Abstract

ITCH (Itchy E3 Ubiquitin Protein Ligase) deficiency is an exceptionally rare autosomal recessive genetic disorder caused by alterations in the ITCH gene, leading to immunodeficiency and systemic autoimmunity. A 12-year-old Chilean girl presented with chronic malnutrition, short stature, dysmorphic features, global developmental delay, and intellectual disability. She had chronic lung damage, exocrine pancreatic insufficiency, immune-mediated diabetes mellitus, congenital hypothyroidism, and hypoparathyroidism. At 10 years, she experienced severe pneumonia, followed by recurrent respiratory infections. Physical examination findings included alopecic foci on the scalp, skin pigmentation disorder, bilateral crackles on lung auscultation, and a distended abdomen. Laboratory analysis showed hyperglycemia and dyslipidemia. The complete blood cell count revealed normal leukocytes (8870 cells/?L), mild lymphopenia (1130 cells/?L), and mild neutrophilia (6760 cells/?L). Lymphocyte subpopulations demonstrated abnormalities: decreased CD8+ T cells (284 cells/?L) and natural killer cells (38 cells/?L), decreased total memory B cells CD19+/CD27+ (7 cells/?L) with a predominance of naive B cells, and decreased regulatory T cells CD4+/CD127-/CD25+ (20 cells/?L). A chest computed tomographic scan revealed bilateral bronchiectasis secondary to recurrent pneumonia and mediastinal and hilar adenopathies. Genetic testing revealed a likely pathogenic homozygous variant in the ITCH gene c.1569?+?1G>T (splice donor). Despite its rarity, health care clinicians should consider this condition in patients displaying signs of immunodeficiency and systemic autoimmunity due to its potentially life-threatening nature. We report a case of ITCH deficiency associated with the c.1569?+?1G>T variant of the ITCH gene, resulting in growth failure, dysmorphic features, global developmental delay, intellectual disability, chronic lung damage, exocrine pancreatic insufficiency, immune-mediated diabetes mellitus, congenital hypothyroidism, iron deficiency anemia, and hypoparathyroidism. © © 2025 by the American Academy of Pediatrics.