A girl with MIRAGE syndrome who developed steroid-resistant nephrotic syndrome: a case report

Abstract

Background: MIRAGE syndrome is a recently discovered rare genetic disease characterized by myelodysplasia (M), infection (I), growth restriction (R), adrenal hypoplasia (A), genital phenotypes (G), and enteropathy (E), caused by a gain-of-function mutation in the SAMD9 gene. We encountered a girl with molecularly-confirmed MIRAGE syndrome who developed steroid-resistant nephrotic syndrome. Case presentation: She was born at 33 weeks gestational age with a birth weight of 1064 g. She showed growth failure, mild developmental delays, intractable enteropathy and recurrent pneumonia. She was diagnosed as MIRAGE syndrome by whole exome sequencing and a novel SAMD9 variant (c.4615 T > A, p.Leu1539Ile) was identified at age four. Biopsied skin fibroblast cells showed changes in the endosome system that are characteristic of MIRAGE syndrome, supporting the genetic diagnosis. Proteinuria was noted at age one, following nephrotic syndrome at age five. A renal biopsy showed focal segmental glomerulosclerosis (FSGS) with immune deposits. Steroid treatment was ineffective. Because we speculated that her nephrosis was a result of genetic FSGS, we decided not to introduce immunosuppressive agents and instead started enalapril to reduce proteinuria. Although her proteinuria persisted, her renal function was normal at age eight. Conclusions: This is the first detailed report of a MIRAGE syndrome patient with nephrotic syndrome. Because patients with MIRAGE syndrome have structural abnormalities in the endosomal system, we speculate that dysfunction of endocytosis in podocytes might be a possible mechanism for proteinuria.

Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes

“…syndrome (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures) 34 or B cell aplasia 8 and missense SAMD9 mut in steroid-resistant nephrotic syndrome 35 . Thus far, 64 mostly missense germline mutations (38 SAMD9 and 26 SAMD9L) have been reported 6,7,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][34][35][36][37] . However, none of the studies was performed in population-based registries but, rather, using institutional cohorts driven by specific phenotypes.…”

The case of a patient with MIRAGE syndrome with familial dysautonomia-like symptoms

“…LAMP-1 visualization showed a remarkable increase in the lysosome number in the patient’s fibroblasts (Fig. 2D ), which is a characteristic of MIRAGE syndrome 1 , 4 . Thus, the patient was posthumously diagnosed with this syndrome.…”

“…Myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital problems, and enteropathy (MIRAGE) syndrome is a genetic disorder caused by gain-of-function SAMD9 mutations, which lead to a multisystemic growth restriction disorder 1 . Recently, several cases of patients with MIRAGE syndrome presenting with dysautonomia have been reported [2][3][4] . Familial dysautonomia (FD) is a rare genetic disease caused by a founder variant in the ELP1 gene [5][6][7][8][9] .…”

“…Dysautonomia, including insensitivity and anhidrosis, has been reported in several MIRAGE syndrome cases [2][3][4] . Conversely, dysautonomia at birth, feeding difficulties, poor growth, and frequent lung infections are observed only in FD and not in any other form of dysautonomia 9 .…”

Emerging phenotypes linked to variants in SAMD9 and MIRAGE syndrome

“…To date, more than 50 patients have been reported with severe growth restriction phenotypes due to gain-of-function changes in SAMD9 (9,10,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). Although endocrine features such as primary adrenal insufficiency and gonadal dysgenesis were originally a core part of the syndrome, it is emerging that these features may be more variable.…”