What is the definition of Singleton-Merten Syndrome?

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. Severe systemic lupus erythematosus can also occur with Singleton-Merten syndrome.  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). Inheritance is autosomal dominant, but it may also occur sporadically (in individuals with no history of the condition in their family).  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. The genes  causing Singeleton-Merten syndrome can activate type I interferon (IFN1) responses. Diseases related to INF1 are known as type I interferonopathies. 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).

What are the alternative names for Singleton-Merten Syndrome?

  • Merten-Singleton syndrome
  • SM syndrome
  • Widened medullary cavities of bone, aortic calcification, abnormal dentition, and muscular weakness
  • Syndrome of widened medullary cavities of the metacarpals and phalanges, aortic calcification and abnormal dentition
  • Singleton-Merten dysplasia

What are the symptoms for Singleton-Merten Syndrome?

Singleton-Merten syndrome main symptoms are:
  • 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:
  • 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 

What are the current treatments for Singleton-Merten Syndrome?

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:
  • 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:
  • 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.

How is Singleton-Merten Syndrome diagnosed?

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:
  • 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.

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