Vitiligo-Like Depigmentation Reported in NHEJ1-Related Radiosensitive SCID

A new case report published in JAAD Case Reports describes vitiligo-like depigmentation in a 2-year-old girl with NHEJ1-related radiosensitive severe combined immunodeficiency (SCID), a pigmentary finding not previously documented in this genetic disorder. The case details congenital generalized depigmentation, eczematous dermatitis, and silvery-white scalp hair, with progressive repigmentation following matched-sibling hematopoietic stem cell transplantation (HSCT). The authors, led by Alanoud Alhaider, MD, of King Saud University, propose the finding broadens the phenotypic range of DNA repair-related immunodeficiencies.¹

NHEJ1-related SCID arises from pathogenic variants in the gene encoding Cernunnos-XLF, a scaffolding protein required for DNA end ligation during nonhomologous end-joining repair. The disorder typically presents with a TB-NK+ immunophenotype, microcephaly, growth retardation, and radiation sensitivity. Pigmentary abnormalities have not factored into its recognized clinical spectrum, unlike depigmentation syndromes such as Chediak-Higashi, Griscelli, and Hermansky-Pudlak, which stem from melanosome transport defects rather than DNA repair pathway disruption.¹

Case Findings and Posttransplant Repigmentation Pattern

The patient was born at term to biologic parents with no family history of vitiligo. Her skin appeared lighter than expected from birth, and she developed a generalized pruritic erythematous rash within the first month of life. Complete hair loss occurred at 3 months of age. At 5 months, dermatologic examination revealed well-demarcated depigmented patches covering approximately 90% of body surface area, without palmoplantar keratoderma, nail dystrophy, or dental abnormalities, with scalp hair described as sparse, fine, and black.¹

Her medical history included oral thrush, pneumonia, recurrent otitis media, and failure to thrive, with laboratory findings of lymphopenia and hypogammaglobulinemia. Whole exome sequencing in May 2023 confirmed a homozygous pathogenic NHEJ1 variant. At 9 months, she underwent matched-sibling HSCT without conditioning chemotherapy due to radiosensitivity risk, with an uncomplicated posttransplant course and no clinical signs of acute or chronic graft-vs-host disease (GVHD).¹

By 2 to 3 months post transplant, faint tan macules appeared on the trunk and extremities, coalescing into areas of repigmentation. One year later, the patient showed diffuse residual depigmentation alongside sharply defined islands of normal pigmentation, most prominent on the face, hands, and feet, with scalp hair regrown as a mix of black and silvery-white strands. Repigmentation continued through 2025, though it remained incomplete at last follow-up.¹

Proposed Mechanisms Behind the Pigmentary Changes

The authors offer 2 nonexclusive explanations for the depigmentation. The first centers on immune dysregulation: Aberrantly developing T or B cells in SCID may become autoreactive and target melanocytes, a mechanism described in related DNA repair disorders including Artemis and LIG4 deficiency, which share the NHEJ1 repair pathway. The second points to intrinsic melanocyte fragility, reasoning melanocytes lacking functional DNA repair may be more vulnerable to ultraviolet and oxidative damage.¹

The authors considered GVHD as an alternative explanation, as maternal T-cell engraftment occurs in up to 40% of patients with SCID and can produce GVHD-like skin findings, sometimes prior to transplantation itself. They favored a vitiligo-like mechanism instead, citing the absence of other clinical GVHD features and a repigmentation pattern tracking with immune reconstitution rather than following a fixed or inflammatory course. Histopathologic confirmation of vitiligo was not obtained.¹

Alhaider and colleagues noted repigmentation after HSCT has been reported previously in patients with SCID broadly but not specifically in those with NHEJ1 mutations, citing a 2009 report of 2 patients with SCID with dyschromia and subsequent repigmentation.² They wrote that the case "highlights that vitiligo, although rare, can develop in primary immunodeficiency syndromes," and that immune correction through HSCT may extend beyond infection control to reversal of pigmentary abnormalities tied to immune reconstitution.^1,2

The authors suggest recognizing this association may help clinicians distinguish autoimmune pigmentary signs from GVHD in immunodeficient patients and anticipate the potential for recovery after transplantation. They identify this as the first reported case linking pigmentary change with NHEJ1 deficiency, raising the possibility that immune or DNA repair mechanisms contribute to melanocyte homeostasis more broadly.¹

References

1. Alhaider A, Almutairi M, Alomari A, Altuwaijri A, Almarshoud G, Alakrash L. Vitiligo like depigmentation in a patient with NHEJ1 deficiency related radiosensitive SCID: a case report. JAAD Case Rep. 2026;73:106-110. doi:10.1016/j.jdcr.2026.05.010
2. Heath CR, Burk CJ, Lawley LP, Mancini AJ, Connelly EA. Severe combined immunodeficiency (SCID)-associated dyschromia with subsequent repigmentation: a report of two patients. Pediatr Dermatol. 2009;26(2):162-8. doi:10.1111/j.1525-1470.2009.00876.x