Dorfman–Chanarin syndrome with cirrhosis

Pathology

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Dorfman–Chanarin syndrome with cirrhosis P. Gupta, Kajal Kiran Dhingra, Vibha Kawatra, T. Singh & S. Yadav To cite this article: P. Gupta, Kajal Kiran Dhingra, Vibha Kawatra, T. Singh & S. Yadav (2008) Dorfman–Chanarin syndrome with cirrhosis, Pathology, 40:6, 650-653 To link to this article: https://doi.org/10.1080/00313020802321166

Published online: 06 Jul 2009.

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Pathology (2008), 40(6), October

FIG. 3 (A) Brain lesions with H&E stain showing perivascular cuffing (arrows) and neuronophagia (arrowheads) in the rabies case (6100). (B) The viral lesions are predominantly located in the lateral and rostral areas (cross section) and (C) dorsal portion (longitudinal section) of the medulla.

are the possible causes of acute lung injury or ARDS in patients with rabies. Yung-Hsiang Hsu* Hsing I. Chen{ *Department of Pathology, and {Institute of Integrative Physiology and Clinical Sciences, Tzu Chi University and Tzu Chi General Hospital, Hualien, Taiwan Contact Dr Y-H. Hsu. E-mail: [email protected]

7. Hsu YH, Kao SJ, Lee RP, et al. Acute pulmonary oedema: rare causes and possible mechanisms. Clin Sci 2003; 104: 259–64. 8. Chen HI, Liao JF, Kuo L, et al. Centrogenic pulmonary hemorrhagic edema induced by cerebral compression in rats. Mechanism of volume and pressure loading in the pulmonary circulation. Circ Res 1980; 47: 366–73. 9. Chen HI, Kao SJ, Wang D, et al. Acute respiratory distress syndrome. J Biomed Sci 2003; 10: 588–92. 10. Tomashefski JF Jr. Pulmonary pathology of the adult respiratory distress syndrome. Clin Chest Med 1990; 11: 593–619. 11. Chai CY, Wang SC. Localization of central cardiovascular control mechanism in lower brain stem of the cat. Am J Physiol 1962; 202: 25– 30. 12. Su CF, Yang FL, Chen HI. Inhibition of inducible nitric oxide synthase attenuates acute endotoxin-induced lung injury in rats. Clin Exp Pharmacol Physiol 2007; 34: 339–46.

DOI: 10.1080/00313020802320689 1. Kao SJ, Yang FL, Hsu YH, et al. Mechanism of fulminant pulmonary edema caused by enterovirus 71. Clin Infect Dis 2004; 38: 1784–8. 2. Chen HI, Kao SJ, Hsu YH. Pathophysiological mechanism of lung injury in patients with leptospirosis. Pathology 2007; 39: 339–344. 3. Bureau of Disease Control, Ministry of National Health, Taiwan. Record of Infectious Disease, 2006. Taiwan: Ministry of National Health, 2006. 4. Su CF, Kuo TB, Kuo JS, et al. Sympathetic and parasympathetic activities evaluated by heart-rate variability in head injury of various severities. Clin Neurophysiol 2005; 116: 1273–9. 5. Shi SR, Key ME, Kalra KL. Antigen retrieval in formalin-fixed, paraffin-embedded tissues: An enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections. J Histochem Cytochem 1991; 39: 741–8. 6. Halon CA, Corey L. Rabies virus and other rhadoviruses. In: Kasper DL, Brunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, editors. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005; 1155–60.

Dorfman–Chanarin syndrome with cirrhosis Sir, Dorfman–Chanarin syndrome (CDS), also known as neutral lipid storage disease with icthyosis (NLSDI), is a rare, autosomal recessive, neutral lipid storage disease. It is characterised by non-bullous congenital ichthyosiform erythroderma and presence of intracellular neutral lipid droplets in most tissues including the skin, muscle, liver, central nervous system and granulocytes due to errors of triacylglycerol metabolism.1–4

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There is great variability in dermatological severity and pattern and degree of systemic involvement.2,4 It may present clinically as monosymptomatic congenital icthyosis.5 There is clinical heterogeneity of the ichthyosiform dermatoses observed in CDS.6 The presence of Oil Red O positive, neutral lipid droplets in leukocytes on blood and/or in tissue biopsies7 and a nonbullous congenital ichthyosis coupled with a constellation of multisystem abnormalities are together diagnostic of NLSDI.6,8–11 The disease is rare and since the initial case report by Dorfman in 1974,12 only 32 cases have been reported worldwide,4 the majority of them from the Middle East. We report a classical case of CDS with hepatic involvement and with hyperlipidaemia, due to its rarity and to highlight the fact that a simple test like peripheral smear examination coupled with a simple stain Oil Red O provides an important clue to its final diagnosis. A 3-year-old female with delayed milestones presented with dry, scaly skin involving the entire body, including the face and flexural areas since birth. However, there was no history of difficulty in feeding, icterus, dark-colored urine or clay-coloured stools. She was the first child and was born at full term by normal delivery to non-consanguineous parents. There was no history of prolonged or obstructed labour or history of spontaneous abortion or stillbirth in the mother. There was no history of maternal infection or exposure to drugs, radiation, smoking or alcohol by the mother during pregnancy. No other family member had similar illness. General physical examination was within normal limits besides pallor. Cutaneous examination revealed presence of generalised scaling with mild background erythema all over the body including the face and the scalp. There was marked involvement of flexures in the form of corrugated appearance, hyperpigmentation and scaling. The palms and soles were diffusely hyperkeratotic. Abdominal examination revealed generalised distension. There was firm, non-tender hepatomegaly and the liver was palpable 5 cm below the costal margin (BCM) in the midclavicular line. The spleen was palpable 3 cm BCM. There was no free fluid and the bowel sounds were normal. There was no neurological deficit and muscle tone, power and deep tendon reflexes were normal. There was no gait abnormality nor was there any proximal muscle weakness or tenderness. The rest of the systemic examination was within normal limits. The lipid profile was deranged with elevated triglycerides (126 mg/dL), decreased high density lipoprotein (HDL; 29 mg/dL), cholesterol 218 mg/dL, low density lipoprotein (LDL) and very low density lipoprotein (VLDL) levels of 105 and 26 mg/dL, respectively. The liver functions were deranged with elevated enzymes [serum glutamic pyruvic transaminase (SGPT) 146 U/L, serum glutamic oxaloacetic transaminase (SGOT) 149 U/L, alkaline phosphatase (ALP) 859 U/L]. All haematological parameters were normal besides haemoglobin (Hb) which was 4 g/dL. The peripheral smear was normocytic normochromic but revealed vacuolated neutrophils and eosinophils, characteristic of CDS. The vacuoles stained red with Oil Red O (Fig. 1). The blood glucose, urea, electrolytes, calcium, phosphorous, lactate dehydrogenase and urinary examination were within normal limits. Brainstem evoked responses; electrocardiography (ECG), electroencephalogram (EEG) and computed

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tomography (CT, brain) did not reveal any abnormality. Parents and sibling did not have any cutaneous, haematological or biochemical stigmata suggestive of a carrier state. Ultrasound of the abdomen revealed hepatomegaly with homogenously increased echotexture. Liver biopsy showed fatty changes in hepatocytes with focal lobular inflammatory infiltrates with cirrhosis with Oil Red O positivity within the hepatocytes (Fig. 2). Symptomatic treatment was provided in the form of local application of emollients and the patient was put on a generally low-fat diet with minimum amount of saturated fat in consultation with a dietician. Dorfman–Chanarin syndrome, a rare, autosomal recessive, neutral lipid storage disease, is characterised by the presence of congenital ichthyosis and leukocyte neutral lipid vacuoles with or without deposition of neutral lipid droplets (Jordan bodies) in multiple organs.6,8–10 Lipid droplets (LDs) are a class of ubiquitous cellular organelles that are involved in lipid storage and

FIG. 1 Peripheral smear showing vacuolated cytoplasm in neutrophils and eosinophils (Giemsa, 6400). Inset: neutrophils showing Oil Red O positive granules.

FIG. 2 (A) Liver biopsy showing fatty change, focal lobular inflammatory infiltrates and cirrhosis (H&E, 6 400). (B) Liver biopsy showing Oil Red O positive hepatocytes entrapped within cirrhotic nodules.

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metabolism. Although the mechanisms of the biogenesis of LDs are still unclear, a set of proteins called the PAT domain family have been characterised as factors associated with LDs. Perilipin, a member of this family, is expressed exclusively in the adipose tissue and regulates the breakdown of triacylglycerol in LDs via its phosphorylation. CGI-58, present at the surface of LDs, co-localises with perilipin. This interaction seems physiologically important because CGI-58 mutants carrying an amino acid substitution identical to that found in CDS lose the ability to be recruited to LDs. These mutations significantly weaken the binding of CGI-58 with perilipin, indicating that the loss of this interaction is involved in the aetiology of CDS.13 Adipose triglyceride lipase (ATGL) has recently been identified as an important triacylglycerol (TG) hydrolase promoting the catabolism of stored fat in adipose and nonadipose tissues. Efficient ATGL enzyme activity requires activation by CGI-58.14 CGI-58 interacts with ATGL stimulating its TG hydrolase activity up to 20-fold. Point mutations in the human CGI-58 gene associated with CDS fail to activate ATGL, as a result of which TG accumulates excessively in the form of intracellular neutral lipid droplets in various tissues14 such as the skin, muscles, liver, central nervous system, gastrointestinal tract (rectal, gastric and small bowel mucosa), granulocytes, monocytes, mast cells and in the bone marrow in megakaryocytes, promyelocytes, myelocytes and metamyelocytes.15,16 This may lead to myriad clinical features including neurological abnormalities. Our patient clinically had congenital icthyosis, hepatosplenomegaly and developmental delay. Her investigations revealed hyperlipidaemia, anaemia and deranged liver function tests with elevated liver enzymes. Peripheral smears showed vacuoles in neutrophils and eosinophils. Vacuoles stained red with Oil Red O indicating the presence of neutral lipid in these vacuoles. Liver biopsy showed fatty changes in hepatocytes with focal lobular inflammatory infiltrates with cirrhosis. Henceforth, a final diagnosis of CDS was made as the present case had all the diagnostic criteria required6–9 for this diagnosis. There are limited case reports reporting splenomegaly17 and hyperlipidaemia3 along with CDS. The present case had both hyperlipidaemia with elevated triglycerides and splenomegaly which could be a direct result of cirrhosis. Very few authors7 have previously confirmed the presence of neutral lipid in neutrophil vacuoles characteristic of CDS. In the present case the neutral lipid content of neutrophil vacuoles was confirmed using Oil Red O, which stains neutral lipids red, thereby further confirming the diagnosis. CDS is considered a rare cause of steatohepatitis;18 however, there are limited case reports with cirrhosis.19 Liver involvement is histologically difficult to distinguish from other causes of steatohepatitis, but in the presence of syndromic systemic disease the diagnosis of CDS was made. The present case had progressed to cirrhosis. Therefore, we recommend early assessment of liver disease in the form of measuring enzymes and timely biopsy in CDS. The patient’s parents and sibling did not have any cutaneous, haematological or biochemical stigmata suggestive of a carrier state. Various previous workers have

Pathology (2008), 40(6), October

emphasised the importance of peripheral blood smear examination of clinically unaffected members for Jordan’s anomaly to help in the detection of heterozygous carriers.20 Conductor analysis on both parents and sibling with a peripheral smear was negative in our case. We also screened peripheral blood eosinophils for lipid vacuoles for carrier detection, as suggested by a few authors5 as an alternative to traditional screening of neutrophils, and found similar results. Patients with this syndrome demonstrate a great variability of clinical involvement. Because of this wide spectrum of clinical variability, mild cases might escape diagnosis. Therefore, it is suggested that every case of icthyosis should have a peripheral blood smear evaluation for the presence of vacuoles in leukocytes characteristic of this syndrome. However, on Giemsa stained smears negative spots in granulocytes and monocytes may result from cell inclusions not containing neutral lipids.7 Henceforth, it is important to confirm the presence of neutral lipid in these vacuoles by Oil Red O staining.7 This stain can be easily performed, thus providing an essential laboratory finding that is critical for the diagnosis of CDS. This will increase the number of reported Dorfman–Chanarin syndrome cases, and the pathogenesis and progression of the disease will become clearer. Awareness of this condition helps in prompt diagnosis and avoids unnecessary further investigations. P. Gupta* Kajal Kiran Dhingra* Vibha Kawatra* T. Singh* S. Yadav{ Departments of *Pathology, and {Pediatrics, Maulana Azad Medical College, New Delhi, India Contact Dr K. K. Dhingra. E-mail: [email protected]

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11. Wolf R, Zaritzky A, Pollak S. Value of looking at leukocytes in every case of ichthyosis. Dermatologica 1988; 177: 237–40. 12. Dorfman ML, Hershko C, Eisenberg S, Sagher F. Ichthyosiform dermatosis with systemic lipidosis. Arch Dermatol 1974; 110: 261–6. 13. Yamaguchi T, Omatsu N, Matsushita S, Osumi T. CGI-58 interacts with perilipin and is localized to lipid droplets. Possible involvement of CGI-58 mislocalization in Chanarin-Dorfman syndrome. J Biol Chem 2004; 279: 30490–7. 14. Lass A, Zimmermann R, Haemmerle G, et al. Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome. Cell Metab 2006; 3: 309–19. 15. Tullu MS, Muranjan MN, Save SU, Deshmukh CT, Khubchandani SR, Bharucha BA. Dorfman-Chanarin syndrome: A rare neutral lipid storage disease. Indian Pediatr 2000; 37: 88–93.

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16. Judge MR, Atherton DJ, Salvayre R, et al. Neutral lipid storage disease: Case report and lipid studies. Br J Dermatol 1994; 130: 507–10. 17. Srebrnik A, Tur E, Perluk C, et al. Dorfman-Chanarin syndrome: A case report and a review. J Am Acad Dermatol 1987; 17: 801–8. 18. Amarapurkar AD, Kher A, Agrawal R, Meenakshi B, Kandalkar BM, Deshpande JR. A rare cause of steatohepatitis. Trop Gastroenterol 2004; 25: 176–7. 19. Srinivasan R, Hadzic N, Fischer J, Knisely AS. Steatohepatitis and unsuspected micronodular cirrhosis in Dorfman-Chanarin syndrome with documented ABHD5 mutation. J Pediatr 2004; 144: 662–5. 20. Nanda A, Sharma R, Kanwar AJ, Kaur S, Dash S. Dorfman-Chanarin syndrom. Int J Dermatol 1990; 29: 349–51.

DOI: 10.1080/00313020802321166