Additional diverse findings expand the clinical presentation of DOCK8 deficiency

Abstract

We describe seven Turkish children with DOCK8 deficiency who have not been previously reported. Three patients presented with typical features of recurrent or severe cutaneous viral infections, atopic dermatitis, and recurrent respiratory or gastrointestinal tract infections. However, four patients presented with other features. Patient 1-1 featured sclerosing cholangitis and colitis; patient 2-1, granulomatous soft tissue lesion and central nervous system involvement, with primary central nervous system lymphoma found on follow-up; patient 3-1, a fatal metastatic leiomyosarcoma; and patient 4-2 showed no other symptoms initially besides atopic dermatitis. Similar to other previously reported Turkish patients, but in contrast to patients of non-Turkish ethnicity, the patients' lymphopenia was primarily restricted to CD4(+) T cells. Patients had homozygous mutations in DOCK8 that altered splicing, introduced premature terminations, destabilized protein, or involved large deletions within the gene. Genotyping of remaining family members showed that DOCK8 deficiency is a fully penetrant, autosomal recessive disease. In our patients, bone marrow transplantation resulted in rapid improvement followed by disappearance of viral skin lesions, including lesions resembling epidermodysplasia verruciformis, atopic dermatitis, and recurrent infections. Particularly for patients who feature unusual clinical manifestations, immunological testing, in conjunction with genetic testing, can prove invaluable in diagnosing DOCK8 deficiency and providing potentially curative treatment.

Figure 1

Pedigrees of the families studied. Genotypes are indicated below each individual, where “+” designates normal DOCK8 allele, and “m” or “Δ” designates mutated or deleted DOCK8 allele, respectively. Numbers about the pedigrees correspond to the family identifiers, whereas patient identifiers are indicated below the symbols. A closed symbol designates an affected individual, whereas an open symbol designates an unaffected individual. Squares designate males; circles, females; arrows, probands; and slashes, deceased individuals.

Figure 2

Skin lesions in patient 1-1. Human papillomavirus-associated pinkish, hypopigmented flat papules on dorsal hands (A) and buttocks (B). C) Histopathology shows hyperkeratosis and acanthosis, with vacuolated cells in the stratum malpighii (arrow), keratinocytes having abundant slightly basophilic cytoplasm (small arrow), and occasional large, round, empty-appearing nuclei (arrowhead). Patients 2-1, 2-2, 3-1, and 3-2 had similar lesions.

Figure 3

Cranial MRI in patient 2-1. A) Transverse T2 weighted (W) fat-suppressed (left) and B) contrast enhanced (ce) fat-suppressed T1W (right) spin-echo (SE) images, at initial presentation. A T2-hyperintense and Gadolinium-enhancing lesion with irregular border in the left buccal space and retromolar trigone is seen (arrowheads in A, B). C). Transverse T2W turbo SE images, at five months, show bilateral pulvinar T2 hyperintensities (arrowheads) and cerebral volume loss. D) Axial Gadolinium-enhanced T1W SE shows a lesion with rim enhancement (long arrow). E) Axial diffusion-weighted imaging (DWI), at eighteen months, shows hyperintensity in the parenchyma and in the lesion, especially at the periphery.

Figure 4

Peripheral blood enumerations of lymphocyte subsets, quantitative serum immunoglobulin isotypes, and eosinophils. Patient 1-1, open circle; patient 2-1, open square; patient 3-1, cross; patient 3-2, X; patient 4-1, open inverted triangle; patient 4-2, filled-in circle. Shaded in grey are the ranges for normal age-matched controls. For lymphocytes and their subsets, published 10^th to 90^th percentiles are shown in grey. For immunoglobulin isotypes, the 95 % confidence interval is shown. For eosinophils, arbitrarily thresholds for mild, moderate, and severe eosinophilia are as indicated.

Figure 5

DOCK8 expression data for mutations in patients from families 1 and 3. A) PCR amplification of exons 19 to 24 of DOCK8 from cDNA shows a smaller product from patient 1-1, which corresponds to an aberrantly spliced mRNA. B) Immunoblotting shows destabilized DOCK8 protein in 293T cells that have been transiently transfected with a plasmid encoding the full-length mutant (C1447R), as compared to wildtype, DOCK8. Patients 3-1 and 3-2 only express this mutant form of DOCK8.