New tight junction protein 2 variant causing progressive familial intrahepatic cholestasis type 4 in adults: A case report

Table 1 Clinical and biochemical parameters and FibroScan data of tested family members on the day of the first presentation

TJP2 status	P1.1	P1.2	P2.1	P2.2	P2.3	P2.4	P2.5	P2.6	P2.7	P2.8	P2.9	P2.10-12
	+/wt	+/wt	+/+	+/wt	wt/wt	+/+	+/+	+/+	+/+	+/wt	+/+	NA
Gender	M	F	M	F	M	M	M	F	M	M	M	F, F, F
Age in 2018 (yr)	60	55	36	32	31	25	23	21	19	16	15	NA
ALAT (< 45 female; < 70 male; (U/L)	16	19	114	15	10	43	37	44	97	21	22	NA
Bilirubin (5-25 μmol/L)	8	4.7	29	4.4	14	12	45	10	17	14	11	NA
Alkaline phosphatase (35-105 U/L)	101	104	120	65	50	112	212	117	115	104	121	NA
GGT (10-80 U/L)	72	21	61	14	12	44	156	55	86	12	15	NA
Coagulation II, VII, X/INR	1.0	1.2	1.2	0.81	1	1.2	1.7	1.1	0.73	0.75	0.72	NA
Albumin (36-48 g/L)	44	41	36	37	44	46	29	37	27	44	47	NA
Creatinine (60-105 μmol/L)	68	40	71	49	62	68	66	37	71	67	53	NA
Cholesterol (< 5.0 mmol/L)	5.7	6.5	5	4.3	3.4	3.8	3.2	4.4	NA	3.3	4.7	NA
HDL cholesterol (> 1.0 mmol/L)	0.91	1.1	1.8	2.0	0.92	2	1.7	1.9	NA	1.1	1.3	NA
LDL cholesterol (< 3 mmol/L)	3.3	3.7	2.7	1.9	2.2	1.4	1.1	2.2	NA	1.8	3	NA
Triglyceride (< 2 mmol/L)	3.3	3.5	1.1	0.9	1.1	1	1	0.7	NA	0.9	1	NA
Leucocytes (3.5-10.0 10^9/L)	11.7	4.72	4.19	6.96	5.8	7.03	4.25	6.44	5.78	7.8	5.7	NA
Hemoglobin (> 7.3 female; > 8.3 male, mmol/L)	9.4	7.8	9.3	7.5	9.9	10.1	7.8	8	9.9	10.3	9.6	NA
Platelets (165-400, × 109/L)	335	405	77	266	229	218	64	191	210	379	339	NA
sCD163 (0.69-3.86 mg/L)	2.32	1.94	NA	1.90	2.95	3.96	5.23	6.03	3.91	1.31	1.75	NA
FibroScan (kPa)	4.4	3.3	75	4-7	6.6	8.1	24	9.1	5.9	5.7	7.8	NA

TJP2 status is indicated by +/+ (homozygous) +/WT (heterozygous), and wt/wt indicating wild type. NA: Not applicable; WT: Wild type.

Table 2 Genetic variations discovered in the family using the gene panel approach

Patient ID	Age (yr)	Gender	TJP2 variation	TJP2 genotype	Other gene variations	Phenotype
P2.1	36	M	TJP2 [NM_004817.3]:c.[3334C>T];[3334C>T]	Homozygous	ABCB11[NM_003742.2]:c.[1331T>C];[=]	PFIC4 with cirrhosis, portal hypertension and acute-on-chronic liver failure; Liver transplantation
					ABCC2[NM_000392.3]:c.[3563T>A];[4544G>A]1
					ABCG5[NM_022436.2]:c.[148C>T];[=]
					UGT1A1[NM_000463.2]C.-53TA[6];[7]
P2.5	23	M	TJP2 [NM_004817.3]:c.[3334C>T];[3334C>T]	Homozygous	ABCB11[NM_003742.2]:c.[1331T>C];[1331T>C]2	PFIC4 with cirrhosis, portal hypertension. Primary liver cancer; Liver transplantation
					ABCC2[NM_000392.3]:c.[3563T>A];[4544G>A]1
					ABCG5[NM_022436.2]:c.[148C>T];[=]
P2.4	25	M	TJP2 [NM_004817.3]:c.[3334C>T];[3334C>T]	Homozygous	ABCB11[NM_003742.2]:c.[1331T>C];[1331T>C]2	Elevated liver enzymes
					ABCC2[NM_000392.3]:c.[3563T>A];[4544G>A]1
					ABCG5[NM_022436.2]:c.[148C>T];[=]
P2.6	21	F	TJP2 [NM_004817.3]:c.[3334C>T];[3334C>T]	Homozygous	ABCB11[NM_003742.2]:c.[1331T>C];[=]	Elevated liver enzymes; Severe cholestasis in pregnancy
					ABCC2[NM_000392.3]:c.[3563T>A];[4544G>A]1
					ABCG5[NM_022436.2]:c.[148C>T];[=]
					UGT1A1[NM_000463.2]C.-53TA[6];[7]
P2.7	19	M	TJP2 [NM_004817.3]:c.[3334C>T];[3334C>T]	Homozyg-ous	ABCB11[NM_003742.2]:c.[1331T>C];[=]	Elevated liver enzymes
					ABCC2[NM_000392.3]:c.[3563T>A];[4544G>A]1
					ABCG5[NM_022436.2]:c.[148C>T];[=]
					UGT1A1[NM_000463.2]C.-53TA[6];[7]
P1.1	60	M	TJP2 [NM_004817.3]:c.[3334C>T];[3334=]	Heterozyg-ous	ABCB11[NM_003742.2]:c.[1331T>C];[1331T=]	Normal
					ABCC2[NM_000392.3]:c.[3563T>A];[4544G>A]1
					UGT1A1[NM_000643.2]C.-53TA[6];[7]
P1.2	55	F	TJP2 [NM_004817.3]:c.[3334C>T];[3334=]	Heterozyg-ous	ABCB11[NM_003742.2]:c.[1331T>C];[=]	Normal
					ABCG5[NM_022436.2]:c.[148C>T];[=]
P2.2	32	F	TJP2 [NM_004817.3]:c.[3334C>T];[3334=]	Heterozygous	ABCB11[NM_003742.2]:c.[1331T>C];[=]	Mild cholestasis in pregnancy
					ABCG5[NM_022436.2]:c.[148C>T];[=]
P2.8	16	M	TJP2 [NM_004817.3]:c.[3334C>T];[=]	Heterozygous	ABCB11[NM_003742.2]:c.[1331T>C];[1331T=]1	Normal
					ABCG5[NM_022436.2]:c.[148C>T];[=]
					UGT1A1[NM_000463.2]C.-53TA[6];[7]
P2.3	31	M	TJP2 [NM_004817.3]:c.[3334=];[3334=]	Wild type	ABCG5[NM_022436.2]:c.[148C>T];[=]	Normal
P2.9	15	M	TJP2 [NM_004817.3]:c.[3334=];[3334=]	Wild type	ABCB11[NM_003742.2]:c.[1331T>C];[1331T>C]2	Normal
					ABCC2[NM_000392.3]:c.[3563T>A];[4544G>A]1
P2.10	-	F	-		-	Mild cholestasis, 4 pregnancies?
P2.11	-	F	-		-	Mild cholestasis, 3 pregnancies?
P2.12	-	F	-		-	Mild cholestasis, 2 pregnancies?

¹Compound heterozygosity for the ABCC2 gene variant coding for multidrug resistance protein 2 (MRP2) may be associated with pruritus in patients with primary biliary cholangitis.

²Homozygosity for ABCB11 gene variant coding for bile salt export pump (BSEP) protein is associated with cholestasis in pregnancy and drug-induced cholestasis. M: Male; F: Female.

Table 3 Literature review of findings of genetically verified tight junction protein 2 variants

Ref.	TJP2 gene	Age	Liver enzymes	Bile acids	Fibrosis	Pruritus	ICP	HCC	Liver failure	TJP2 mutation	TJP2/Included
Vitale et al[2]	Heterozyg-ous	37-51 yr	Elevated	Elevated	Normal FibroScan	1 with obvious symptoms	1 with DIC and ICP	NK	NK	p.[T62M]; [=]p.[I875T]; [=]	10/48
Sambrotta et al[6]	12 children Homozyg-ous	1-3 mo	Low or normal	Elevated	Cirrhosis and portal hypertension age 4 and 7	No	No	Not described	9 liver transplantations	c.766_769delGCCT, c.885delC	12/12
									1.5-4 years age	c.782delA, c.1361delC, c.1992-2A>G, c.953-735_2356-249del
									1 died 13 months	c.3408-?_3573+?del and c.1894C>T
Wang et al[10]		21-68 yr	NK	NK	NK	NK	NK	NK	NK	c.2081G>A(p.G694E)	8/21 Hearing loss
Dixon et al[11]	Heterozyg-ous	NK	Elevated	Elevated	NK	Yes	All confirmed ICP	NK	NK	p.Thr62Met; p.Thr626Ser	3/26
							1 stillbirth			c.1877C > G. p.Thr626Aer
Ge et al[14]	Compound heterozyg-ous	23 mo	Elevated	Elevated	NK	Alleviated after treatment	-	NK	NK	c.2448 + 1G > C	1/1
										c.2639delC (p.T880Sfs*12)
Zhou et al[15]	Compound heterozyg-ous	26 mo	Elevated	NK	Both with cirrhosis	NK	No	Yes	Yes	2668-1G>T /c.2438dupT (p.Asn814Glnfs	2/2
	Homozyg-ous	6 mo	Elevated					Yes, age 2 years	NK	c.817delG (p.A273fs
Vij et al[16]	Homozyg-ous	7 yr	Normal	Elevated	Cirrhotic explant liver and high-grade dysplastic nodule	Yes	No	Yes, early well- differentiated	No	c.(2659+1_2660-1)/(2760+1_2761-1)	1/1
Shagrani et al[17]	Heterozyg-ous	0-12 yr	Elevated	Normal	1 with congenital hepatic fibrosis	No	No	No	NK	c.2038delA:p.R680fs	12/37
	Homozyg-ous								But 4 patients required liver transplantation	c.1012C>T:p.R338X
										c.1012C>T:p.R338X
										c.1013delG:p.R338fs
										c.1190C>T:p.P397L
										c.1373delC:p.A458fs
										c.1373delC:p.A458fs
Chen et al[18]	Heterozyg-ous	> 1 yr	NK	Elevated but no detailed data	NK	No	No	No	NK	c.2174G>A,	4/33
										c.343A>G/c.1377T>G
										c.343A>G/c.1377T>G
										c.925C>T
Carlton et al[19]	Homozyg-ous	1-8 yr	Almost normal	Almost normal or NK	NK	Yes	NK	NK	NK	143C/143C	11 individuals with familial hypercholanemia in 8 families

Table 4 Common known phenotypes of the genes included in the panel including characteristics of progressive familial intrahepatic cholestasis[24,25]

Mutated gene (deficiency)	Disease association (autosomal recessive)	Disease association (autosomal dominant)
ATP8B1(FIC1)	PFIC1(2009) BRIC1	ICP
ABCB11(BSEP)	PFIC2(2009) BRIC2	ICP Drug-induced cholestasis
ABCB4 (MDR3)	PFIC3	ICP LPAC Drug-induced cholestasis
TJP2(TJP2)	PFIC4	ICP
ABCC2(MRP2)	Dubin-Johnson	ICP
ABCG5(ABCG5)	Sitosterolemia	Cholelithiasis
UGT1A1(UGT1A1)	Crigler-Najjar syndrome type 1; Crigler-Najjar syndrome type 2; Gilbert syndrome (promotor regions)
NR1H4(FXR)	Intralobular cholestasis	Posttransplant hepatic steatosis
MYO5B(MYO5B)	Microvillus inclusion disease (MVID); Cholestasis without MVID

ICP: Intrahepatic cholestasis during pregnancy; LPAC: Low phospholipid-associated cholelithiasis; PFIC: Progressive familial intrahepatic cholestasis; BRIC: Benign recurrent intrahepatic cholestasis.