Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: HCK

I don't know

Comment on list classification: There are now 5 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Recurrent infections were noted in 2 unrelated individuals (PMIDs: 34536415, 41382121) . Hence, the Autoinflammatory disorders panel may be more appropriate for this gene - leaving as Amber on Primary immunodeficiency or monogenic inflammatory bowel disease.

Created: 29 Jul 2026, 10:48 a.m. | Last Modified: 29 Jul 2026, 10:57 a.m.

Panel Version: 9.25

PMID: 41920357 Price-Kuehne et al., 2026
Family A - female proband with systemic vasculitis due to a de novo heterozygous variant in HCK c.1545 C > A, p.(Tyr515Ter) - exome seq; she was treated with allogeneic haematopoietic stem cell transplantation. She subsequently developed epistaxis, haemolacria and blood-stained stools leading to iron-deficiency anaemia requiring transfusion. From 18 months of age, she developed chronic cough and haemoptysis; chest CT scan demonstrated enlarged hilar lymph nodes and bilateral inflammatory changes and pulmonary haemorrhage.

Family B - male proband with a cutaneous-limited phenotype (purpuric rash, predominantly affecting the limbs, starting at 4hrs after birth); Skin biopsy showed leukocytoclastic vasculitis; WES identified a novel HCK missense variant c.1565A > T, (p.Tyr522Phe). Proband's father is het for the same HCK variant, and also had neonatal-onset leukocytoclastic vasculitis, now healthy.

PMID: 41382121 Berdeli, Ismayilova, & Gürbüz 2025
Report of a 6-year-old female patient with recurrent fevers, cutaneous petechial rashes, chronic cough, exertional dyspnea, and suspected recurrent lower respiratory tract infections since age 1.5 years. No cutaneous manifestations were observed, but elevated acute-phase reactants and pulmonary findings were noted. WES revealed a heterozygous splice variant c.1016-5T>C in HCK.

doi: 10.11648/j.ajp.20190504.15 Bronz et al., 2019
Family with suspected Finkelstein-Seidlmayer disease (benign small-vessel leukocytoclastic vasculitis) - affected mother and her 3 sons. History of red-to-purpuric skin lesions with neonatal onset, no systemic involvement. WES detected a heterozygous HCK variant c.1555G>T; p.Glu519* in all 4 affected individuals. Variant not present in gnomAD v4.1.1.

Created: 29 Jul 2026, 10:33 a.m. | Last Modified: 29 Jul 2026, 10:42 a.m.

Panel Version: 9.24

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Autoinflammation with pulmonary and cutaneous vasculitis, OMIM:620296; autoinflammation with pulmonary and cutaneous vasculitis, MONDO:0957204

Publications

• 41382121
• 41920357

Comment on list classification: Single case reported to date as per review by Boaz Palterer. Rating Red until further cases emerge.

Created: 18 Jul 2022, 12:36 p.m. | Last Modified: 18 Jul 2022, 12:36 p.m.

Panel Version: 2.567

Green List (high evidence)

Two additional reports:
Priece-Kuehne et al. describing 3 additional kindreds with HCK GOF, similar phenotype and mechanism ( https://link.springer.com/article/10.1007/s10875-026-01998-z )
Berdeli et al. additional kindred with similar phenotype and mechanism (https://pmc.ncbi.nlm.nih.gov/articles/PMC12801773/)

Now reaching criteria for green rating

Created: 14 Apr 2026, 7:01 p.m. | Last Modified: 14 Apr 2026, 7:01 p.m.

Panel Version: 8.99

Kanderova et al. described a single patient with an autoinflammatory phenotype characterized by early-onset cutaneous vasculitis and lung inflammation leading to fibrosis.
A de novo truncating mutation (p.Tyr515*) in the HCK leading to the loss of the C-terminal inhibitory tyrosine Tyr522 was identified.
Variant pathogenicity was confirmed ex vivo in primary cells and in vitro in transduced cell lines.
Sources: Literature

Created: 25 May 2022, 1:26 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease

Publications

• 34536415
• 41382121

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments