Omenn Syndrome due to RAG1 Mutation Presenting With Nonimmune Hydrops Fetalis in Two Siblings

Omenn syndrome (OS) is a rare variant of severe combined immunodeficiency characterized by susceptibility to severe opportunistic infections and peculiar manifestations, such as protein-losing erythroderma, alopecia, hepatosplenomegaly, lymphadenopathies, and severe diarrhea. The typical form of the disease is caused by hypomorphic mutation of the recombination-activating genes (RAG1 and RAG2), which are critical in initiating the molecular processes leading to lymphocyte and immunoglobulin receptor formation. Affected patients lack B cells, whereas autoreactive oligoclonal T cells infiltrate the skin, gut, spleen, and liver. In the absence of hematopoietic stem cell transplantation, patients with OS usually succumb early in life because of opportunistic infections. The incidence of OS is estimated to be <1 per 1 000 000; however, the actual frequency is difficult to ascertain. We report 2 siblings affected by OS due to a homozygous frameshift mutation (NM_000448.3:c.519delT, p.E174Sfs*26) in the RAG1 gene presenting with nonimmune hydrops fetalis (NIHF). To the best of our knowledge, this is the first reported association between OS and NIHF. NIHF specifically refers to the presence of ≥2 abnormal fluid collections in the fetus, without red blood cell alloimmunization. A broad spectrum of pathologies is associated with NIHF; however, in ∼20% of the cases, the primary cause remains unclear. Understanding the etiology of NIHF is essential for guiding clinical management, determining prognosis, and informing parents regarding recurrence risk. Our case contributes to expanding the spectrum of OS presentation and highlights the importance of a complete immunologic and genetic workup in otherwise unexplained cases of NIHF.

Case Report: Whole Exome Sequencing Revealed Two Novel Mutations of PIEZO1 Implicated in Nonimmune Hydrops Fetalis

Nonimmune hydrops fetalis (NIHF) is a serious and complex fetal condition. Prenatal diagnosis of hydrops fetalis is not difficult by ultrasound. However, determining the underlying etiology of NIHF remains a challenge which is essential to address for prenatal counseling. We extracted DNA from a proband prenatally diagnosed unexplained NIHF. Trio-whole exome sequencing (WES) was performed to filter candidate causative variants. Two gene mutations were identified as a compound heterozygous state in the proband. Both variants located on the PIEZO1 gene: c.3895C > T, a missense mutation in exon 27 paternally inherited; c.4030_4032del, a maternally inherited in-frame deletion in exon 28. Both variants were first reported to be related to NIHF. PIEZO1 gene mutations, leading to an autosomal recessive congenital lymphatic dysplasia, which can present as NIHF and partial or complete resolution postnatally. In conclusion, WES can aid in the elucidation of the genetic cause of NIHF and has a positive effect on the assessment of prognosis.