Introduction
Methods
Patients and Controls
ID | Origin | Investigated CMC patients | Mutation carriers | Invest. healthy members | Mutation carriers | Affected domain | Affected exon | BP change | AA change |
---|---|---|---|---|---|---|---|---|---|
Families
| |||||||||
Fam01 | BRA | 2 | 2 | 0 | 0 | Coiled-coil | 8 | c.604A > G | p.M202V |
Fam02 | USA | 7 | 4 | 6 | 0 | Coiled-coil | 10 | c.800C > T | p.A267V |
Fam03 | NOR | 3 | 3 | 8 | 0 | Coiled-coil | 10 | c.800C > T | p.A267V |
Fam04 | NOR | 3 | 3 | 7 | 0 | Coiled-coil | 10 | c.820C > T | p.R274W |
Fam05 | GER | 3 | 3 | 0 | 0 | Coiled-coil | 10 | c.820C > T | p.R274W |
Fam06 | GER | 4 | 4 | 3 | 1 | Coiled-coil | 10 | c.821G > A | p.R274Q |
Fam07 | SVK | 2 | 2 | 1 | 0 | Coiled-coil | 10 | c.877C > T | p.P293S |
Fam08 | GER | 2 | 2 | 0 | 0 | DNA-binding | 14 | c.1189A > G | p.N397D |
Fam09 | CAN | 3 | 3 | 0 | 0 | DNA-binding | 14 | c.1211 T > A | p.F404Y |
Fam10 | NOR | 3 | 0 | 6 | 0 | No mutation found | n.a. | n.a. | n.a. |
Fam11 | COL | 7 | 0 | 4 | 0 | No mutation found | n.a. | n.a. | n.a. |
Total | 39 | 26 | 35 | 1 | |||||
Sporadic patients
| |||||||||
Spor01 | GER | 1 | 1 | n.a. | n.a. | Coiled-coil | 7 | c.514 T > C | p.F172L |
Spor02 | UK | 1 | 1 | n.a. | n.a. | Coiled-coil | 10 | c.859 T > G | p.Y287D |
Spor03 | BEL | 1 | 1 | n.a. | n.a. | DNA-binding | 14 | c.1154C > T | p.T385M |
Spor04 | BRA | 1 | 1 | n.a. | n.a. | DNA-binding | 14 | c.1154C > T | p.T385M |
Spor05 | COL | 1 | 1 | n.a. | n.a. | DNA-binding | 14 | c.1154C > T | p.T385M |
Spor06 | GER | 1 | 1 | n.a. | n.a. | DNA-binding | 14 | c.1154C > T | p.T385M |
Spor07 | USA | 1 | 1 | n.a. | n.a. | DNA-binding | 14 | c.1154C > A | p.T385K |
Spor08 | BEL | 1 | 1 | n.a. | n.a. | DNA-binding | 14 | c.1162A > G | p.K388E |
Spor09 | UK | 1 | 1 | n.a. | n.a. | DNA-binding | 17 | c.1398C > G | p.S466R |
Spor10 | UK | 1 | 0 | n.a. | n.a. | (Coiled-coil) | (10) | (c.796G > A) | (p.V266I) |
Spor11 | UK | 1 | 0 | n.a. | n.a. | No mutation found | n.a. | n.a. | n.a. |
Spor12 | UK | 1 | 0 | n.a. | n.a. | No mutation found | n.a. | n.a. | n.a. |
Spor13 | DEN | 1 | 0 | n.a. | n.a. | No mutation found | n.a. | n.a. | n.a. |
Spor14 | COL | 1 | 0 | n.a. | n.a. | No mutation found | n.a. | n.a. | n.a. |
Spor15 | CAN | 1 | 0 | n.a. | n.a. | No mutation found | n.a. | n.a. | n.a. |
Spor16 | GER | 1 | 0 | n.a. | n.a. | No mutation found | n.a. | n.a. | n.a. |
Spor17 | IND | 1 | 0 | n.a. | n.a. | No mutation found | n.a. | n.a. | n.a. |
Spor18 | UK | 1 | 0 | n.a. | n.a. | No mutation found | n.a. | n.a. | n.a. |
Total | 18 | 9 |
PCR and Sequencing Analysis
STAT1 Phosphorylation
Results
Identification of STAT1 Mutations in 61 % of all CMC Patients
STAT1 Hyper-Phosphorylation in PBMC of CMC Patients upon IFN-α, IFN-γ and IL-27 Stimulation
Clinical Phenotype of CMC Patients with STAT1 GOF Mutations
No. of patients | % of patients | |
---|---|---|
Infection of oral mucosa
| ||
Oral candidiasis | 19/26 | 73 % |
Duration | ||
• Recurrent | 11/19 | 58 % |
• Chronic | 8/19 | 42 % |
Response to treatment | ||
• Complete | 6/16 | 38 % |
• Partial | 10/16 | 62 % |
• No | 0/16 | 0 % |
Aphthous stomatitis | 18/26 | 69 % |
• Severe | 10/26 | 38 % |
• Moderate | 8/26 | 31 % |
Duration | ||
• Recurrent | 14/17 | 82 % |
• Chronic | 3/17 | 18 % |
Response to treatment | ||
• Complete | 6/13 | 46 % |
• Partial | 6/13 | 46 % |
• No | 1/13 | 8 % |
Infection of intestinal tract
| ||
Esophageal candidiasis | 15/23 | 65 % |
Other | 1/23 | 4 % |
Duration | ||
• Recurrent | 13/15 | 87 % |
• Chronic | 2/15 | 13 % |
Response to treatment | ||
• Complete | 8/12 | 67 % |
• Partial | 4/12 | 33 % |
• No | 0/12 | 0 % |
Skin infections
| ||
Intertrigo | 13/26 | 50 % |
Pustules | 12/26 | 46 % |
Intertrigo and/or Pustules | 20/26 | 77 % |
Duration | ||
• Recurrent | 9/18 | 50 % |
• Chronic | 9/18 | 50 % |
Response to treatment | ||
• Complete | 4/16 | 25 % |
• Partial | 12/16 | 75 % |
• No | 0/16 | 0 % |
Infection of scalp
| 11/25 | 44 % |
Duration | ||
• Recurrent | 3/9 | 33 % |
• Chronic | 6/9 | 67 % |
Response to treatment | ||
• Complete | 4/8 | 50 % |
• Partial | 4/8 | 50 % |
• No | 0/8 | 0 % |
Infection of nails
| ||
Onychomycosis | 16/25 | 64 % |
Paronychia | 9/23 | 39 % |
Duration | ||
• Recurrent | 4/17 | 24 % |
• Chronic | 13/17 | 76 % |
Response to treatment | ||
• Complete | 3/15 | 20 % |
• Partial | 12/15 | 80 % |
• No | 0/15 | 0 % |
Infection of vulva and vagina
| 6/9 | 67 % |
Limited to vulva | 2/6 | 33 % |
Extended to surrounding areas | 4/6 | 67 % |
Duration | ||
• Recurrent | 5/6 | 83 % |
• Chronic | 1/6 | 17 % |
Response to treatment | ||
• Complete | 4/5 | 80 % |
• Partial | 1/5 | 20 % |
• No | 0/5 | 0 % |
No. of patients | % of patients | |
---|---|---|
Other Infections
| ||
Ears, nose and throat | ||
• Sinusitis | 12/25 | 48 % |
• Otitis | 4/25 | 16 % |
• Conjunctivitis | 1/21 | 5 % |
• Tonsillitis | 3/25 | 12 % |
Respiratory tract | ||
• Bronchitis | 9/22 | 41 % |
• Pneumonia | 9/22 | 41 % |
• Bronchiectasis | 3/22 | 14 % |
Cutaneous infections | ||
• Furunculosis | 2/22 | 9 % |
• Folliculitis | 7/22 | 32 % |
• Abscess | 1/22 | 5 % |
Urinary infections | 1/22 | 5 % |
Dermatophyte | 3/22 | 14 % |
Other fungi / parasites | 0/22 | 0 % |
Viral infections | ||
• Herpes | 4/22 | 18 % |
• Papillomavirus | 3/22 | 14 % |
• Zoster | 2/22 | 9 % |
• Severe varicella | 1/22 | 5 % |
• Epstein Barr | 1/19 | 5 % |
Sepsis | 2/22 | 9 % |
Non-infectious diseases
| ||
Auto-immunity | ||
• Thyroid | 11/25 | 44 % |
• Alopecia | 1/21 | 5 % |
• Vitiligo | 1/21 | 5 % |
• Systemic Lupus Erythematosus | 0/25 | 0 % |
• Multiple Sclerosis | 0/25 | 0 % |
Neurological complications | ||
• Cerebral aneurysm | 2/25 | 8 % |
• Cerebral vasculitis | 1/25 | 4 % |
Malignancies | 0/21 | 0 % |
Increased | Normal | Decreased | Unknown | |||||
---|---|---|---|---|---|---|---|---|
No. of patients | % | No. of patients | % | No. of patients | % | No. of patients | % | |
White blood cell count
| ||||||||
WBC | 3/22 | 14 % | 18/22 | 82 % | 1/22 | 5 % | 4/26 | 15 % |
Granulocytes | 4/23 | 17 % | 18/23 | 78 % | 1/23 | 4 % | 3/26 | 12 % |
Lymphocytes | 0/23 | 0 % | 20/23 | 87 % | 3/23 | 13 % | 3/26 | 12 % |
Monocytes | 4/23 | 17 % | 19/23 | 83 % | 0/23 | 0 % | 3/26 | 12 % |
Eosinophils | 1/20 | 5 % | 14/20 | 70 % | 5/20 | 25 % | 6/26 | 23 % |
Percentage of lymphocytes
| ||||||||
CD3+ | 3/21 | 14 % | 16/21 | 76 % | 2/21 | 10 % | 5/26 | 19 % |
CD4+ | 0/21 | 0 % | 18/21 | 86 % | 3/21 | 14 % | 5/26 | 19 % |
CD8+ | 0/21 | 0 % | 20/21 | 95 % | 1/21 | 5 % | 5/26 | 19 % |
CD19+ | 2/21 | 10 % | 17/21 | 81 % | 2/21 | 10 % | 5/26 | 19 % |
CD16+/CD65+/CD3- | 1/19 | 5 % | 8/19 | 42 % | 10/19 | 53 % | 6/26 | 24 % |
Immunoglobulins serum levels
| ||||||||
IgG | 7/22 | 32 % | 14/22 | 64 % | 1/22 | 5 % | 4/26 | 15 % |
• IgG1 | 4/12 | 33 % | 8/12 | 67 % | 0/12 | 0 % | 14/26 | 54 % |
• IgG2 | 1/12 | 8 % | 7/12 | 58 % | 4/12 | 33 % | 14/26 | 54 % |
• IgG3 | 2/11 | 18 % | 9/11 | 82 % | 0/11 | 0 % | 15/26 | 58 % |
• IgG4 | 0/10 | 0 % | 3/10 | 30 % | 7/10 | 70 % | 16/26 | 62 % |
IgM | 2/23 | 9 % | 19/23 | 83 % | 2/23 | 9 % | 3/26 | 12 % |
IgA | 1/23 | 4 % | 16/23 | 70 % | 6/23 | 26 % | 3/26 | 12 % |
IgE | 0/21 | 0 % | 13/21 | 62 % | 8/21 | 38 % | 5/26 | 19 % |
Thyroid markers
| ||||||||
TSH | 9/22 | 41 % | 12/22 | 55 % | 1/22 | 5 % | 4/26 | 15 % |
T3
| 2/13 | 15 % | 8/13 | 62 % | 3/13 | 23 % | 13/26 | 50 % |
T4
| 0/20 | 0 % | 16/20 | 80 % | 4/20 | 20 % | 6/26 | 23 % |
Autoantibodies
| ||||||||
Anti-thyroglobulin antibody | 3/16 | 19 % | 13/16 | 81 % | n.a. | 10/26 | 38 % | |
Anti-thyroid peroxidase antibody | 0/21 | 0 % | 21/21 | 100 % | n.a. | 5/26 | 19 % | |
Anti-microsomal antibody | 1/8 | 13 % | 7/8 | 88 % | n.a. | 18/26 | 69 % | |
Anti-adrenal antibody | 0/11 | 0 % | 11/11 | 100 % | n.a. | 15/26 | 58 % | |
Anti-insulin antibody | 1/9 | 11 % | 8/9 | 89 % | n.a. | 17/26 | 65 % | |
Anti-GAD65 antibody | 1/9 | 11 % | 8/9 | 89 % | n.a. | 17/26 | 65 % | |
Anti-pancreatic islet cell antibody | 0/9 | 0 % | 9/9 | 100 % | n.a. | 17/26 | 65 % |