Background: Sitosterolemia is a rare autosomal recessive disorder characterized by diverse clinical manifestations ranging from asymptomatic cases to the development of xanthomas, hypercholesterolemia, premature atherosclerosis, or even sudden death during childhood. It results from homozygous or compound heterozygous pathogenic variants in the ABCG5 or ABCG8 genes. Prompt detection and intervention are essential to managing this condition and preventing severe outcomes. Methods: This study aims to retrospectively analyze the phenotype, genotype, treatment, and outcomes of 14 children—seven boys and seven girls—all of Vietnamese origin, diagnosed with sitosterolemia at the Vietnam National Children’s Hospital between March 2015 and July 2024. Results: The median ages at disease onset and diagnosis were 5.7 years (range: 1.5–17.9) and 7.2 years (range: 1.7–17.9), respectively. Xanthomas were observed in 85.7% of patients (12/14), arthralgia in 14.3% (2/14), and anemia in 7.1% (1/14), with no cases of thrombocytopenia. At diagnosis, all patients exhibited elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), with considerably higher levels in patients with xanthomas compared to those without. Mutations in the ABCG5 gene were identified in 71.4% (10/14) of the patients, while 28.6% (4/14) had mutations in the ABCG8 gene. Fourteen variants were detected, nine in ABCG5 and five in ABCG8, with five variants reported for the first time in sitosterolemia patients. Initial management for all patients involved dietary modifications. After three months, 10 patients with persistently elevated TC and LDL-C received ezetimibe or cholestyramine treatment. Among the eight patients who continued treatment for over three months, the median TC and LDL-C concentrations decreased by 54.9% and 67.3%, respectively. Conclusions: Among Vietnamese patients with sitosterolemia, variants in the ABCG5 gene were more prevalent than those in the ABCG8 gene. Patients showed a positive response to ezetimibe or cholestyramine treatment. Genetic testing is essential for establishing a diagnosis of sitosterolemia and guiding accurate management strategies.

Background: Vitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by mutations in the CYP27B1 gene, leading to a deficiency in active vitamin D (1,25-dihydroxyvitamin D). This study examines the genotypic and phenotypic characteristics of VDDR1A in Vietnamese children. Patients and Methods: A retrospective analysis was conducted on 19 Vietnamese children diagnosed with VDDR1A. Clinical, radiological, biochemical, and molecular data were collected. Rickets Severity Scores (RSSs), biochemical parameters, and height standard deviation scores (HtSDSs) were used to assess the severity of the condition. Results: The study included 19 children from 17 families (ten males and nine females). The median age of rickets diagnosis was 19.2 months, while with VDDR1A, the median time of diagnosis was 7.5 months. Common symptoms among the children included thickened wrists and ankles (19/19), genu varum or genu valgum (18/19), failure to thrive (18/19), rachitic rosary (12/19), and delayed walking (11/19). The radiographic features showed that all children had cupping, splaying, and fraying, twelve children had rachitic rosary, and six exhibited pseudofractures. The biochemical findings showed severe hypocalcemia, normal or mildly low serum phosphate, elevated alkaline phosphatase and parathyroid hormone levels, and normal serum 25-hydroxyvitamin D levels. Genetic analysis identified biallelic CYP27B1 variants, including one known pathogenic frameshift mutation, c.1319_1325dup p.(Phe443Profs*24), one novel likely pathogenic missense variant, c.616C>T p.(Arg206Cys), and one novel pathogenic frameshift mutation, c.96_97del p.(Ala33Thrfs*299). The c.1319_1325dup p.(Phe443Profs*24) variant was the most common, present in 18 out of 19 children. Conclusions: The children with VDDR1A in this study presented with growth failure and skeletal deformities. Key findings included severe hypocalcemia, elevated alkaline phosphatase and parathyroid hormone levels, normal or elevated 25(OH)D, and high RSSs. Predominant frameshift mutations in CYP27B1, especially c.1319_1325dup, highlighted the importance of early genetic diagnosis for optimal management. Additionally, two novel CYP27B1 variants were identified, expanding the known mutation spectrum of VDDR1A.

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMGCS2D) is a rare metabolic disorder that impairs the body’s ability to produce ketone bodies and regulate energy metabolism. Diagnosing HMGCS2D is challenging because patients typically remain asymptomatic unless they experience fasting or illness. Due to the absence of reliable biochemical markers, genetic testing has become the definitive method for diagnosing HMGCS2D. This study included 19 patients from 14 unrelated families diagnosed with HMGCS2D in our department between October 2018 and October 2024. The clinical presentations, biochemical findings, molecular characteristics, and management strategies were systematically summarized and analyzed. Of the 19 cases studied, 16 were symptomatic, and 3 were asymptomatic. The onset of the first acute episode occurred between 10 days and 28 months of age. Triggers for the initial crisis in the symptomatic cases included poor feeding (93.8%), vomiting (56.3%), diarrhea (25.0%), and fever (18.8%). Clinical manifestations during the first episode were lethargy/coma (81.3%), rapid breathing (68.8%), hepatomegaly (56.3%), shock (37.5%), and seizures (18.8%). The biochemical abnormalities observed included elevated plasma transaminases (100%), metabolic acidosis (75%), hypoglycemia (56.3%), and elevated plasma ammonia levels (31.3%). Additionally, low free carnitine levels were found in seven cases, elevated C2 levels were found in one case, dicarboxylic aciduria was found in two cases, and ketonuria was found in two cases. Abnormal brain MRI findings were detected in three patients. Genetic analysis revealed seven HMGCS2 gene variants across the 19 cases. Notably, a novel variant, c.407A>T (p.D136V), was identified and has not been reported in any existing databases. Two common variants, c.559+1G>A and c.1090T>A (p.F364I), were present in 11 out of 19 cases (57.9%) and 10 out of 19 cases (55.5%), respectively. The implementation of a high glucose infusion and proactive management strategies—such as preventing prolonged fasting and providing enteral carbohydrate/glucose infusion during illness—effectively reduced the rate of acute relapses following accurate diagnosis. Currently, all 19 patients are alive, with ages ranging from 5 months to 14 years, and exhibit normal physical development. To the best of our knowledge, this study represents the first reported cases of HMGCS2D in Vietnamese patients. Our findings contribute to a broader understanding of the clinical phenotype and expand the known spectrum of HMGCS2 gene variants, enhancing current knowledge of this rare metabolic disorder.

Background and Objectives: Hyperornithinemia–hyperammonemia–homocitrullinuria syndrome (HHH; OMIM 238970) is one of the rare urea cycle disorders. Ornithine carrier 1 deficiency causes HHH syndrome, characterized by failure of mitochondrial ornithine uptake, hyperammonemia, and accumulation of ornithine and lysine in the cytoplasm. The initial presentation and time of diagnosis in HHH highly varies. Genetic analysis is critical for diagnosis. Materials and Methods: This study encompassed retrospective and prospective analyses of four unrelated Vietnamese children diagnosed with HHH syndrome. Results: The age of diagnosis ranged from 10 days to 46 months. All four cases demonstrated hyperornithinemia and prolonged prothrombin time. Three out of four cases presented with hyperammonemia, elevated transaminases, and uraciluria. No homocitrulline was detected in the urine. Only one case depicted oroticaciduria. Genetic analyses revealed three pathogenic variants in the SLC25A15 gene, with the c.535C>T (p.Arg179*) variant common in Vietnamese patients. The c.562_564del (p.Phe188del) and c.408del (p.Met137Cysfs*10) variants were detected in one case. The latter variant has yet to be reported in the literature on HHH patients. After intervention with a protein-restricted diet, ammonia-reducing therapy, and L-carnitine supplementation, hyperammonemia was not observed, and liver enzyme levels returned to normal. Conclusions: Our results highlighted the clinical and biochemical heterogeneity of HHH syndrome and posed that HHH syndrome should be considered when individuals have hyperammonemia, elevated transaminase, and decreased prothrombin time.

Vitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by mutations in the CYP27B1 gene, leading to a deficiency in active vitamin D (1,25-dihydroxyvitamin D). This study examines the genotypic and phenotypic characteristics of VDDR1A in Vietnamese children. A retrospective analysis was conducted on 19 Vietnamese children diagnosed with VDDR1A. Clinical, radiological, biochemical, and molecular data were collected. Rickets severity score (RSS), biochemical parameters, and height standard deviation score (HtSDS) were used to assess the severity of the condition. The study included 19 children from 17 families (10 males and nine females). The median age of rickets diagnosis was 19.2 months and with VDDR1A, while the median age of VDDR1A diagnosis was 7.5 months. Common symptoms among the children included thickened wrists and ankles (19/19), genu varum or genu valgum (18/19), failure to thrive (18/19), rachitic rosary (12/19), and delayed walking (11/19). Radiographic features showed that all children had cupping, splaying, and fraying, 12 children had rachitic rosary, and six exhibited pseudofracture. Biochemical findings showed severe hypocalcemia, normal or mildly low serum phosphate, elevated alkaline phosphatase and parathyroid hormone levels, and normal serum 25-hydroxyvitamin D level. Genetic analysis identified biallelic CYP27B1 variants, including one known pathogenic frameshift mutation c.1319_1325dup p.(Phe443Profs*24), one novel likely pathogenic missense variant c.616C>T p.(Arg206Cys), and one novel pathogenic frameshift mutation c.96_97del p.(Ala33Thrfs*299). The c.1319_1325dup p.(Phe443Profs*24) variant was the most common, present in 18 out of 19 children. Children with VDDR1A in this study presented with growth failure and skeletal deformities. Key findings included severe hypocalcemia, elevated alkaline phosphatase and parathyroid hormone levels, normal or elevated 25(OH)D, and high RSS. Predominant frameshift mutations in CYP27B1, especially c.1319_1325dup, highlight the importance of early genetic diagnosis for optimal management. Additionally, two novel CYP27B1 variants were identified, expanding the known mutation spectrum of VDDR1A.

October 17, 2024 Dear Prof. Dr. Rizzo and Dr. Oshiro, Prof. Dr. Rizzo: Editor-in-Chief of the Endocrinology section. Dr. Oshiro: Guest Editor of the “Advances in Clinical Diabetes, Obesity, and Metabolic Diseases” special Issue. I would like to submitt the manuscript entitled “Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome in Vietnamese Patients” by Khanh Ngoc Nguyen et al. to be considered for publication as an article in the “Advances in Clinical Diabetes, Obesity, and Metabolic Diseases” of the “Medicina” journal. This study included retrospective and prospective analyses of four unrelated Vietnamese children diagnosed with Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. HHH syndrome is one of the rarest urea cycle disorders and is characterized by failure of mitochondrial ornithine uptake, hyperammonemia, and accumulation of ornithine and lysine in the cytoplasm. Genetic analysis is key for diagnosis. In this study, we report the phenotype, genotype, treatment, and outcome of the four patients. To our best knowledge, this study is the first report of HHH patients in Vietnam. A diverse onset age and delayed diagnosis were observed. All four cases showed hyperornithinemia and prolonged prothrombin time. Three out of four cases presented with hyperammonemia, elevated transaminases, and uraciluria. No homocitrulline was detected in the urine. Genetic analyses identified three pathogenic variants in the SLC25A15 gene. The c.535C>T (p.Arg179*) variant is a common variant in Vietnamese patients. The c.562_564del (p.Phe188del) and c.408del (p.Met137Cysfs*10) variants were found in one case. The latter variant has yet been reported in the HHH patients in the literature. After intervention with a protein-restricted diet, ammonia-reducing therapy, and L-carnitine supplementation, no case had hyperammonemia and liver enzyme levels returned to normal range. Our results high-lighted clinical and biochemical heterogeneity of HHH syndrome and suggested that HHH syndrome should be considered when individuals present with hyperammonemia, elevated transaminase, and decreased prothrombin time. We believe these findings will be of interest to the readers of Medicina. We confirm that neither the manuscript nor any parts of its content are currently under consideration for publication with or published in another journal. All authors approved the final version of the manuscript and agree with its submission to Medicina. Thank you for your time and effort. We look forward to hearing from you regarding our submission. Yours sincerely, Chi Dung Vu (PhD., Assoc. Prof.) Center of Endocrinology, Metabolism, Genetic/Genomics and Molecular Therapy, Vietnam National Children’s Hospital, 18/879 La Thanh, Dong Da, Hanoi, Vietnam Email: dungvu@nch.gov.vn. Tel: +84-246-2747643