The present study enrolled 5 patients from the same family with JIAPs referred for genetic diagnostic by whole exome sequencing (WES) to (Rostock, Germany) Centogene AG. DNA was extracted from salivary samples and exome capture was carried out with the method described before (4). All inheritance patterns were considered, and advanced genotype-phenotype are used to evaluate identified variants concerning their pathogenicity and causality. The generated library sequenced on an Illumina platform ensured a sequencing coverage level of at least 20x targeting for more than 98% of the human coding exome. All variants related to the phenotype of the patients with minor allele frequency (MAF) of less than 1% were considered. Low-quality single nucleotide variants and all relevant deletion/insertion variants are confirmed by Sanger sequencing.
Patients
Clinical and biological features are presented in Table1.
Table 1. Clinical and biological features of a juvenile idiopathic arthritis family.
Patients
|
III: 4
|
IV: 4
|
IV: 5
|
IV: 6
|
IV: 7
|
Age
|
40
|
20
|
17
|
16
|
13
|
Age of onset
|
8
|
11
|
8
|
10
|
8
|
Cesarean
|
N
|
Y
|
Y
|
Y
|
Y
|
Birth weight
|
2800
|
2700
|
3320
|
3340
|
3370
|
Breastfeeding ≥ 6 months
|
N
|
N
|
N
|
N
|
N
|
Maternal smoking during pregnancy
|
N
|
N
|
N
|
N
|
N
|
Passive smoking
|
N
|
N
|
N
|
N
|
N
|
Living in a rural area
|
Y
|
Y
|
Y
|
Y
|
Y
|
Living on a farm during first year of life
|
N
|
N
|
N
|
N
|
N
|
Household pets
|
Y
|
Y
|
Y
|
Y
|
Y
|
Periodontitis/ rhinitis
|
N
|
N
|
N
|
N
|
N
|
Antibiotics exposure
|
N
|
N
|
N
|
N
|
N
|
Psoriasis
|
Y
|
N
|
N
|
Y
|
N
|
Asthma
|
Y
|
Y
|
N
|
N
|
Y
|
Disease activity
|
Low
|
High
|
High
|
Low
|
High
|
Serum alpha-1antitrypsin
|
0,59 g per liter.
|
0,99 g per liter.
|
0,78 g per liter.
|
0,68 g per liter.
|
0,97 g per liter.
|
Y=Yes, N=No
|
III: 4, the case-index, 40 years, had the onset at 8 years, at the entry to primary school, with back pain, talalgias, interphalangeal digital arthritis and psoriasis (scaling skin, scales on the scalp and pruritus). Physician global assessment (PGA) and patient global assessment (PtGA) of disease activity show minimal disease activity. She has also asthma and alpha-1-antitrypsin deficiency (AATD) with a low AAT level at 0,59 g per liter. No biological therapies were administered.
IV: 4, a 20-year-old girl, the eldest daughter of index case, has juvenile arthritis with asymmetric oligoarthritic pattern without skin changes. At the age of 11 years, she experienced joint swelling in both knees. She suffers from asthma and has prolonged QT interval with notion of sudden death of her paternal grandfather at age 46. Currently, she has a treatment by adalimumab at a posology of 40 mg administered twice monthly. The serum alpha-1-antitrypsin (AAT) is at 0,99 g per liter.
IV: 5, a 17-year-old boy, the eldest son of index case, has polyarticular juvenile arthritis. The first manifestation was at 8 years old like a sacroiliac pain and joint effusion of the hips more severe in the right. He suffers from dactylitis of all toes, metatarsophalangeal joints, thumbs, and heels. On physical examination, he had bilateral synovial thickening of the proximal interphalangeal joints of the fingers even more in the metacarpo-phalanx of the right thumb, metatarsal, and metacarpal-phalangeal joints. Psoriasiform lesions appeared on elbows and scalp but there are no nail anomalies. One episode of uveitis was reported with no recurrences. He is not relieved by diclofenac and indomethacin therefore methotrexate at a posology of 10 mg per week used in combination with etanercept at the posology is 0,8 mg per kg was started at the age of 13. A few months later, a severe arthritis flare occurred, with an aggressive polyarticular course. He thus needed a wheelchair and an increased dose of etanercept at 35 mg per week. Dactylitis of all toes was noted on physical examination with a very painful limitation of the right hip and impossibility to stand up. JADAS (juvenile arthritis disease activity score) is 12. The AAT level is at 0, 78 g/L.
IV: 6, a 16-year-old girl was born by cesarean section like her brothers. She is followed for psoriasis lesions on elbows and scalp and psoriatic oligoarticular arthritis with the age of onset at 10 years. She has also AATD with a low AAT level at 0,68 g/L. Currently, she is completely asymptomatic and has no biological-based therapies. She was experiencing losses of consciousness and is followed by cardiologists because of a familial record of sudden death.
IV: 7, a 13-year-old boy who had his first rheumatic manifestation at 8 years. The joints were involved in an asymmetric pattern with recurrent hip arthritis, back pain, right wrist, shoulders, and right heel pain. He has high disease activity with painful swelling of the left knee, along with morning stiffness at about 30 minutes and limited range of motion. Treatments by indomethacin then naproxen were not effective. Methotrexate was started at the age of 12. The evolution is unfavorable for two years with hips, right heel, and right wrist aches and back pain. On physical examination, were noted arthritis of the wrists, knees, ankles, distal and proximal interphalangeal joints with typical “sausage digit”, and limited range of motion of hips at about 10 degrees of abduction. JADAS score is 14. Considering the poor clinical control achieved with the current medications, anti-TNF alpha therapy (adalimumab), was administered subcutaneously at the dose of 40 mg twice monthly in association with the non-steroidal anti-inflammatory drugs therapy. Clinical remission was noted with a partial resolution of articular manifestations involving essential the right hip and back. He has also asthma related to AATD and low serum concentration at 0,78 g/L.
The mother of the index-case (II: 4) has granulomatosis with polyangiitis (Wegener disease) involving the respiratory tract related to AATD. Her sister (III: 5) has an inflammation of the knees without skin changes. Her aunt (II: 2) has multiple sclerosis and her great uncle (II: 5) has symptomatic AATD (emphysema). In our patients’ rheumatoid factor (RF), HLA-B27, and anti-nuclear antibodies (ANAs) are negative.
Genetic analysis
The study was performed in accordance with the modified version of the Helsinki declaration. Written informed consent was obtained from the index-case and parents of the young patients.