SAM9 Deficiency – Definition
SAMD9 deficiency (OMIM #617053) is a genetic disorder caused by mutations in the SAMD9 gene. It is also known as MIRAGE syndrome, an acronym made up of the most frequently observed symptoms: Myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital abnormalities, and enteropathy. In addition, numerous other abnormalities can occur in various organs. The disease is often fatal within the first decade of life, usually due to severe infections.
Synonym:
MIRAGE Syndrome
Gene:
SAMD9 (sterile alpha motif domain-containing protein-9 gene)
Gene product:
SAMD9
Function:
Growth repressor
mutations of the SAMD9 gene lead to gain-of-function
Pattern of inheritance:
Autosomal dominant, mostly de novo mutations
Prevalence:
Unknown
Genotype-phenotype correlation:
Very homogeneous phenotype in the patients diagnosed to date
Penetrance:
Unknown
SAM9 Deficiency – Diagnosis
Genetic Diagnostics
The “SAMD9 deficiency” diagnosis is confirmed by detecting a heterozygous germline mutation of the SAMD9 gene by sequence analysis.
In hematopoietic cells of carriers of a SAMD9 mutation, the mutation is “toxic”. The frequently observed loss of genetic material from chromosome 7 (e.g., monosomy 7) in hematopoietic cells of affected individuals leads to a loss of the mutated allele (adaptation-by-aneuploidy mechanism). Therefore, it may be useful to analyze non-hematopoietic tissue for diagnostic purposes. The frequently observed monosomy 7 appears to be an important leukemogenesis step in these patients.
Differential Diagnoses
- SAMD9L deficiency
- IMAGe syndrome – Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia, genital anomalies (mutation in the CDKN1C gene)
Clinical Presentation
SAMD9 deficiency can lead to diseases in various organ systems.
Myelodysplasia
Hematological abnormalities include transient or persistent thrombocytopenia and/or anemia, which usually occur in infancy but resolve spontaneously. Mild lymphopenia may also occur, and some patients may develop leukopenia. Rarely, myelodysplastic syndrome (MDS) may develop.
Infections
Almost all patients diagnosed to date have developed severe, sometimes recurrent infections, often in the form of sepsis, meningitis, or systemic mycosis. Recurrent viral or bacterial infections can also occur. Severe infections are often fatal before the child reaches the age of two.
Retarded Growth
Patients with the SAMD9 mutation are characterized by retarded longitudinal growth and low body weight, both pre-and postnatally. Some patients also have intellectual and/or motor developmental delays.
Adrenal Hypoplasia
Adrenal hypoplasia, which is frequently described in the context of a SAMD9 mutation, is usually noticeable due to skin hyperpigmentation even before salt loss symptoms occur. Adrenal hypoplasia has been diagnosed in all patients examined sonographically to date.
Genital Anomalies
All patients with a male karyotype showed genital underdevelopment in the form of micropenis, cryptorchidism, hypospadias and even a completely female external genitalia. Patients with a female karyotype may have hypoplastic or dysgenetic ovaries with only a few primordial follicles. The ovaries may also be completely absent.
Enteropathy
Enteropathy is manifested by chronic diarrhea and colonic dilatation in the context of a SAMD9 mutation. Gastroesophageal reflux may also be present.
Furthermore, an open ductus arteriosus, a hypoplastic or absent thymus, recurrent urinary tract infections and skeletal anomalies (congenital scoliosis, radial club hand, overlapping fingers, club feet, congenital flat feet) have been described.
Special Features of Treatment
The treatment of patients with SAMD9 deficiency should be interdisciplinary, and the therapy should be individually adapted to the respective manifestation.
If MDS occurs, it is advisable to discuss it with the EWOG-MDS study management. A bone marrow transplant may be an option for patients with MDS.
Diagnosis ofSAM9 Deficiency- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis ofSAM9 Deficiency- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
As SAMD9 deficiency is a sporadic disease, there is insufficient data to make standardized early detection recommendations. As with other leukemia predisposition syndromes, the following examinations should be carried out regularly:
- Clinical examinations
- Annual complete blood count
- Bone marrow puncture once initially and then in the event of unstable blood values/clinical suspicion of MDS
- A bone marrow puncture once a year should be considered (with punch, aspirate, cytogenetics)
SAM9 Deficiency – Further Information
Additional Resources
Unfortunately, we are not aware of any support groups for patients with SAMD9 Deficiency. We will add new information as soon as it becomes available.
