Novel TTC37 Mutations in a Patient with Immunodeficiency without Diarrhea: Extending the Phenotype of Trichohepatoenteric Syndrome

Abstract

Unbiased genetic diagnosis has increasingly associated seemingly unrelated somatic and immunological phenotypes. We report a male infant who presented within the first year of life with physical growth impairment, feeding difficulties, hyperemesis without diarrhea, and abnormal hair findings suggestive of trichorrhexis nodosa. With advancing age, moderate global developmental delay, susceptibility to frequent viral illnesses, otitis media, and purulent conjunctivitis were identified. Because of the repeated infections, an immunological evaluation was pursued and identified impaired antibody memory responses following pneumococcal vaccine administration. Immunoglobulin replacement therapy and nutritional support were employed as mainstays of therapy. The child is now aged 12 years and still without diarrhea. Whole exome sequencing identified compound heterozygous mutations in the TTC37 gene, a known cause of the trichohepatoenteric syndrome (THES). This case extends the known phenotype of THES and defines a potential subset for inclusion as an immune overlap syndrome.

Management of syndromic diarrhea/tricho-hepato-enteric syndrome: A review of the literature

“…However, there is some variability and 17% of the patients did not require parenteral nutrition. Except for some cases (19,24), it is not clear whether the absence of parenteral nutrition was due to non-availability or for some other reason. With parenteral nutrition, weaning can be achieved in nearly 50% of the patients as already reported in the literature (35).…”

“…Nonetheless, an improvement of either the number of infections or of the diarrhea was noticed for 5/6 patients. Thus, immunoglobulin supplementation could probably be useful in some cases of SD/THE if an immune defect is present (notably low levels of immunoglobulin), but also in case of recurrent infection, as we know that immunoglobulin function is impaired (19). In all cases a discussion with immunologists appears mandatory.…”

“…Three reported a diminution of infection (4,19,21), 2 a reduction of diarrhea (4,23) and 1 described no effect either on diarrhea or infection (34).…”

Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa

“…Their study described a novel TTC37 mutation in a patient who presented with frequent otitis media, viral infections, purulent conjunctivitis, woolly hair and distinctive facial features without the characteristic severe diarrhoea of infancy seen in THE-S [15]. …”

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

“…While this study suggests that the diarrhea in THES patients might be a result of intrinsic defects in enterocytes, most of the patients also develop humoral immune defects with low protective immunoglobulin (Ig) levels or poor vaccination response. A recent discovery identified a patient with TTC37 mutation, presenting with immunodeficiency but without diarrhea . While quantitative Ig concentrations were normal, response to pneumococcal vaccination was abnormal with rapid loss of protective titers, pointing to a B‐cell defect characteristic for this deficiency.…”