Information on JAK1D

Name: JAK1 deficiency | Acronym: JAK1D
Alt. names: JAK1-LOF | JAK1 loss-of-function

Gene: JAK1 | MOI: Autosomal recessive | Mechanism of action: Loss of Function

No. of cases in DB: 1 | First reported in: 2016

Last updated on: 2023-08-17 by Andr�s Caballero-Oteyza

OMIM:

Orphanet: -

MONDO: -

DOID: -

ClinGen:

Description

Thus far, only one patient with partial JAK1 deficiency has been described in the literature - a 22 year old Pakistani man born to consanguineous parents who presented with a history of global developmental delay, poor growth and recurrent sinorespiratory infections beginning in the first year of life (PMID: 28008925, 31552026, 36159783). He was found to have systemic atypical mycobacterial infections involving his lymph nodes, skeleton and mediastinum, as well as skin infections such as warts, onychomyosis and scabies. He passed away at age 23 from high-grade metastatic transitional cell carcinoma of the bladder. Immunophenotyping was notable for initially normal T and B cell counts with reduced naive CD4+ and CD8+ T cell populations, normal specific antibody responses, and normal to mildly reduced responses to proliferative responses to mitogen and antigen stimulation. IgG levels remained persistently elevated but initially normal IgM levels eventually fell below normal range and a persistent mild T lymphopenia developed over time. The authors showed that the patient�s 2 homozygous variants (P733L and P832S) together exerted a hypomorphic effect on JAK/STAT signaling via reduced kinase function and slightly reduced JAK1 protein expression, with downstream reductions in STAT phosphorylation and target gene expression (PMID: 28008925). Subsequent work showed that the susceptibility to mycobacterial infection arose predominantly via impaired IFN-γ signaling in myeloid cells, while impairment of type I IFN signaling in response to viral infections was more variable across cell types (PMID: 36159783).

Management

The patient mentioned above remained on long-term antibiotic prophylaxis with Clarithromycin and Ciprofloxacin for atypical mycobacterial infections. Of note, the patient had received childhood vaccines�including Bacillus Calmette-Guerin (BCG) vaccine at birth without any history of disseminated BCGosis and had normal-course chicken pox at age 3 with one subsequent episode of shingles.

Summary of clinical findings

[Considering only Definitive and Possible cases]

Rank	Clinical phenotype	Present
1	(unusual) Skin infection	1 (99.9%)
2	Recurrent lower respiratory tract infections	1 (99.9%)
3	Mass on thoracic imaging	1 (99.9%)
4	Mediastinal mass	1 (99.9%)
5	Lymphadenopathy	1 (99.9%)
6	Recurrent ear infections	1 (99.9%)
7	Lymphopenia	1 (99.9%)
8	Nontuberculous Mycobacteria infection	1 (99.9%)
9	Global developmental delay	1 (99.9%)
10	Abnormal myocardium morphology	1 (99.9%)
11	Recurrent respiratory infections	1 (99.9%)
12	Reduced proportion of CD8 T cells	1 (99.9%)
13	Leukocytosis	1 (99.9%)
14	Cardiovascular system abnormality	1 (99.9%)
15	short stature	1 (99.9%)
16	Recurrent infections	1 (99.9%)
17	Anemia	1 (99.9%)
18	Enteropathy	1 (99.9%)
19	Reduced T cell count	1 (99.9%)
20	Intestinal polyp	1 (99.9%)
21	Growth delay	1 (99.9%)
22	Osteomyelitis	1 (99.9%)
23	Cardiomyopathy	1 (99.9%)
24	Neoplasm of the gastrointestinal tract	1 (99.9%)
25	Cervical lymphadenopathy	1 (99.9%)
26	Abnormal leukocyte count	1 (99.9%)
27	Abnormal T cell count	1 (99.9%)
28	Abnormal neutrophil count	1 (99.9%)
29	Neutrophilia	1 (99.9%)
30	Bladder neoplasm	1 (99.9%)
31	Disseminated nontuberculous mycobacterial infection	1 (99.9%)
32	Urinary tract neoplasm	1 (99.9%)
33	Reduced proportion of CD4 T cells	1 (99.9%)
34	Neoplasm by anatomical site	1 (99.9%)
35	Frequent skin infections	1 (99.9%)
36	Abnormality of erythrocytes	1 (99.9%)
37	Musculoskeletal physiology abnormality	1 (99.9%)
38	Neurodevelopmental delay	1 (99.9%)
39	Abnormal proportion of CD4 T cells	1 (99.9%)
40	Abnormal proportion of CD8 T cells	1 (99.9%)
41	Abnormality of body height	1 (99.9%)
42	Increased inflammatory response	1 (99.9%)

Age of onset
distribution

Summary of treatment outcomes