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Jyonouchi. J Transl Genet Genom 2023;7:274-90 https://dx.doi.org/10.20517/jtgg.2023.32 Page 278

need to be addressed for proper management.

Kabuki syndrome
Kabuki syndrome (KS) is another complex syndrome with overlapping features of CATCH-22 syndrome,
[31]
occurring approximately at 1 in 32,000 . It is characterized by facial dysmorphism resembling kabuki
makeup, psychomotor developmental delay, growth retardation, and other highly variable clinical
[32]
features . KS was first found to be associated with pathogenic variants of KMT2D, which codes histone
lysine methyltransferase that regulates chromatin remodeling and subsequently affects the expression of
numerous genes . Up to 75% of KS patients express KMT2D gene variants, while about 5% of KS patients
[32]
reveal variants of KDM6A, which codes histone demethylase [32,33] . In addition to variable developmental
issues, KS patients manifest difficult behavioral symptoms with overlapping features of ASD [32,33] . In
addition, KS patients often present with functional neurological abnormalities including muscular
[33]
hypotonia, and dysarthria . Partial seizures are also found at high frequency (around 17%) in KS
patients . KS patients are also characterized by immunodeficiency (usually antibody deficiency) and
[34]
autoimmune complications. Hypogammaglobulinemia is reported to be seen in up to 58% of KS patients
and may become more apparent with age, as seen in patients with common variable immunodeficiency
(CVID) and so are autoimmune complications . Neuropsychiatric symptoms overlapping features of ASD
[33]
may lead to a diagnosis of ASD in KS patients, despite characteristic facial dysmorphism and other clinical
features. In our clinic, we encountered two KS patients who were originally diagnosed with ASD, but other
clinical manifestations led to Dx of KS with identified pathogenic variants of KMT2D. In both patients,
recurrent infection was a major trigger of worsening behavioral symptoms and seizure cluster: starting
supplemental Ig treatment dramatically improved recurrent respiratory infection and subsequent seizure
controls. Thus, clinicians are encouraged to be familiar with characteristic facial dysmorphism of KS, since
genetic diagnosis is relatively easy through target gene sequencing offered by commercial laboratories.

The syndromes described above often develop impaired humoral immunity over time, as typically seen in
DS patients. Because of thymic hypoplasia, these patients may not show hypogammaglobulinemia , but
[9]
specific antibody production may become more apparent with age, as typically shown by loss of response to
vaccine antigens, especially less immunocompetent polysaccharide antigens: PPV23 was typically used for
[35]
assessing such responses . Anti-microbial therapy is important for the above-described syndrome, given
impaired T cell immunity. Typically, prophylaxis antibiosis is aimed to cover intracellular organisms that
are not well covered by supplemental immunoglobulin (Ig) treatment. Trimethoprim-sulfamethoxazole
(TMP-SMX) has been typically used for patients with impaired T cell immunity to cover PJP (pneumocystis
jirovecii pneumonia) and other intracellular organisms in patients with predominant T cell defects .
[36]
Partial DGS patients may only require TMP-SMX prophylaxis for the 1st few of life, while other patients
described in this section may continue to require such prophylaxis measures. Over time, many of these
patients with the above-described syndromes, especially KS patients, require supplemental Ig treatment .
[37]
When these patients also suffer from difficult behavioral symptoms, it may be challenging to administer Ig
intravenously. It is our experience that many patients with underlying primary immunodeficiency have
difficulty in tolerating a high dose of Ig for presumed autoimmune conditions, which may be attributed to
prior antigen load. In our clinic, one KS patient had a severe adverse reaction to high-dose (HD)
intravenous immunoglobulin (IVIg) administered by other providers who initially diagnosed the individual
with autoimmune diseases before confirming the KS diagnosis. This patient tolerates supplemental Ig
administered subcutaneously with improvement in recurrent respiratory infection and infection-induced
seizure clusters. The dose and route of administration may require consideration in these patients.