Paola Sabrina Buonuomo1, Lorenzo Iughetti2, Livia Pisciotta3, Claudio Rabacchi4, Francesco Papadia5, Patrizia Bruzzi2, Albina Tummolo5, Andrea Bartuli1, Claudio Cortese6, Stefano Bertolini7, Sebastiano Calandra8. 1. Rare Diseases and Medical Genetics, Bambino Gesù Children Hospital, Rome, Italy. 2. Department of Medical and Surgical Sciences of the Mothers, Children and Adults, Paediatric Unit, University of Modena & Reggio Emilia, Modena, Italy. 3. Department of Internal Medicine, University of Genova, Genova, Italy. 4. Department of Life Sciences, University of Modena & Reggio Emilia, Modena, Italy. 5. University Pediatric Hospital Giovanni XXIII, O.U. Metabolic and Genetic Diseases, Bari, Italy. 6. Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy. 7. Department of Internal Medicine, University of Genova, Genova, Italy. Electronic address: stefbert@unige.it. 8. Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. Electronic address: sebcal@unimore.it.
Abstract
BACKGROUND AND AIMS: Severe hypercholesterolemia associated or not with xanthomas in a child may suggest the diagnosis of homozygous autosomal dominant hypercholesterolemia (ADH), autosomal recessive hypercholesterolemia (ARH) or sitosterolemia, depending on the transmission of hypercholesterolemia in the patient's family. Sitosterolemia is a recessive disorder characterized by high plasma levels of cholesterol and plant sterols due to mutations in the ABCG5 or the ABCG8 gene, leading to a loss of function of the ATP-binding cassette (ABC) heterodimer transporter G5-G8. METHODS: We aimed to perform the molecular characterization of two children with severe primary hypercholesterolemia. RESULTS: Case #1 was a 2 year-old girl with high LDL-cholesterol (690 mg/dl) and tuberous and intertriginous xanthomas. Case #2 was a 7 year-old boy with elevated LDL-C (432 mg/dl) but no xanthomas. In both cases, at least one parent had elevated LDL-cholesterol levels. For the molecular diagnosis, we applied targeted next generation sequencing (NGS), which unexpectedly revealed that both patients were compound heterozygous for nonsense mutations: Case #1 in ABCG5 gene [p.(Gln251*)/p.(Arg446*)] and Case #2 in ABCG8 gene [p.(Ser107*)/p.(Trp361*)]. Both children had extremely high serum sitosterol and campesterol levels, thus confirming the diagnosis of sisterolemia. A low-fat/low-sterol diet was promptly adopted with and without the addition of ezetimibe for Case #1 and Case #2, respectively. In both patients, serum total and LDL-cholesterol decreased dramatically in two months and progressively normalized. CONCLUSIONS: Targeted NGS allows the rapid diagnosis of sitosterolemia in children with severe hypercholesterolemia, even though their family history does not unequivocally suggest a recessive transmission of hypercholesterolemia. A timely diagnosis is crucial to avoid delays in treatment.
BACKGROUND AND AIMS: Severe hypercholesterolemia associated or not with xanthomas in a child may suggest the diagnosis of homozygous autosomal dominant hypercholesterolemia (ADH), autosomal recessive hypercholesterolemia (ARH) or sitosterolemia, depending on the transmission of hypercholesterolemia in the patient's family. Sitosterolemia is a recessive disorder characterized by high plasma levels of cholesterol and plant sterols due to mutations in the ABCG5 or the ABCG8 gene, leading to a loss of function of the ATP-binding cassette (ABC) heterodimer transporter G5-G8. METHODS: We aimed to perform the molecular characterization of two children with severe primary hypercholesterolemia. RESULTS: Case #1 was a 2 year-old girl with high LDL-cholesterol (690 mg/dl) and tuberous and intertriginous xanthomas. Case #2 was a 7 year-old boy with elevated LDL-C (432 mg/dl) but no xanthomas. In both cases, at least one parent had elevated LDL-cholesterol levels. For the molecular diagnosis, we applied targeted next generation sequencing (NGS), which unexpectedly revealed that both patients were compound heterozygous for nonsense mutations: Case #1 in ABCG5 gene [p.(Gln251*)/p.(Arg446*)] and Case #2 in ABCG8 gene [p.(Ser107*)/p.(Trp361*)]. Both children had extremely high serum sitosterol and campesterol levels, thus confirming the diagnosis of sisterolemia. A low-fat/low-sterol diet was promptly adopted with and without the addition of ezetimibe for Case #1 and Case #2, respectively. In both patients, serum total and LDL-cholesterol decreased dramatically in two months and progressively normalized. CONCLUSIONS: Targeted NGS allows the rapid diagnosis of sitosterolemia in children with severe hypercholesterolemia, even though their family history does not unequivocally suggest a recessive transmission of hypercholesterolemia. A timely diagnosis is crucial to avoid delays in treatment.
Authors: Diego Lucero; Anna Wolska; Zahra Aligabi; Sarah Turecamo; Alan T Remaley Journal: Endocrinol Metab Clin North Am Date: 2022-07-08 Impact factor: 4.748
Authors: Felix Fath; Andreas Bengeser; Mathias Barresi; Priska Binner; Stefanie Schwab; Kausik K Ray; Bernhard K Krämer; Uwe Fraass; Winfried März Journal: Sci Rep Date: 2021-10-14 Impact factor: 4.379