Last updated:
9/30/2025
Years published: 2025
NORD gratefully acknowledges Armando Sanchez-Conde, MS, Sarah Huang, MS, Emily Huang, MS, and MaryAnn Campion, EdD, MS, CGC, Stanford University MS Program in Human Genetics and Genetic Counseling and Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, for the preparation of this report.
Summary
MIRAGE syndrome is a rare genetic disorder that affects multiple parts of the body. MIRAGE is an acronym for:
Not all people with MIRAGE syndrome will exhibit every feature of the acronym, but the core symptoms are important to monitor. Since MIRAGE syndrome affects multiple body systems, the age of onset is typically very early in life, at or shortly after birth. There are some symptoms of MIRAGE syndrome that can be identified during pregnancy (prenatally).
MIRAGE syndrome is caused by changes (variants) in the SAMD9 gene and follows an autosomal dominant pattern of inheritance. In some people, MIRAGE syndrome is not inherited from a parent but due to a new (de novo) genetic change in an affected individual.
Treatment and management for MIRAGE syndrome involves many different medical specialists. It can include hematopoietic stem cell transplantation (HSCT) for bone marrow issues, medications to treat and prevent infections, various therapies such as speech or occupational therapy and surgery.
Introduction
MIRAGE syndrome was first described by Dr. Satoshi Narumi and colleagues at the Keio University School of Medicine in Tokyo, Japan, in 2016. MIRAGE syndrome was named for its most common symptoms.
People affected by MIRAGE syndrome tend to show symptoms very early in life and the problems can be severe. Although these can vary from person to person, many affected children face serious challenges with growth and multiple organ systems.1 As time goes on, the condition may lead to more health complications, especially related to blood cell production. Some children may also experience worsening of their adrenal or gastrointestinal symptoms as they grow older. Not every child will have all the issues listed, but the ones noted are the most typical and important to monitor.
The symptoms and physical features of MIRAGE syndrome can vary from person to person, but frequently include some or most of the following:
The progression to a condition called myelodysplastic syndrome (MDS) is a concern for some people with MIRAGE syndrome. This occurs when the bone marrow begins to produce abnormal and ineffective blood cells. In MIRAGE syndrome, the development of MDS is typically associated with the loss of all or part of chromosome 7, either as monosomy 7 (loss of one entire copy) or as deletion of a portion of its long arm (referred to as del(7q)). These chromosomal changes are considered hallmark indicators of myelodysplasia in this setting.2
MIRAGE syndrome is caused by changes (variants) in the SAMD9 gene, located on chromosome 7.2 The SAMD9 protein, which is coded by the SAMD9 gene, is responsible for many different cell activities including protecting against viruses, forming important structures and controlling growth and division.4 Therefore, an overactive SAMD9 protein can lead to clinical findings in many different parts of the body, as seen in the many signs and symptoms of MIRAGE syndrome. For example, the atypical genital presentation despite having 46, XY chromosomes is thought to be due to the SAMD9 protein not being able to promote proper cell growth during male genital development.4
Changes in the SAMD9 gene that cause MIRAGE syndrome are called gain-of-function, meaning they enhance the function of the SAMD9 protein in a harmful way.2,3 At this time, most known MIRAGE-causing genetic changes are missense variants that result in one protein building block (amino acid) being replaced with a different one and altering the function of the protein. In most reported cases the variants are very rare, and typically only found within individual families.
The overactive SAMD9 protein impairs normal cell growth, particularly in blood-forming (hematopoietic) cells. To escape this growth restriction, some cells may acquire somatic changes, like loss of the chromosome 7 copy carrying the SAMD9 gene, allowing them to grow more freely. However, this chromosomal loss also removes other essential genes, increasing the risk for myelodysplastic syndrome.
However, not all genetic changes involving SAMD9 are harmful. In some people, the body may acquire other types of gene variants that silence or correct the overactive SAMD9 gene without deleting chromosome 7. These changes, such as uniparental disomy or secondary changes affecting the same gene, can help restore normal bone marrow function and may prevent the onset of MDS altogether.2
Some people with a germline SAMD9 gene variant may present only with blood-related features, such as myelodysplasia, and show few or none of the other symptoms typically associated with MIRAGE syndrome.2
Inheritance
MIRAGE syndrome follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. Most variants in SAMD9 that lead to MIRAGE syndrome are thought to be de novo, meaning that they occur for the first time in the affected child and are not present in either parent.3 The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
MIRAGE syndrome is a very rare condition. At this time, around 57 affected individuals have been identified in the medical literature.5 Since it is incredibly rare, there is limited data on which populations are most likely to be impacted, although most individuals have been diagnosed in Japan.6
MIRAGE syndrome is an early-onset disorder; symptoms and signs are most frequently identified at or shortly after birth. Recent research shows that some features of MIRAGE syndrome may even be identified prenatally, or before birth.1
Clinical symptoms such as frequent bruising, ulcers in the mouth, repeating bacterial infections, and trouble with growth can lead to a suspicion for MIRAGE syndrome.2 Lab results that indicate lower than normal levels of blood cells (cytopenia), impaired adrenal gland function (adrenal insufficiency/adrenal aplasia), or certain brain abnormalities (such as white matter changes, or fluid buildup) can also lead to suspicion.9,10
However, these clinical and lab symptoms are not enough for an official diagnosis of MIRAGE syndrome. A genetic test showing a disease-causing variant in SAMD9 is needed to confirm the diagnosis.2
Genetic testing approaches to diagnose MIRAGE syndrome can be either gene targeted testing or broader genetic testing, such as exome or genome testing.
Gene targeted testing includes single-gene testing and panel testing. Single-gene testing involves looking at just the SAMD9 gene to find a variant responsible for the condition. Panel testing involves looking at many genes to find the cause of the condition. Panel testing is broader but still specific to the suspicious features and may contain several genes that have been associated with similarly presenting conditions.
Exome or genomic testing are more comprehensive. This approach can be helpful when the clinical presentation or laboratory findings are not specific enough to determine what gene or gene(s) are likely to be the cause. For this approach, a test that looks at all the coding portions of the DNA (exome sequencing) is commonly used. A test that looks at the entire DNA, including both the coding and non-coding areas, can also be used (genome sequencing).
As commented above, in people with a variant in the SAMD9 gene, a type of genetic change can occur in blood-forming tissue that may “hide” the variant during testing. This happens when cells lose a copy of chromosome 7, where the SAMD9 gene is located. As a result, fewer cells carry the variant, which can lead to a false negative result when testing DNA from blood or bone marrow.2
Because of this, if a doctor strongly suspects MIRAGE syndrome but genetic testing comes back negative, more detailed testing may be needed. This could include special tools like a SNP array or deep genetic sequencing (which looks more closely at the DNA). In some people, testing DNA from other tissues, like skin cells or hair roots, may give more accurate results.2
Clinical Testing and Work-Up
Initial evaluations for MIRAGE syndrome will include a clinical assessment of suggestive features, followed by genetic testing to confirm the diagnosis of the condition. The methods for genetic testing are as described above. Following the initial evaluation and diagnosis of MIRAGE syndrome, there are several screenings that may be recommended. There are no formal guidelines for surveillance of symptoms, though there are some recommendations.2
Growth is monitored through annual assessments of height, head size and weight. A blood test every 4-6 months and annual bone marrow testing can screen for myelodysplasia, a condition where the bone marrow is not producing enough blood cells. An annual physical exam coupled with other blood tests may be done to monitor adrenal gland development (screen for adrenal hypoplasia) and the function of the kidneys. Assessment of developmental milestones may be recommended every 3-6 months in the first year and annually following age one. Assessments of gastrointestinal and nervous system function may be recommended, as needed.
People with MIRAGE syndrome need to be seen by several different specialists. The specialists need to work together as a team in a coordinated manner, for the best management.
For people who have bone marrow failure and are experiencing severe anemia or decreased platelet count in the blood (thrombocytopenia), treatment will involve standard blood transfusion. For people who develop chronic transfusion dependence or have a persistent decrease of the number of neutrophiles (chronic neutropenia), hematopoietic stem cell transplantation (HSCT), a procedure that replaces damaged blood cells with healthy ones can be considered. HSCT can be curative for myelodysplasia.11 Additionally, strategies and precautions to prevent bacterial infection may be considered for these individuals.2
For the treatment of recurring infections, standard treatment with medications such as antibiotics or antivirals may be used. The treatment for growth concerns involves the management of diet and caloric intake by a nutritionist. Diarrhea can be treated with an elemental diet, which involves a specialized liquid formula made of essential amino acids, to aid with gradual whole food reintroduction into the patient’s diet. Esophageal issues that lead to recurrent choking episodes or inhalation of food substances can be relieved by tube feeding.
For people with genital anomalies, the care team may consider surgical interventions. Standard treatment for kidney dysfunction can be recommended by a nephrologist.
People who have developmental delays may be referred to programs to aid in speech therapy, occupational therapy, and feeding therapy.
People who have issues with autonomic nervous system (ANS) function — symptoms which may include blood pressure changes, fainting, sweating and tear duct abnormalities related to adrenal gland differences can be treated by standard approaches recommended by specialists of that body system. For example, an ophthalmologist evaluating tear duct abnormalities due to ANS dysfunction may recommend artificial tear drops for the patient.2
Genetic counseling may be recommended to identify other at-risk relatives. By checking the genetic status of seemingly asymptomatic relatives, it can be possible to identify who in the family may benefit from early surveillance for insufficient blood cell production (myelodysplasia).
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/
All studies receiving U.S. Government funding, and some supported by private industry are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD
website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
INTERNET
MIRAGE Syndrome and Related Disorders Association- Family Support Group (Facebook) https://www.facebook.com/groups/559576374229136/ Accessed Sept 16, 2025.
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