which causes constipation beginning at birth.
Other features seen in McKusick type metaphyseal chondrodysplasia include decreased sperm production (spermatogenesis) and autoimmune diseases in which the immune system mistakenly attacks healthy cells, tissues and organs.
McKusick type metaphyseal chondrodysplasia is caused by changes (variants) in the RMRP gene. More than 90 different disease-causing variants (pathogenic variants) have been reported.
The reason why variants in the RMRP gene cause the symptoms associated with the disorder is unclear at this time. However, current research suggests that the variants may increase the rate of cell death (apoptosis) in affected individuals.
McKusick type metaphyseal chondrodysplasia is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.
Some individuals with McKusick type metaphyseal chondrodysplasia have parents who are related by blood (consanguineous). Parents who are close blood relatives (consanguineous) have a higher chance than unrelated parents to both carry the same disease-causing gene variant, which increases their risk to have children with a recessive genetic disorder.
McKusick type metaphyseal chondrodysplasia affects both males and females in equal proportions. The disease has been reported in about 700 individuals. The most severe form, anauxetic dysplasia (AD) is rare, and has been reported in less than 10 individuals.
Affected individuals have been reported in multiple populations. However, this condition is more common in the Old Order Amish population with an estimated incidence of between 1: 1,000 and 1: 2,000 and the Finnish population with an estimated incidence of 1: 23,000. A disease-causing genetic change that arose many generations ago (founder mutation) called n.71A>G, is present in 100% of Old Order Amish, 92% of Finnish, and 48% of non-Finnish patients.
Due to the high degree of variability in symptoms among affected individuals, there are no formal diagnostic criteria for McKusick type metaphyseal chondrodysplasia. In most patients, a clinical diagnosis can be made by the second or third year of life. Newborn screening for severe combined immunodeficiency (SCID) can identify some individuals with McKusick type metaphyseal chondrodysplasia due to their low levels of immune cells (immunodeficiency).
Diagnosing the disorder clinically requires a thorough physical exam, a detailed patient medical history and a variety of advanced skeletal imaging techniques. A diagnosis should be suspected in individuals with unevenly short arms and legs (short-limbed dwarfism) and thinning of the shafts of the long bones (metaphyseal dysplasia). Full skeletal X-rays with views of the spine can be done to look for the characteristic cupped appearance at the end portions of the long bones (metaphyses).
Children who are diagnosed with McKusick type metaphyseal chondrodysplasia should receive a complete immunology evaluation to determine if low counts (lymphopenia) or impaired T cell or B cell function (immunodeficiency) is present. Additionally, blood tests should be done to detect low levels of red blood cells (anemia).
Genetic Testing
McKusick type metaphyseal chondrodysplasia can also be diagnosed through genetic testing. Reading through (sequencing) the RMRP gene and looking for variants can be done to confirm the diagnosis in individuals who have symptoms. The identification of two disease-causing variants in RMRP confirms a clinical diagnosis of McKusick type metaphyseal chondrodysplasia.
Most individuals with a clinical diagnosis will be found to have two disease-causing variants in the RMRP gene. However, if only one variant is found, another test can be done to look for small pieces of missing or extra DNA (deletions and duplications).
Treatment
The treatment of McKusick type metaphyseal chondrodysplasia is directed toward the specific symptoms that are found in an affected individual. Treatment requires the collaboration of a team of specialists. Pediatricians, physicians who specialize in treating skeletal disorders (orthopedists), physicians who diagnose and treat skin disorders (dermatologists), physicians who specialize in immune disorders (immunologists), physicians who specialize in blood disorders (hematologists), physicians who specialize in intestinal disorders (gastroenterologists), dental specialists, speech therapists, dieticians, physical therapists and other health care professionals may all be involved in the treatment of affected individuals.
Corrective bone surgeries (osteotomies) may be done in late childhood or adolescence for excessive leg bowing (varus deformities). Physical therapy may also be used to help treat skeletal complications, like the limited range of motion in the elbows and legs. Growth hormones have not been shown to be effective in treating the shortened height associated with McKusick type metaphyseal chondrodysplasia.
Patients with Hirschsprung’s disease may require surgery during early childhood to remove the damaged portion of the colon. In some patients, before this procedure is performed, a temporary opening for the colon may be made in the abdominal wall (colostomy) to allow passage of feces from the body.
For treating immunodeficiency, antiviral treatments, antibiotic therapies, immunoglobulin replacement therapy and bone marrow transplantations have all been shown to decrease rates of infection. Physicians may also recommend that certain vaccinations be avoided.
Physicians may regularly monitor affected individuals for the blood symptoms (neutropenia, anemia, lymphopenia) associated with the condition. Individuals with a severe decrease in blood cell production are often treated with recurrent blood cell transfusions. Removing excess iron from the blood (iron chelation therapy) has been shown to improve outcomes in individuals who require recurrent red blood cell transfusions.
Skin protection from the sun is recommended to reduce skin cancer risks. Physicians may closely monitor affected individuals to ensure early detection and treatment.
Genetic counseling is recommended for all affected individuals and their families.
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/for-patients-and-families/information-resources/news-patient-recruitment/
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/
JOURNAL ARTICLES
Riley P, Weiner DS, Leighley B, et al. Cartilage hair hypoplasia: characteristics and orthopaedic manifestations. Journal of Children’s Orthopaedics. 2015;9(2):145-152. doi:10.1007/s11832-015-0646-z.
Obara-Moszynska M, Wielanowska W, Rojek A, Wolnik-Brzozowska D, Niedziela M. Treatment of cartilage-hair hypoplasia with recombinant human growth hormone. Pediatr Int. 2013;55:e162–4.
Kwan A, Church JA, Cowan MJ, et al. Newborn Screening for SCID and T Cell Lymphopenia in California: Results of the First Two Years. The Journal of allergy and clinical immunology. 2013;132(1):140-150. doi:10.1016/j.jaci.2013.04.024.
Warman ML, Cormier-Daire V, Hall C, et al. Nosology and Classification of Genetic Skeletal Disorders: 2010 Revision. American Journal of Medical Genetics Part a. 2011;155(5):943-968. doi:10.1002/ajmg.a.33909.
Baradaran-Heravi A, Thiel C, Rauch A, Zenker M, Boerkoel CF, Kaitila I. Clinical and Genetic Distinction of Schimke Immuno-Osseous Dysplasia and Cartilage-Hair Hypoplasia. American journal of medical genetics Part A. 2008;146A(15):2013-2017. doi:10.1002/ajmg.a.32406.
INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:250250. Last Update: 01/28/2021. Available at: https://www.omim.org/entry/250250?search=250250&highlight=250250 Accessed Nov 14, 2023.
Lippner E, Lücke T, Salgado C, et al. Schimke Immunoosseous Dysplasia. 2002 Oct 1 [Updated 2023 Mar 30]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1376/ Accessed Nov 14, 2023.
Mäkitie O, Vakkilainen S. Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders. 2012 Mar 15 [Updated 2023 May 11]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK84550/ Accessed Nov 14, 2023.
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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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