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Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome(SIFD)

MedGen UID:
863609
Concept ID:
C4015172
Disease or Syndrome
Synonym: Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): TRNT1 (3p26.2)
 
Monarch Initiative: MONDO:0014487
OMIM®: 616084
Orphanet: ORPHA369861

Definition

Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndromic disorder characterized by onset of severe sideroblastic anemia in the neonatal period or infancy. Affected individuals show delayed psychomotor development with variable neurodegeneration. Recurrent periodic fevers without an infectious etiology occur throughout infancy and childhood; immunologic work-up shows B-cell lymphopenia and hypogammaglobulinemia. Other more variable features include sensorineural hearing loss, retinitis pigmentosa, nephrocalcinosis, and cardiomyopathy. Death in the first decade may occur (summary by Wiseman et al., 2013). [from OMIM]

Additional description

From MedlinePlus Genetics
TRNT1 deficiency is a condition that affects many body systems. Its signs and symptoms can involve blood cells, the immune system, the eyes, and the nervous system. The severity of the signs and symptoms vary widely.

A common feature of TRNT1 deficiency is a blood condition called sideroblastic anemia, which is characterized by a shortage of red blood cells (anemia). In TRNT1 deficiency, the red blood cells that are present are unusually small (erythrocytic microcytosis). In addition, developing red blood cells in the bone marrow (erythroblasts) can have an abnormal buildup of iron that appears as a ring of blue staining in the cell after treatment in the lab with certain dyes. These abnormal cells are called ring sideroblasts.

Many people with TRNT1 deficiency have an immune system disorder (immunodeficiency) that can lead to recurrent bacterial infections. Repeated infections can cause life-threatening damage to internal organs. The immunodeficiency is characterized by low numbers of immune system cells called B cells, which normally help fight infections by producing immune proteins called antibodies (or immunoglobulins). These proteins target foreign invaders such as bacteria and viruses and mark them for destruction. In many individuals with TRNT1 deficiency, the amount of immunoglobulins is also low (hypogammaglobulinemia).

In addition, many individuals with TRNT1 deficiency have recurrent fevers that are not caused by an infection. These fever episodes are often one of the earliest recognized symptoms of TRNT1 deficiency, usually beginning in infancy. The fever episodes are typically accompanied by poor feeding, vomiting, and diarrhea, and can lead to hospitalization. In many affected individuals, the episodes occur regularly, arising approximately every 2 to 4 weeks and lasting 5 to 7 days, although the frequency can decrease with age.

Eye abnormalities, often involving the light-sensing tissue at the back of the eye (the retina), can occur in people with TRNT1 deficiency. Some of these individuals have a condition called retinitis pigmentosa, in which the light-sensing cells of the retina gradually deteriorate. Eye problems in TRNT1 deficiency can lead to vision loss.

Neurological problems are also frequent in TRNT1 deficiency. Many affected individuals have delayed development of speech and motor skills, such as sitting, standing, and walking, and some have low muscle tone (hypotonia).

Features that occur less commonly in people with TRNT1 deficiency include hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss), recurrent seizures (epilepsy), and problems with the kidneys or heart.

TRNT1 deficiency encompasses what was first thought to be two separate disorders, a severe disorder called sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) and a milder disorder called retinitis pigmentosa with erythrocytic microcytosis (RPEM), each named for its most common features. SIFD begins in infancy, and affected individuals usually do not survive past childhood. RPEM, on the other hand, is recognized in early adulthood, and the microcytosis usually does not cause any health problems. However, it has since been recognized that some individuals have a combination of features that fall between these two ends of the severity spectrum. All of these cases are now considered part of TRNT1 deficiency.  https://medlineplus.gov/genetics/condition/trnt1-deficiency

Clinical features

From HPO
Nephrocalcinosis
MedGen UID:
10222
Concept ID:
C0027709
Disease or Syndrome
Nephrocalcinosis is the deposition of calcium salts in renal parenchyma.
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Communicating hydrocephalus
MedGen UID:
1058
Concept ID:
C0009451
Disease or Syndrome
A form of hydrocephalus in which there is no visible obstruction to the flow of the cerebrospinal fluid between the ventricles and subarachnoid space.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Delayed gross motor development
MedGen UID:
332508
Concept ID:
C1837658
Finding
A type of motor delay characterized by a delay in acquiring the ability to control the large muscles of the body for walking, running, sitting, and crawling.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Sideroblastic anemia
MedGen UID:
8067
Concept ID:
C0002896
Disease or Syndrome
Sideroblastic anemia results from a defect in the incorporation of iron into the heme molecule. A sideroblast is an erythroblast that has stainable deposits of iron in cytoplasm (this can be demonstrated by Prussian blue staining).
Hypochromic microcytic anemia
MedGen UID:
124413
Concept ID:
C0271901
Disease or Syndrome
A type of anemia characterized by an abnormally low concentration of hemoglobin in the erythrocytes and lower than normal size of the erythrocytes.
Schistocytosis
MedGen UID:
576247
Concept ID:
C0344386
Laboratory or Test Result
The presence of an abnormal number of fragmented red blood cells (schistocytes) in the blood.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
B lymphocytopenia
MedGen UID:
340780
Concept ID:
C1855067
Finding
An abnormal decrease from the normal count of B cells.
Decreased circulating antibody concentration
MedGen UID:
892481
Concept ID:
C4048270
Finding
An abnormally decreased level of immunoglobulin in blood.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Periodic fever
MedGen UID:
798670
Concept ID:
C0015974
Disease or Syndrome
Episodic fever that recurs at regular intervals.
Brittle hair
MedGen UID:
120480
Concept ID:
C0263490
Disease or Syndrome
Fragile, easily breakable hair, i.e., with reduced tensile strength.
Rod-cone dystrophy
MedGen UID:
1632921
Concept ID:
C4551714
Disease or Syndrome
An inherited retinal disease subtype in which the rod photoreceptors appear to be more severely affected than the cone photoreceptors. Typical presentation is with nyctalopia (due to rod dysfunction) followed by loss of mid-peripheral field of vision, which gradually extends and leaves many patients with a small central island of vision due to the preservation of macular cones.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCongenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome

Professional guidelines

PubMed

Fouquet C, Le Rouzic MA, Leblanc T, Fouyssac F, Leverger G, Hessissen L, Marlin S, Bourrat E, Fahd M, Raffoux E, Vannier JP, Jäkel N, Knoefler R, Triolo V, Pasquet M, Bayart S, Thuret I, Lutz P, Vermylen C, Touati M, Rose C, Matthes T, Isidor B, Kannengiesser C, Ducassou S
Br J Haematol 2019 Nov;187(4):530-542. Epub 2019 Jul 23 doi: 10.1111/bjh.16100. PMID: 31338833

Recent clinical studies

Etiology

Fouquet C, Le Rouzic MA, Leblanc T, Fouyssac F, Leverger G, Hessissen L, Marlin S, Bourrat E, Fahd M, Raffoux E, Vannier JP, Jäkel N, Knoefler R, Triolo V, Pasquet M, Bayart S, Thuret I, Lutz P, Vermylen C, Touati M, Rose C, Matthes T, Isidor B, Kannengiesser C, Ducassou S
Br J Haematol 2019 Nov;187(4):530-542. Epub 2019 Jul 23 doi: 10.1111/bjh.16100. PMID: 31338833
Tesarova M, Vondrackova A, Stufkova H, Veprekova L, Stranecky V, Berankova K, Hansikova H, Magner M, Galoova N, Honzik T, Vodickova E, Stary J, Zeman J
Pediatr Blood Cancer 2019 Apr;66(4):e27591. Epub 2018 Dec 26 doi: 10.1002/pbc.27591. PMID: 30588737
DeLuca AP, Whitmore SS, Barnes J, Sharma TP, Westfall TA, Scott CA, Weed MC, Wiley JS, Wiley LA, Johnston RM, Schnieders MJ, Lentz SR, Tucker BA, Mullins RF, Scheetz TE, Stone EM, Slusarski DC
Hum Mol Genet 2016 Jan 1;25(1):44-56. Epub 2015 Oct 22 doi: 10.1093/hmg/ddv446. PMID: 26494905Free PMC Article
Wiseman DH, May A, Jolles S, Connor P, Powell C, Heeney MM, Giardina PJ, Klaassen RJ, Chakraborty P, Geraghty MT, Major-Cook N, Kannengiesser C, Thuret I, Thompson AA, Marques L, Hughes S, Bonney DK, Bottomley SS, Fleming MD, Wynn RF
Blood 2013 Jul 4;122(1):112-23. Epub 2013 Apr 3 doi: 10.1182/blood-2012-08-439083. PMID: 23553769Free PMC Article
Lee AC
Ann Acad Med Singap 2012 Jul;41(7):305-8. PMID: 22892608

Diagnosis

Bardou MLD, Rivitti-Machado MC, Michalany NS, de Jesus AA, Goldbach-Mansky R, Barros JCR, Terreri MTSELRA, Grumach AS
Australas J Dermatol 2021 May;62(2):e276-e279. Epub 2020 Dec 17 doi: 10.1111/ajd.13527. PMID: 33332575
Fouquet C, Le Rouzic MA, Leblanc T, Fouyssac F, Leverger G, Hessissen L, Marlin S, Bourrat E, Fahd M, Raffoux E, Vannier JP, Jäkel N, Knoefler R, Triolo V, Pasquet M, Bayart S, Thuret I, Lutz P, Vermylen C, Touati M, Rose C, Matthes T, Isidor B, Kannengiesser C, Ducassou S
Br J Haematol 2019 Nov;187(4):530-542. Epub 2019 Jul 23 doi: 10.1111/bjh.16100. PMID: 31338833
Giannelou A, Wang H, Zhou Q, Park YH, Abu-Asab MS, Ylaya K, Stone DL, Sediva A, Sleiman R, Sramkova L, Bhatla D, Serti E, Tsai WL, Yang D, Bishop K, Carrington B, Pei W, Deuitch N, Brooks S, Edwan JH, Joshi S, Prader S, Kaiser D, Owen WC, Sonbul AA, Zhang Y, Niemela JE, Burgess SM, Boehm M, Rehermann B, Chae J, Quezado MM, Ombrello AK, Buckley RH, Grom AA, Remmers EF, Pachlopnik JM, Su HC, Gutierrez-Cruz G, Hewitt SM, Sood R, Risma K, Calvo KR, Rosenzweig SD, Gadina M, Hafner M, Sun HW, Kastner DL, Aksentijevich I
Ann Rheum Dis 2018 Apr;77(4):612-619. Epub 2018 Jan 22 doi: 10.1136/annrheumdis-2017-212401. PMID: 29358286Free PMC Article
Wiseman DH, May A, Jolles S, Connor P, Powell C, Heeney MM, Giardina PJ, Klaassen RJ, Chakraborty P, Geraghty MT, Major-Cook N, Kannengiesser C, Thuret I, Thompson AA, Marques L, Hughes S, Bonney DK, Bottomley SS, Fleming MD, Wynn RF
Blood 2013 Jul 4;122(1):112-23. Epub 2013 Apr 3 doi: 10.1182/blood-2012-08-439083. PMID: 23553769Free PMC Article
Lee AC
Ann Acad Med Singap 2012 Jul;41(7):305-8. PMID: 22892608

Therapy

Giannelou A, Wang H, Zhou Q, Park YH, Abu-Asab MS, Ylaya K, Stone DL, Sediva A, Sleiman R, Sramkova L, Bhatla D, Serti E, Tsai WL, Yang D, Bishop K, Carrington B, Pei W, Deuitch N, Brooks S, Edwan JH, Joshi S, Prader S, Kaiser D, Owen WC, Sonbul AA, Zhang Y, Niemela JE, Burgess SM, Boehm M, Rehermann B, Chae J, Quezado MM, Ombrello AK, Buckley RH, Grom AA, Remmers EF, Pachlopnik JM, Su HC, Gutierrez-Cruz G, Hewitt SM, Sood R, Risma K, Calvo KR, Rosenzweig SD, Gadina M, Hafner M, Sun HW, Kastner DL, Aksentijevich I
Ann Rheum Dis 2018 Apr;77(4):612-619. Epub 2018 Jan 22 doi: 10.1136/annrheumdis-2017-212401. PMID: 29358286Free PMC Article

Prognosis

Fouquet C, Le Rouzic MA, Leblanc T, Fouyssac F, Leverger G, Hessissen L, Marlin S, Bourrat E, Fahd M, Raffoux E, Vannier JP, Jäkel N, Knoefler R, Triolo V, Pasquet M, Bayart S, Thuret I, Lutz P, Vermylen C, Touati M, Rose C, Matthes T, Isidor B, Kannengiesser C, Ducassou S
Br J Haematol 2019 Nov;187(4):530-542. Epub 2019 Jul 23 doi: 10.1111/bjh.16100. PMID: 31338833
Tesarova M, Vondrackova A, Stufkova H, Veprekova L, Stranecky V, Berankova K, Hansikova H, Magner M, Galoova N, Honzik T, Vodickova E, Stary J, Zeman J
Pediatr Blood Cancer 2019 Apr;66(4):e27591. Epub 2018 Dec 26 doi: 10.1002/pbc.27591. PMID: 30588737
Barton C, Kausar S, Kerr D, Bitetti S, Wynn R
J Clin Pathol 2018 Mar;71(3):275-278. Epub 2017 Oct 21 doi: 10.1136/jclinpath-2017-204698. PMID: 29055896Free PMC Article
Wiseman DH, May A, Jolles S, Connor P, Powell C, Heeney MM, Giardina PJ, Klaassen RJ, Chakraborty P, Geraghty MT, Major-Cook N, Kannengiesser C, Thuret I, Thompson AA, Marques L, Hughes S, Bonney DK, Bottomley SS, Fleming MD, Wynn RF
Blood 2013 Jul 4;122(1):112-23. Epub 2013 Apr 3 doi: 10.1182/blood-2012-08-439083. PMID: 23553769Free PMC Article

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