Definition

SAMD9 deficiency (OMIM #617053) is a genetic disease caused by mutations in the SAMD9 gene. It is also referred to as MIRAGE syndrome, an acronym coined from its most commonly observed symptoms: myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital abnormalities, and enteropathy. In addition, numerous other anomalies can occur in different organs. The progression of the disease is often lethal within the first decade of life, usually due to severe infections.

Key Data

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Synonym  MIRAGE syndrome
Gene SAMD9 (sterile alpha motif domain-containing protein-9 gene)
Gene product SAMD9
Function Growth repressor
There is a gain of function with mutations in the SAMD9 gene.
Heredity Autosomal dominant, usually de novo mutations
Prevalence Unknown
Genotype-phenotype correlation Very homogeneous phenotype in the patients diagnosed to date
Penetrance Unknown
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Diagnosis

Genetic Diagnostics

The diagnosis of “SAMD9 deficiency” is confirmed by detecting a heterozygous germline mutation in the SAMD9 gene through sequence analysis.

The SAMD9 mutation is “toxic” to hematopoietic cells of carriers. The frequently observed loss of genetic material on chromosome 7 (e.g. monosomy 7) in hematopoietic cells in those affected results in a loss of the mutated allele (adaptation through the aneuploidy mechanism). For this reason, it may be helpful to analyze non-hematopoietic tissue for diagnostic purposes. Commonly observed monosomy 7 appears to be an important leukemogenic step in these patients.

Differential Diagnoses

  • IMAGe syndrome – intrauterine growth retardation, metaphysical dysplasia, adrenal hypoplasia, genital abnormalities (mutation in the CDKN1C gene)

Clinical Presentation

It is possible for diseases to occur in different organ systems as part of a SAMD9 deficiency.

Myelodysplasia

Hematological abnormalities – transient or persisting thrombocytopenia and/or anemia – usually occur during infancy and generally regress spontaneously. In addition, there may be mild lymphopenia, with a few patients developing leukopenia. It is rare for myelodysplastic syndrome (MDS) to develop.

Infections

In nearly all patients diagnosed to date, severe and sometimes recurring infections have developed, often in the form of sepsis, meningitis, or systemic mycosis. 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

Characteristics of patients with a SAMD9 mutation are; retarded longitudinal growth and low body weight, both prenatally as well as postnatally. In a few patients, there are also intellectual and/or motor developmental delays.

Adrenal Hypoplasia

Parathyroid hypoplasia, often described as being part of an SAMD9 mutation, is generally evident due to hyperpigmentation of the skin even before the onset of salt depletion symptoms. Parathyroid hypoplasia has so far been diagnosed in all patients who have undergone an ultrasound examination.

Genital Abnormalities

All patients with a male karyotype have exhibited retardation of genital development in the form of micropenis, cryptorchidism, hypospadias, and even extending to entirely female external genitalia. In patients with a female karyotype, there may be hypoplastic or dysgenetic ovaries with only a few primordial follicles. The ovaries may be completely absent as well.

Enteropathy

Enteropathy as part of a SAMD9 mutation manifests with chronic diarrhea and dilatation of the colon. There may be gastroesophageal reflux as well.

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

Therapeutic Considerations

Patients with SAMD9 deficiency should be treated by an interdisciplinary team, with the treatment individually adapted to the respective manifestation.

If MDS 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

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

  • A bone marrow puncture once a year should be considered (with a punch, aspirate, cytogenetics).

Additional Information

Open Clinical Trials / Registries

Support Groups

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.