NORD gratefully acknowledges Lusha Liang, M.D. and Emile R. Mohler III, MD, Director of Vascular Medicine, University of Pennsylvania Health System, for assistance in the preparation of this report.
Singleton-Merten syndrome, an extremely rare disorder, is characterized by abnormalities of the teeth (dental dysplasia), abnormal accumulation of calcium deposits (calcifications) in the major artery of the body (aorta) and certain valves of the heart (i.e., aortic and mitral valves), and/or progressive thinning and loss of protein of the bones (osteoporosis). Between the ages of four to 24 months, most affected infants experience generalized muscle weakness and loss or wasting away (atrophy) of muscle tissue. Affected infants may also exhibit delays in general physical (somatic) development, possibly resulting in short stature, and/or delays in the ability to coordinate muscles and perform certain tasks (motor development).
Abnormalities affecting the teeth also occur at an early age in individuals with Singleton-Merten syndrome. Affected infants may develop cavities (caries) and lose their primary (deciduous) teeth prematurely. Certain secondary (permanent) teeth may not develop (erupt) or may erupt late; those permanent teeth that do develop are usually malformed (dysplastic). In some patients, permanent teeth may also be lost prematurely.
By late infancy or early childhood, affected individuals may experience symptoms associated with the progressive accumulation of calcium deposits (calcifications) in the major artery of the body (aorta) and on certain valves of the heart (i.e., aortic and mitral). The aorta arises from the lower pumping chamber of the heart (left ventricle) and supplies oxygen-rich (oxygenated) blood to all the arteries of the body (excluding the pulmonary artery). In individuals with Singleton-Merten syndrome, deposits of calcium (calcifications) form in the portion of the aorta nearest the heart (proximal thoracic aorta). The accumulation of calcium deposits is progressive and typically causes blockage and narrowing of the aorta (calcific aortic stenosis), obstructing the flow of oxygenated blood. In some cases, abnormal calcium deposits may also develop around the valve on the left side of the heart (mitral valve calcification). As a result of calcification of these various structures, affected individuals may experience high blood pressure (hypertension), abnormal transmission of electrical impulses (conduction) that coordinate the activity of the heart muscle (heart block), abnormal contractions of the heart (systolic murmurs), and/or abnormal enlargement of the heart (cardiomegaly). By late adolescence, the heart may be unable to pump blood effectively (heart failure), leading to life-threatening complications.
Infants with Singleton-Merten syndrome may also experience abnormal thinning and weakness of the bones (osteoporosis). As a result, bones are frequently brittle and may fracture easily. Osteoporosis may occur in the skull and the long bones of the arms and legs, but is most prominent in the bones of the hands and fingers.
Other findings associated with Singleton-Merten syndrome may include malformations of the hips and feet that may occur due to muscle weakness; wearing away (erosion) of the bones in the tips of the fingers (terminal phalanges); and/or a chronic skin condition characterized by red, thick, scaly patches of skin (psoriasiform skin eruption). Some affected individuals may have abnormal accumulation of pressure of the fluid of the eye (glaucoma) and/or abnormal sensitivity to light (photosensitivity). Typical facial features have also been described in individuals with Singleton-Merten syndrome including a high anterior hairline, broad forehead, drooping of the upper eyelids (ptosis), a loss of the vertical groove between the base of the nose and upper lip (philtrum), and a thin upper lip border (vermillion).
Singleton-Merten syndrome is an extremely rare disorder that is likely an autosomal dominant condition with highly variable expression. Individuals with a mild form of Singleton-Merten syndrome may show only one symptom, such as a skin rash (psoriasis). Individuals with a severe form may exhibit all the main features of Singleton-Merten syndrome including calcifications in the heart and aorta as well as skeletal and dental abnormalities.
Singleton-Merten syndrome is caused by a mutation in the IFIH1 gene. This gene is responsible for making a protein called melanoma differentiation-associated gene 5 (MDA5) protein. When it functions normally, MDA5 is activated by the presence of viruses. Upon activation it leads to production of certain molecules that can increase activity of the immune system. However, the form of the MDA5 protein in individuals with Singleton-Merten syndrome appears to always be activated, even when there are no viruses present. This leads to an overactive immune system. This constant state of inflammation may promote disordered calcium metabolism in the body, leading to abnormal calcification of the aorta and heart valves and loss of calcification in the bones.
There has also been another gene identified, DDX58, which has been associated with atypical Singleton-Merten syndrome. DDX58 is a gene responsible for making a protein called retinoic-acid-inducible gene (RIG-I). One family of individuals with this mutation were affected by vision problems, aortic calcification, and skeletal abnormalities but had normal dentition. Another family of individuals with this mutation had vision problems and skeletal abnormalities but had normal aortas and normal dentition.
Singleton-Merten syndrome is an extremely rare inherited disorder that, in theory, affects males and females in equal numbers. However, in reported cases, females have been affected more frequently than males (3:1). Fewer than 10 individual cases and three families (kindred) with multiple affected members have been reported in the medical literature.
Atypical Singleton-Merten syndrome has been identified in two families. One family with 8 affected individuals were affected by vision problems, aortic calcification, and skeletal abnormalities but had normal dentition. Another family with 3 affected individuals had vision and skeletal abnormalities but no problems with their arteries and teeth.
The diagnosis of Singleton-Merten syndrome may be suspected during infancy based upon the identification of characteristic physical findings (i.e., muscle weakness, muscle atrophy, dental abnormalities, and skeletal changes). A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history, and/or a variety of specialized tests. The identification of calcium deposits in the aorta, in association with the other findings described above, strongly suggests a diagnosis of Singleton-Merten syndrome.
X-ray tests may be used to confirm the presence and extent of calcium deposits (calcifications) in the aorta. Obstruction or narrowing (stenosis) of the heart valves, particularly the aortic and mitral valves, may be confirmed by cardiac catheterization. During this procedure, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart. This procedure allows physicians to determine the rate of blood flow through the heart and measure the pressure within the heart. X-ray studies may also be performed to confirm the presence and extent of osteoporosis. Osteoporosis may be suspected when bone fractures occur more frequently than usual. X-ray tests may also reveal abnormal widening of the hollow parts of the bones that contain soft fatty tissue (bone marrow cavities) within the bones of the hands and/or feet (e.g., metacarpals, carpals, phalanges, etc.).
The treatment of Singleton-Merten syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who diagnose and treat abnormalities of the heart (cardiologists), dental specialists, physical therapists, specialists who diagnose and treat conditions of the skin (dermatologists), and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.
Specific therapies for the treatment of Singleton-Merten syndrome are symptomatic and supportive. Special services that may be beneficial to affected children may include special social support, physical therapy, and other medical, social, and/or vocational services. Genetic counseling will be of benefit for affected individuals and their families.
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