Rare Genetic Disorder Diagnosed in Adult Woman After Lifelong Illness

A 33-year-old Palestinian woman who spent her life battling recurrent severe chest infections, kidney stones, and unexplained growth failure has finally received a unifying genetic diagnosis, thanks to whole-exome sequencing. The case, published in Frontiers in Genetics, reveals an adult presentation of a rare autosomal recessive condition known as the SLC29A3-related disorder spectrum, caused by a recurrent homozygous pathogenic variant in the SLC29A3 gene. The diagnosis is remarkable not only because it was made in adulthood, when most cases are identified in childhood, but also because of the exceptional severity of the patient’s humoral immunodeficiency and the presence of renal manifestations that are rarely reported in this disease spectrum.

The SLC29A3 gene encodes equilibrative nucleoside transporter 3, or ENT3, a protein essential for shuttling nucleosides across lysosomal and mitochondrial membranes. When biallelic mutations disrupt this transporter, the result is a multisystem disorder historically described under separate names, including H syndrome, Faisalabad histiocytosis, pigmented hypertrichosis with insulin-dependent diabetes, and familial Rosai-Dorfman disease. These entities are now recognized as a single clinical spectrum characterized by overlapping features such as histiocytic infiltration, lymphadenopathy, hyperpigmentation, hypertrichosis, and endocrine dysfunction. The clinical phenotype is remarkably diverse, with significant variability both between and within families, which often leads to delayed diagnosis, particularly in adults.

Born to first-degree cousin parents, the patient presented with a lifelong history of recurrent severe lower respiratory tract infections requiring multiple hospitalizations since childhood. She also suffered from chronic vomiting and recurrent nephrolithiasis, having previously undergone ureteroscopic lithotripsy and double-J stent placement. On physical examination, she exhibited significant growth failure, with height and weight below the 3rd percentile for her age. She had microcephaly, dysmorphic facial features, long and dense eyelashes, and generalized hirsutism. Skeletal findings included bilateral hallux valgus and mild flexion contractures of the fingers. Notably, her cognitive development was fully preserved.

Laboratory investigations revealed severe hypogammaglobulinemia, with IgG below 320 mg/dL against a reference range of 700 to 1600 mg/dL, IgA below 25 mg/dL against a reference of 70 to 400 mg/dL, and IgM below 25 mg/dL against a reference of 40 to 230 mg/dL. Hematologic evaluation showed microcytic anemia associated with iron deficiency. Liver function tests showed mildly elevated transaminases. Endocrine evaluation confirmed severe vitamin D deficiency with secondary hyperparathyroidism, although diabetes screening, including fasting blood glucose and HbA1c, was normal at the time of presentation. Chest computed tomography demonstrated chronic post-infectious small-airway changes, minimal bronchiectasis, and segmental consolidation in the right middle lobe. Abdominal imaging revealed right ureteric stones with associated hydronephrosis and a chronically small right kidney.

Genetic testing via whole-exome sequencing identified a homozygous missense variant in SLC29A3: c.1309G>A, resulting in the amino acid substitution p.Gly437Arg. The variant was classified as pathogenic according to American College of Medical Genetics and Genomics criteria and confirmed by Sanger sequencing. Parental segregation analysis was not performed because the parents were unavailable for testing. Copy-number variant analysis using an internally validated pipeline yielded no additional significant findings, establishing a diagnosis within the SLC29A3-related disorder spectrum.

The p.Gly437Arg variant identified in this patient is a known pathogenic allele frequently reported in Palestinian and Arab populations. In the original gene-discovery study, the variant was identified in several geographically clustered Arab families, and haplotype analysis showed a shared disease-associated haplotype among the analyzed families, consistent with a shared origin of the variant. Despite carrying a recurrent variant, this patient’s phenotype is notable for several reasons that expand the known clinical spectrum of the disease.

First, the severity of the immunologic phenotype is exceptional. While immunodeficiency and recurrent infections are recognized features of the SLC29A3-related disorder spectrum, the degree of hypogammaglobulinemia observed here, with nearly undetectable IgA and IgM and severely low IgG, is unusual. This raises the possibility that ENT3 deficiency may influence B-cell maturation or function, although the underlying mechanism remains unclear. Second, the associated renal manifestations, specifically recurrent nephrolithiasis and a small kidney, are noteworthy. Renal involvement has been reported in approximately 6 percent of cases within the spectrum, including hydronephrosis and renal asymmetry. It remains unclear whether these findings are a direct consequence of ENT3-related metabolic dysfunction or secondary to chronic inflammation and infection.

Following the diagnosis, a multidisciplinary management plan was initiated. Immunoglobulin replacement therapy was recommended and initiated, leading to a reduction in the frequency of respiratory infections during the initial six months of follow-up. The patient also received vitamin D supplementation and was referred to nephrology for management of recurrent stones and to endocrinology for ongoing diabetes surveillance. Comparison with previously reported cases of the same variant reveals significant phenotypic heterogeneity. While some patients present with predominant cutaneous and endocrine features, others exhibit a more severe immunologic and skeletal phenotype, suggesting the influence of genetic modifiers or environmental factors.

This case underscores the importance of considering the SLC29A3-related disorder spectrum in adults with longstanding multisystem disease. The combination of growth failure, skeletal anomalies, and immunodeficiency should prompt genetic evaluation even in the absence of the classic cutaneous hyperpigmentation often seen in H syndrome. Early genetic diagnosis using whole-exome sequencing is crucial for establishing a unifying diagnosis and guiding targeted multidisciplinary care, including immunoglobulin replacement therapy, which may substantially reduce infection-related morbidity, and vigilant surveillance for endocrine and renal complications. As a single case report, the study is limited by the absence of parental segregation analysis, functional studies of ENT3 activity, extended immune phenotyping, and detailed renal metabolic evaluation. Future studies are needed to determine whether nephrolithiasis is a primary metabolic manifestation of ENT3 deficiency or an incidental finding.

Subject of Research: Adult presentation of SLC29A3-related disorder spectrum with marked hypogammaglobulinemia due to a recurrent homozygous pathogenic variant (G437R): a case report

Article Title: Adult presentation of SLC29A3-related disorder spectrum with marked hypogammaglobulinemia due to a recurrent homozygous pathogenic variant (G437R): a case report

Article References: Ishqair, M. A., Masalma, A. K. H., Saleh, M., Awad, F., Khalili, A., Ishqair, A. A., Salah, S., & Saleh, A.-R. N. (2026). Adult presentation of SLC29A3-related disorder spectrum with marked hypogammaglobulinemia due to a recurrent homozygous pathogenic variant (G437R): a case report. Frontiers in Genetics, 17, Article 1904219. https://doi.org/10.3389/fgene.2026.1904219

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1904219

Keywords: Adult, presentation, SLC29A3-related, disorder, spectrum, marked, hypogammaglobulinemia, recurrent, homozygous, pathogenic, variant, G437R