Clinical and laboratory manifestations and treatment of children with TNFRSF1A gene variants

doi:10.5409/wjcp.119428

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World Journal of Clinical Pediatrics

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2219-2808

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Retrospective Cohort Study

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World J Clin Pediatr. Sep 9, 2026; 15(3): 119428
Published online Sep 9, 2026. doi: 10.5409/wjcp.119428

Table 1 Variants of the TNFRSF1A gene identified based on molecular genetic research data, n (%)

Number of patients (n = 33)	Number of options (n = 35)	*Nucleotide and protein variants of the gene TNFRSF1A* (NM_001065.4)**	Population frequency of the minor allele, gnomAD v.4.1.0	Description in the literature in patients with AIDs
1 (3)	1 (2.9)	c.337_339del, p.Glu113del in a heterozygous state	No data	Not described
1 (3)	1 (2.9)	c.362G>A, p.Arg121Gln in a homozygous state	1.5%	[17-19]
24 (73)	24 (68.3)	c.362G>A, p.Arg121Gln in a heterozygous state	1.5%	[17-19]
1 (3)	1 (2.9)	c.792del, p.Lys265Serfs*87 in a heterozygous state	No data	Not described
1 (3)	2 (5.7)	c.362G>A, p.Arg121Gln in a heterozygous state	1.5%	[17-19]
1 (3)	2 (5.7)	c.242G>T, p.Cys81Phe in a heterozygous state	No data	Not described
1 (3)	1 (2.9)	c.596T>C, p.Ile199Thr in a heterozygous state	0.006%	[20,21]
1 (3)	1 (2.9)	c.374G>A, p.Cys125Tyr in a heterozygous state	No data	[3]
1 (3)	1 (2.9)	c.184T>A, p.Cys62Ser in a heterozygous state	No data	Not described
1 (3)	2 (5.7)	c.472+6С>Т, p.? in a heterozygous state	0.003%	[3]
1 (3)	2 (5.7)	c.362G>A, p.Arg121Gln in a heterozygous state	1.5%	[17-19]
1 (3)	1 (2.9)	c.194-14G>A, p.? in a heterozygous state	0.02%	[22]

AID: Autoinflammatory disease.

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Table 2 Demographic and clinical characteristics of patients with gene variants TNFRSF1A and systemic juvenile idiopathic arthritis at disease onset and at the time of diagnosis of systemic juvenile idiopathic arthritis, n (%)/median (interquartile range)

Indicator	At onset				At time of sJIA diagnosis
Indicator	Total group (n = 66)	*Patients with gene variants TNFRSF1A(n = 33)*	Patients with sJIA (n = 33)	P value	Total group (n = 66)	*Patients with gene variants TNFRSF1A(n = 33)*	Patients with sJIA (n = 33)	P value
Boys	24 (36.4)	12 (36.4)	12 (36.4)	1.0	24 (36.4)	12 (36.4)	12 (36.4)	1.0
Girls	42 (63.6)	21 (63.6)	21 (63.6)	1.0	42 (63.6)	21 (63.6)	21 (63.6)	1.0
Age at the time of disease onset (years)	4.73 (2.0-7.4)	5.3 (1.6-7.6)	4.3 (2.6-6.9)	0.97	5.8 (3.39.3)	6.1 (3.49.0)	4.8 (3.27.7)	0.7
Duration of period between onset and verification of the diagnosis of rheumatic disease (years)					0.22 (0.1-0.6)	0.33 (0.2-0.8)	0.18 (0.1-0.4)	0.08
Burdened heredity for periodic febrile syndromes	1 (1.5)	1 (3)	0 (0)	1.0	1 (1.5)	1 (3)	0 (0)	1.0
History of appendectomy	2 (3)	2 (6.1)	0 (0)	0.49	4 (3)	4 (12.1)	0 (0)	0.11
Fever	65 (98.5)	32 (97)	33 (100)	1.0	61 (92.4)	33 (100)	28 (84.8)	0.07
Fever characteristics
Subfebrile (37.1 °C-38.0 °C)	5 (7.6)	5 (15.1)	0 (0)	0.053	4 (6.1)	1 (3)	3 (9.1)	0.48
Febrile (38.1 °C-39.0 °C)	52 (78.8)	25 (75.8)	27 (81.9)	0.76	51 (77.2)	28 (84.8)	23 (69.6)	0.24
Pyretic (39.1 °C-40 °C)	8 (12.1)	2 (6.1)	6 (18.1)	0.25	6 (9.1)	4 (12.1)	2 (6.1)	0.43
Number of attacks
Once a month	1 (1.5)	1 (3)	0 (0)	1.0	0 (0)	0 (0)	0 (0)	1.0
2 times a month	4 (6.1)	4 (12.1)	0 (0)	0.11	2 (3)	2 (6.1)	0 (0)	0.49
3 times a month	4 (6.1)	4 (12.1)	0 (0)	0.11	23 (34.8)	23 (69.7)	0 (0)	0.0001
> 4 times a month	7 (10.7)	7 (21.2)	0 (0)	0.01	5 (7.6)	5 (15.1)	0 (0)	0.053
Continuous fever	49 (74.2)	16 (48.5)	33 (100)	0.0001	36 (54.6)	3 (9.1)	28 (100)	0.0001
Duration of fever
1-3 days	1 (1.5)	1 (3)	0	1.0	0 (0)	0 (0)	0 (0)	1.0
5-6 days	15 (22.7)	15 (45.5)	0	0.0001	18 (27.2)	18 (54.5)	0 (0)	0.0001
> 7 days	49 (74.2)	16 (48.5)	33 (100)	0.0001	48 (72.8)	15 (45.5)	28 (100)	0.002
Rash	55 (83.3)	22 (66.7)	33 (100)	0.0001	52 (78.8)	19 (57.6)	29 (87.8)	0.01
Rash characteristics
Maculopapular	43 (65.1)	10 (30.3)	33 (100)	0.0001	41 (62.1)	8 (24.2)	29 (87.8)	0.0001
Small-spotted	7 (10.6)	7 (21.2)	0 (0)	0.01	6 (9.1)	6 (18.1)	0 (0)	0.02
Large-spotted	4 (6.1)	4 (12.1)	0 (0)	0.11	4 (6.1)	4 (12.1)	0 (0)	0.11
Vesicular	1 (1.5)	1 (3)	0 (0)	1.0	1 (1.5)	1 (3)	0 (0)	1.0
Joint syndrome	43 (65.1)	26 (78.8)	17 (51.5)	0.03	47 (71.2)	27 (81.8)	20 (60.6)	0.1
Characteristics of joint syndrome
Oligoarthritis	29 (44)	18 (54.5)	11 (33.3)	0.21	33 (50)	18 (54.5)	15 (45.5)	0.47
Polyarthritis	14 (21.2)	8 (24.2)	6 (18.1)	0.76	14 (21.2)	9 (27.2)	5 (15.1)	0.36
Hepatomegaly	40 (60.6)	21 (63.6)	19 (57.6)	0.8	54 (81.8)	23 (69.7)	31 (94)	0.025
Lymphadenopathy	30 (45.5)	17 (51.5)	13 (39.4)	0.45	37 (56)	18 (54.5)	19 (57.6)	1.0
Splenomegaly	28 (42.4)	14 (42.4)	14 (42.4)	1.0	37 (56)	16 (48.5)	21 (63.6)	0.32
Nervous system lesion	26 (39.4)	18 (54.5)	8 (24.2)	0.02	18 (27.2)	14 (42.4)	4 (12.1)	0.01
Characteristics of neurological symptoms
Headache	22 (33.3)	14 (42.4)	8 (24.2)	0.19	15 (22.7)	11 (33.3)	4 (12.1)	0.07
Aseptic meningitis	1 (1.5)	1 (3)	0 (0)	1.0	0 (0)	0 (0)	0 (0)	1.0
Hydrocephalus	1 (1.5)	1 (3)	0 (0)	1.0	1 (1.5)	1 (3)	0 (0)	1.0
Delay in psycho-speech development	2 (3)	2 (6.1)	0 (0)	0.49	2 (3)	2 (6.1)	0 (0)	0.49
Hearing loss	1 (1.5)	1 (3)	0 (0)	1.0	3 (4.5)	3 (9.1)	0 (0)	0.23
Myalgia	17 (25.8)	14 (42.4)	3 (9.1)	0.004	18 (27.2)	17 (51.5)	1 (3)	0.0001
Pericarditis	10 (15.1)	5 (15.1)	5 (15.1)	1.0	12 (18.2)	7 (21.1)	5 (15.1)	0.75
Pleurisy	3 (4.5)	2 (6)	1 (3)	1.0	4 (6.1)	2 (6.1)	2 (6.1)	1.0
Abdominal pain	8 (12.1)	6 (18.1)	2 (6.1)	0.25	10 (15.1)	10 (30.3)	0 (0)	0.001
Chest pain	4 (6)	4 (12.1)	0	0.11	4 (6.1)	4 (12.1)	0 (0)	0.11
Eye afflictions	5 (7.5)	5 (15.1)	0 (0)	0.053	8 (12.1)	8 (24.2)	0 (0)	0.004
Characteristics of eye damage
Unilateral uveitis	1 (1.5)	1 (3)	0 (0)	1.0	5 (7.5)	5 (15.1)	0 (0)	0.053
Bilateral uveitis	3 (4.5)	3 (9.1)	0 (0)	0.23	1 (1.5)	1 (3)	0 (0)	1.0
Retinal angiopathy	1 (1.5)	1 (3)	0 (0)	1.0	2 (3)	2 (6.1)	0 (0)	0.49
Periorbital edema	3 (4.5)	3 (9.1)	0 (0)	0.23	4 (6.1)	4 (12.1)	0 (0)	0.11
Aphthous stomatitis	2 (3)	2 (6.1)	0 (0)	0.49	2 (3)	2 (6.1)	0 (0)	0.49
Clinical manifestations of gastrointestinal tract lesions	11 (16.7)	9 (27.2)	2 (6)	0.04	8 (12.1)	8 (24.2)	0 (0)	0.004
Clinical manifestations of gastrointestinal tract lesions
Liquid stool	5 (7.5)	4 (12.1)	1 (3)	0.35	3 (4.5)	3 (9.1)	0 (0)	0.23
Liquid stool with an admixture of blood	2 (3)	2 (6.1)	0 (0)	0.49	2 (3)	2 (6.1)	0 (0)	0.49
Vomiting	3 (4.5)	2 (6.1)	1 (3)	1.0	2 (3)	2 (6.1)	0 (0)	0.49
Vomiting combined with liquid stool	1 (1.5)	1 (3)	0 (0)	1.0	1 (1.5)	1 (3)	0 (0)	1.0
Changes in gastrointestinal endoscopic examination data					36 (54.5)	20 (60.6)	16 (48.5)	0.45
Changes in gastrointestinal endoscopic examination data
Gastritis	17 (25.8)	9 (27.2)	8 (24.2)	1.0	3 (4.5)	3 (9.1)	0 (0)	0.49
Erosive gastritis					1 (1.5)	1 (3)	0 (0)	1.0
Erosive esophagitis + duodenitis					1 (1.5)	0 (0)	1 (3)	1.0
Erosive esophagitis + bulbitis					1 (1.5)	0 (0)	1 (3)	1.0
Erosive proctitis + erosive gastritis + duodenitis + jejunit					1 (1.5)	1 (3)	0 (0)	1.0
Erosive ileitis + erosive gastritis + duodenitis					1 (1.5)	1 (3)	0 (0)	1.0
Erosive sigmoiditis + gastritis + jejunitis					1 (1.5)	1 (3)	0 (0)	1.0
Gastritis + bulbitis	1 (1.5)	1 (3)	0 (0)	1.0	1 (1.5)	0 (0)	1 (3)	1.0
Gastritis + duodenitis + jejunitis					3 (4.5)	3 (9.1)	0 (0)	0.23
Gastritis + bulbitis + duodenitis					4 (6.1)	0 (0)	4 (12.1)	0.11
Gastritis + duodenitis					11 (16.7)	3 (9.1)	8 (24.2)	0.185
Bulbitis + duodenitis	1 (1.5)	1 (3)	0 (0)	1.0	1 (1.5)	1 (3)	0 (0)	1.0
Bulbitis					2 (3)	2 (6.1)	0 (0)	0.49
Duodenitis	2 (3)	1 (3)	1 (3)	1.0	2 (3)	1 (3)	1 (3)	1.0
Sigmoiditis					3 (4.5)	3 (9.1)	0 (0)	0.23
MAS	8 (12.1)	1 (3)	7 (21.2)	0.052	15 (22.7)	7 (21.2)	8 (24.2)	1.0
Amyloidosis	0 (0)	0 (0)	0 (0)	1.0	1 (1.5)	1 (3)	0 (0)	1.0

MAS: Macrophage activation syndrome; sJIA: Systemic juvenile idiopathic arthritis.

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Table 3 Laboratory parameters of patients with TNFRSF1A gene variants and systemic juvenile idiopathic arthritis at disease onset the and at the time of systemic juvenile idiopathic arthritis diagnosis, median (interquartile range)

Laboratory indicators	Normal values	Total group (n = 66)	*Patients with gene variants TNFRSF1A(n = 33)*	Patients with sJIA (n = 33)	P value	Total group (n = 66)	*Patients with gene variants TNFRSF1A(n = 33)*	Patients with sJIA (n = 33)	P value
Red blood cells, (million/mL)	4-5.2	4.0 (3.6-4.2)	4.0 (3.8-4.2)	3.9 (3.4-4.0)	0.06	4.4 (3.9-4.8)	4.27 (3.8-5.01)	4.4 (4.01-4.7)	0.97
Hemoglobin (g/L)	115-145	100 (94-104)	101 (95-106)	98 (90-102)	0.03	110 (101-119.2)	108 (101-118)	112 (100-120)	0.45
Leukocytes (thousand/mL)	4.5-11.5	17.9 (12.3-22.7)	12.6 (11.2-18.8)	20.3 (17.8-24.2)	0.0001	12.7 (8.9-17)	11.2 (8.9-15.2)	13.5 (9.9-18.6)	0.27
Neutrophils (thousand/mL)	1.1-9.9	14.5 (8.5-18.2)	9.1 (6.7-14.6)	17.6 (14.5-19.1)	0.0001	8.8 (4.8-12.2)	7.6 (4.3-10.2)	9.9 (5.7-13.2)	0.13
Platelets (thousand/mL)	150-450	456 (353.3-599)	415 (334-456)	556 (456-660)	0.0001	410 (340-521.5)	372 (316-469)	425 (353-528)	0.19
ESR (mm/hour)	0-20	53 (37-61)	45 (35-60)	55 (43-60)	0.2	34.5 (15-52)	34 (15-52)	35 (24-52)	0.93
СRP (mg/L)	< 5	66.5 (34.1-115.7)	47.5 (26.7-68)	84.7 (60-128)	0.001	37.8 (10.5-102)	43 (7.8-102.4)	40.5 (11.2-92.8)	0.86
ALT (U/L)	< 40	24 (20-34)	23 (20-30)	24 (20-46)	0.31	16 (11.8-24.5)	19 (11-26)	15 (12-24)	0.89
AST (U/L)	< 42	27.5 (23-36)	26 (20-35)	30 (24-40)	0.19	25.5 (22-33.2)	28 (23-37)	24 (20-30)	0.1
LDH (U/L)	91-295	243.5 (203-289)	228 (167-284)	246 (225-289)	0.09	243 (198-301.5)	237 (173-301)	247 (200-298)	0.46
Ferritin (ng/mL)	12-84	113.5 (75.7-259)	102.3 (67.6-227.4)	167.9 (98.6-357.9)	0.03	120.3 (53.3-473.2)	129.3 (54.2-349.2)	118.9 (65.7-450.4)	0.65
Physician's VAS, (mm)	0-100					56.5 (33.8-70)	65 (48-76)	74 (56-80)	0.005
Parent/patient's VAS (mm)	0-100					64.5 (44-74.3)	70 (54-78)	78 (40-70)	0.26
CHAQ	0-3					0.75 (0.125-1)	0.75 (0.5-1.5)	0.5 (0.125-0.75)	0.002
JADAS71						17.4 (13-22.6)	16.2 (12-21.5)	18.6 (15.5-25)	0.37

sJIA: Systemic juvenile idiopathic arthritis; ESR: Erythrocyte sedimentation rate; CRP: C-reactive protein; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; LDH: Lactate dehydrogenase; VAS: Visual analogue scale; CHAQ: Childhood Health Assessment Questionnaire; JADAS71: Juvenile arthritis disease activity score 71.

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Citation: Alexeeva EI, Shingarova MS, Dvoryakovskaya TM, Isaeva KB, Chomakhidze AM, Fetisova AN, Chibisova KV, Krekhova EA, Kriulin IA, Kriulina TY, Tsulukiya IT, Botova MS, Kondratyeva NM, Kokina MY, Makunc AA, Dostiev NA, Savostyanov KV, Pushkov AA, Zhanin IS, Demyanov DS, Kostik MM. Clinical and laboratory manifestations and treatment of children with TNFRSF1A gene variants. World J Clin Pediatr 2026; 15(3): 119428
URL: https://www.wjgnet.com/2219-2808/full/v15/i3/119428.htm
DOI: https://dx.doi.org/10.5409/wjcp.119428

Alexeeva EI, Shingarova MS, Dvoryakovskaya TM, Isaeva KB, Chomakhidze AM, Fetisova AN, Chibisova KV, Krekhova EA, Kriulin IA, Kriulina TY, Tsulukiya IT, Botova MS, Kondratyeva NM, Kokina MY, Makunc AA, Dostiev NA, Savostyanov KV, Pushkov AA, Zhanin IS, Demyanov DS, Kostik MM. Clinical and laboratory manifestations and treatment of children with TNFRSF1A gene variants. World J Clin Pediatr 2026; 15(3): 119428 [DOI: 10.5409/wjcp.119428]

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