Successful Long-Term Correction of Autosomal Recessive Hyper-IgE Syndrome due to DOCK8 Deficiency by Hematopoietic Stem Cell Transplantation

Abstract

Autosomal dominant hyper-IgE syndrome (AD-HIES), characterised by eczema, increased susceptibility to skin and lung infections, elevated IgE and skeletal abnormalities is associated with heterozygous STAT3 mutations. The autosomal recessive variant (AR-HIES) has similar immunological findings but mainly lacks extraimmune manifestations. Several AR-HIES patients have recently been shown to harbour mutations in the gene for dedicator of cytokinesis 8 (DOCK8). Here, we present the long-term outcome of a girl having received a hematopoietic stem cell graft for an at that time genetically undefined combined immunodeficiency associated with severe eczema, multiple food allergies, excessively elevated serum IgE levels and eosinophilia. She was recently found to carry a homozygous nonsense mutation in the DOCK8 gene. HSCT resulted in complete immunological correction, even though mixed donor chimerism occurred. Clinically, the outcome was characterised by disappearance of skin manifestations and severe infections, improvement of pulmonary function and constant decline of IgE levels. Outcome in untransplanted DOCK8 deficient patients is poor because of frequent life-threatening infections, CNS bleeding and infarction, and increased susceptibility to malignancy. This argues for early curative therapeutic approaches, supported by this report of successful long-term outcome after HSCT.

Zusammenfassung

Das durch STAT3-Mutationen verursachte autosomal dominante Hyper-IgE-Syndrom (AD-HIES) zeichnet sich durch schweres Ekzem, rezidivierende Haut- und Lungeninfektionen, erhöhtes Serum-IgE sowie Skelettveränderungen aus. Eine autosomal rezessiv vererbte Variante zeigt ein ähnliches klinisches Bild, jedoch ohne die Skelettveränderungen. Vor Kurzem gelang bei einigen Patienten mit klinischen Zeichen eines autosomal-rezessiven HIES der Nachweis von Mutationen im Gen für Dedicator of cytokinesis 8 (DOCK8). In dieser Arbeit wird der Langzeitverlauf eines Mädchens dargestellt, das sich wegen eines damals noch unklassifizierten kombinierten Immundefektes mit schwerem Ekzem, multiplen Nahrungsmittelallergien, hohem Serum-IgE und Eosinophilie einer Stammzelltransplantation (SZT) unterzogen hatte und dessen Gendefekt nun durch Mutationsanalyse im DOCK8-Gen identifiziert werden konnte. Nach SZT kam es bei dieser Patientin trotz gemischtem Chimärismus zur vollständigen immunologischen Rekonstitution mit Abnahme des Serum-IgE, vollständiger Rückbildung des Ekzems und Verschwinden der Infektanfälligkeit. Die Prognose der bislang beschriebenen, nicht transplantierten DOCK8-defizienten Patienten ist aufgrund lebensbedrohlicher Infektionen, ZNS-Blutungen und Infarkten sowie erhöhtem Malignomrisiko ungünstig. Dies spricht für ein kuratives Vorgehen im Management dieser Erkrankung, was durch unseren Bericht mit gutem Langzeitverlauf nach SZT verstärkt wird.

Key words

Hyper-IgE syndrome - DOCK8 deficiency - hematopoietic stem cell transplantation - atopic dermatitis

Schlüsselwörter

Hyper-IgE Syndrom - DOCK8-Defizienz - hämatopoetische Stammzelltransplantation - atopische Dermatitis

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