SAMD9 Deficiency – Definition
SAMD9 deficiency (OMIM #617053) is a genetic disorder caused by pathogenic variants 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
pathogenic variants 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
SAMD9 Deficiency – Diagnosis
Genetic Diagnostics
The “SAMD9 deficiency” diagnosis is confirmed by detecting a heterozygous pathogenic germline variant of the SAMD9 gene by sequence analysis.
In hematopoietic cells of carriers of a pathogenic SAMD9 variant, the pathogenic variant 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 (pathogenic variant 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 pathogenic variant in SAMD9 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 pathogenic SAMD9 variant, 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 pathogenic variant in SAMD9. 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 ofSAMD9 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 of SAMD9 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
Patients with SAMD9 deficiency should be referred to a centre where they can receive appropriate haemato-oncological care and genetic counselling.
Early detection measures should include
- Regular clinical examinations
- CBC including reticulocytes every 3-4 months
- Bone marrow aspiration and biopsy and somatic gene panel annually
- Patients with SAMD9 deficiency, their families and their physicians should be aware of suspicious clinical symptoms that may indicate the development of leukaemia
- Family history should be regularly updated for neoplasia, cytopenias and haemorrhages
