DOCK8 deficiency is a combined immunodeficiency associated with defective actin polymerization and immune cell mobilization. It affects both the innate and adaptive compartments of the immune system. Affected individuals present with chronic eczema, recurrent sinopulmonary infections, and have an increased predisposition to malignancies [7].
Skin is the most commonly affected organ affected in DOCK8 deficiency. The spectrum of cutaneous involvement includes eczema, viral infections and skin abscesses[4]. Defective cytoskeletal organisation results in a peculiar complication called cytothripsis, that causes cell death as they try to mobilise through tissues. As a result, generation of long-lived memory CD8 positive T cells is compromised and this is the key reason for recalcitrant cutaneous viral infections in these patients[8]. In the cohort of 136 patients reported by Aydin et al, 96% of DOCK8 deficient patients had eczema. Eczema was particularly difficult to treat in 57% of these cases (73/134)[4]. Out of 17 patients with DOCK8 deficiency reported by Gowri et al, 16 had eczema, while five had severe eczema[6]. In congruence with these reports, 16 patients (94%) in our cohort had eczema, and three patients (17.6%) required oral immunomodulation, including steroids(n = 3) and cyclosporine(n = 2). P5 was managed with topical tacrolimus. The most common virus known to cause cutaneous infections in this setting is Herpes Simplex Virus (HSV). Aydin et al. observed that 62% of their DOCK8 deficient patients had HSV infections, followed by Human Papillomavirus (HPV) (40%), molluscum contagiosum virus (37%), Varicella-Zoster virus (VZV) (23%), Epstein–Barr virus (EBV) (20%) and Cytomegalovirus (CMV) (14%)[4]. In contrast to the available literature, only four events of cutaneous viral infections were reported in three of our patients ,i.e. two patients had recurrent herpetic eruptions, one had molluscum lesions, and one had genital warts. This difference could possibly be explained by the relatively younger age of our cohort. Mean age of patients in our cohort was five years eight months(range, 4 months − 18 years) while, it was eleven years(range, 1.3–47.7 years) in the cohort by Aydin et al[4].
Sinopulmonary infections are the most common type of infection reported in DOCK8 deficiency. Recurrent respiratory infections were noted in
91%(n = 124) as per Aydin et al. The most frequently isolated organisms included Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae[4]. Seventy six percent (n = 13) of patients in our cohort had recurrent sinopulmonary infections; and, Pneumococcus was isolated in one patient with pneumonia and meningoencephalitis. There is some data to suggest regional variations in the spectrum of infections in DOCK8 deficiency. Gastrointestinal (GI) involvement was sparingly reported in western cohorts of DOCK8 deficiency. Engelhardt et al. reported one case of rotavirus enteritis amongst 64 patients[4, 9]. Although they reported parasitic infections with Entamoeba histolytica and Cryptosporidium, it was unclear if these organisms indeed caused GI involvement in their patients[4]. This was in contrast to the cohort published by Gowri et al. that reported recurrent diarrhoea in 70%(12/17) patients[6]. Twenty nine percent(5/17) of our patients had GI involvement. Systemic viral infections is another common finding in DOCK8 deficiency patients. Aydin et al. reported a varied spectrum of systemic involvement, involving lungs, central nervous system and eyes. CMV, EBV, VZV, HSV and Rotavirus were reported to cause systemic infections[4]. Besides the respiratory viruses, Gowri et al. also reported CMV viremia (n = 1) and HSV (n = 1) in nasopharyngeal secretions in their cohort[6]. In our cohort, only one patient (P17) had enteroviral meningitis. Paucity of viral infections in our cohort could partly be explained by the younger age of patients.
Autoimmunity has been reported in patients with DOCK8 deficiency. Immunological studies in DOCK8 deficiency have revealed impaired TH17 differentiation and decreased number and function of regulatory T (Treg) cells, leading to immune dysregulation. Also, autoreactive antibodies directed against cytosolic antigens are increased due to lost peripheral B cell immunotolerance[10]. Aydin et al. reported autoimmunity in 13%(17/136) of patients, vasculitis(8/17) and AIHA(6/17) being the most prevalent manifestations in their cohort[4]. Hypothyroidism and systemic lupus erythematosus have also been reported in DOCK8 deficient patients[1]. Twenty-three per cent (4/17) of patients in our cohort had autoimmunity. The mean age at onset of autoimmunity was 4.5 years. Two patients developed AIHA at one year and 14 years of age, respectively. Three of four patients with autoimmunity had a fatal outcome, however, autoimmunity directly contributed to poor outcome in one of them. None of our patients developed malignancy, possibly due to younger age of our cohort.
More than 130 types of mutations have been reported in patients with DOCK8 deficiency, the most common being deletions[11]. The DOCK8 gene, located on chromosome 9p24.3, contains up to 48 exons and is 190 kb in size. Multi-exonic and single-exonic deletions have been reported in 45% and 13% of large cohorts with DOCK8 deficiency, respectively. (Venegas-Montoya E) Fifty-eight per cent (10/17) of patients in our study had exonic deletions, which included eight single-exonic and two multi-exonic deletions. We noted ten novel mutations, that included four deletions, five missense mutations, and one duplication-causing frameshift mutation. There is poor genotype-phenotype correlation in DOCK8 deficiency. Case reports suggest splice site mutations are associated with neurological manifestations[11]. We did not find any specific correlation between the genotype and phenotype in our cohort.
Patients with DOCK8 deficiency have significant morbidity and mortality. Aydin et al. reported mortality in 25% (n = 34/136), with infections being the leading cause, followed by malignancy and other causes[4]. Severe infections contributed to significant mortality, in our study, with four patients succumbing to pneumonia and two to chronic diarrhoea. P1 had CNS vasculitis, while the cause was uncertain in one patient. Ayden et al. observed that the approximate survival probability was 87% at ten years, and it dropped to 33% at 30 years in the absence of a hematopoietic stem cell transplant. Outcomes post HSCT have been getting better and a survival of up to 84% has been reported[12]. However, offering HSCT to all patients is often fraught with financial and social challenges in resource-constrained settings. While three patients underwent HSCT in our cohort, two of them died. Details of transplants were not available, to draw any further conclusions.
We hereby report one of the largest single-centre cohorts of DOCK8 deficiency from the Indian subcontinent. We acknowledge the limitations of our study. Due to limited availability, the lymphocyte subset aberrations could not be determined in all patients. We could not perform detailed immunological work-up in all patients, including DOCK8 protein expression.