Immuno-skeletal Dysplasia with Neurodevelopmental Abnormalities complicated with Omenn Syndrome in a case of a compound heterozygous variants of exostosin-like 3 gene

Abstract

IntroductionSevere combined immunodeficiency (SCID) encompasses over thirty monogenic disorders. Exostosin like glycosyltransferase 3 (EXTL3) is a ubiquitously expressed gene encoding an enzyme involved in the synthesis of heparan sulfate. EXTL3 deficiency results in an ultra-rare autosomal recessive condition called Immuno-skeletal Dysplasia with Neurodevelopmental Abnormalities (ISDNA).This report describes a patient with compound heterozygous variants in the EXTL3 gene with ISDNA. Case DescriptionA 2-week-old Caucasian full-term male with multiple dysmorphisms (Table 1), in-utero ischemic brain injury, and discoordinated feeding admitted to the Neonatal Intensive Care Unit was noted to have undetectable T-cell receptor excision circle (TREC) on his newborn screen. The workup revealed profound T-cell deficiency, undetectable CD4+CD45RA+CD31+ cells (CD4RTE), and normal CD19+ B- and CD16+/CD56+ NK-cell counts (Figure 1). Trio rapid genome sequencing, including non-consanguineous parents, detected compound heterozygous variants in the EXTL3 gene (Figure 2). [Display omitted] [Display omitted] Table 1Clinical signs and symptoms observed in the caseSystemClinical signsFacial/AxialUpslanted palpebral fissures, epicanthal foldsDepressed nasal bridgePosteriorly rotated earsSmooth philtrumCleft soft palateMicrognathia and retrognathiaWidely spaced nipplesAppendicular skeletonClinodactyly of left 5th toe and overriding 3rd and 4thleft toesNeurologyMicrocephalyGeneralized hypotoniaSuckling difficultyGastrointestinalGastroesophageal refluxHepatic cystsGallstonesDiarrheaGrowth parameters at birth (per WHO chart)Length: 6.38 percentileWeight: 72.3 percentileHead Circumference: 27.4 percentileAt six weeks of age, the patient developed Omenn syndrome, characterized by diarrhea, scaly maculopapular rash, and a rise in his T-cell and eosinophil count. He was treated with cyclosporine and steroids with a good response to therapy. He required gastric tube placement for poor oropharyngeal coordination and was started on ursodeoxycholid acid for gallstones (Table 1).The artificial thymic organoid (ATO) platform test (NIH Protocol # NCT03610802, LDN is supported by the Division of Intramural Research, NIAID, NIH) indicated that the patient had no hematopoietic cell autonomous defects in the ability of CD34+ cells to differentiate into mature T cells in ATO, suggesting extra-hematopoietic causes of T-cell lymphopenia. He is currently undergoing an evaluation for a thymic transplant. ConclusionTo our knowledge, this is the sixteenth reported case of ISDNA, and the first caused by compound heterozygous variants of EXTL3. In the fifteen previously reported cases, facial dysmorphism and abnormalities in the skeletal system were consistently observed. In contrast, the degree and frequency of the immune and neurological impairment varied. Furthermore, our case describes an extensive gastrointestinal impairment in ISDNA, and the benefits of ATO in guiding curative therapy for SCID.