Novel SAMD9 Mutation in a Patient With Immunodeficiency, Neutropenia, Impaired Anti-CMV Response, and Severe Gastrointestinal Involvement

Abstract

Mutations in the Sterile alpha motif domain containing 9 (SAMD9) gene have been described in patients with severe multisystem disorder, MIRAGE syndrome, but also in patients with bone marrow (BM) failure in the absence of other systemic symptoms. The role of hematopoietic stem cell transplantation (HSCT) in the management of the disease is still unclear. Here, we present a patient with a novel mutation in SAMD9 (c.2471 G>A, p.R824Q), manifesting with prominent gastrointestinal tract involvement and immunodeficiency, but without any sign of adrenal insufficiency typical for MIRAGE syndrome. He suffered from severe CMV (cytomegalovirus) infection at 3 months of age, with a delayed development of T lymphocyte functional response against CMV, profound T cell activation, significantly reduced B lymphocyte counts and impaired lymphocyte proliferative response. Cultured T cells displayed slightly lower calcium flux and decreased survival. At the age of 6 months, he developed severe neutropenia requiring G-CSF administration, and despite only mild morphological and immunophenotypical disturbances in the BM, 78% of the BM cells showed monosomy 7 at the age of 18 months. Surprisingly, T cell proliferation after CD3 stimulation and apoptosis of the cells normalized during the follow-up, possibly reflecting the gradual development of monosomy 7. Among other prominent symptoms, he had difficulty swallowing, requiring percutaneous endoscopic gastrostomy (PEG), frequent gastrointestinal infections, and perianal erosions. He suffered from repeated infections and periodic recurring fevers with the elevation of inflammatory markers. At 26 months of age, he underwent HSCT that significantly improved hematological and immunological laboratory parameters. Nevertheless, he continued to suffer from other conditions, and subsequently, he died at day 440 post-transplant due to sepsis. Pathogenicity of this novel SAMD9 mutation was confirmed experimentally. Expression of mutant SAMD9 caused a significant decrease in proliferation and increase in cell death of the transfected cells.Conclusion: We describe a novel SAMD9 mutation in a patient with prominent gastrointestinal and immunological symptoms but without adrenal hypoplasia. Thus, SAMD9 mutations should be considered as cause of enteropathy in pediatric patients. The insufficient therapeutic outcome of transplantation further questions the role of HSCT in the management of patients with SAMD9 mutations and multisystem involvement.

Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes

“…Initial clinical presentation is heterogeneous and can range from severe disease with high infant mortality, to transient cytopenia and immune dysfunction. Patients with MIRAGE ( SAMD9 ) phenotype present with early onset adrenal hypoplasia and primary adrenal insufficiency, intrauterine growth restriction, genital phenotypes (46XY females, bifid shawl scrotum, testicular dysgenesis, intra-abdominal or inguinal testes, clitoromegaly), gastrointestinal issues (enteropathy, reflux, achalasia), severe systemic infections, as well as thrombocytopenia and anemia at birth - which in some patients can be self-limiting during infancy [ 37 , 118 , 119 , [128] , [129] , [130] , [131] , [132] , [133] , [134] , [135] , [136] , [137] , [138] , [139] ]. Patients with SAMD9L mutations might show disease-specific neurological findings with very variable age of onset and dynamics of progression.…”

“…However, the majority of non-syndromic SAMD9/9L -MDS patients generally do not appear to have increased risk to develop immune dysfunction and severe infections. Decreased peripheral B/NK-cells, low IgG and IgM or increased TNF-alpha and IL-6 levels were documented in cases with SAMD9/9L mutations [ 121 , 125 , 128 , 131 , 135 , 143 ]. Other rare dysmorphic features documented in single patients include skeletal abnormalities (scoliosis, joint contracture at wrist and ankles), hearing loss, dysmorphic facial features, camptodactyly, arachnodactyly, glomerular proteinuria, dysautonomia and speech delay [ 129 , 131 ].…”

“…The unique aspect of SAMD9/9L disease mechanism is ‘adaptation by aneuploidy’ that is achieved by the non-random loss chromosome 7 (−7/del(7q)) which contains mutated SAMD9/9L gene copy ( Fig. 2 ) [ 118 , 119 , 121 , 122 , 124 , 125 , 127 , 129 , 134 , 135 , [141] , [142] , [143] , [144] , [145] ]. The decrease of mutant allele in haematopoiesis poses a diagnostic challenge, since germline SAMD9/9L mutations show decreased variant allele frequency (VAF), with VAF even below 5% (own observations), necessitating germline validation in non-haematopoietic specimens, i.e.…”

MIRAGE Syndrome Caused by a De Novo c.3406G>C (p. Glu1136Gln) Mutation in the SAMD9 Gene Presenting With Neonatal Adrenal Insufficiency and Recurrent Intussusception: A Case Report

“…PAI is a highly consistent feature, seen in 94% of patients from the two larger cohorts. Except for the few exceptions in cases without adrenal insufficiency ( 3 , 4 ), we believe that PAI is almost pathognomonic in MIRAGE syndrome given that SAMD9 expression is found to be highest in the foetal adrenal gland. Postmortem biopsies revealed hypoplastic glands with dysgenetic adrenocortical cells ( 1 , 6 ).…”

“…It is a very rare condition with only around 40 cases reported ( 2 ) with variable phenotypic expressions. Most of the SAMD9 mutations occur de novo except in two reported families where it was transmitted from asymptomatic mothers ( 3 , 4 ). We present here a case of MIRAGE syndrome in a girl with de novo mutation c.3406G>C and describe the unique features of this case as well as the presentation of recurrent intussusception which has not been previously reported.…”