Journal of Cytology
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Year : 2017  |  Volume : 34  |  Issue : 4  |  Page : 227-229
Role of cytology in early diagnosis of cerebrotendinous xanthomas

Department of Pathology, Burdwan Medical College, Burdwan, West Bengal, India

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Date of Web Publication6-Oct-2017


Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid storage disease characterized by widespread tissue deposition of two neutral sterols, cholestenol and cholesterol, resulting in tendinous xanthomas, juvenile cataracts, progressive neurological defects, and premature death from arteriosclerosis. Because it is a treatable cause of cerebellar ataxia and dementia, its early diagnosis is desirable. Here, we have reported the case of an 11-year-old boy with this disorder who was diagnosed based on the cytological findings of fine needle aspiration and clinical features.

Keywords: Cerebellar ataxia, cerebrotendinous xanthomatosis, cholestenol

How to cite this article:
Roy S, Bandyopadhyay A, Bose K, Bhattacharyya S. Role of cytology in early diagnosis of cerebrotendinous xanthomas. J Cytol 2017;34:227-9

How to cite this URL:
Roy S, Bandyopadhyay A, Bose K, Bhattacharyya S. Role of cytology in early diagnosis of cerebrotendinous xanthomas. J Cytol [serial online] 2017 [cited 2022 Oct 5];34:227-9. Available from:

   Introduction Top

Cerebrotendinous xanthomatosis is a rare inborn disorder of bile acid synthesis in which hepatic conversion of cholesterol to cholic and chenodeoxycholic acids is impaired.[1] The diverse symptoms include bilateral juvenile cataracts and chronic diarrhoea, followed by progressive cerebellar ataxia and pyramidal tract signs, mental retardation, dementia, seizures, intellectual decline, premature atherosclerosis, and the development of tendon xanthomas (particularly of the Achilles tendons) in late adolescence and early adulthood.[2] Early diagnosis is important because patients benefit from therapy and the progress of the disease can be prevented.[3] Most cases have been reported to be diagnosed by neurological and radiological findings. Here, we report a case of cerebrotendinous xanthomatosis in a 11-year-old boy wherein cytomorphology has played an important role in the early diagnosis of the syndrome.

   Case Report Top

A 11-year-old boy was referred to our department for fine needle aspiration cytology of multiple bilateral swellings of the legs by the orthopaedic outpatient department. The patient had bilateral presenile cataracts, subaverage intelligence, ataxia, and psychiatric symptoms (behavioral changes, agitation, aggression, depression) from an early age. There was history of frequent attacks of diarrhoea during childhood. He was the youngest of three siblings. There was no history of consanguinity or similar illness in the family.

The swellings were insidious in onset and noted for the last 5 years. On examination, they were found to be firm, painless, not adherent to the underlying bone, and had a smooth surface. They were present bilaterally along the Achilles tendon, both ankles, and upper end of tibia [Figure 1]a.
Figure 1: (a) Multiple swellings around both ankles, with arrow pointing at xanthoma around Achilles tendon. (b) Smear shows foreign body type giant cell with extracellular cholesterol crystals (Leishman stain ×400). (c) Smear shows Touton giant cell (Leishman stain ×400).

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Roentgenogram of the swellings showed soft tissue shadows without any bony involvement. Fine needle aspiration was done from three sites of both the legs. The stained smears showed foamy histiocytes admixed with Touton giant cells having multiple nuclei arranged in a garland-like fashion surrounded by foamy cytoplasm. Some foreign body type of giant cells, few polymorphs, and large number of extracellular cholesterol crystals were present in the background [Figure 1]b and [Figure 1]c.

Biochemical tests revealed hemoglobin, total count, blood sugar and thyroid profiles within normal limits. Lipid profile revealed total serum cholesterol – 210 mg/dl, triglyceride – 92 mg/dl, HDL – 46 mg/dl, and VLDL – 36 mg/dl, which were again found to be within normal limits. Serum cholestenol levels could not be done due to financial constraints of the patient.

Because this was the first time the patient had sought medical advice for his ailment, a diagnosis of cerebrotendinous xanthoma was made based on the classical clinical features, cytomorphological findings, X-ray, and biochemical tests.

   Discussion Top

Cerebrotendinous xanthomatosis was first described by Vas Bogaert in 1937. Its unique chemical feature, i.e., deposition of cholestenol, a derivative of cholesterol within nervous system was uncovered only in 1968 by Menkes.[4] This is caused by a mutation in the sterol 27-hydroxylase gene (CYP27A1)[5] coding for the hepatic oxidation of the side chain of the cholesterol molecule in bile acid biosynthesis. Its deficiency decreases bile acid synthesis. This reduces feedback inhibition on cholesterol 7-alpha hydroxylase, resulting in synthesis and accumulation of more cholestenol.[6]

This disease is exceptionally rare in the Indian population. More than 300 patients with CTX have been reported to date worldwide, and approximately 50 different mutations have been identified in the CYP27A1 gene, which is localized on the long arm of chromosome 2.[7] However, the prevalence of this syndrome is estimated to be several-fold higher (3 to 5 per 100,000).[8] These underdiagnoses could be attributed to the absence of noticeable clinical manifestations in most cases, such as the apparent absence of xanthomas, especially when presenting only with neuropsychiatric symptoms.[2]

Tendon xanthomas, especially over the Achilles tendon, are characteristic of the disorder, however, they can also present elsewhere such as around elbow, patella, neck muscle tendons as well as affecting CNS, lungs, and bones.[4] In our case, the xanthomas were present in unusual sites such as around both ankles and upper end of tibia. Very few articles are available on the cytological features of tendinous xanthomas.[9],[10],[11] They have clinical and cytological resemblance to those seen in familial hypercholesterolemia or hyperlipoproteinemia, however, biochemical analysis reveals that they contain high amounts of cholestenol and normal cholesterol.

Although our patient had many classic features of cerebrotendinous xanthomatosis (including cataracts, tendon xanthomas, diarrhoea, and a complex neurodegenerative disorder), the relative timing and combination of these features was distinctive and expands the cerebrotendinous xanthomatosis clinical spectrum. While the patients typically develop cataracts in their second or third decade and neurological symptoms usually occur after the third or fourth decade, our patient was unusual in presenting with both in the first decade of life.

Conventional magnetic resonance imaging studies are sensitive for diagnosis, and have shown focal/diffuse white matter abnormalities and different degrees of cerebral and cerebellar atrophy in these patients. The bilateral nonhomogeneous, hyperintense magnetic resonance signal in dentate nuclei, and surrounding cerebellar white matter can be considered as a neuroradiological feature suggestive of cerebrotendinous xanthomas and could become an important diagnostic marker.[6]

The presentation and course widely vary, and treatment can dramatically alter the natural history, especially with early initiation before the widespread deposition of cholestenol in neural tissues has occurred. The management includes replacement therapy, surgery, and other symptomatic therapy. A combination of chenodeoxycholic acid with HMG-CoA reductase inhibitors is the mainstay of therapy.[12]

   Conclusion Top

Unfortunately, as in our case, the disease is not usually diagnosed before cholestenol has already been extensively deposited in many tissues. In Indian population, as also in our case, the socioeconomic condition of the patient who could not afford the diagnostic brain magnetic resonance imaging or confirmatory genetic analysis posed a hindrance for early therapy. Here lies the utility of aspiration cytology along with classical clinical features and normal serum cholesterol levels to diagnose cerebrotendinous xanthomatosis.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Mohammed HM, Gerald S, Jiri JF, Charles HS. Cerebrotendinous Xanthomatosis: A Rare Disease with Diverse Manifestations. Arch Neurol 2002;59:527-9.  Back to cited text no. 1
Kumar MK, Malve GNR, Naveen N, Dhanraj P, Babu KR. A Case of Bilateral Achilles Tendon Xanthomas in Cerebrotendinous Xanthomatosis: Medically Unresponsive Treated by Surgical Excision and Reconstruction. Int J Sci Stud 2014;2:217-21.  Back to cited text no. 2
Muhammad K, Nandkumar G, Saritha S. Cerebrotendinous xanthomatosis: Need for early diagnosis. Indian J Dermatol Venereol Leprol 2006;72:354-5.  Back to cited text no. 3
Mukherjee AA, Chawla BP, Rathi SS, Puthran RS. Cerebrotendinous xanthomatosis: A treatable cause of metabolic ataxia. J Assoc Physicians India 2007;55:655-7.  Back to cited text no. 4
Björkhem I, Hansson M. Cerebrotendinous xanthomatosis: An inborn error in bile acid synthesis with defined mutations but still a challenge. Biochem Biophys Res Commun 2010;396:46-9.  Back to cited text no. 5
Jha S, Khateeb M, Sonker K. Cerebrotendinous xanthomatosis, early diagnosis mandatory: Report of a case from North India. Neurol Asia 2008;13:125-8.  Back to cited text no. 6
Gallus GN, Dotti MT, Federico A. Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurol Sci 2006;27:143-9.  Back to cited text no. 7
Matthew TL, Shirley R, Donald T, John KF. Cerebrotendinous Xanthomatosis Possible Higher Prevalence Than Previously Recognized. Arch Neurol 2005;62:1459-63.  Back to cited text no. 8
Srinivas BH, Patnayak R, Rao IS, Prayaga A, Khan AK, and Narasimhlu G. Cerebrotendinous Xanthomatosis: A Case Report. Acta Cytol 2007;51:654-6.  Back to cited text no. 9
Aggarwal S, Gandhi A, Arora AK. Cytomorphological diagnosis of tendinous xanthomatosis: A case report. Diagn Cytopathol 2010;38:287-9.  Back to cited text no. 10
Chatterjee G, Chakraborty I, Das TK, Datta C. Cerebrotendinous xanthomatosis in a family. Indian J Dermatol 1999;44:153-6.  Back to cited text no. 11
  [Full text]  
Shuke N, Guiqin C, Xuebing C, Yunjian Z. Cerebrotendinous xanthomatosis: A comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 2014;9:179.  Back to cited text no. 12

Correspondence Address:
Shreosee Roy
Department of Pathology, Burdwan Medical College, Burdwan, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JOC.JOC_127_15

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