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Disease Profile

Singleton-Merten syndrome

Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

<1 / 1 000 000

US Estimated

Europe Estimated

Age of onset

No data available




Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.


Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.


dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.


recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.


Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.


Not applicable


Other names (AKA)

Merten-Singleton syndrome; SM syndrome; Widened medullary cavities of bone, aortic calcification, abnormal dentition, and muscular weakness;


Congenital and Genetic Diseases; Immune System Diseases; Musculoskeletal Diseases


Singleton-Merten syndrome is a very rare disease that affect many organs. The main features are tooth abnormalities with gum infection; calcifications in the aorta artery and in certain valves of the heart (i.e., aortic and mitral valves); and progressive thinning and weakening of the bones (osteoporosis), especially in the upper and back portions of the skull. Other findings may include neurologic problems, generalized short stature, muscle weakness; poor muscle tone (hypotonia); progressive wasting of the muscles (muscle atrophy); heart arrhythmia, growth and developmental delay; skin problems such as psoriasis; malformation of the hips and/or feet and limbs or fingers, joint problems, tendon rupture, distinct facial features, and vision problems due to glaucoma.[1][2][3] Severe systemic lupus erythematosus can also occur with Singleton-Merten syndrome.[2] Singleton-Merten syndrome is caused by mutations in the IFIH1 gene, and in the DDX58  genes (which causes anatypical form of Singleton-Merten syndrome where there are no teeth problems).[1][2] Inheritance is autosomal dominant, but it may also occur sporadically (in individuals with no history of the condition in their family).[1] 

Commonly, people with type I interferonopathies are treated with high doses of intravenous methylprednisolone, oral prednisone and intravenous immunoglobulins during the acute phases with often only partial control of the flares. There are studies trying to find a more effective treatment.[2][4]

The genes causing Singeleton-Merten syndrome can activate type I interferon (IFN1) responses. Diseases related to INF1 are known as type I interferonopathies.[4] Type I interferonopathies are a group of rheumatic diseases that are frequently severe and have an early-onset. These diseases include Aicardi-Goutières syndrome, familial chilblain lupus, spondyloenchondrodysplasia, the proteasome associated autoinflammatory syndromes, IFN-stimulated gene 15 (ISG15) deficiency, Singleton-Merten syndrome, STING-associated vasculopathy with onset in infancy (SAVI).[4]


Singleton-Merten syndrome main symptoms are:[1][2]

  • Cavities and early loss of baby (primary) teeth, deformed permanent teeth with late eruption or early lost of these teeth
  • Blockage and narrowing of the aorta due to calcified aortic stenosis leading to obstructing the flow of oxygenated blood
  • Mitral valve calcification causing high blood pressure (hypertension)
  • Abnormal transmission of the electrical impulses of the heart muscle (heart block)
  • Abnormal contractions of the heart (systolic murmurs)
  • Abnormal enlargement of the heart (cardiomegaly), with inability of the heart to pump blood causing heart failure by late adolescence
  • Abnormal and progressive thinning and weakness of the bones (osteoporosis) resulting in bones that are frequently brittle and may fracture easily, affecting the skull and the long bones of the arms and legs, and the bones of the hands and fingers

Other symptoms that may occur may include: [1][2][3]

  • Generalized muscle weakness and loss of muscle tissue (muscle atrophy) starting between the ages of four to 24 months, that usually begin after a feverish illness
  • Growth delay resulting in short stature Delay in acquiring motor skills
  • Malformation of the hips and/or feet and limbs or fingers Destruction of the tips of the bones of the fingers
  • Chronic skin condition characterized by red, thick, scaly patches of skin (psoriasiform skin eruption)
  • Vision loss due to an abnormal accumulation of pressure of the fluid of the eye (glaucoma) and/or abnormal sensitivity to light (photosensitivity)
  • Neurologic problems,
  • Poor muscle tone (hypotonia)
  • Joint problems and tendon rupture
  • Distinct facial features such a wide forehead with a high hairline, drooped eyelids (ptosis), decreased space between the nose and upper lip, and a thin upper lip border (vermillion).
  • Severe systemic lupus erythematosus 

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
Percent of people who have these symptoms is not available through HPO
Aortic arch calcification
Aortic valve calcification
Aortic valve stenosis
Narrowing of aortic valve
Autosomal dominant inheritance
Broad forehead
Increased width of the forehead
Wide forehead

[ more ]

Enlarged heart
Increased heart size

[ more ]

Carious teeth
Dental cavities
Tooth cavities
Tooth decay

[ more ]

Congestive heart failure
Cardiac failure
Cardiac failures
Heart failure

[ more ]

Coxa valga
Cutaneous photosensitivity
Photosensitive skin
Photosensitive skin rashes
Sensitivity to sunlight
Skin photosensitivity
Sun sensitivity

[ more ]

Decreased body weight
Decreased weight
Low body weight
Low weight
Weight less than 3rd percentile

[ more ]

Expanded metacarpals with widened medullary cavities
Expanded metatarsals with widened medullary cavities
Expanded phalanges with widened medullary cavities
Generalized hypotonia
Decreased muscle tone
Low muscle tone

[ more ]

Genu valgum
Knock knees
High anterior hairline
High frontal hairline
Hip dislocation
Dislocated hips
Dislocation of hip

[ more ]

Hip subluxation
Partial hip dislocation
Hypoplasia of the maxilla
Decreased size of maxilla
Decreased size of upper jaw
Maxillary deficiency
Maxillary retrusion
Small maxilla
Small upper jaw
Small upper jaw bones
Upper jaw deficiency
Upper jaw retrusion

[ more ]

Hypoplasia of the tooth germ
Decreased size of tooth bud
Small tooth bud

[ more ]

Hypoplastic distal radial epiphyses
Mitral valve calcification
Muscle fiber atrophy
Muscle fiber degeneration
Muscle weakness
Muscular weakness
Muscular hypotonia
Low or weak muscle tone
Close sighted
Near sighted
Near sightedness

[ more ]

Detachment of nail
Osteolytic defects of the phalanges of the hand
Breakdown of small bones of fingers
Pes cavus
High-arched foot
Recurrent respiratory infections
Frequent respiratory infections
Multiple respiratory infections
respiratory infections, recurrent
Susceptibility to respiratory infections

[ more ]

Shallow acetabular fossae
Short stature
Decreased body height
Small stature

[ more ]

Smooth philtrum
Subvalvular aortic stenosis
Narrowing of blood vessel below aortic heart valve
Talipes equinovarus
Club feet
Club foot

[ more ]

Tendon rupture
Rupture of tendons
Ruptured tendon

[ more ]

Unerupted tooth
Failure of eruption of tooth
Waddling gait
'Waddling' gait
Waddling walk

[ more ]



The diagnosis of Singleton-Merten syndrome is based on the signs and symptoms including the teeth abnormalities, calcification of the aorta and heart valves and bone changes, as well as muscle weakness and atrophy. Other special exams that may help to make the diagnosis include:[1]

  • X-ray tests to confirm the presence and extent of calcifications in the aorta, osteoporosis, and bone defects
  • Cardiac catheterization showing obstruction or narrowing (stenosis) of the heart valves, particularly the aortic and mitral valves. Catherization is a procedure where a hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart, allowing to determine the rate of blood flow through the heart and to measure the pressure within the heart.


There is still no cure. The treatment is done to treat the symptoms that may be present. The Singleton-Merten syndrome is an interferonopathy. Drug options that have improved symptoms during the acute phase in people with an interferonopathy include: [1][2][4]

  • Intravenous methylprednisone
  • Oral prednisone
  • Intravenous immunoglobulin

Other medications that have being used include anti-rheumatic drugs such as metrotrexate, mycophenolate mofetil, azathioprine, as well as infliximab, etanercept, anakinra, tocilizumab, and rituximab but have not been effective in most cases.

Other possible treatment include:[2][4]

  • Treatment of tooth decay and use of dental implants as well as regular visits to the dentist
  • Treatment of heart problems which may include surgery and medications
  • Glaucoma treatment with eye drops, pills, laser surgery, and/or traditional surgery
  • Ostoeporosis treatment such as medications known as biphosphonates
  • Skin problems treatment 

Treatment may require a team of medical specialists, depending on the different symptoms. Special social support, physical therapy, and other medical, social, and/or vocational services may benefit the people with the disease. Genetic counseling would be of benefit for affected individuals and their families.

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Singleton-Merten syndrome. Click on the link to view a sample search on this topic.


  1. Singleton Merten syndrome. NORD. https://rarediseases.org/rare-diseases/singleton-merten-syndrome/.
  2. Pettersson M, Bergendal B, Norderyd J, Nilsson D, Anderlid BM, Nordgren A & Lindstrand A. Further evidence for specific IFIH1 mutation as a cause of Singleton-Merten syndrome with phenotypic heterogeneity. Am J Med Genet A. May, 2017; 173(5):1396-1399. https://www.ncbi.nlm.nih.gov/pubmed/28319323.
  3. Ghadiam H & Mungee S. Singleton Merten Syndrome: A Rare Cause of Early Onset Aortic Stenosis. Case Reports in Cardiology. 2017; 2017:https://www.hindawi.com/journals/cric/2017/8197954/.
  4. Volpi S, Picco P, Caorsi R, Candotti F & Gattorno M. Type I interferonopathies in pediatric rheumatology. Pediatric Rheumatology Online Journal. 2016; 14:35. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893274/.

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