Cerebrotendinous xanthomatosis (CTX) is an inborn error of bile acid metabolism with autosomal recessive inheritance that is caused by biallelic variants in the CYP27A1 gene. Although historically it has been considered an adult disease, there is growing evidence that CTX manifests in childhood with early signs that are frequently overlooked, resulting in diagnostic delays that affect its prognosis. Early detection is crucial, as treatment with bile acids can prevent neurologic progression if it is initiated before irreversible damage occurs.1–3

We present the cases of two siblings in whom CTX was diagnosed during childhood that illustrate the early phenotypic variation of the disease and the value of family screening. The first case corresponded to a boy with a history of chronic diarrhea since early childhood, self-limited infantile epilepsy and marked short stature. At age 7 years, he was hospitalized due to encephalitis secondary to influenza B infection, with a favorable outcome. After resolution of the infection, subtle neurologic signs persisted (mild bilateral patellar hyperreflexia and impaired tandem gait) combined with generalized background slowing on the video encephalogram (vEEG). The diagnostic evaluation was expanded, and clinical exome sequencing identified two pathogenic variants in trans configuration in the CYP27A1 gene (compound heterozygosity). This finding guided further blood chemistry testing, which confirmed marked elevation of plasma β-cholestanol, while the targeted ophthalmological evaluation detected previously unsuspected bilateral posterior cataracts.

The second case involved his sister, aged 12 years, who was asymptomatic and diagnosed through family screening after the diagnosis of the index case. The chemistry panel evinced significant elevation of plasma β-cholestanol and genetic testing identified the same pathogenic variants in CYP27A1 found in her brother. The vEEG showed subclinical interictal epileptiform activity.

Both patients started treatment with chenodeoxycholic acid. It achieved rapid resolution of diarrhea in the first patient and normalization of plasma levels β-cholestanol in both. While plasma β-cholestanol is the marker customarily used in follow-up and is useful for dose adjustment, its correlation with clinical outcomes is weak, so urine 23S-pentol has been proposed as a more sensitive and robust prognostic marker.4

Several key points are illustrated by these cases: early-onset chronic diarrhea, present in 90% of pediatric cases, and pediatric cataracts must be considered sentinel symptoms of CTX. The absence of tendinous xanthomata does not rule out the diagnosis in children, as this feature is only present in 1% of pediatric cases.5 In addition, subclinical electroencephalographic abnormalities support the presence of early neurologic involvement. The natural history of CTX, from the early stages with initial nonspecific signs to progressive and irreversible neurologic deterioration, offers a window of opportunity for treatment during childhood. As Fig. 1 illustrates, initiation of treatment with bile acids in the early stages of CTX is associated with preserved neurodevelopment, while diagnostic delay increases the risk of permanent sequelae. In this context, family screening is of vital importance, as it enables identification of presymptomatic cases and initiation of treatment before irreversible damage occurs.6

Figure 1.

Natural history of cerebrotendinous xanthomatosis through the end of childhood. Diagram of the progression of CTX from the initial symptoms in childhood to progressive neurologic deterioration. The diagram highlights the early sentinel symptoms (chronic diarrhea and pediatric cataracts) and the early therapeutic time window during which initiation of treatment with bile acids can prevent irreversible neurologic damage.

In Spain, CTX is not included in the newborn metabolic screening program. Thus, early diagnosis depends on the recognition of early clinical warning signs and targeted family screening.