Dedicator of cytokinesis 8 deficiency (DOCK8, OMIM 611432) is a combined immunodeficiency (1–3) with clinical presentation of severe susceptibility to infections, immune dysregulation as atopic disease, autoimmunity, and elevated IgE, as well as predisposition for cancer (4, 5). Atopic disease most commonly manifests as eczema and food allergies (5, 6). Most patients display severe viral infections of the skin due to herpes simplex virus (HSV), human papilloma virus (HPV), and molluscum contagiosum (MC), followed by bacterial skin abscesses and mucocutaneous candidiasis (5, 7). Rare features include vasculopathy in part associated with cerebral events and sclerosing cholangitis due to chronic infection with cryptosporidium (4, 5, 7, 8). Nearly all patients display highly elevated IgE. Increased levels of IgG and IgA, along with low levels of IgM, are seen in many cases (5). Chronic Epstein-Barr virus (EBV) viremia likely results in higher risk for malignancies (5, 9). DOCK8 protein (190 kDa, 1,701 amino acids, cytogenic localization 9p24.3) (10) is part of the actin remodeling process (11). Biallelic homozygous or compound heterozygous mutations or deletions in the DOCK8 gene impact the persistence and activation of CD8+ T and NK cells, dysfunctional regulatory T cells (Treg) (12), and cause an imbalanced differentiation and cytokine production of T helper cells (5, 8, 13–15). The differentiation of B cells and their capacity of immunoglobulin production are impaired as well (4, 13, 16–19). AlloHSCT is the only life-saving treatment in DOCK8-deficient patients (13, 20–22). The importance of an early alloHSCT and adequate control of disease complications pre-transplant has been shown (23, 24).

Aydin et al., on behalf of the EBMT Inborn Errors Working Party (IEWP), studied the natural course of the disease in DOCK8 deficiency. In their manuscript published in 2015, they showed that both overall survival and event-free survival rapidly decreased beyond the age of 10 years (4).

In 2019, a study was published on the outcome of alloHSCT in patients with DOCK8 deficiency, including data analysis by age at transplantation. Although the analysis did not reach significance level, there was a tendency toward inferior outcome for patients above the age of 8 years (22). Based on these two large EBMT IEWP studies, we decided to conduct a literature review and focus on patients over 8 years of age.

Literature search for alloHSCT in DOCK8 deficiency in patients older than 8 years included information on comorbidities, immune modulating treatment, post-transplantation complications, survival, and outcome. This retrospective study was performed in the Division for Stem Cell Transplantation and Immunology in Frankfurt/Main, Germany (EBMT Centre Code 138). Written informed consent was obtained from the parents. The study was approved by the local ethics committee of the Frankfurt Goethe University (IRB approval no. 167/16). The results of this study add valuable information to the literature, especially when clinicians counsel patients with a delayed diagnosis of DOCK8 deficiency.

An 11-year-old boy of Syrian descent was referred for further treatment after a diagnosis of homozygous biallelic frameshift mutation in the DOCK8 gene (c.3339delT) was established. The patient suffered from inflammatory bowel disease, eczema, and transfusion-dependent autoimmune-hemolytic anemia since his early childhood. Skin diseases included verrucae vulgares due to HPV infection, tinea capitis, xerosis cutis, candida albicans, and superinfection with methicillin-resistant Staphylococcus aureus (MRSA) resulting in therapy-resistant ulcerations ( Figure 1 ). Furthermore, he suffered from recurrent sinopulmonary infections and one episode of severe catheter-related sepsis due to MRSA. Ophthalmology work up revealed chronic conjunctivitis and uveitis, possibly due to the underlying CMV infection, resulting in corneal scars and loss of sight on both eyes. Evolving symptoms are displayed in Figure 2 . He showed significant growth delay ( Figure 1 ).

The review of literature included a systemic research of Medline database from the National Library of Medicine (NLM) via PubMed using terms such as DOCK8, HSCT, dupilumab, and rituximab. Results were filtered for DOCK8-deficient patients who underwent alloHSCT at the age of 8 years or older. Duplications were excluded (13, 20, 28). Diagnosis in the screened references was determined through either genetic mutation detection and/or flow cytometrical detection of the loss of DOCK8 protein. Donors are considered matched [either matched sibling donors (MSD), or matched unknown donors (MUD)] if displaying an HLA-match of at least 9 out of 10.

The literature review revealed 173 patients with DOCK8 deficiency who underwent alloHSCT ( Figure 4 ). Eighty-one out of 173 were reported and analyzed in a large study of Aydin et al. and will be referred to separately (22). Out of the remaining 92 patients, 53 were transplanted at the age of 8 years or older (53/92, 57.6%) (13, 20, 21, 23, 24, 28–37). Within this cohort of older patients, there were more female patients (64%; 34 females, 18 males). The age ranged from 8 to 27 years. Pre-transplant morbidity ranged from recurrent respiratory tract and skin infections with eczema in nearly all patients to less frequent complications as liver disease due to chronic cryptosporidium infection, vasculopathy, and malignancy. IgE levels ranged from 8.3 to 36.000 U/ml, while five cases were over 15.000 U/ml (12.5%) and two over 34.000 U/ml (5%). Immune-modulating pre-treatment was initiated in EBV-positive patients using rituximab (n = 6), and one patient was treated with mycophenolate mofetil (MMF) due to aortitis (35) ( Table 1 ).

In this work we present an 11-year-old DOCK8-deficient patient with a severe inflammatory disease manifestation and very high IgE levels. To reduce the inflammatory disease prior to alloHSCT, dupilumab was used in combination with rituximab. A substantial decrease in IgE levels and amelioration of skin eczema were achieved. Treatment was well tolerated without adverse events.

Dupilumab, an IL-4/IL-13 receptor inhibitor, suppresses the overwhelming T-helper type 2 inflammatory response (13, 38–40). There is growing evidence for the use of dupilumab either bi-weekly or once every 4 weeks in patients with immunodeficiency syndromes (35, 41–45). The bi-weekly administration seems to be more effective (40). To our knowledge, there is no larger study available on pre-transplantation use of dupilumab in pediatric patients. Nevertheless, there is some evidence for the efficacy of dupilumab in DOCK8 deficiency (35, 45, 46). Ollech et al. described two patients (2 and 10 years of age) receiving dupilumab and discussed the use of dupilumab as a bridge to alloHSCT. However, at the time of publication, none of their patients had received an alloHSCT (35). Additionally, we could find one recent case report on dupilumab and DOCK8 deficiency with high IgE levels in a 6-year-old girl resulting in a successful remission of disseminated eczema herpeticum (46).

Our case is the first reported DOCK8-deficient patient who underwent alloHSCT shortly after treatment with dupilumab. One year post-transplant, the patient’s IgE levels remained slightly elevated. Prolonged elevation of IgE post-transplant in DOCK8 deficiency has been reported in the literature and presumably is due to long lasting chemo-evading plasma B cells, which decline with variable delay (22, 23, 47). The eosinophile count increased after initiation of treatment and eventually decreased over time. This phenomenon is also reported in the literature (25). The patient’s eczema improved significantly before alloHSCT and eventually disappeared within a few weeks after transplantation. No skin toxicity or skin GvHD occurred in our patient. This might be due to the effective control of the patient’s skin disease by pre-transplant use of dupilumab and should be investigated in a larger cohort of patients with DOCK8 deficiency undergoing alloHSCT.

In our patient omalizumab, which is an anti-IgE antibody, was discussed at the time of treatment initiation (2020). Since there is an IgE level and body weight-dependent dosing strategy recommended for this antibody, we decided not to utilize omlizumab for our patient.

The current dosing recommendation is given only for IgE levels below 1,300 IU/ml in the US and 1,500 IU/ml in EU (48). In a study by Menzella et al. published in 2023, the authors conducted a detailed literature review on the efficacy and safety of omalizumab in patients with severe allergic asthma and other allergic diseases focusing on data of patients with higher IgE levels (49). This literature review included a small number of patients with IgE levels above 1,500 IU/ml. Also, in these patients, a beneficial effect of omalizumab could be shown, while there were no severe adverse events reported. Therefore, the authors suggested further analyzing the optimal dose in patients with (very) high IgE levels and eventually extending the dosing recommendation for this patient group (49). Comparative data for the efficacy of dupilumab versus omalizumab for patients with (very) high IgE levels are not available; nevertheless, we postulate that dupilumab might be more effective in this setting as it targets the hyper-IgE disease at the level of cell signaling.

Patients affected by DOCK8 deficiency suffer from combined immune deficiency with severe immune dysregulation. Clinical presentation and laboratory findings might overlap with other IEI, including “treg-o-pathies” (16, 50, 51), Wiskott–Aldrich syndrome (WAS) (4, 52) and hyper-IgE syndromes (autosomal dominant and recessive HIES) (15, 53). Unlike HIES, there are usually no syndromic features in DOCK8 deficiency (4, 54). Patients’ long-term outcome is poor due to an accumulation of life-threatening infections, especially by the age of 20 years, and a predisposition to malignancies (4). To date, alloHSCT is the only curative treatment option (13, 20, 22, 24, 28, 52). Several cohorts have shown promising results also for patients receiving a haploidentical transplantation (28, 37, 55). In almost all surviving patients, the skin disease resolved after successful alloHSCT (13, 22, 24, 28). In a few cases, other comorbidities, including vasculopathy (28, 30, 35), stroke (28), and malignancy (23, 24, 28), were also reported as being in remission. In some cases, remaining food allergies were described (23, 47). There is common agreement on offering alloHSCT to the affected individuals at an early stage of the disease, prior to the accumulation of organ damage, to achieve an optimal transplantation outcome (20, 24, 28, 30, 36). Fatal outcome was observed in five patients (P1, P2, P3, P4, P5), including three patients receiving a haploidentical graft (P1, P4, P 5). For P1, data was incomplete. In P2, P4, and P5, there was a high disease activity pre-transplant. P3 suffered from fulminant bacterial infection at +d58 post-alloHSCT. With regard to malignancy in DOCK8 deficiency, the predisposition to virus-driven malignancy after an alloHSCT remains to be investigated. A successful alloHSCT results in an excellent CD3+-chimerism (13, 20, 24) and recovery of CD8+ cytotoxic T-cell response after alloHSCT (13), which should be preventive of viral-driven malignancy development; nevertheless, long-term data focusing on malignancy and late-onset post-transplant complications are indicated.

In this review of the literature, we focused on DOCK8-deficient patients over 8 years of age receiving alloHSCT and pointed out severe comorbidities and complications related to the accumulation of organ damage by the underlying disease. Especially, for patients with high disease activity, an anti-inflammatory pre-treatment prior to alloHSCT is indicated. A short course of treatment by dupilumab was beneficial in our patient. Further studies in larger IEI cohorts with elevated IgE levels are indicated to confirm a possible improvement of the transplant outcome in these patients.