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Short Communication: Hepatology

Progressive Familial Intrahepatic Cholestasis Associated With USP53 Gene Mutation in a Brazilian Child

Porta, Gilda; Rigo, Paula S.M.; Porta, Adriana; Pugliese, Renata P.S.; Danesi, Vera L.B.; Oliveira, Eliene; Borges, Cristian C.V.; Ribeiro, Cristiane; Miura, Irene K.

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Journal of Pediatric Gastroenterology and Nutrition: May 2021 - Volume 72 - Issue 5 - p 674-676
doi: 10.1097/MPG.0000000000003110
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See “Progressive Familial Intrahepatic Cholestasis: Is It Time to Transition to Genetic Cholestasis?” by Squires and Monga on page 641.

What Is Known/What Is New

What Is Known

  • Pathological variants in ATP8B1, ATP-binding cassette subfamily B member 11, nuclear receptor subfamily1 group H member 4, TJP2, MY05B, and farnesoid X receptor are implicated in low-GGT intrahepatic cholestasis.
  • In about 20% of children with cholestasis and normal or low serum GGT, no etiology is identified.

What Is New

  • Recently, ubiquitin-specific peptidase 53 (USP53) gene mutations associated with low-γ-GGT cholestasis have been identified.
  • Cholestasis is transient in most cases, although early fibrosis has been described.
  • Hearing disorders and hypocalcemia may be related to USP53 gene mutations.

Cholestatic jaundice affects approximately one in 2500 infants and has multiple etiologies (1). Familial intrahepatic cholestasis (PFIC) accounts for 9–12% of pediatric cholestasis (2–4). PFIC represents a group of disorders characterized by defective bile excretion, causing a multitude of clinical manifestations with variable severity often beginning in childhood. Different gene mutations have been linked to PFIC in the last few decades, and PFIC is currently divided into six types. Applying exome sequencing, Maddirevula et al (5) recently described two novel mutations causing defects in ubiquitin-specific peptidase 53 (USP53 protein) in children with cholestatic liver disease and low γ-glutamyl transferase (GGT). Zhang et al discovered pathogenic variants of USP53 in seven patients from seven unrelated families, which were associated with cholestasis (6).

We report a Brazilian child with normal GGT associated with neonatal cholestasis and a genetic study revealing a very rare PFIC type, not previously reported in South America.


A 4-month-old boy presented with cholestasis at 10 days of life, with jaundice, fecal hypocholia, and coluria. He was born via cesarean section at a gestational age of 39 weeks with a birth weight of 3340 g. Apgar score was 7 of 9. Parents were not consanguineous. Routine newborn hearing screening test results were normal. Four paternal relatives had intrahepatic cholestasis with severe pruritus, which had improved with rifampicin, but recurred with the withdrawal of the medication. Viral and other metabolic liver diseases were excluded. Physical examination revealed jaundice and hepatomegaly. Laboratory data showed normal blood count, blood urea nitrogen, creatinine, and electrolytes. Serum bile acid levels were 216 mg/dL (upper limit of normal [ULN]: 10); aspartate aminotransferase 130 IU/L (ULN: 30); alanine aminotransferase 69 IU/L (ULN: 35); GGT 37 IU/L (ULN: 19 IU/L); total bilirubin 8.98 mg/dL; direct bilirubin 6.69 mg/dL; total cholesterol level 271 mg/dL; international normalize ratio 1.71; serum calcium 9.3 mg/dL (8.5–10.5), and albumin 3.4 g/dL. Liver ultrasound revealed homogeneous hepatomegaly and cholelithiasis. Liver biopsy at 5 months of age showed marked cholestasis, giant cell transformation, portal septal fibrosis, and a periportal ductular proliferation (Fig. 1). A cholestatic gene panel revealed novel homozygous mutations c.1687_1688delinsC p.Ser563Profs25 in the USP53 gene. The parents carried the same heterozygous mutation in the USP53 gene. During follow-up, the child developed hemorrhagic stroke, and arteriovenous malformation was suspected. Computed tomography revealed an intracranial hemorrhage. The patient fully recovered with clinical treatment, without sequelae, and a cholecystectomy was performed. After hospital discharge, the cholestasis improved. At last follow up, he had normal length and weight for age (18 months), no jaundice, moderate pruritus, and normal transaminases, on treatment with ursodeoxycholic acid (UDCA) and rifampicin.

Cholestasis, giant cell transformation, portal septal fibrosis, and a periportal ductular proliferation.


In humans, USP53 encodes a protein ubiquitin carboxyl-terminal hydrolase 53 (USP53) that is crucial in physiological functions. Our patient, a Brazilian child, not of Arabic or Chinese descent, had neonatal cholestasis with elevated serum bile acid levels, low GGT, and normal serum calcium. Cholestatic gene panel test identified homozygosity for another novel defect in the USP53 gene. Mutations in this gene are associated with progressive hearing loss and cholestasis. Animal models have shown that USP53 is a component of the tight junction complex (7). In a mouse-deafness model, tight-junction-associated proteins are involved in the survival of auditory hair cells and hearing, modulating the barrier properties and mechanical stability of tight junctions. Biallelic variants of tight junction protein 2 (TJP2) are implicated in hearing impairment (8) and low-GGT intrahepatic cholestasis. Primary loss of the P4-ATpase phospholipid transporting 8 B1 (ATP8B1), known to cause PFIC1, is also associated with deafness. Zhang et al suggested that USP53 mutation may cause a partial phenocopy of TJP2 disease in both liver and ear. They reported seven patients with USP53 disease who also had heterozygous mutations in other genes associated with cholestasis such as TJP2, myosin VB (MY05B), and VPS33B in three patients. The importance of these findings warrants further investigation.

The clinical characteristics of the 11 patients, previously reported, with normal or low GGT cholestasis and USP53 gene mutations, including the present case, are shown in Table 1. All patients developed cholestasis before 7 months of age, and cholestasis was transient in eight patients (73%). Hearing disorders were observed in three patients, one of them received a cochlear implant. Hypocalcemia was present in all three Saudi children. The medications prescribed were UDCA, cholestyramine, and rifampicin. One case (from Saudi Arabia) was transplanted at the age of 6 years due to intractable pruritus. There was one loss of follow-up. In the present case, moderate itching persists, despite the use of UDCA and rifampicin. None of the patients died. Excluding the case of loss of follow up, none of the patients remained jaundice, and the transaminases were completely normal in seven cases. Liver biopsy was performed in four Chinese patients, and showed intralobular cholestasis and fibrosis in all. The three patients from Saudi Arabia were from the same family (two sisters and a cousin), hence carried the same pathogenic variant c.951del:p. (Phe317Leufs6). In the Zhang series, two known and eight novel pathogenic variants were described—the two previously reported variants were c.1012C>T (p.Arg338Ter) and c.1426C>T (p.Arg476Ter), and the eight novel variants included five that are undoubtedly pathogenic—c.569+2T>C; c.169C>T (p.Arg57Ter); c.581delA (p.Arg195GlufsTer38); c831_832insAG (p.Val279GlufsTer17), and c.1558C>T (p.Arg520Ter); three were likely pathogenic: c.297G>T (p.Arg99Ser); c.395A>G (p.His132Arg) and c.878G>T (p.Gly293Val). In the present case, we describe a new homozygous mutation in the USP53 gene: c.1687_1688delinsC p.Ser563Profs25.

TABLE 1 - Characteristics of patients with normal or low-GGT cholestasis associated to USP53 gene mutations
Author Patient Sex Age Deafness Hypocalcemia Medications AST/ALT ALP/GGT TB/DB Outcome
Maddirevula et al, 2019 1 Female 4 mo Yes Yes nr 97/82 6316/35 159/132 Liver transplantation at 6 y. Alive at 23 y
2 Female 5 mo Yes Yes Rifampicin 25/29 4432/39 26/20 Sister of pt 1. Alive at 15 y
3 Male 1 y No Yes Rifampicin 136/352 2557/30 402/298 Cousin of pts 1 and 2. Alive at 3 y
Zhang J et al, 2020 4 Female 3 days No nr UDCA and cholestyramine 215/184 330/23 23/19 Alive at 2 y
5 Male 2 days No nr UDCA and cholestyramine 71/70 548/72 90/65 Alive at 3 y 6 mo
6 Female 6 mo No nr UDCA 121/103 nr/34 212/159 Alive at 5 y
7 Male 5 mo No nr UDCA and cholestyramine 84/32 636/39 308/167 Alive at 17 mo
8 Female 1 mo No nr UDCA 51/28 543/40 275/216 Lost to follow-up
9 Male 5 mo Yes nr UDCA and cholestyramine 41/26 342/27 85/72 Alive with 1 y 3 mo; cochlear implant at 1 y 3 mo
10 Male 7 mo No nr UDCA and cholestyramine 225/18 283/22 153/137 Alive at 1 y 1 mo
Porta et al, 2020§ 11 Male 10 days No No UDCA and rifampicin 130/69 579/37 153/114 Alive at 18 mo with moderate itching
nr = not reported.
Reference values AST/ALT 0–40 U/L; ALP 250–350 U/L; GGT 0–30 U/L; TB/DB 5–17 mmol/L.
Reference values ALT 0–40 IU/L; AST 15–60 IU/L; ALP 42–383 IU/L; GGT 7–50 IU/L; TB 5.1–20 mmol/l; DB 0–6 mmol/L.
§Reference value ULN ALT 35 IU/L; AST 30 IU/L; ALP 390 IU/L; GGT 30 IU/L; TB reference values 0.6–1.4 mg/dL; DB reference values 0–0.6 mg/dL.ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, DB = direct bilirubin, GGT = γ-glutamyl transferase, TB = total bilirubin, UDCA = ursodeoxycholic acid, ULN = upper limit of normal.

In conclusion, defects in USP53 can be considered a new genetic cause of low-GGT cholestatic liver disease, beginning early in life, which can occur in different ethnicities and may be associated with several genetic variants. Cholestasis seems to be transient, but liver fibrosis can appear early. Hearing loss and hypocalcemia have been described in some cases.


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cholestasis; γ-glutamyltranspetidase; pathogenic variant

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