Mild humoral immunodeficiency in a patient with X-linked Kabuki syndrome

TO THE EDITOR

Kabuki syndrome (KS) is a multiple malformation syndrome that is characterized by a typical facial appearance, skeletal abnormalities, cardiac malformations, and mild to moderate developmental delay [Niikawa et al., 1981]. In addition, postnatal failure to thrive and recurrent infections (mostly otitis media) can be found in KS patients [Niikawa et al., 1981]. Humoral immunodeficiency in patients with type-1 Kabuki syndrome (KS1) caused by autosomal dominant KMT2D mutations, is well described and resembles common variable immunodeficiency (CVID) [Lin et al., 2015; Lindsley et al., 2015]. More than 80% of KS1 patients display hypogammaglobulinemia and diminished memory B-cell populations. Impaired somatic hypermutation in IgG transcripts and disrupted terminal differentiation can also be demonstrated in primary B cells [Lindsley et al., 2015].

Mutations in KDM6A are a less frequent, recently discovered genetic abnormality causing X-linked type-2 Kabuki syndrome (KS2) [Lederer et al., 2012; Banka et al., 2015]. Humoral immunodeficiency in KS2 has not been fully characterized. Frequent respiratory tract infections were reported in only 25% of the 20 patients described with KS2 [Banka et al., 2015], while 47–80% of KS1 patients have recurrent otitis media [Li et al., 2011; Micale et al., 2011; Banka et al., 2012; Lin et al., 2015; Lindsley et al., 2015].

We here present a patient with KS2 and humoral immunodeficiency. The boy was diagnosed with KS at the age of 10 months, based on typical clinical and morphological features, but no variants in KMT2D were found. He suffered from recurrent upper and lower respiratory tract infections, mainly recurrent otitis media and pneumonia, from the age of 5 months. Recurrent unexplained fever episodes with high inflammatory markers were also noted, up to more than once monthly. He was treated with prophylactic antibiotics and chest physiotherapy from the age of 6 months. After failure of medical treatment, gastro-oesophageal reflux and swallowing dysfunction were treated with a Nissen fundoplication and gastrostomy placement at the age of 11 months, resulting in some improvement in the frequency of pneumonia. Additionally, he received tympanostomy tubes at age 20 months. An additional risk factor for recurrent lung infections was the presence of an atrium septum defect type 2, which was corrected at the age of 2 years. No cleft palate was present.

At the age of 5 years, whole exome sequencing was performed after obtaining informed consent from the parents. A novel de novo hemizygous KDM6A nonsense variant (NM_021140: c.3835C>T, p.Arg1279Ter) was identified and confirmed by Sanger sequencing. The sequencing dataset was further investigated for known genetic causes of immunodeficiency and/or autoinflammation [Picard et al., 2015]. The only identified variant was a heterozygous TNFRSF13B missense variant (NM_012452: c.542C>A, p.Alu181Glu) inherited from the healthy mother. The latter variant has been associated with CVID (in homo- and heterozygous form) but can also be found in healthy controls, suggesting that its impact is regulated by other gene products and/or the environment [Freiberger et al., 2012; Martinez-Gallo et al., 2013]. The allele frequency of the TNFRSF13B variant is 0.7% in the European population [Exome Aggregation Consortium, 2015], suggesting that the variant is more frequently found in healthy persons than in CVID patients (estimated incidence 1:10.000–1:50.000). As the patient's mother had no severe/frequent infections, no signs of autoimmunity or inflammatory gastrointestinal disorders, no additional immunological testing was performed.

In our patient, B cell and memory B cell numbers were normal (Table I). There was, however, an impaired antibody response to vaccination with hepatitis B and poliovirus. Evaluation of the antibody response to the unconjugated pneumococcal and Haemophilus influenzae vaccine was not performed. IgG and IgG₂ levels slightly decreased after the age of 6 years, for which subcutaneous immunoglobulin therapy was initiated. Thereafter, the frequency and severity of respiratory infections improved significantly.

KMT2D modifies gene expression through methylation of lysine 4 on histone 3 (H3K4) and is the core protein of the KMT2D COMPASS complex [Smith et al., 2011]. KDM6A is a cofactor associated with this complex and exhibits demethylase activity at lysine 27 on histone 3 (H3K27) [Lee et al., 2007]. KMT2D also binds the paired box (PAX) transactivation domain-interacting protein (PTIP), which is essential for B-cell terminal differentiation. PTIP binds the B-cell master transcription factor PAX5 and targets KMT2D–mediated H3K4 trimethylation to switch regions within the immunoglobuline heavy chain (IGH) locus during class switch recombination [Schwab et al., 2011].

The mild humoral immunodeficiency found in this patient contrasts with the findings in KS1 and suggests a less essential role for KDM6A (H3K27 demethylation) in B-cell differentiation and function than for KMT2D (H3K4 methylation) [Lin et al., 2015; Lindsley et al., 2015]. However, further investigation on the exact role of KDM6A in B-cell function is still required. It should also be noted that the variant in TNFRSF13B could contribute to the observed immunologic phenotype.

As the IgG and IgG₂ levels were normal before the age of six, we recommend to repeat immunoglobulin determinations in KS2 patients with recurrent infections even if they initially present with normal immunoglobulin levels. Our data also suggests that in studies on the humoral immune function in KS2, the possibility of other contributing genes should be considered.