Abstract Background Progressive familial intrahepatic cholestasis (PFIC) is a group of rapidly progressive autosomal recessive disorders characterized by intrahepatic cholestasis. PFIC-3 is caused by mutations in the ATP-binding cassette subfamily B member 4 gene (ABCB4), which encodes multidrug resistance protein 3 (MDR3/ABCB4). Patients are usually in infancy or childhood, but cirrhosis and portal hypertension may be the first manifestation in older children or young adults. Case presentation A 25-year-old young woman with recurrent abnormal hepatic function was mainly characterized by increased gamma glutamyl transpeptidase (GGT) and bile acid with cryptogenic cirrhosis. After 7 months of treatment with ursodeoxycholic acid (UDCA), her hepatic pathology suggested there were also obvious widening and venous fibrosis around the portal vein, and slight bile duct hyperplasia at the edge of the portal area. Infiltration of inflammatory cells around the portal vein and hepatocyte ABCB4/MDR3 protein was basically normal. Sequencing indicated the patient had heterozygous mutations in the ABCB4 gene: c.2696C > G and wes [hg19]7q21.12(87032513–87033422) × 1. Through SWISS-MODEL Predict for protein structures, the missense mutation results in protein side chain missing a methyl group (-CH3), and the deletion mutation results in the serious damage to the structure of MDR3 protein which lead to phosphatidylcholine deficiency of bile in the capillary bile ducts. The toxic effect of bile salts then damages the bile ducts, causing cholestasis and cholangitis, which can then develop into biliary cirrhosis. Through the analysis of pathogenicity prediction software, the mutations led to PFIC3. After treatment of UDCA for 29 months, her cirrhosis was improved, hepatic function was close to normal. Conclusion Novel heterozygous mutations are the molecular pathological cause of PFIC3 in this patient. All young adult patients with occult cirrhosis should be tested for ABCB4. Early diagnosis of PFIC3 and continued treatment with UDCA are key to improving prognosis and delaying the onset of end-stage liver disease.

Transl Pediatr 2021 | https://dx.doi.org/10.21037/tp-21-199 Thanks for letting us have the comments and concerns raised by Finsterer on our article entitled “Identification of a novel large deletion of the mitochondrial DNA in an infant with Pearson syndrome: a case report” which was published on Transl Pediatr [2021;10(1):204-208]. The comments and concerns are really valuable for our in-depth understanding and subsequent investigation of mitochondrial diseases. Firstly, heteroplasmy is defined as the presence of a mixture of more than one type of an organellar genome within a cell or tissue (1). High-throughput sequencing results of mitochondrial DNA (mtDNA) by using blood sample of our patient suggested that the heteroplasmy rate of the mtDNA deletion was about 73%. However, the heteroplasmy rate in other tissues or organs remains unclear due to lacking relevant samples. Secondly, biochemical investigations of the respiratory chain were not carried out due to technical limitations. Given the fact that the infant suffered from chronic hepatomegaly, liver dysfunction, anemia and lactic acidosis over 1 year and so many genes encoding for subunits of complex-I and tRNAs were deleted, the function of the respiratory chain complex was believed to be impaired, at least in the liver and bone marrow. Thirdly, the comment on muscle biopsy was believed to be reasonable, but the patient was just an outpatient in our hospital, and muscle biopsy was not performed due to lacking of the relevant informed consent from the parents. Fourthly, we absolutely agree that early recognition of multisystem involvement was crucial for initiating early symptomatic treatment and thus improving quality of life and outcome of an individual patient, and that is why close follow-up in our clinic was suggested. We will update this case report if involvement of the brain, eyes, ears, endocrine organs, heart, kidneys, muscle or peripheral nerves is observed in the future. Finally, we do need to add and clarify the following information. When aged 16 days, the patient underwent urinary organic acid analysis in another hospital, which revealed elevated 4-hydroxyphenyllactic acid and 4-hydroxyphenylpyruvate. His liver was normal in size and texture at the age of 18 hours, but hepatomegaly was noticed since his age 1 month as described in his medical records, and was confirmed at his referral to our clinic when aged 13 months. Once again, the authors cordially appreciate Finsterer for sharing his expertise in mitochondrial diseases, and any further comments and concerns on our article will be welcome.

Pearson syndrome (PS), also known as Pearson marrow-pancreas syndrome, is a rare, multi-systemic disorder caused by large-scale deletion of mitochondrial DNA (mtDNA) ranging from 2.3 kb to 9 kb, with 4,977 bp in length as the most common variant. This paper reported a novel mtDNA deletion of 4,734 bp in size, spanning from nucleotide 11,220 to 15,953. The infant suffered from chronic hepatomegaly, liver dysfunction, anemia and lactic acidosis over 1 year. Evidences of any infections were negative. Bone marrow aspiration and whole exome sequencing covering nearly 20,000 nucleus genes were performed when aged 3.3 and 6 months, respectively, but no genetic cause was identified. However, at his age 13 months, multiplex ligation-dependent probe amplification assay of the mtDNA in the patient detected a large deletion of 4,734 bp in size spanning the mitochondrial genes MTND4, MTTH, MTTS2, MTTL2, MTND5, MTND6, MTTE, MTCYB and MTTT which were functionally crucial for the intact oxidative phosphorylation pathway and adenosine triphosphate production, and PS was thus definitely diagnosed. This large deletion was negative in his parents and elder brother. Oral ursodeoxycholic acid, fat-soluble vitamins and blood transfusions were administrated, his clinical and laboratory presentations remained stable so far, but the long-term prognosis needed to be followed up. These findings enriched the variant spectrum of mtDNA, and demonstrated the importance of considering mitochondrial disorder in patient with intractable anemia, liver dysfunction and lactic acidosis as well as the significance of appropriate choosing of relevant genetic tools in the etiology diagnosis of such patients.

Ataxia-telangiectasia (AT) is a hereditary neurodegenerative disease. We presented a Chinese family with healthy non-consanguineous parents and all-five children presenting with unsteady gait. Genetic analysis of two living siblings showed an ATM homozygous nonsense mutation (c.6100C>T) that has not been reported in Chinese patients, while both parents were compound heterozygous. Limited expertise and lack of diagnosis may lead to the neglect of disease and bring a great tragedy to the family. Prenatal diagnosis may be desirable to identify fetuses at risk of AT when the nature and location of ATM mutation in a family have been identified.

Kabuki syndrome (KS) is a rare genetic syndrome characterized by multiple congenital anomalies and varying degrees of mental retardation. Patients with KS often present with facial, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies and immunological defects. Mutation of the lysine methyltransferase 2D (KMT2D) gene (formerly known as MLL2) is the primary cause of KS. The present study reported the case of a 4-year-old Chinese girl who presented with atypical KS, including atypical facial features, unclear speech and suspected mental retardation. A diagnosis of KS was confirmed by genetic testing, which revealed a nonsense mutation in exon 16 of KMT2D (c.4485C>A, Tyr1495Ter). To the best of our knowledge, this is a novel mutation that has not been reported previously. The present case underscores the importance of genetic testing in KS diagnosis.