SCIDISH – AN UNPREDICTED CASE OF T CELL LYMPHOPENIA, HYPOCALCEMIA, AND SKELETAL ANOMALIES

Abstract

<h3>Introduction</h3> Biallelic pathogenic variants in <i>PAX1</i> lead to autosomal recessive otofaciocervical syndrome 2 (OTFCS2), characterized by facial and ear abnormalities, hearing loss, skeletal dysplasia, intellectual disability, branchial defects, and athymia. This rare case describes an infant who presented with T cell lymphopenia and hypocalcemia and was diagnosed with a novel homozygous PAX1 variant. <h3>Case Description</h3> A 6-day-old boy born to consanguineous parents was admitted for an abnormal newborn screen (TREC=0) and primary immunodeficiency with T-B+NK- immunophenotype (33/uL CD3+T-cells, 30/uL CD3/CD4/CD45RO cells, undetectable CD3/CD4/CD45RA cells, undetectable CD16/CD56NK-cells). Exam showed dysmorphic facial features, left preauricular pit, and sacral and should dimples. He received prophylactic antimicrobials, and immunoglobulin replacement for hypogammaglobulinemia. He developed seizures, attributed to hypocalcemia secondary to hypoparathyroidism. Further workup indicated presence of NK cells, absent thymic shadow, ASD and PFO on echocardiogram, failed hearing screen, mild laryngomalacia, kyphosis, and spinal subluxation of L5 on S1. FISH and microarray were negative for 22q11.2 deletion. Invitae Primary Immunodeficiency Panel revealed homozygous VUS (c.509C>A(p.Pro170His)) in PAX1, and parents are heterozygous carriers. Patient's clinical picture was most consistent with OTFCS2 with athymia. He was referred for thymus transplantation. <h3>Discussion</h3> Primary thymic defects should be considered in patients with abnormal SCID NBS, specifically in those with hypoparathyroidism. We suggest early genetic testing, as identification of the underlying defect is crucial for prognosis and management. As T-cell dysfunction in OTFCS2 is due to aberrant thymic development, allogeneic thymus transplantation is the expected curative treatment, whereas patients with PAX1 defects who underwent hematopoietic stem cell transplantation failed to gain T cell reconstitution.