A number sign (#) is used with this entry because of evidence that MIRAGE syndrome (MIRAGE) is caused by heterozygous mutation in the SAMD9 gene (610456) on chromosome 7q21.

Heterozygous mutation in the SAMD9 gene can also cause monosomy 7 myelodysplasia and leukemia syndrome-2 (M7MLS2; 619041), which shows overlapping features.

MIRAGE syndrome (MIRAGE) is a form of syndromic adrenal hypoplasia, characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. The condition is often fatal within the first decade of life, usually as a result of invasive infection (Narumi et al., 2016).

Narumi et al. (2016) studied 11 patients who exhibited strikingly similar phenotypes, including moderate to severe growth restriction both prenatally and postnatally. Intellectual development was variably affected; 4 of 8 patients who survived to 1 year of life were unable to hold their head up or say a word. Adrenal insufficiency was usually suspected because of skin hyperpigmentation, even before onset of symptoms of salt loss; adrenal hypoplasia was documented in the 7 patients who underwent ultrasonography. Six of 7 patients with a 46,XY karyotype exhibited genital underdevelopment, with microphallus, cryptorchidism, and hypospadias; 1 patient had completely female-appearing external genitalia at birth and had been assigned female. In early infancy, all patients experienced thrombocytopenia and/or anemia requiring transfusions, but these resolved spontaneously. Severe invasive infections, including sepsis, meningitis, and fungal infections, were invariably observed; 6 patients died before 2 years of age, chiefly as a result of invasive infection. Immunologic testing in 8 patients showed some abnormalities, including mild lymphopenia, but did not reveal a shared severe defect. In addition, 9 patients had chronic diarrhea with colonic dilation. Mosaic monosomy 7 (see 619041) was detected in 2 patients, who both developed myelodysplastic syndrome and died from the complication. Postmortem histologic analysis in 2 female patients showed very small adrenal glands that were highly disorganized, with the medulla only partially surrounded by cortex. The dysgenetic adrenocortical cells had a foamy appearance, and the layered architecture of the cortex was disturbed. Ovaries were also markedly hypoplastic, with few primordial follicles, and the thymus was hypoplastic with a decreased number of cortical lymphocytes. Narumi et al. (2016) proposed the designation MIRAGE syndrome.

The heterozygous mutations in the SAMD9 gene that were identified in patients with MIRAGE syndrome by Narumi et al. (2016) arose de novo, except in 1 family with 2 affected sibs, where parental germline mosaicism was suspected.

By whole-exome sequencing in 6 Japanese patients with suspected syndromic adrenal hypoplasia, Narumi et al. (2016) identified 3 different heterozygous missense mutations in the SAMD9 gene (610456.0002-610456.0004) in 4 of the patients. Sequencing of SAMD9 in another 18 Japanese patients identified 7 additional patients with SAMD9 missense variants. The mutations were shown to have arisen de novo in all families for which parental DNA was available, except for 1 family with 2 affected sibs, where parental germline mosaicism was suspected. None of the mutations were found in 400 in-house Japanese control samples or in public variant databases. Genetic analysis in 2 patients with monosomy 7 who developed myelodysplastic syndrome (see 619041) showed loss of the signal derived from the mutant allele, suggesting that there was an expansion of the cells that lost chromosome 7 carrying the mutation. Because functional analysis demonstrated potent growth-restricting activity with the SAMD9 mutants, Narumi et al. (2016) suggested that the loss of chromosome 7 occurred as an adaptation to the growth-restricting conditions.