Immunodeficiency 90 with Encephalopathy, Functional Hyposplenia, and Hepatic Dysfunction

Immunodeficiency 90 with encephalopathy, functional hyposplenia and hepatic dysfunction also called IMD90 is a very rare autosomal recessive inherited complex immunological deficiency syndrome with systemic organ manifestations (hyposplenia, hepatic dysfunction) in addition to primary immunodeficiency. The cause is a homozygous or heterozygous mutation in the FADD gene (602457) on chromosome 11q13.

Kohn et al (2020) identified one heterozygous mutation in the FADD gene (602457.0002 and 602457.0003). The mutations, found by whole-exome sequencing and confirmed by Sanger sequencing, were consistent with disease in the family. The patients' T cells had decreased FADD protein levels compared with controls.

Affected individuals become ill in infancy or early childhood.

Inflammatory signs with recurrent fever and bacterial or viral infections are prominent. These inflammatory signs are accompanied by central nervous symptoms, including irritability, drowsiness, variable seizures, and white matter abnormalities on brain imaging.

Hepatic dysfunction and functional hyposplenism lead to increased susceptibility to invasive pneumococcal infections, which can be fatal.

A subset of patients exhibit congenital heart malformations. Most affected individuals exhibit developmental delay and speech delay.

Laboratory findings in affected individuals resemble those of autoimmune lymphoproliferative syndrome (ALPS; 601859), including high circulating CD4-/CD8-/TCR-alpha-beta+ (double-negative) T-cell (DNT) counts and elevated IL10 (124092) and FASL (TNFSF6; 134638) levels.

Massive lymphadenopathy and associated autoimmune features are not observed in IMD90 (Bolze et al. 2010, Savic et al. 2015; Kohn et al. 2020).

Susceptibility to viral infections likely results from impaired interferon immunity.

Kohn et al (2020) reported on a boy born to unrelated parents with IMD90. He presented at 14 months of age with the first of several episodes of fever, rash, vomiting, status epilepticus, and respiratory failure. The enlarged neck lymph nodes regressed with antibiotics and steroids, although no infectious agent was found.

Family history included an older brother who suffered a similar acute episode 5 days after his MMR vaccination; he died at 18 months of age. Based on the family history, the proband was not vaccinated.

Laboratory examination of the patient revealed an elevated total lymphocyte count with an increased percentage of double-negative CD3+ T cells, elevated CD19+ B cells, Howell-Jolly bodies suggestive of functional hyposplenism, intermittently elevated liver enzymes, elevated IL10, elevated serum FASL, and impaired Fas-mediated cell death. The patient had mild neurodevelopmental delay and white matter changes in the corpus callosum. Cytopenias, autoimmune features, hepatosplenomegaly, and massive lymphadenopathy were not observed. He was treated with subcutaneous immunoglobulins.

1. Bolze A et al (2010) Whole-exome-sequencing-based discovery of human FADD deficiency. Am J Hum Genet 87: 873-881.
2. Kohn LA et al (2020) Novel compound heterozygote variations in FADD identified to cause FAS-associated protein with death domain deficiency. J Clin Immun 40: 658-661.
3. Marín-Rubio JL et al (2019) FADD in Cancer: Mechanisms of Altered Expression and Function, and Clinical Implications. Cancers (Basel) 11:1462.
4. Savic S et al (2015) A new case of Fas-associated death domain protein deficiency and update on treatment outcomes. J Allergy Clin Immun 136: 502-505.