Recurrent acute liver failure (RALF) is a rare and life-threatening disorder often triggered by infections or febrile episodes. Variants in genes regulating vesicular transport, including RINT1, NBAS have been implicated in RALF and are classified as infantile liver failure syndromes type 2 and 3 (ILFS2 and ILFS3), often associated with multisystemic manifestations. We conducted comprehensive clinical, laboratory and genetic evaluations of a proband presenting with RALF and neutropenia. Whole-exome sequencing (WES), whole-genome sequencing (WGS), Sanger analysis, autozygosity mapping and 3D protein structural modeling were conducted to identify and characterize the pathogenic variant. A novel homozygous variant in the RINT1 gene (NM_021930.6:c.1435G > C, p.Ala479Pro) was identified in a proband from Chuvashia presenting with RALF and neutropenia, with both parents confirmed as heterozygous carriers. Structural modeling suggested a destabilizing effect on the RINT1/TIP20 domain. Two siblings with identical symptoms further supported the pathogenicity of this variant and its autosomal recessive inheritance. Runs of homozygosity (ROH) analysis indicated a possible founder effect in the Chuvash population. Our study expands the phenotypic spectrum of RINT1-related ILFS3, which in this case lacked the skeletal or neurological features previously described but included neutropenia. We report a novel RINT1 variant cause ILFS3 and neutropenia, supporting its classification as a potential population-specific disorder. These findings highlight the importance of early genetic screening and clinical monitoring in affected populations.

We report a pediatric case of cholestatic liver disease associated with two novel compound heterozygous variants in the USP53 gene: a truncating c.1219A>T (p.Lys407*) variant inherited from the father and a maternally inherited gross deletion involving exons 13–19. Despite the disruptive nature of these variants, the patient presented with a benign recurrent intrahepatic cholestasis (BRIC) characterized by episodic pruritus, jaundice and elevated bile acids with preserved liver function between episodes. Liver histology revealed fibrosis with a cholestatic component, consistent with mild progressive familial intrahepatic cholestasis (PFIC) features. Molecular diagnosis was confirmed by whole-exome sequencing (WES), chromosomal microarray, and Sanger sequencing. A systematic review of 39 published cases was conducted, revealing that USP53 -related disease exhibits broad clinical variability, ranging from BRIC to PFIC7. Our findings expand the spectrum of USP53 variants, underscore the relevance of large deletions and emphasize the inclusion of USP53 in genetic panels for idiopathic low-gamma-glutamyl transferase (GGT) cholestasis.

Background: Hemoglobin Rothschild (Hb Rothschild), NM_000518.5(HBB):c.112T>C, is an ultra-rare low-oxygen-affinity hemoglobin variant that persistently causes reduced peripheral oxygen saturation on pulse oximetry despite normal arterial oxygenation. Fewer than ten cases have been reported worldwide, and only one involved a child—an asymptomatic carrier identified incidentally. Methods: The patient underwent clinical examination, growth assessment, blood tests, hemoglobin electrophoresis, chest CT, abdominal ultrasound, echocardiography, and pulmonary perfusion scintigraphy. Whole genome sequencing (WGS) of the proband and parents was performed, followed by bioinformatic analysis and ACMG-based variant interpretation. A PRISMA-guided PubMed literature review was conducted. Results: We report on the first pediatric case exhibiting a symptomatic clinical course. A 4-year-old boy was referred for chronically low peripheral oxygen saturation (SpO₂), 78–86%, on pulse oximetry and recurrent lower respiratory tract infections. Early developmental history revealed episodes of apnea in infancy, perioral cyanosis, poor exercise tolerance, and low weight gain. Repeated cardiopulmonary assessments, chest computed tomography (CT), echocardiography, and pulmonary perfusion scintigraphy yielded unremarkable findings. Arterial blood gas analysis consistently showed normal arterial partial pressure of oxygen (PaO₂), excluding true hypoxemia. Hemoglobin electrophoresis revealed an abnormal HbD fraction; WGS identified a heterozygous variant NM_000518.5(HBB):c.112T>C inherited from the patient’s asymptomatic father. This variant increases the partial pressure of oxygen at which hemoglobin is 50% saturated (p50), thereby decreasing hemoglobin’s oxygen affinity and shifting the oxyhemoglobin dissociation curve to the right. These alterations explain the discordance between low peripheral oxygen saturation (SpO₂) and preserved oxygen delivery to tissues. Conclusions: This case expands the clinical spectrum of Hb Rothschild and demonstrates that symptomatic presentation may occur in early childhood. Awareness of low-affinity hemoglobin variants is essential to avoid misdiagnosis and unnecessary cardiopulmonary interventions. Early genetic testing facilitates accurate diagnosis and appropriate counseling.

Background: ARCN1-related syndrome (short stature-micrognathia syndrome, SSMG; OMIM #617164) is an autosomal dominant disorder caused by loss-of-function variants in the ARCN1 gene, which encodes the δ-COP (COPD) subunit of the COPI coatomer complex. The condition is classically characterized by intrauterine growth restriction (IUGR), short stature with rhizomelic shortening, microcephaly, micrognathia, facial dysmorphism, and global developmental delay. Methods: Clinical examination, blood tests and genetic analysis were performed. Whole-exome sequencing and Sanger analysis were conducted, followed by bioinformatics analysis and ACMG-based variant interpretation to identify and characterize the pathogenic variant. Results: We report a male proband with a previously undescribed variant in the ARCN1 gene, presenting with an atypical phenotype. Notably, the patient lacked the classical syndromic features, including short stature, microcephaly, IUGR, and developmental delay. The predominant clinical manifestation was transient hepatic dysfunction occurring during febrile episodes, which resolved between acute events. On physical examination, rhizomelic shortening and dysmorphic facial features, including mild micrognathia, were found. Overall, identified symptoms were mild in severity, which may be associated with the variant’s location within the gene. Conclusions: We describe a novel likely pathogenic variant in the ARCN1 gene associated with a mild phenotype of SSMG. This case expands the phenotypic spectrum of ARCN1-related syndrome and highlights the importance of considering this diagnosis in patients with unexplained recurrent liver injury, even in the absence of classical syndromic features.

Biallelic pathogenic variants of the AIRE gene lead to the development of autoimmune polyglandular syndrome type 1 (APS1; OMIM: 240300). The syndrome most often manifests with chronic candidiasis of the skin and mucous membranes in early childhood. As the disease progresses, hypoparathyroidism and Addison’s disease may be observed in the clinical picture. However, the symptoms of the disease are diverse and vary widely even among members of the same family. This article describes a patient - a three-year-old boy with signs of severe diarrhea and symptoms of hepatobiliary tract involvement. Skin and endocrine manifestations were absent at disease onset. Whole exome sequencing (WES) identified two previously described pathogenic variants in the AIRE gene: NM_000383.4: c.769C>T p.(Arg257Ter) and NM_000383.4: c.1302C>A p.(Cys434Ter). Sanger sequencing and family testing confirmed the compound heterozygous position of these variants. This case demonstrates an atypical manifestation of APS1: diarrhea with malabsorption syndrome and cholestatic liver disease.

Background: Progressive liver cirrhosis in pediatric patients characterized by clinical and genetic variability. Infantile cirrhosis caused by biallelic variants in the FOCAD gene is an extremely rare multi-system disorder leading to the progressive liver dysfunction. A small number of patients with limited survival were described so far, and any new clinical observation can provide a new insight for complete phenotypic spectrum and perspectives on available treatment to meet patient’s needs. Methods: We performed clinical, instrumental, histological and laboratory evaluation of the family with patient (male, 3 y.o.) with progressive liver cirrhosis and apparently healthy parents. Genetic study was performed using whole-exome sequencing. Validation of the rare variant found on WES and cascade familial screening were performed by capillary Sanger sequencing. Functional validation included RNA analysis from patient-derived fibroblasts and in silico protein modeling. Results: The patient exhibited an expanded phenotype including microcephaly, macrotia and neutropenia. Genetic testing revealed a novel homozygous FOCAD splice-site variant NM_001375570.1:c.1455 + 1G > T FOCAD (NM_001375570.1):c.1455 + 1G > T affecting RNA splicing with in-frame deletion of 36 nucleotides. Aberrant protein lacks 12 aminoacids (p.Thr475_Val486del) resulting in loss of two conserved α -helices. Structural modeling predicted impaired protein stability. At 25 months, the patient underwent a living-donor liver transplantation with a good clinical result, and favorable outcome in 1 year post-liver transplant. Conclusion: Canonic splice site variant NM_001375570.1:c.1455 + 1G > T FOCAD (NM_001375570.1):c.1455 + 1G > T realizes through in-frame deletion of 12 amimoacids (p.Thr475_Val486del) of the FOCAD protein with detectable expression in patient-derived cells. Homozygous carrier of this pathogenic variant exhibits progressive hepatic failure expanded with neutropenia. Liver transplantation had a good long-term result, and can be considered as a promising surgical approach for patients with FOCAD -related infantile cirrhosis.