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Cerebrotendinous xanthomatosis in a 10-year-old male presenting with Achilles tendon xanthoma and mild intellectual disability: A case report
Journal of Genetic Medicine 2022;19:22-26
Published online June 30, 2022;
© 2022 Korean Society of Medical Genetics and Genomics.

Ji Hye Yoon1, Ka Young Kim1, Sang-Yun Lee1,2, Soo Yeon Kim3, Young Ah Lee1,2, Chang-Seok Ki4, Junghan Song5,6, Choong Ho Shin1,2, and Yun Jeong Lee1,*

1Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Korea
2Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
3Department of Genomic Medicine, Seoul National University Hospital, Seoul, Korea
4GC Genome, Yongin, Korea
5Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
6Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
Yun Jeong Lee, M.D.
Department of Pediatrics, Seoul National University Children’s Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea.
Tel: +82-2-2072-2811, Fax: +82-2-747-5130, E-mail:
Received February 6, 2022; Accepted April 7, 2022.
cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cerebrotendinous xanthomatosis (CTX) is a rare genetic disease caused by a defciency of enzymes for the synthesis of bile acid, resulting in the accumulation of cholestanol with reduced chenodeoxycholic acid (CDCA) production and causing various symptoms such as chronic diarrhea in infancy, juvenile cataracts in childhood, tendon xanthomas in adolescence and young adulthood, and progressive neurologic dysfunction in adulthood. Because oral CDCA replacement therapy can effectively prevent disease progression, early diagnosis and treatment are critical in CTX. This study reports the case of CTX in a 10-year-old male who presented with Achilles tendon xanthoma and mild intellectual disability. Biochemical testing showed normal cholesterol and sitosterol levels but elevated cholestanol levels. Genetic testing showed compound heterozygous variants of CYP27A1, c.379C>T (p.Arg127Trp), and c.1214G>A (p.Arg405Gln), which confrmed the diagnosis of CTX. The patient had neither cataracts nor other focal neurologic defcits and showed no abnormalities on brain imaging. The patient received oral CDCA replacement therapy without any adverse effects; thereafter, the cholestanol level decreased and no disease progression was noted. The diagnostic possibility of CTX should be considered in patients with tendon xanthoma and normolipidemic conditions to prevent neurological deterioration.
Keywords : Cerebrotendinous xanthomatosis, Xanthoma, CYP27A1 protein, Intellectual disability.

Tendon xanthomas are fatty deposits on the tendons under the skin and are related to lipid metabolism disorders. Although xanthomas usually occur in hyperlipidemic conditions such as familial hypercholesterolemia, they have also been reported in sitosterolemia or cerebrotendinous xanthomatosis (CTX), a rare genetic disorder without hyperlipidemia [1].

CTX is an autosomal-recessive genetic disorder of bile acid synthesis caused by CYP27A1 gene mutations, leading to deficiency of sterol 27-hydroxylase production [2]. Patients with CTX have elevated blood cholestanol levels and, consequently, exhibit symptoms such as chronic diarrhea in infancy, juvenile cataracts in childhood, tendon xanthomas in adolescence to young adulthood, and progressive neurologic dysfunction in adulthood [3]. Although early diagnosis and treatment are essential to prevent irreversible progression of the disease, delayed or missed diagnosis is common due to the pleomorphic clinical phenotype [4].

In this study, the first Korean pediatric case of CTX presenting with Achilles tendon xanthoma and intellectual disability is reported. The patient was diagnosed at an early stage of the disease and treated with chenodeoxycholic acid (CDCA).

This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB no. 2103-025-1201). Written informed consent was obtained from the patient and the patient’s parents for publication of this case report.


A 10-year and 8-month-old male was referred to a tertiary center for evaluation of swelling on the Achilles tendon, which was first observed 4 months ago. He was born at 40 weeks of gestation, with a birth weight of 3.4 kg and without perinatal problems; he belonged to a non-consanguineous family. There was no significant family history of primary dyslipidemia, xanthoma, or early atherosclerotic cardiovascular disease. The patient had a mild intellectual disability with cognitive and language impairment; however, his motor development was normal. He had chronic diarrhea from infancy and a history of idiopathic central precocious puberty diagnosed at 8 years of age, for which, he had been treated with a gonadotropin-releasing hormone agonist for a year.

At presentation, the patient showed normal growth with a height of 159 cm (95th-97th percentile) and weight of 47.9 kg (75th-90th percentile). Physical examination showed bilateral firm and non-tender fixed masses on the Achilles tendon area (left, 5.5 cm×4.0 cm; right, 3.0 cm×2.0 cm, Fig. 1A). The patient showed no focal neurologic deficits. Laboratory examination revealed normal cholesterol levels (total cholesterol level, 155 mg/dL; low-density lipoprotein cholesterol level, 104 mg/dL) and hypertriglyceridemia (triglyceride level, 200 mg/dL). Serum sitosterol level was normal, but serum cholestanol was elevated (3.54 mg/dL; reference range, 0.41-0.66 mg/dL) [5,6]. The patient had normal hepatic and renal function (Table 1). Ankle magnetic resonance imaging (MRI) showed diffuse fusiform thickening of the left Achilles tendon with T1/T2 high signal intensity and mild enhancement, which was suggestive of tendon xanthoma (Fig. 1B).

For evaluation of the xanthoma, massively parallel sequencing was performed using a molecular panel of 31 target genes associated with lipid metabolism disorders, as described previously [6]. Target enrichment was achieved via hybridization with oligonucleotide probes, and sequencing was conducted on an Illumina MiSeqDX (Illumina, San Diego, CA, USA) platform. Two heterozygous variants, c.379C>T (p.Arg127Trp) and c.1214G>A (p.Arg405Gln), were identified in CYP27A1, both of which were known pathogenic variants for CTX [7]. Sanger sequencing of the two variants in the patient’s father and mother showed that both the parents were heterozygous carriers of each variant. The patient’s younger sister and brother were also identified as carriers of CTX (Fig. 2).

After diagnosis, further evaluation of the systemic manifestations of CTX, including ophthalmologic, neurologic, and cardiologic examinations, was conducted. Brain MRI showed no focal lesion in the brain parenchyma, and there was no evidence of a premature cataract. The patient had normal cardiac structure and function, as revealed by echocardiography. Although initial myocardial single-photon emission computed tomography showed decreased perfusion of the left anterior descending territory during exercise, a follow-up examination after 6 months showed normal findings. Vascular stiffness did not increase with pulse wave velocity, and there were no abnormal ST segment changes on the treadmill exercise test. Dual energy X-ray absorptiometry showed low bone mineral density (z-score for lumbar spine, -2.9) and low 25-hydroxyvitamin D level (11.9 ng/mL).

Oral CDCA treatment (250 mg three times a day, 13.9 mg/kg/d) was initiated in the patient at 11 years and 6 months of age. He also received nutritional education about adequate vitamin D and calcium intake and was started on 1,000 IU/day of vitamin-D3 supplementation. Treatment was well tolerated, and no adverse effects such as elevation of liver enzyme levels or aggravation of diarrhea were observed. Four months after initiation of CDCA treatment, the serum cholestanol level decreased to 1.89 mg/dL. One year after treatment, the size of the xanthoma and the patient’s neurological status remained stable.


This case report describes a male with Achilles tendon xanthoma and mild intellectual disability diagnosed as CTX with clinical suspicion, biochemical evaluation, and genetic testing. Early recognition and diagnosis of the disease led to early treatment with CDCA, which is expected to delay the progression of neurological symptoms.

CTX is a rare lipid storage disease caused by mutations in the CYP27A1 gene, which encodes sterol 27-hydroxylase, a mitochondrial enzyme for bile acid synthesis [2]. A deficiency of this enzyme leads to reduced production of CDCA and subsequent accumulation of cholestanol in various tissues, resulting in diverse systemic and neurologic clinical manifestations [8]. Systemic symptoms include chronic diarrhea beginning in infancy, childhood-onset cataracts, tendon xanthoma, osteoporosis, and coronary heart disease [9]. When untreated, progressive neurologic dysfunction develops, including intellectual disability, pyramidal and extrapyramidal signs, cerebellar signs, peripheral neuropathy, epilepsy, and psychiatric changes [4,10].

In our case, CTX was suspected due to the presence of tendon xanthoma and mild intellectual disability with normal cholesterol levels. The patient’s sitosterol level was normal, whereas cholestanol level was elevated, and genetic testing confirmed the diagnosis of CTX. When a patient with tendon xanthoma presents with a relatively normal cholesterol level, clinicians should consider CTX or sitosterolemia and measure serum cholestanol and sitosterol levels [1,11]. An approach to patients with appropriate biochemical and genetic workups could lead to a correct diagnosis.

As observed in our case, intellectual disability or learning difficulties often begin in childhood, which is one of the most frequent clinical features of CTX [4,10,12]. Typical MRI findings of CTX include cerebellar atrophy, symmetric hyperintensities in dentate nuclei, and surrounding cerebellar white matter [8,13]; however, brain MRI revealed normal findings for our patient, which is possibly associated with the early stage of the disease. Thus, early diagnosis and treatment are critical for avoiding severe neurological sequelae. However, delayed diagnosis is common due to various clinical presentations and unawareness of the disease. Patients usually present symptoms from childhood or adolescence at 9 to 19 years of age, but the mean age of diagnosis is 33 to 38 years with a significant diagnostic delay [4,12]. The treatment of choice is long-term CDCA replacement therapy, which is effective in normalization of cholestanol levels [14]. A recent cohort study reported that starting CDCA treatment at an early age (<24 years) could reverse and even prevent the development of neurologic symptoms in patients with CTX [15]. In our study, the patient was diagnosed with CTX and CDCA treatment was initiated at 11 years and 6 months of age when he exhibited mild intellectual disability without focal lesions on brain MRI. Although it is difficult to evaluate the outcomes of this case due to the short duration of follow-up, early diagnosis and treatment are expected to prevent neurologic deterioration in our patient.

Patients with CTX often show multi-organ involvement, and close monitoring and management of systemic symptoms with a multidisciplinary team can be helpful. Our patient had low bone mineral density, and vitamin-D3 supplementation was provided along with CDCA treatment. Osteoporosis with an increased risk of fracture is a common clinical manifestation of CTX; however, the underlying pathogenesis remains unknown [8]. Evaluation of the cardiovascular system in our patients showed no significant abnormality. Although most of the patients with CTX show normal cholesterol levels, an increased risk of premature atherosclerotic cardiovascular disease has been reported, with a prevalence of 7% to 20% [4,16]. The mechanism leading to premature atherosclerosis is unknown, but subendothelial accumulation of cholestanol or reduced capacity for reverse cholesterol transport caused by 27-hydroxylase deficiency has been suggested [17]. Regular follow-up examination for various systemic symptoms was also needed in our patient.

To the best of our knowledge, this study reports the first Korean pediatric case of CTX in a patient who was diagnosed and treated at an early age. Since prompt initiation of treatment is critical for neurologic outcomes, CTX should be considered as a differential diagnosis in patients with tendon xanthoma without hypercholesterolemia.

Conflict of interest

The authors declare that they do not have any conflicts of interest.


This study was supported by a grant from the SNUH Research Fund (grant no. 03-2020-0410). This study was supported by a grant from the Korean Society of Pediatric Endocrinology (grant no. 2020-01). This work was supported by grants from the Seoul National University College of Medicine (grant no. 800-20200462).

Author’s Contributions

Conceptualization and design: YJL. Acquisition of data: JHY, KYK. Analysis and interpretation of data: none. Drafting the article: JHY, KYK. Critical revision of the article: SYL, SYK, YAL, CHS, JS, CSK, YJL. Final approval of the version to be published: all authors.

Fig. 1. (A) Clinical photograph showing Achilles tendon xanthoma at the posterior aspect of both the ankle joints. (B) Ankle magnetic resonance imaging findings showing diffuse fusiform-shaped thickening of the left Achilles tendon with T1/T2 high signal intensity and mild enhancement (arrows).
Fig. 2. Identification of CYP27A1 mutation in patient’s family. (A) The pedigree showing inheritance of CYP27A1 variants in the patient’s family. (B) Sanger sequencing confirmation of heterozygous variant of CYP27A1 gene from the patient’s family.

Laboratory findings of the patient at the time of diagnosis

Variable Value Reference range
Aspartate aminotransferase (IU/L) 24 13.0-34.0
Alanine aminotransferase (IU/L) 21 5.0-46.0
Uric acid (mg/dL) 7.8 3.0-7.0
Blood urea nitrogen (mg/dL) 8 7-17
Creatinine (mg/dL) 0.59 0.37-0.72
Calcium (mg/dL) 10 8.5-10.5
Phosphorus (mg/dL) 5.1 3.8-5.9
Alkaline phosphatase (IU/L) 422 144-386
Cholesterol (mg/dL) 155 <170
High-density lipoprotein cholesterol (mg/dL) 34 >45
Low-density lipoprotein cholesterol (mg/dL) 104 <110
Triglyceride (mg/dL) 200 <90 (for 10 to 19-year-old adolescents)
Sitosterol (mg/dL) 0.56 <1.49
Cholestanol (mg/dL) 3.54 0.41-0.66

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