A Novel Homozygous TRNT1 Mutation in a Child With an Early Diagnosis of Common Variable Immunodeficiency Leading to Mild Hypogammaglobulinemia and Hemolytic Anemia

Abstract

Although sideroblastic anemias (SAs) may be associated with different etiologies, deterioration of mitochondrial heme biosynthesis in bone marrow erythroid cells is a general abnormality. Congenital SA associated with immunodeficiency, periodic fever, and developmental delay is because of loss-of-function mutations in the TRNT1 gene. We report a patient with a novel homozygous mutation in the TRNT1 gene presenting with anemia with siderocytes, hypogammaglobulinemia, hepatosplenomegaly, and brittle hair but without periodic fever or developmental delay. The patient was presented to emphasize the power of reverse phenotyping in the differential diagnosis of primary immunodeficiency patients with atypical features and to raise awareness for TRNT1 disease in case of coexistent SA and hypogammaglobulinemia.

Clinical and Therapeutic Aspects of Sideroblastic Anaemia with B-Cell Immunodeficiency, Periodic Fever and Developmental Delay (SIFD) Syndrome: a Systematic Review

“…Brain MRI normal Vomiting and diarrhoea during episodic fever, hypertransaminasemia, Mouth ultcers Normal No Episodic welling of fingers/cellulitis. Eczema and Brittle hair Arthritis Normal 54 [ 24 ] M Homozygous mutation c.914A > T, p.Asp305Val Exon 7 Missense 6 m + - Microcytic anaema, anosocytosis, poikilocytosis, basophilic stippling on the peripheral blood smear B-cell immunodeficiency, inverted CD4/CD8 + Low None None Normal Normal Brittle Hairs None Hepatosplenomegaly, Hperferritinaemia, mild mitralic insufficiency 55 [ 25 ] F Compound Heterozygous c.495_498del, p.F167Tfs * 9 Exon 5 Frameshift c.1246A > G, p.K416E Exon 8 Missense 6 m + + SA B-cell immunodeficiency, Immunoglobulin deficit + Low Developmental delay None Cataract Sensorineural deafness Neutrophilic dermatosis None 56 [ 27 ] F Compound heterozygous: c.498_501delATTT.Phe167fs,Exon5 Frameshift c.947C > T p.Ala316Val; Exon 7 Missense 2 m + + No B-cell immunodeficiency with Hypogammaglobulinaemia + Low Developmen...…”

“…The child had no further febrile episodes or seizures 52 [ 22 ] Compound heterozygous: c.525delT; p.Leu176X, Exon 5 deletion c.938 T > C; p.Leu313Ser Exon 7 missense 7 m Immunoglobulin replacement for 1 year Short term prednisone during fever Alive at 4 years 10 months, time between attacks increase to 3–4 months 53 [ 23 ] Compound heterozygous: c.383A > G p.D128G Exon 4 Missense c.1168G > A Gly390Ser Exon 8 Missense 4 m Immunoglobulin replacement since he was 4 months 2 RBC transfusions Anakinra + colchicine for 12 months switched to Etanercept + colchicine alive at 3 years and 1 month. Since he started Etanercept good control of fever episodes 54 [ 24 ] Homozygous mutation c.914A > T, p.Asp305Val Exon 7 Missense 6 m Immunoglobulin replacement Alive at 14 years olds. Stopped Immunoglobulin replacement at 12 years old 55 [ 25 ] Compound Heterozygous c.495_498del, p.F167Tfs * 9 Exon 5 Frameshift c.1246A > G, p.K416E Exon 8 Missense 6 m RBC transfusions Immunoglobulin replacement Etanerceot Alive at 4 years with resolution of the main manifestations 56 [ 27 ] Compound heterozygous: c.498_501delATTT.Phe167fs,Exon5 Frameshift c.947C > T p.Ala316Val; Exon 7 Missense 2 m Immunoglobulin replacement Alive at 7 years old 57 [ 28 ] Compound heterozygous: c.407 C > G, p.Ala136Lys Exon 4 Missense c.361 G > A; p.Glu121Lys Exon 4 Missense 1 m Immunoglobulin replacement Corticosteroids Etanercept Alive 58 [ 29 ] Heterozygous NA Immunoglobulin replacement Anakinra Colchicine …”

“…Splenomegaly was reported in 16 patients [ 1 – 4 , 8 , 17 , 23 , 24 ], while cardiomyopathy in 7 patients mainly a hypertrophic cardiomyopathy with a case of non-compacted cardiomyopathy [ 1 , 2 , 5 , 8 , 12 , 16 , 17 ].…”

Blood cytopenias as manifestations of inherited metabolic diseases: a narrative review

“…Comprehension and communication are profoundly impaired in many children. It can be confused with a diagnosis of early onset common variable immunodeficiency [ 31 – 33 ].…”

Spontaneous, simultaneous bilateral osteonecrosis of the femoral heads in a patient with sideroblastic anaemia with B-cell immunodeficiency, periodic fever and developmental delay syndrome

“…The exact pathogenesis is under study but many clinical signs may be linked to oxidative phosphorylation (OXPHOS) defects and dysfunctional translation, particularly in the mitochondria 5 6. Thus far, 58 patients with SIFD have been described: the syndrome is notable for the diversity of phenotypes, with siblings bearing the same mutations having different clinical presentations 1 2 5 7–31…”