What is SAMD9 deficiency?

SAMD9 deficiency is a disease caused by mutations – or genetic changes – in the SAMD9 gene. It is also referred to as MIRAGE syndrome, an acronym made up of the most frequently observed symptoms: Myelodysplasia (disease of the bone marrow), Infection, Restriction of growth, Adrenal hypoplasia (underdevelopment of the adrenal glands), Genital phenotypes, and Enteropathy (disease of the intestine). Besides these, numerous other anomalies can occur in different organs as well. The progression of the disease is often lethal within the first ten years of life, usually due to severe infections.

How is SAMD9 deficiency diagnosed?

Genetic Diagnostics

The diagnosis of “SAMD9 deficiency” is confirmed by detection of a mutation, i.e. a genetic change in the SAMD9 gene.

What is the risk of cancer?

The known malignant new formation with SAMD9 deficiency is myelodysplastic syndrome (MDS). MDS is a rather rare manifestation associated with SAMD9 deficiency. The exact risk of developing MDS is still unknown, however.

In addition, it is possible for diseases associated with SAMD9 deficiency to occur in different organ systems.

Bone Marrow Insufficiency or “Myelodysplasia”

A disease of the bone marrow linked to the defective production of blood cells is one of the most common manifestations. This can lead to thrombocytopenia (a lack of blood platelets) and/or anemia (a lack of red blood cells), which usually occur during infancy, although these generally resolve spontaneously. There may also be mild lymphopenia (a lack of certain immune cells), with some patients developing leukopenia (a lack of white blood cells).

Infections

In nearly all patients diagnosed to date, severe and sometimes recurring infections have developed, often in the form of blood poisoning, meningitis, or severe fungal disease. Recurring viral or bacterial infections may occur as well. It is not uncommon for severe infections to have a lethal outcome before the patient reaches the age of two.

Retarded Growth

Characteristic of patients with a SAMD9 mutation is retarded longitudinal growth and low body weight, both before and after birth. In a few patients, there is also intellectual and/or motor developmental delay.

Adrenal Hypoplasia

The underdevelopment of the adrenal glands (adrenal hypoplasia) – frequently described as associated with an SAMD9 mutation – is generally evident through increased pigmentation of the skin. Later on, signs of salt depletion can occur, with vomiting, weight loss, and even clouding of consciousness, brought about by the hormonal disturbances in the adrenal glands. Adrenal hypoplasia has so far been found in every patient who has undergone an ultrasound.

Genital Abnormalities

Genetically male patients exhibit genital underdevelopment in the form of a very small penis, testicles located within the abdominal cavity, a displaced aperture of the urethra, and even external genitals that are completely female. Genetically female patients can have defectively developed ovaries. The ovaries may be completely absent as well.

Enteropathy

A disease of the intestine as part of an SAMD9 mutation manifests through chronic diarrhea and dilatation of the colon. There may also be acid reflux in the esophagus.

In addition, open ductus arteriosus, an underdeveloped or absent thymus, recurring urinary tract infections, and skeletal abnormalities (scoliosis, clubhand, overlapping fingers, clubfeet, congenital flat feet) have also been described.

What causes SAMD9 deficiency?

SAMD9 deficiency is caused by a mutation – or genetic change – in the SAMD9 gene. This gene encodes for the SAMD9 protein, which functions as a growth suppressor; in other words, it blocks the proliferation of cells in our body. Now if the SAMD9 gene is altered, this causes the activity of the protein to increase, thereby blocking cell growth even more and leading to diseases characterized by maldevelopment or underdevelopment of various organs.

In most of the cases known to date, new mutations – called de novo mutations – are involved. In addition, autosomal-dominant heredity is described.

Is there a treatment?

Patients with SAMD9 deficiency should be treated by a coordinated team of doctors from different specialist disciplines such as pediatrics, hematology/oncology, infectiology, endocrinology, genetics, and possibly others as well, with the treatment individually adapted to the respective manifestation.

If a blood formation disorder occurs, it is helpful to discuss this with the EWOG MDS principal investigator. A bone marrow transplant may be an option for patients with MDS.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

Since SAMD9 deficiency is a very rare disease, there is not yet sufficient data to provide standardized surveillance recommendations.

As with other leukemia predisposition syndromes, the following examinations should be conducted on a regular basis:

  • Clinical examinations

  • Complete blood count once a year

  • Bone marrow puncture once to begin with and then if there are suspicions of unstable blood values / clinical MDS

  • Bone marrow puncture once a year should be considered.

Self-Care and Support

What should I pay special attention to?

You should consult a doctor as soon as you notice any frequent infections, increased or hard-to-stop bleeding (e.g. long-lasting or frequent nose bleeds), increased bruises, fatigue or a feeling of sickness, fever, night sweats, or paleness. You should also see a doctor right away if you suffer from increased skin pigmentation, vomiting, weight loss, other gastrointestinal complaints, or clouding of consciousness. If you develop new symptoms or complaints, they should likewise be evaluated as soon as possible.

Support Groups and Additional Information

Unfortunately, we are as yet unaware of any existing support groups for patients with SAMD9 deficiency. We will add new information as it becomes available.