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 Candidate, Metabolic Bone Diseases Group, 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.
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. In McKusick type metaphyseal chondrodysplasia, 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 McKusick type metaphyseal chondrodysplasia are non-Hodgkin lymphoma, squamous 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.
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, McKusick type metaphyseal chondrodysplasia 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 now been reported in around 700 individuals, and has been extensively studied in the Finnish population. The symptoms of McKusick type metaphyseal chondrodysplasia 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 around 100% of affected individuals. Increased inward curvature of the lower spine (lumbar lordosis) and increased side curvature of the rest of the spine (scoliosis) also cause shorter heights in affected individuals. Median height is estimated to be around 4 feet 3 inches in men and 4 feet 0 inches in women. 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 individuals, 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 decreased red cell production has only been reported in 6% of individuals.
Decreased white blood cell production (lymphopenia) and decreased immune cell production lead 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 McKusick type metaphyseal chondrodysplasia is estimated to be around 11%. Most cancers tend to be diagnosed under 44 years old. The most common cancers are non-Hodgkin lymphoma, squamous 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. However, it does not appear to be related to decreased immune cell production (immunodeficiency).
In about 8% of individuals, their intestines have difficulty absorbing nutrients from food (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. Also, some individuals have Hirschsprung’s disease, an absence of nerve cells in the intestine, which presents with constipation from birth.
Other features seen in McKusick type metaphyseal chondrodysplasia include decreased sperm production (spermatogenesis) and intellectual disability.
McKusick type metaphyseal chondrodysplasia is inherited in an autosomal recessive pattern. Genetic disorders are determined by the status of two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of a non-working gene for the same trait, one from each parent. If an individual inherits one working gene and one non-working gene, the person will be a carrier for the disorder but usually will not show symptoms. The risk for two carrier parents to both pass on a non-working 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 working genes from both parents is 25%. The risks are 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 non-working gene, which increases their risk to have children with a recessive genetic disorder.
Scientists have determined that McKusick type metaphyseal chondrodysplasia is caused by genetic changes (mutations) in the mitochondrial RNA-processing endoribonuclease (RMRP) gene. More than 90 different disease causing changes (pathogenic mutations) have been reported.
The reason why gene changes (mutations) in the RMRP gene cause the symptoms associated with the disorder is still unclear at this time. However, current research suggests that the disorder may be caused by increased rates of cell death (apoptosis) in affected individuals.
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, McKusick type metaphyseal chondrodysplasia 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), g.70A>G, is present in 100% of Old Order Amish individuals, 92% of Finnish individuals, and 48% of non-Finnish individuals.
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 cases, 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 of McKusick type metaphyseal chondrodysplasia 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 impaired T cell or B cell function (immunodeficiency) is present. Additionally, blood tests should be done to detect low levels of red (anemia) and or white blood cells (lymphopenia).
McKusick type metaphyseal chondrodysplasia can also be diagnosed through genetic testing. Reading through (sequencing) the RMRP gene and looking for mutations can be done to confirm the diagnosis in individuals who have symptoms. The identification of two disease causing genetic changes (pathogenic mutations) in RMRP confirms a clinical diagnosis of McKusick type metaphyseal chondrodysplasia.
Most individuals with a clinical diagnosis will be found to have two genetic changes (mutations) upon reading through (sequencing) the RMRP gene. However, if only one mutation is found upon sequencing the gene, another test can be done to look for small pieces of missing or extra DNA (deletions and duplications). No deletions or duplications have been reported thus far.
In individuals of Old Order Amish or Finnish ancestry, targeted genetic testing should be done first to search for the g.70A>G mutation that is present in 100% of Amish and 92% of Finnish individuals.
The treatment of McKusick type metaphyseal chondrodysplasia is often 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.
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.
No specific recommendations for reducing cancer risks are available at this time. However, physicians may closely monitor affected individuals to ensure early detection and treatment.
Individuals with Hirschsprung’s disease may require surgery during early childhood to remove the damaged portion of the colon. In some cases, 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.
Genetic counseling is recommended for all affected individuals and their families.
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