Introduction

Sideroblastic anaemia with B-cell immunodeficiency, periodic fever and developmental delay (SIFD) syndrome is a novel rare multisystem disorder to be considered in infants and children [1, 2]. In 2013 and 2014, Wiseman et al. and Chakraborty et al. reported the first 12 patients with SIFD syndrome with a homozygous or compound heterozygous mutation in TRNT1 gene [1, 2]. TRNT1 encodes for a transfer RNA (tRNA) nucleotidyl-transferase 1 [2] that is responsible for the 3′ end adding trinucleotide sequence consisting of cytosine-cyto-sine-adenine (CCA). It is necessary for mitochondrial and cytosolic protein syntheses in positioning tRNAs on ribosomes and in terminating protein translation. Therefore, this protein has a crucial role in the protein maturation, in the mitochondrial electron transport chain and in the prevention of intracellular oxidative stress. After the first reports, the phenotypic spectrum and the insight in pathophysiology of this syndrome have been widely expanded [3, 4]. The aim of this systematic review is to describe the phenotype spectrum and the detected mutations currently described in literature.

Materials and Methods

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A systematic search was conducted to identify studies reporting cases of patients with SIFD syndrome. The literature search and evaluation were performed in 2 databases, MEDLINE (PubMed) and EMBASE, for articles published up to the 30th of July 2021. The key words, inclusion and exclusion criteria, type of study to include, the methodology used to select papers and extract data were widely described in the Supplementary material.

Results

The search identified 264 eligible articles, of which 50 were duplicates, and, after title and abstract screening, 159 articles were excluded. The full-text length of 55 articles was assessed for eligibility and 29 articles were included (Fig. 1; Supplementary Table 1). The articles 1 and 2 were included because article number 1 describes the phenotypic characteristics of patients reported in article 2 where the genetic results are shown.

Fig. 1
figure 1

PRISMA flow diagram. Presentation of the procedure of literature searching and selection with numbers of articles at each stage

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Genetic Characteristic

TRNT1 is composed by 7 introns and 8 exons, most of the mutations reported were found in the exonic regions (Fig. 2). Forty-one unique mutations have been reported to date: 17 patients presented a homozygous mutation in TRNT1, while 38 showed compound heterozygosity and 3 were heterozygous for a single mutation (Tables 1, 2 and 3). The type of reported mutations are more frequently missense mutations. Cases of frameshift and splicing mutations are however identified. These lasts were only in the intronic regions, conversely to the other types reported across the entire gene. When homozygosity was evaluated, the found mutation is typically a missense mutation with the exception of one patient where a homozygosity for frameshift mutation was discovered c.218_219ins22 NA Exon 3 [5].

Fig. 2
figure 2

Schematic representation of TRNT1 gene, with the different mutations reported

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Table 1 Clinical and laboratory description of patients with SIFD. F, female; M, male; SA, sideroblastic anaemia; m, months; y, years; IQ, intelligence quotient
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Table 2 List of TRNT1 mutation reported in 57 SIFD patients. h = homozigous
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Figure 2 is a schematic representation of the TRNT1 gene, with the different reported mutations at different sites. The two most frequent reported mutations were the c.295C > T R99W Exon 3 (Missense) and the c.668 T.C p.I223T Exon 6 (Missense).

Clinical Aspects

Fifty-eight patients were identified, including 32 females (56.1%), with a median age at onset of symptoms of 4 months of life (range 0–252 m) and a mean of 18.3 months (Standard deviation 49.01). Of these, 12 were Asian, 26 Caucasian, 2 African, 2 Latin-American, while ancestry was not reported for 16. We recorded 12 instance of familial consanguinity and 15 of disease in relatives.

The most frequent features were haematologic manifestations such as microcytic anaemia or sideroblastic anaemia (54/58, 93.1%), recurrent fever (52/58, 89.6%), neurologic impairment (48/58, 82.7%), immunologic abnormalities in particular a humoral immunodeficiency (48/58, 82.7%), gastrointestinal signs and symptoms (37/58, 63.7%), eye diseases as cataract and retinitis pigmentosa (27/58, 46.5%), failure to thrive (26/58, 45.8%), mucocutaneous involvement (29/58, 50%), sensorineural deafness (19/58, 32.7%) and others (Fig. 3 and Tables 1, 3 and 4). Only 38/58 (65%) patients showed the complete phenotype characterized by anaemia, recurrent fever, immunodeficiency e neurodevelopmental delay. Nineteen patients died, of whom 3 due to complication of stem cell transplantation.

Fig. 3
figure 3

Distribution of main features in 58 patients with SIFD syndrome

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Table 3 Description of treatments performed in each patient and outcomes. IVIG, intravenous immunoglobulin; m, month; NR, not reported; HSCT, hematopoietic stem cell transplantation; AZA, azathioprine; MOF, multi-organ failure
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Table 4 Main features of SIFD syndrome
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The following description is based on the 58 reported cases (Tables 1, 3, 4).

Haematological Manifestation

Haematologic involvement is the most frequent finding (54/58 patients), usually sideroblastic anaemia (37), while in a minority of cases microcytosis and hypochromasia without prominent ring sideroblasts was reported [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. Peripheral blood smears typically showed hypochromasia, microcytosis, target cell, variable schistocytosis, anisocytosis, elliptocytes, basophilic stippling and nucleate erythrocytes (1–4, 6). Pancytopenia was reported in 4 patients [4, 15, 20] with extramedullary erythropoiesis reported in 2 patients by Barton et al. [8]. Furthermore, in 2 patients, haemophagocytosis was evaluated in the bone marrow, but without fulfilling the HLH-2004 criteria [3, 23].

Bone marrow examination showed in several patients ring sideroblasts that represent more than the 50% of erythroid precursors, erythroid hyperplasia and dyserythropoiesis and in 3 patients, abundant megakaryopoiesis with dysplastic morphology [1,2,3,4, 6, 12]. Furthermore, two patients experienced unprovoked recurrent thromboembolic events [3].

Fever

Recurrent episodes of high spiking fever with upset and elevated inflammatory markers were reported in 52 patients (89.6%) [1,2,3,4,5,6,7, 10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29]. Typically, episodes were reported to last for 3–7 days with recurrence every 2–4 weeks or in rare cases every week. Over several years, the interval between attacks had tendency to increase in many cases.

Immunologic Abnormalities

Immunologic abnormalities were documented in 48/58 (82.75%) patients, all showing an impairment in number of B-cell or circulating Immunoglobulin levels [1,2,3,4,5, 7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25, 27, 28]. Extensive investigation of B-cell subsets highlighted an early defect in B-cell maturation with a block in the pre-B-II stage [1, 20]. Furthermore, Yang et al. described in their patient an impaired number of B memory cell with a reduced number of B switched compared to healthy control [22].

T and Natural killer lymphocytes were fluctuant or decreased in 16 patients [1,2,3, 9, 13, 16, 18, 20, 22, 23]. Moreover, Wiseman et al. evaluated a progressive decline in T and NK cells seen in several cases of their cohort [1]. High expression of double-negative T cells in the peripheral blood has been reported in 2 patients by Giannaleou et al. [28]. Furthermore Lougaris et al. demonstrated in their patient a severe decrease in T cell receptor excision circles (TRECs) and Kappa-deleting recombination excision circles (KRECs) [16].

Cytokine analysis of blood, performed in some patients during episodes of fever or in the absence of fever, recorded high levels of IL-1β, IL-2R, IL-6, IL-8, IL-18 and TNFα, mildly raised IL-10 and interferon-α induced proteins [3, 9, 18]. The authors of these papers did not specify if the value of these cytokines and interferon-α induced proteins return to the normal value.

Neurologic Features

Neurological manifestations are reported in 48/58 (82.75%) patients with a widely variable phenotypic spectrum [1,2,3,4,5, 7,8,9,10,11,12, 14,15,16,17,18, 21,22,23, 26, 28] (Table 1). The most frequent manifestations are developmental delay or progressive regression in 41 patients, cerebellar symptoms in 15/45 and partial or complex seizures in 15/45 [1,2,3,4,5, 7,8,9,10,11,12, 14,15,16,17,18, 21, 22, 26]. Brain MRI appearances were widely variable, reporting abnormal results in the 28% cases including cerebral and cerebellar atrophy, hydrocephalus, delayed cortical white matter myelination, lesions in external capsule and thalamus, and hyperintense lesions in the white matter [1,2,3,4,5, 7,8,9,10,11,12, 14,15,16,17,18, 21,22,23, 26].

Gastrointestinal Manifestations

Vomiting, diarrhoea and hepatic disease diseases were described in 38/58 (65%) patients, especially during fever episodes and 5 experienced an exocrine pancreatic insufficiency [1,2,3,4,5, 8,9,10, 14,15,16,17,18,19, 23, 29]. Partial villous atrophy or acute and chronic inflammation in bowel mucosa was recorded in 5 patients [3, 4, 9, 19].

Cutaneous Manifestations

Skin abnormalities were reported in 29/58 SIFD population (49%) mainly brittle hair or ichthyotic skin, panniculitis, erythema nodosum, morfea and aspecific rash [1,2,3,4,5, 7, 9, 11,12,13,14, 17,18,19, 21,22,23,24,25, 27,28,29]. A biopsy of erythematous nodule lesions showed a lobular and septal neutrophilic panniculitis [13, 18, 25, 28]. Jfri’s adult patient (40 years old) showed lichen sclerosus and atrophicus and morphea [19].

Ophthalmologic Abnormalities

Ocular involvement was recorded in 27/58 (47.4%) patients, of whom retinitis pigmentosa in 16 and cataract in 11 patients, respectively [1,2,3,4,5,6,7, 9, 15, 17, 19, 25, 27].

Metabolic Abnormalities

Metabolic abnormalities were documented in 10 patients with a wide spectrum of reports including metabolic acidosis, hyperlactacidaemia, hyperalaninaemia, aminoaciduria with increased urinary metabolites of the tricarboxylic acid pathway and in one case Leigh syndrome [1, 2, 4, 5, 15, 26].

Giannelou et al. in their paper described an increased reactive oxygen species (ROS) production in 3 patients’ fibroblasts compare to healthy controls [3]

Additional Features

Sensorineural hearing loss was described in 20 patients in different age [1,2,3,4, 7, 9, 10, 14, 15, 17, 19, 25, 26].

Splenomegaly was reported in 16 patients [1,2,3,4, 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].

Musculoskeletal involvement was reported in 15 patients of 57 and the most frequent reports are arthritis (8) and myositis (3) and dactylitis [1,2,3, 5, 6, 8, 17, 19, 21, 23].

Renal disease was reported in 7 patients of these 2 showed Fanconi syndrome, 2 tubulopathy and 4 nephrocalcinosis [1,2,3,4, 26].

Treatment and Outcome

At the time of this systematic review, 19 patients were reported to have died at a median age of 28 months (range 0–168 months): 16 deaths were directly related to the underlying disease course (9 due to multiorgan failure during sepsis-like episodes, 3 to heart failure, 3 to neurologic complications and 1 due to septic shock) and 3 following complications post-stem cell transplantation. Four of the nineteen patients died before five years old. Thirty-three patients remained alive at time of publication (at a median life of 120 months with a range of 21–504 months. Of these 33 patients alive, 16 (48.4%) were older than 10 years old. For 5 patients, clinical outcome was not reported [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22, 26].

We can distinguish two different therapeutic approaches that have been applied: one supportive, based on blood transfusions, immunoglobulin replacement, antibiotics and electrolyte supplementation; the other with intent to modify the disease course (Table 5). For the latter, hematopoietic cell stem transplantation (HCST) and anti-TNFα drugs have been used with some reports of successful disease modification. HCST was performed in 5 patients as rescue therapy: 3 died due to complications during the first weeks post-transplantation, while 2 remained alive at time of publication with reported complete resolution of episodic fevers, immunodeficiency, haematologic abnormalities and improvement of growth and neurologic features. One developed retinitis pigmentosa during the post-transplant period [1,2,3,4, 8].

Anti-TNFα drugs, Etanercept or Infliximab, were used in 10 patients with resolution of fever and associated symptoms, improvement of growth, inflammatory bowel disease and neurologic symptoms [3, 17, 21, 23, 25, 28]. Anakinra, an anti-IL1, was used in 6 patients but discontinued in 5 because of lack of efficacy and in 1 for allergy [1,2,3, 17, 23]. Colchicine (4/58) and corticosteroids (13/58) were used in attempt to manage febrile episodes, as symptomatic treatment. Anecdotical reports of patients successfully treated with methotrexate (1 patient, due to arthritis) and azathioprine (1 patient, due to inflammatory bowel disease) were also identified [3, 6].

Discussion

With an expanding landscape of novel, diverse but rare monogenic causes of autoinflammatory syndromes and immunodeficiencies, our first collation of reported cases provides a useful update of the recently described SIFD syndrome [1,2,3,4, 13, 18, 20, 30,31,32,33]. Our systematic review, summarising the 58 reported cases so far, summarises the spectrum of phenotypic manifestations, treatment approaches and clinical outcomes in this rare syndrome. All reported cases were associated with biallelic mutation in the TRNT1 gene, with the exception of 3 cases associated with only a discernible heterozygous mutation [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29].

Mutation in TRNT1 causes partial loss of function of the TRNT1 RNA polymerase, an essential enzyme necessary for maturation of transfer RNA (t-RNA) in the nucleus and mitochondria, and for respiratory chain function [1,2,3,4]. In particular in the mitochondria negatively affect the mature function, with an oxidative phosphorylation defect and decreased enzymatic activities of complexes I, II and IV of the mitochondrial electron transport chain and energy production. This leads to an impaired intracellular stress response, impairment in protein clearance and dysfunctional autophagy. Thus, defective maturation of t-RNA in the mitochondria and cytosol leads to defective protein synthesis, clearance system, dysfunctional autophagy as well as translation of multiple tRNA[1,2,3,4, 9]. This mechanism affects not only the iron metabolism in the mitochondria of the erythroblast causing congenital sideroblastic anaemia, but also B-cell lymphocyte maturation, and diverse impacts on several other tissues characterized by high production of protein [3, 9, 19]. The accumulation of cellular stress, secondary to dysregulated protein metabolism, leads to cell destruction and periodic inflammation.

However, based on data of the literature is not possible to say if the metabolic abnormalities, in terms of lactic acidosis or increased of ROS or aminoacidic alterations, are always present or only during fever episodes. Moreover, as a consequence of metabolic abnormalities in several patients, nephrocalcinosis was frequently described in terms of renal tubular acidosis that led to hypercalciuria and electrolytes imbalance. While hyperferritinaemia was reported in several cases, a consequence of the hyperinflammation but also of the iron overload because of diserytropoiesis and blood transfusions (1–3).

While the immunological abnormalities, one of the predominant characteristics of this syndrome, seem to be probably a consequence of defective maturation of B-cell with an increase’s percentage of immature B-cell and decrease production of Immunoglobulins of different classes. TRNT1 enzyme has a crucial role in the protein maturation and degradation, and B-cell differentiation was stopped I at pre-bell steps as demonstrated by Kumaki et al. [20]. Immunoglobulin levels may widely vary reflecting the severity of the enzyme deficiency and B-cell immunodeficiency, and the most affected are the IgG. Moreover, during the episodes of fever, some patients showed a drop of B-cell. However, Wiseman et al. evaluated a progressive decline in the lymphopoiesis in general suggesting a general impact on lymphopoiesis [1].

If we take a carefully look in the different pathogenic variants on TRNT1, it seems that more severe forms are more likely associated with mutations in the catalytic region of the protein, while the milder phenotypes are associated with mutations in the N- or C-terminal or an inheritance in heterozygosis manner. A recent study by Leibovitch showed that while some mutations (e.g., T154I, L166S) impair the protein stability, other mutations (e.g., M158V, R190I and I223T) impact both the CCA-adding catalytic activity as well as protein stability [34]. However, according to the current literature, a clear genotype–phenotype correlation is far to be identified, since patients with the same genotype showed totally different phenotypes with completely different outcomes [8].

SIFD syndrome is heterogenous and patients may not only present with the classic sideroblastic anaemia, B-cell immunodeficiency, fever or developmental delay but can also have a wide variety of other manifestations including retinitis pigmentosa, cataract, inflammatory bowel disease, pseudo-juvenile-arthritis, sensorineural deafness, panniculitis, cardiomyopathy and cutaneous disease configuring a TRNT1 relating disease. Indeed, only the 65% of cases showed the complete phenotype, probably mirroring a different enzymatic residual activity but also a different penetrance of the mutation and the different effect of the environment. A complete correlation between genotype-phenotype, as in other metabolic disease, at the moment is not possible, based on the current knowledge, but future prospective study will help in understanding it. Moreover, sometimes, the typical manifestation may be absent; thus, based on these findings, it would be more appropriate to think this syndrome as a TRNT1-related disorders. Consideration of SIFD in the differential diagnosis could be crucial for prompt and tailored treatment in order to delay its natural history, prevent complications and potentially direct patients to potentially curative allogeneic stem cell transplant. However, the phenotypic spectrum of this novel autoinflammatory disease is still emerging, with some distinctive common features but a diverse set of clinical phenotypes and patterns of system involvement described. Effective recognition, diagnosis and management planning thus mandates increased awareness amongst diverse specialists, including neurologists, haematologists, rheumatologists and immunologists, and close multidisciplinary working for individual diagnosed patients. Furthermore, the increased knowledge about its pathophysiology is opening the route to new possible treatments. Anti-TNFα agents currently represent a real opportunity for these patients while bone marrow transplantation needs to be considered carefully taking into consideration the risk of complications including those correlated to severe lactic acidosis [1, 3, 17]. Maybe a conditioning with TNF-inhibitors will help in the future in these patients even though there are not enough evidence at the moment. Moreover, we need to consider that the treatment may change across the different age of the patients, as the need of red blood cells transfusion seems to decrease based on literature data. As well as the course of the main manifestations of this rare syndrome may be widely variable, based on the different phenotypes.

Two different groups, independently, suggested a fascinating link between mitochondrial disease and interferonopathies, based on the constitutive activation of the type I IFN pathway in patients with biallelic mutations in TRNT1. A potential role of type I IFN in the pathogenesis of SIFD has been therefore suggested [3, 18].

The reactive oxygen species produced by mitochondria are currently emerging as critical factors in signalling pathways regulation, triggering NLRP3 inflammasome activation and type I IFN production [3, 18]. It was also hypothesised that a mutual activation of ROS and type I IFN results in type I IFN-mediated autoinflammatory disease. This might be potential putative mechanisms able to explain the wide range of different autoinflammatory manifestations occurring in SIFD. Therefore, the evidence of a positive interferon signature during the inflammatory episodes might suggest a possible role for JAK-inhibitors. Controlled studies are warranted, but the rarity of this disease hampers this possibility. [2, 3 9, 14, 19, 21].

This systematic review has some limitations. The data extracted from the different papers were not homogenous, due to the different nature of the selected studies, and their different aims. We decided to include single case reports in order to not miss any reporting peculiar phenotype of a such rare disease. We recognize that this may led to a positive selection bias (publication bias), however, the rarity of the disease might also overcome this issue. Notably, we did not include studies when it was not possible to extract information on potentially eligible patients and about their phenotype. The data provided from the different papers are very various and the functional tests, that are crucial to understand the real mechanism of the disease, are not performed in all the patients studied. Considering all these points this systematic review provides a low quality of evidence.

A comprehensive study reporting prospectively the complete natural history of the disease from the onset to the development of the different manifestations and different laboratory abnormalities would be helpful for clinicians. We propose the need for an international, multicentre collaborative registry to collect a comprehensive, standardized dataset to better define the natural history of the disease. The clinical summaries of SIFD syndrome herein provided may be a useful tool to select patients with autoinflammatory syndromes and immunodeficiencies to direct specific testing for TRNT1 gene and therefore starting a more appropriate treatment according to the current knowledge.

Questions

  1. 1)

    SIFD may presents with?

    • a. Recurrent Fever

    • b. Immunodeficiency

    • c. Developmental delay

    • d. Anaemia

    • e. All of the above *

  2. 2)

    Which is the most frequent immunodeficiency associated with SIFD?

    • a. T immunodeficiency

    • b. Humoral immunodeficiency*

    • c. NK deficit

    • d. Neutrophil deficit

    • e. None

  3. 3)

    TRNT1 is

    • a. An enzyme essential for the maturation of mRNA

    • b. A nucleolar enzyme essential for the maturation of DNA

    • c. RNA polymerase, essential enzyme necessary for maturation of transfer RNA (t-RNA) in the nucleus and in the mitochondria and respiratory chain function*

    • d. A mitochondrial enzyme

    • e. A protein of the respiratory chain function in the mitochondria

  4. 4)

    Which is the possible therapeutic approach?

    • a. Immunoglobulins, Blood transfusions, corticosteroids

    • b. Colchicine and Anti-IL1

    • c. IVIG

    • d. Based on clinical phenotype with the possibility to use immunoglobulins, blood transfusions, anti-TNF, Hematopoietic stem cell transplantation *

    • e. Corticosteroids

  5. 5)

    Which part of the body can be involved?

    • a. Heart

    • b. Eye and ears

    • c. Joints

    • d. Brain

    • e. All of the above*