Immunodeficiency 59 And Hypoglycemia

A number sign (#) is used with this entry because of evidence that immunodeficiency-59 and hypoglycemia (IMD59) is caused by compound heterozygous mutation in the HYOU1 gene (601746) on chromosome 11q23. One such patient has been reported.

Description

Immunodeficiency-59 is an autosomal recessive primary immunologic disorder characterized by combined immunodeficiency and recurrent septic infections of the respiratory tract, skin, and mucous membranes, as well as disturbed glucose metabolism. Granulocytopenia and B-cell and dentritic cell deficiency are present (Haapaniemi et al., 2017).

Clinical Features

Haapaniemi et al. (2017) reported a 45-year-old woman with symptoms of combined immunodeficiency and episodes of stress-induced hypoglycemia since birth. From infancy to adulthood, she suffered from numerous septic infections of the respiratory tract, skin, and mucous membranes. Other infections included septic herpetic gingivostomatitis in childhood, and in adulthood she had herpetic encephalitis followed by recurring condylomatous warts on her thighs and genital area. An immunodysregulatory component was evident, as the patient developed hidradenitis suppurativa in her teens and relapsing Takayasu arteritis as an adult. In her late 20s, she underwent several spontaneous miscarriages due to placental bleeding, and 2 pregnancies resulted in placental thrombosis and microabscesses, septic infection, and fetus mortus at week 20 to 22. The patient showed broad abnormalities in the myeloid lineage including constant granulocytopenia, and she also had microcytic anemia and fluctuating thrombocytopenia. Neutrophils showed poor chemotaxis and increased activation. Bone marrow biopsies showed inconstant myeloid maturation arrest that resolved on granulocyte colony stimulating-factor treatment. Antigen presentation and adaptive immunity were affected. Both plasmacytoid and monocytoid dendritic cells were reduced in peripheral blood, and the expression of costimulatory CD86 molecule was low in both monocytoid dendritic cells and monocytes. These findings, together with a low PHA stimulation response, suggested impaired antigen presentation. The proportions of CD4+ and CD8+ T cells were within normal range, with naive CCR7+ CD45RA+ cells dominating the repertoire. Her B-cell count was very low, and B-cell development skewed toward mature B cells with reduced switched memory B cells. Despite normal immunoglobulin levels, responses to polysaccharide antigens were completely absent.

Molecular Genetics

By whole-exome sequencing in a 45-year-old woman with an immunometabolic syndrome, Haapaniemi et al. (2017) identified compound heterozygosity for missense mutations in the HYOU1 gene (A419P, 601746.0001 and Y231H, 601746.0002). Her unaffected parents were each heterozygous for one of the mutations.

History

Lonsdale et al. (1967) described 3 brothers who died at ages 12 months, 6 years, and 41 months from overwhelming infection. The bone marrow picture indicated maturation arrest, and in 2 patients episodes of leukocytosis of unknown cause punctuated the course. Total gamma globulins were low in the serum.