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Cerebrotendinous Xanthomatosis Diagnosed with Bilateral Achilles Tendon Masses

Nimesh B. Patel, Robert Treuting

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We report a patient presenting to an orthopaedic clinic with bilateral Achilles tendon masses who was subsequently diagnosed with cerebrotendinous xanthomatosis. This is a lipid-storage disease secondary to a disruption in cholesterol metabolism. In the absence of the key enzyme, sterol 27-hydroxylase, other metabolites are increased such as cholestanol. This elevated concentration results in characteristic clinical findings such as bilateral cataracts, tendon xanthomas, and neurologic impairments including debilitating cerebellar ataxia and cerebral degeneration. Treatment with chenodeoxycholic acid (CDCA) replenishes the key bile acid in humans and as a result prevents the up-regulation of cholesterol and cholestanol synthesis. This remedy may decrease the size of xanthomas; however, reversing neurologic deficits is rarely successful. Ultimately, early diagnosis and initiation of treatment is critical for the future well being of these patients before permanent detrimental effects take place.

J.Orthopaedics 2008;5(3)e13


Cerebrotendinous xanthomatosis is a rare lipid-storage disease producing and storing excessive cholestanol1,2.  Various presentations include cataracts, neurological dysfunction and tendon xanthomas.  The tendinous manifestations typically precede the onset of neurological symptoms by decades1.  Due to a mutation of the CYP27 gene on chromosome 23, the sterol 27-hydroxylase enzyme is rendered inactive and unable to appropriately metabolize cholesterol to bile acids4,5.   

Although not reversible, the progression of neurologic demise associated with this autosomal recessive disease can be arrested with appropriate treatment6,7.  Early diagnosis of this disease is critical to the patientís successful long term outcome.  Here we report a patient with a mild presentation of cerebrotendinous xanthomatosis presenting only with bilateral Achilles tendon masses without neurologic deficit.

Case Report :

An 18-year-old female presented complaining of slowly enlarging masses overlying both distal Achilles tendons (Fig. 1).  They were soft and not tender to palpation, however she did complain that closed countered shoes caused significant pain over the area.  Despite being treated with non-steroidal anti-inflammatory as well as oral steroid regimens, growth continued over the past six years.

Fig. 1.  Clinical preoperative photograph of Achilles tendon mass.

Past medical history was unremarkable for the most part.  At age 6, bilateral cataracts were treated with cataract removal and intraocular lens placement.  She has not suffered any developmental delay or exhibited mental retardation.  No other family members have shown similar symptoms or signs of hypercholesterolemia.  Currently, she takes no medications and has no known drug allergies. 

On physical exam, each fusiform mass measured 8 cm in length starting approximately 2 cm proximal from the Achilles tendon insertion.  No neurologic impairment was noted and she exhibited symmetrical 2+ deep tendon reflexes.  Her muscle strength, ankle range of motion and gait pattern were unaffected.  Close inspection did not disclose cutaneous xanthomas or yellowish discoloration.  

No osseous pathology was noted on plain radiographs.  Magnetic resonance images revealed a soft tissue mass on each Achilles tendon exhibiting a heterogenous signal (Fig. 2). 

Fig. 2.  Axial T2-weighted image with fat suppression exhibiting a heterogenous signal within the Achilles tendon. 

Since non-operative treatment failed, the patient requested surgical removal of both swellings.  The senior author (R.T.) agreed to remove one and then assess her improvement and satisfaction before continuing with the next.  A posterolateral approach to the Achilles tendon exposed a xanthoma (Fig. 3).  Fatty yellow deposits infiltrated the tendinous fibers; consequently, the mass could not be completely excised.  The Achilles tendon was debrided while paying careful attention to minimize further insult to the healthy fibers; essentially, the mass was debulked.

Fig. 3.  Lateral view of the exposed Achilles tendon xanthoma

The pathology department prepared the tissue sample in formalin and examined it under light microscopy.  Innumerable foamy macrophages were visualized with cleft-like spaces consistent with dissolved cholesterol secondary to cellular processing.  There were no indications of malignancy (Fig. 4).

Fig. 4.  A tissue sample photomicrograph from the Achilles tendon exhibiting foamy macrophages, cholesterol clefts, and multinucleatd giant cells (Stain, hematoxylin and eosin, original magnification ◊200). 

Liver enzymes and a lipid panel found no abnormalities except for an elevated cholestanol level of 28.9 ug/mL (normal value is 4.2 +/- 1.2 ug/mL).  At this point, a pediatric endocrinologist also evaluated her and concurred with the diagnosis of cerebrotendinous xanthomatosis.  A treatment regimen was initiated immediately and consisted of daily chenodeoxycholic acid as described by Berginer et al10.

Discussion :

Sterol 27-hydroxylase cleaves a cholesterol side chain thereby yielding bile acids, specifically chenodeoxycholic acid.  In the absence of this enzyme, other metabolites are produced i.e. cholestanol and bile alcohols.  It is theorized that without the negative feedback loop of bile acids, cholesterol and cholestanol production are upregulated2

 This increased concentration results in the characteristic clinical findings:  bilateral cataracts, tendon xanthomas, premature cardiovascular disease and neurologic impairments.  Cataracts in the pediatric patient is usually the earliest presentation of cerebrotendinous xanthomatosis.  Unfortunately, this can be mistaken for an isolated presentation of congenital cataracts8.  Although Achilles tendons are the most common location, patellar and triceps tendon xanthomas have been described as well7. 

Neurologic presentation may occur at any given time during the diseaseís natural history.  Key findings include cerebellar ataxia, dementia, pyramidal signs, decreased intelligence, brain atrophy and seizure disorder9.  The exact mechanism in which cholestanol produces neurologic dysfunction is unknown, however, this disease process has been shown to up-regulate apoptotic pathways thereby explaining the often noted cerebral atrophy10.  

The earliest symptoms in an infant consists of chronic diarrhea and cataracts followed by tendon xanthomas in early adulthood11.  Immediately, the possibility of cerebrotendinous xanthomatosis should be considered.  In the presence of a positive diagnosis, all family members should be screened as well.  Molecular genetic testing allows identification of heterozygotes and therefore possibility for genetic counseling3. 

When evaluating patients with xanthomas and cataracts , the differential diagnosis should include familial hypercholesterolemia12 and sitosterolemia, a lipid disorder in which plant sterols are not appropriately metabolized and therefore excessively deposited13.  Both disorders in effect are associated with elevated cholesterol levels.  Interestingly, neither result in neurologic dysfunction further indicating that cholestanol itself directly leads neural pathology. 

In addition to the clinical findings, diagnosis is confirmed primarily with laboratory tests. Usually a lipid panel would be sufficient to reveal the metabolic abnormality causing xanthomas, however, this patient demonstrated normal plasma lipid and cholesterol levels.  Only the cholestanol was grossly elevated.  Additional studies showing elevated plasma and urine bile alcohol can also support the diagnosis2

Therapeutic options have been developed based on cholesterol metabolism.  Due to its lack of production, bile acid replacement remains the cornerstone of cerebrotendinous xanthomatosis treatment.  Chenodeoxycholic acid (CDCA) replenishes the key bile acid in humans and as a result limits cholesterol, cholestanol and bile alcohol synthesis.  This remedy has been shown to halt neurologic deterioration as well as decrease the size of Achilles tendon masses6,7.  Ursodeoxycholic acid, a bile acid commonly used for treatment of primary biliary cirrhosis and small gallstones, is ineffective for cerebrotendinous xanthomatosis.   It is not actually a human bile acid but instead developed commercially based on a bile acid from the Chinese black bear.  Because of this, ursodeoxycholic acid is ineffective in providing the negative feedback regulation14.  There have been several reports that 250mg CDCA three times daily results in successful outcomes6,15; unfortunately, this has not always been effective14. 


The case report we present is unique in that cerebrotendinous xanthomatosis was diagnosed in an adolescent presenting with bilateral Achilles tendons despite having no neurological deficits.  A goal of this paper is to make orthopaedic surgeons aware of this disease process.  Ultimately, early diagnosis and initiation of treatment is critical for the future well being of these patients.  Chenodeoxycholic acid may help decrease xanthoma sizes, however, reversing neurologic deficits is rarely successful.

Reference :

1.     Bjorken I, Boberg KM, Leitersdoef E. Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol. In: Scriver Cr, Beaudet AL, editors. The metabolic and molecular bases of inherited diseases. 8th ed. New York: McGraw-Hill; 2001. p 2970-8.

2.     Moghadasian M. Cerebrotendinous xanthomatosis: clinical course, genotypes and metabolic backgrounds. Clinical Investigative Medicine 2004; 27: 42-50.

3.     Meiner V, Meiner Z, Reshef A, Bjorkhem I, Leitersdorf E. Cerebrotendinous Xanthomatosis: molecular diagnosis enables presymptomatic detection of a treatable disease. Neurology 1994; 44: 288-90.

4.     Cali JJ, Hsieh CL, Francke U, et al.  Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis.  Journal of Biological Chemistry. 1991; 266: 7779-83.

5.     Lee MH, Hazards S, Carpaten JD, Yi S, Cohen J. Gerhardt GT, Salen G, Patel SB.  Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees.  Journal of Lipid Research 2001; 42: 159-169.

6.     Berginer VM, Salen G, Shefer S. Long term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. New England Journal of Medicine 1984; 311: 1649-52.

7.     Lamon-Fava S. Schaefer EJ. Garuti R. Salen G, Calandra S. Two novel mutations in the sterol 27-hydroxylase gene causing cerebrotendinous xanthomatosis.  Clinical Genetics 2002; 61:185-91.

8.     Cruysberg JR, Wevers RA, van Engelen BG, Pinckers A, van Spreeken A, Tolboom JJ. Ocular and systemic manifestations of cerebrotendinous xanthomatosis. American Journal of Opthamology 1995; 20: 597-604.

9.     Federico A and Dotti MT. Cerebrotendinous Xanthomatosis: Clinical Manifestations, Diagnostic Criteria, Pathogenesis, and Therapy. Journal of Child Neurology. 2003; 18: 633-638.

10.  Inoue K, Kubota S, Seyama Y. Cholestanol induces apoptosis of cerebellar neuronal cells.  Biochemical and Biophysical Research Communications 1999; 256: 198-203.

11.  Cruyaberg JR, Wevers RA, Tolboom JJ. Juvenile cataract associated with chronic diarrhea in pediatric cerebrotendinous xanthomatosis. American Journal of Opthalmology. 1991; 112: 606-607.

12.  Carranza-Bencano, A et al.  Xanthomas of the Achilles Tendon: Report of a Bilatreal Case and Review of the Literature.  Foot and Ankle International. 1999; 20(5): 314-316.

13.  Nguyen LB, Shefer S, Salen G. Molecular defect in cholesterol synthesis in sitosterolemia with xanthomatosis. Journal of Clinical Investigation 1990; 86: 926-31.

14.  Brodsky J, Beischer A, Dip Anat C, Soltero E, Tint S, Salen G, Silverman J. Cerebrotendinous Xanthomatosis: A Rare Cause of Bilateral Achilles Tendon Swelling and Ataxia. Journal of Bone and Joint Surgery 2006; 88A: 1340-44.

15.  Batta AK, Shefer S, Batta M, Salen G. Effects of chenodeoxycholic acid on biliary and urinary acids and bile alcohols in cerebrotendinous xanthomatosis; monitoring by high performance liquid chromatography. Journal Lipid Research 1985; 26: 690-8.



This is a peer reviewed paper 

Please cite as : SNimesh B. Patel : Cerebrotendinous Xanthomatosis Diagnosed with Bilateral Achilles Tendon Masses

J.Orthopaedics 2008;5(3)e13





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