Neonatal onset inflammatory bowel disease and immunodeficiency due to compound heterozygous variants in RIPK1: Expanding the phenotypic spectrum and literature review

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a key regulator of apoptosis, necroptosis, and inflammation. Over the last decades, the function of RIPK1 has been extensively studied in mouse models. But the phenotype associated with RIPK1 deficiency in humans was unknown until 2018. Pathogenic RIPK1 variants have been described as the cause of two different inborn errors of immunity. Beyond biallelic RIPK1 loss-of-function mutations associated with primary immunodeficiency and very early-onset inflammatory bowel disease (VEOIBD), which were reported in 2018, a dominantly inherited autoinflammatory disorder caused by impaired caspase-8 cleavage of RIPK1 was identified in 2020. This condition, resulting from a gain-of-function mutation in RIPK1, is referred to as cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome. Here, we present the case of a boy with neonatal onset inflammatory bowel disease, severe malnutrition and recurrent infections, found to have novel compound heterozygous variants in RIPK1 (c.1835T > C p.I162T and c.1934C > T p.T645M), the former of which is a novel mutation. In addition to multiple ulcers and pseudopolypoid hyperplasia revealed during ileocolonoscopic examination. Massive lymphoid hyperplasia presenting as nodular lesions were also detected. He also has a large polypoid hyperplasia (about 2*5cm) protruding out of the anus. This phenotype has not been reported in previous literatures. Subsequently, we carried out a comprehensive review of the clinical characteristics of 18 reported cases with biallelic RIPK1 mutations and 21 cases with CRIA syndrome. We found that the disease onset time was extremely early in patients with biallelic RIPK1 variants. All patients developed symptoms within 9 months after birth. The most common clinical presentation included recurrent infections (100%) and gastrointestinal involvement (100%), followed by joints involvement (36.8%, 7/19). In addition, most patients combined with growth failure (94.7%, 18/19) and perianal lesions (89.5%,17/19). For patients with CRIA syndrome, the disease onset time was also very early, 85% (17/20) within the first 6 months of life. Almost all (20/21, 95.2%) affected individuals displayed periodic fever. Lymphadenopathies were present in 90% (18/20) of cases.