Clinical characteristics.

MIRAGE syndrome is an acronym for the major findings of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. Cytopenias are typically seen soon after birth; Thrombocytopenia is the most common followed by anemia and pancytopenia. Recurrent infections from early infancy include pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. Reported genital phenotypes in those with 46,XY karyotype included hypospadias, microphallus, bifid shawl scrotum, ambiguous genitalia, or complete female genitalia. Hypoplastic or dysgenetic ovaries have been reported in females. Gastrointestinal complications include chronic diarrhea and esophageal dysfunction. Moderate-to-severe global developmental delay is reported in most affected individuals. Autonomic dysfunction and renal dysfunction are also reported.

Diagnosis/testing.

The diagnosis of MIRAGE syndrome is established in a proband with suggestive findings and a heterozygous germline gain-of-abnormal-function pathogenic variant in SAMD9 identified by molecular genetic testing.

Management.

Treatment of manifestations: Individuals with severe anemia and thrombocytopenia due to bone marrow failure should be treated with standard transfusion approaches; bacterial infection prevention including antibiotic prophylaxis and fever precautions in individuals with severe neutropenia. Individuals with severe neutropenia and chronic transfusion requirements, along with individuals who develop monosomy 7 myelodysplastic syndrome should be considered for hematopoietic stem cell transplantation. Standard treatment of infections with antibiotics, antiviral or antifungal agents as needed; consider prophylactic intravenous immunoglobulin if endogenous immunoglobulin levels are low; management by nutritionist to ensure adequate caloric intake and to assist with elemental diet for chronic diarrhea; hydrocortisone and fludrocortisone as needed for adrenal hypoplasia; surgical removal of dysgenetic gonads or surgical intervention may be considered for those with external genital anomalies; consider duodenal tube feeding in those with recurrent aspiration pneumonia; early intervention with occupational, physical, speech and feeding therapy for developmental delay; artificial tear solutions and treatment per ophthalmologist for ocular manifestations of autonomic dysfunction such as hypolacrima; management of ambient temperature for those with temperature instability; management of renal dysfunction per nephrologist.

Surveillance: Complete blood count with differential every four to six months; annual bone marrow aspirate and biopsy (with analysis for somatic alterations including chromosome 7 abnormalities) in those with cytopenias including anemia, thrombocytopenia, or neutropenia; at least annual assessment of height, weight, head circumference, physical examination for features of adrenal hypoplasia, and measurement of serum sodium, potassium, glucose, cortisol, and ACTH. Assess for diarrhea, feeding issues, and esophageal dysfunction as needed; monitor developmental milestones every three to six months in the first year of life and at least annually thereafter; assess for keratoconjunctivitis sicca, corneal ulcer, and temperature instability as needed; at least annual measurement of serum creatinine, blood urea nitrogen, and urinalysis to evaluate renal function.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from evaluation for myelodysplasia.

Genetic counseling.

MIRAGE syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with MIRAGE syndrome have the disorder as the result of a variant inherited from a heterozygous parent with no apparent features of MIRAGE syndrome. If the proband has an SAMD9 pathogenic variant that is not detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism or the possibility of a false negative result in a parent due to preferential loss of the chromosome with the SAMD9 pathogenic variant. Once the SAMD9 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

MIRAGE syndrome should be suspected in individuals with the following clinical, laboratory, and radiographic features.

Clinical features

• Easy bruising, mucocutaneous bleeding, oral ulcers, fatigue, pallor
• Recurrent bacterial infections including pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. The most common organisms associated with these infections are enteric pathogens such as Klebsiella and Enterococcus. Affected individuals may also be at higher risk for viral (e.g., cytomegalovirus), bacterial respiratory pathogens, and fungal infections (e.g., Candida).
• Growth deficiency (intrauterine growth restriction with premature birth; persistent failure to thrive)
• Diffuse skin hyperpigmentation, severe dehydration, and hypotension (due to primary adrenal insufficiency) which may be life threatening
• Atypical external genitalia in 46,XY individuals (e.g., hypospadias, microphallus, bifid shawl scrotum, ambiguous genitalia, or complete female genitalia)
• Chronic intractable diarrhea
• Dysphagia, recurrent aspiration pneumonia, gastroesophageal reflux

Laboratory features

• Mono- or multilineage cytopenia, either transient or persistent
• Bone marrow aspirate and biopsy may show hypocellularity/aplasia with absent megakaryocytes, or it may show myelodysplastic syndrome and/or acute myelogenous leukemia (AML) with monosomy 7. Monosomy 7 may be transient if the clone is small, or it may persist for years before transformation to AML. Additional somatic pathogenic variants may correlate with transformation to AML.
• Laboratory features of primary adrenal insufficiency: hyponatremia, hyperkalemia, hypoglycemia, low cortisol, and markedly elevated corticotropin (ACTH). Impaired cortisol response to cosyntropin stimulation is a confirmatory finding of primary adrenal insufficiency.

Radiographic features

• Adrenal aplasia or hypoplasia on ultrasound
• Microcephaly, hydrocephalus, and white matter abnormalities on brain MRI

Establishing the Diagnosis

The diagnosis of MIRAGE syndrome is established in a proband with suggestive findings and a heterozygous germline gain-of-abnormal-function pathogenic variant in SAMD9 identified by molecular genetic testing (see Table 1).

Note: Identification of a heterozygous SAMD9 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with growth restriction, myelodysplasia, and/or adrenal hypoplasia are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

MIRAGE syndrome is a rare disorder characterized by six core features: myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy.

To date, no consensus clinical diagnostic criteria for MIRAGE syndrome are available. In this review, a diagnosis of MIRAGE syndrome is defined as:

• 46,XY individuals with four or more of the core features; or
• 46,XX individuals with three or more of the core features.

Using these diagnostic criteria, 44 individuals with features of MIRAGE syndrome and a pathogenic variant in SAMD9 have been identified to date [Narumi et al 2016, Buonocore et al 2017, Bluteau et al 2018, Jeffries et al 2018, Kim et al 2018, Sarthy et al 2018, Shima et al 2018a, Shima et al 2018b, Wilson et al 2018, Ahmed et al 2019, Csillag et al 2019, Formankova et al 2019, Mengen et al 2020, Perisa et al 2019, Roucher-Boulez et al 2019, Yoshizaki et al 2019, Zhang et al 2019, Onuma et al 2020, Viaene & Harding 2020]. The following description of the phenotypic features associated with MIRAGE syndrome is based on these reports.

Myelodysplasia and bone marrow failure. Age of onset of hematologic abnormalities is variable. Two distinct groups with respect to prognosis and severity of cytopenias include individuals diagnosed with severe cytopenias between birth and age two years (~60%) and individuals diagnosed later in childhood (~40%) [Rentas et al 2020]. Prior to the onset of hematopoietic clonal evolution, individuals may present with bone marrow hypoplasia and features consistent with congenital amegakaryocytic thrombocytopenia [Sarthy et al 2018]. Thrombocytopenia is the most common manifestation, followed by anemia and pancytopenia. Severe cytopenias may occur in distinct acute episodes associated with myelosuppressive infections or may be chronic, requiring frequent transfusions. Of note, cytopenias may improve with age in some individuals.

Evolution to myelodysplastic syndrome (MDS) is defined by acquisition of monosomy 7 or del(7q) in the setting of multilineage bone marrow dysplasia. Although myelodysplasia is included as a core feature of MIRAGE syndrome, myelodysplasia in these individuals appears to be due to an acquired deletion of SAMD9, primarily of the SAMD9 allele with a germline gain-of-abnormal-function pathogenic variant. Notably, individuals with a germline gain-of-abnormal-function SAMD9 pathogenic variant may acquire somatic alterations (including uniparental disomy 7 or SAMD9 pathogenic variants in cis with the germline variant) that do not predispose to MDS and may actually improve hematopoietic function (see Penetrance).

Individuals with a germline gain-of-abnormal-function SAMD9 pathogenic variant may present with myelodysplasia and develop no additional or only limited features of MIRAGE syndrome [Schwartz et al 2017, Hockings et al 2020].

Recurrent infections. Most individuals with MIRAGE syndrome develop recurrent bacterial infections from early infancy including pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. The most common organisms associated with these infections are enteric pathogens such as Klebsiella and Enterococcus. Affected individuals may also be at higher risk for complications from both viral (e.g., cytomegalovirus) and bacterial respiratory pathogens. Affected individuals with severe immune deficiency due either to native immune dysfunction or to stem cell transplant are also at risk for severe fungal infections (e.g., Candida). To date, the etiology of the increased susceptibility to infections is unknown. It may be partly explained by hypogammaglobulinemia or lymphopenia. In four individuals, the thymus was hypoplastic [Narumi et al 2016, Sarthy et al 2018]. Incomplete lasting immunity to vaccinations has been reported in two affected individuals [Jeffries et al 2018].

Growth restriction / growth deficiency. Typically, affected individuals are delivered premature by emergency cæsarean section due to fetal growth failure and suspected fetal distress. Most individuals have persistent growth deficiency (weight, height/length, and head circumference are commonly all below -2.0 SD) despite adequate caloric supply, with the exception of two individuals who showed normal growth after birth [Shima et al 2018b, Roucher-Boulez et al 2019].

Adrenal hypoplasia. Approximately 80% of individuals have primary adrenal insufficiency. They present with prominent diffuse skin hyperpigmentation at birth and may develop severe dehydration and hypotension, which can be life-threatening. The diagnosis of primary adrenal insufficiency is confirmed by low cortisol and markedly elevated ACTH levels. Aplastic or hypoplastic adrenal glands are found on ultrasound examination. Rarely, adrenal insufficiency may emerge in late childhood [Perisa et al 2019].

Genital anomalies. Reported findings in those with 46,XY karyotype included hypospadias, microphallus, bifid shawl scrotum, ambiguous genitalia, or complete female genitalia. The testes were usually hypoplastic or dysgenetic. One individual, age three days, was reported to have undetectable testosterone [Roucher-Boulez et al 2019]. One individual, age 16 years, was reported to have testicular failure [Wilson et al 2018].

No external genital anomalies were reported in individuals with 46,XX karyotype, but four were found to have hypoplastic or dysgenetic ovaries [Narumi et al 2016, Sarthy et al 2018, Viaene & Harding 2020].

Gastrointestinal complications. Chronic diarrhea occurs in about 80% of affected individuals and often results in severe diaper rash. It usually occurs after initiating enteral nutrition. About one third of individuals with MIRAGE syndrome have esophageal problems often accompanied by recurrent aspiration pneumonia. Clinical manifestations include dysphagia, gastroesophageal reflux, vomiting, esophageal hypoperistalsis, esophageal stricture, and achalasia.

Neurologic development. Moderate-to-severe global developmental delay is reported in most affected individuals. Reported individuals are often nonambulatory with absent or limited language development. Neuropathologic findings such as microcephaly, hydrocephalus, white matter abnormalities, and perivascular calcifications may be present [Viaene & Harding 2020].

Autonomic dysfunction. Symptoms compatible with autonomic dysfunction such as hypolacrima with corneal ulcer, hypo/anhidrosis with temperature instability, or hyperhidrosis were reported in seven individuals [Jeffries et al 2018, Sarthy et al 2018, Shima et al 2018a, Shima et al 2018b].

Renal dysfunction including proteinuria and renal tubular acidosis were reported in five of 17 individuals who lived beyond age three years. Renal biopsies were performed in four individuals; two were found to have focal segmental glomerular sclerosis [Ahmed et al 2019, Perisa et al 2019], one to have interstitial nephritis [Shima et al 2018b], and one to have C1q nephropathy [Wilson et al 2018].

Prognosis. The median age of death in affected individuals is three years. Nearly 60% of the deaths were due to infectious diseases. The oldest affected individual was reported to be alive at age 20 years [Bluteau et al 2018].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Penetrance

Penetrance is unknown. Of note, one asymptomatic female with a germline gain-of-abnormal-function SAMD9 pathogenic variant (which she transmitted to her child, who had a typical MIRAGE phenotype) also had a somatic loss-of-function SAMD9 variant in cis, presumably acquired in an early stage of development [Roucher-Boulez et al 2019].

Prevalence

To date, 44 affected individuals have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MIRAGE syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations