Cerebrotendinous Xanthomatosis - Clinical Manifestation in Two Slovak Children

Katarina Brennerova ¹ Pavol Durina ³ Imre Bohuniczky ⁴ Katarina Okalova ⁵ Miriama Juhosova ³ Michaela Pietrzykova ³ Marcel Repisky ³ Miriam Kolnikova ⁶ Vladimir Bzduch ² Jan Chandoga ³

¹Paediatric Clinic, Medical Faculty of Comenius University and National institute of Children´s Diseases, Slovakia
³Institute of Medical Biology, Genetics and Clinical Genetics, Medical faculty of Comenius University and University Hospital Molecular and Biochemical Genetics – Centre for Rare Genetic Diseases, Slovakia
⁴Clinic of Paediatric oftalmology Medical Faculty of Comenius University and National institute of Children diseases, Slovakia
⁵Paediatric Clinic of Slovak Medical University, Univerity Children Hospital, Banská Bystrica, Slovakia
⁶Clinic of Paediatric Neurology Medical Faculty of Comenius University and National institute of Children´s Diseases, Slovakia

Introduction: Cerebrotendinous xanthomatosis (CTX) is a hereditary bile acid synthesis disease. The deficiency of sterol 27-hydroxylase causes an accumulation of cholestanol and 7-dehydrocholesterol within the body. The clinical manifestations of the disease vary by age: transient cholestasis in newborns, diarrhoea in smaller children, and cataracts most often occur before the age of 10, with a fully developed clinical picture in adults (mainly tendon xanthomas and neuropsychiatric symptomatology).

Case studies: A 8-year-old girl presented with mild neurological symptoms (hypotonia, dyslalia) and an extended metabolic screening was recommended because of a juvenile cataract. The serum cholestanol concentration was significantly increased (63 µmol/l; NV to 16 µmol/l). Genetic analysis confirmed compound heterozygosity of two pathogenic variants in the CYP27A1 gene: c.379CT and c.1183CT. A 5-year-old boy with slightly delayed psychomotor development and subsequent speech development disorder suffered from diarrhoea of unclear aetiology. At the age of 4, he had a pathological finding on an EEG without convulsions and no cataracts. Repeated extended metabolic screenings were negative. The high serum cholestanol concentration (46.3 µmol/l) led to the molecular genetic analysis of the CTX gene and he was compound heterozygous for the pathogenic variants c.379CT and c.1263+5GA.

Conclusion: CTX may be underdiagnosed in children due to non-specific symptoms in the first few years of life. Since it is a treatable hereditary metabolic disorder, the determination of the serum cholestanol concentration is crucial for the differential diagnosis of children with neonatal cholestasis, neurological symptomatology associated with chronic diarrhoea or juvenile cataracts.