Case Report: Analysis of Preserved Umbilical Cord Clarified X-Linked Anhidrotic Ectodermal Dysplasia With Immunodeficiency in Deceased, Undiagnosed Uncles

Abstract

Family history is one key in diagnosing inborn errors of immunity (IEI); however, disease status is difficult to determine in deceased relatives. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is one of the hyper IgM syndromes that is caused by a hypomorphic variant in the nuclear factor kappa beta essential modulator. We identified a novel IKBKG variant in a 7-month-old boy with pneumococcal rib osteomyelitis and later found that his mother has incontinentia pigmenti. Genetic analysis of preserved umbilical cords revealed the same variant in two of his deceased maternal uncles. Analysis of preserved umbilical cord tissue from deceased relatives can provide important information for diagnosing IEI in their descendants.

Keywords: NEMO; anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID); case report; hyper IgM syndrome; preserved umbilical cord.

Figure 1

The profile of the index patient. The patient, a 7-month-old boy indicated by an arrow in the pedigree diagram (A), had sparse hair and eyebrows and a depressed nasal bridge (B). Flow cytometric analysis of peripheral blood revealed normal CD40 ligand (CD154) expression (C) and decreased NEMO expression in CD3⁺ cells and CD14⁺ cells (D). Sequencing of the IKBKG gene revealed hemizygous mutation c.262_264delGAG in exon 3 (red arrow) (E). NEMO, nuclear factor kappa beta essential modulator.

Figure 2

Findings for the mother. Flow cytometric analysis of maternal peripheral blood revealed mixed expression of normal and mutated NEMO (A). Sequencing of the IKBKG gene revealed the heterozygous variant c.262_264delGAG (red arrow) (B). The mother’s left arm exhibited linear hyperpigmentation following the Blaschko line (blue arrows) (C). NEMO, nuclear factor kappa beta essential modulator.

Figure 3

Functional analysis of the variant. NF-κB reporter gene analysis using NEMO-deficient HEK293 cells revealed a loss of activity of the IKBKG variant ∆E88, as compared with the wild type, and no response against TNF-α. Hypomorphic variants already reported, i.e., E390RfsX5 and P398S (14), were also included to the analysis to ensure the accuracy of this experiment. Data are shown as the mean and standard error of triplicate measurements. NF-κB, nuclear factor kappa beta; NEMO, nuclear factor kappa beta essential modulator; TNF-α, tumor necrosis factor-alpha.

Figure 4

Preserved umbilical cords from deceased relatives. A-I is from the older uncle (Uncle III-2), and A-II is from the younger uncle (Uncle III-3) (A). Sequencing of the IKBKG gene revealed the heterozygous variant c.262_264delGAG in both uncles (B).