Congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD)

Order Genetic Testing

Acronym:
SIFD

SAID group:
Generation of Intracellular Stress; Congenital Sideroblastic Anemias (CSAs)

Gene:
TRNT1

Inheritance:
Autosomal recessive.

Ethnicity:
Unknown

Frequency:
Unknown-rare.

Timing of symptoms:
Flares every 2-4 weeks lasting 5-7 days. Some have predictable fever and flare patterns, but most have random attacks, ranging from weekly, to every 3-4 weeks. One case had weekly fevers in infancy, that become bi-monthly in childhood. Periodic fevers with vomiting, and diarrhea starting in infancy for most cases. [89]

Age of onset:
Most have symptoms present in the neonatal period or prior to 3 months of age. Once case with onset at 18 months. [89]

Skin cutaneous:
Rash is uncommon. Some with notable pallor at birth. A few with brittle hair. [89] One case with chronic icthyosis, erythema and/or hypopigmentation of the skin. Biopsy showed perivascular lymphohistiocytic infiltrate and electron microscopy found a few spots of fibrillar amyloid-like material. [89]

Neurologic:
Periodic fevers, progressive cognitive delay and developmental delay, speech and comprehension challenges, cerebral atrophy. [89] Seizures, some with cerebellar ataxia. Neurodegeneration, abnormalities in the cerebellum. [89]

Auditory:
Sensorineural hearing loss. [89]

Ophthalamic:
Retinitis pigmentosa. One case of atypical retinitis pigmentosa and variant retinitis punctata albescens. [89]

Cardiopulmonary:
Dilated cardiomyopathy. [89] Cardiac failure was the leading cause of death in most cases. [89] [91] Immunodeficiency and higher risk of sinusitis, pneumonia/pulmonary infections (not during SIFD flares). [89]

Abdominal:
Vomiting and diarrhea with fever and flares. Mild hepatomegaly and splenomegaly (hepatosplenomegaly) Nephrocalcinosis. [89] High risk of death from multi-organ failure. [91] Cyclic vomiting with metabolic acidosis, feeding poorly, gastrointestinal upset, abdominal pain, and other intestinal issues accompanied by fevers. [89]

Lymphatic:
Immunodeficiency. Lymphadenopathy, splenomegaly. Once case of fatal adrenal hemmorhage. [89]

Joints bones muscles cartilage:
Hypotonia (generalized or tructal) with increasing severity. Gross motor delay and developmental delay, avascular necrosis. One case with muscular metabolic myopathy. [89]

Vasculitis:
Not noted. [89] [91]

Amyloidosis:
Nt noted. [89] [91]

Abnormal labs:
High during flares: ESR, CRP, ferritin, high transferritin, hypercalciuria.[89] Common during flares: metabolic acidosis, aminoaciduria and metabolic abnormalities. Severe sideroblastic anemia, that is extremely microcytic. B cell lymphopenia, variable panhypogammoglobulinemia and/or low levels of mature CD19+ B cells in the blood. Immunodeficiency. [89] Bone marrow biopsy pathology: Erythroid precursors featuring perinuclear mitochondrial iron deposits (“ringed sideroblasts”). [89]

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