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| CASE REPORT |
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| Year : 2014 | Volume
: 60
| Issue : 3 | Page : 332-334 |
Chanarin-Dorfman syndrome: Clinical report and novel mutation in ABHD5 gene
PM Tamhankar1, S Iyer1, S Sanghavi2, U Khopkar2
1 Genetic Research Center, National Institute for Research in Reproductive Health (NIRRH), Parel, Mumbai, Maharashtra, India
2 Department of Dermatology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, India
| Date of Submission | 09-Jan-2013 |
| Date of Decision | 17-Jun-2013 |
| Date of Acceptance | 11-Sep-2013 |
| Date of Web Publication | 14-Aug-2014 |
Correspondence Address:
Dr. P M Tamhankar
Genetic Research Center, National Institute for Research in Reproductive Health (NIRRH), Parel, Mumbai, Maharashtra
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0022-3859.138826
Chanarin-Dorfman syndrome (CDS) is a multisystem, autosomal recessive genetic disorder characterized by congenital non-bullous ichthyosiform erythroderma with accumulation of lipid droplets in granulocytes and basal keratinocytes. An 18-month-old female child presented with typical dermatological features of CDS. She was born as a collodion baby. Liver biopsy showed micronodular cirrhosis along with macrovesicular hepatic steatosis. Sequencing of all exons and exon-intron boundaries of the ABHD5 gene showed that the patient was homozygous for a novel mutation g.24947delG (c.773 + 1delG) in intron 5. This is the first Indian child with mutation proven CDS.
Keywords: ABHD5, Chanarin-Dorfman syndrome, ichthyosis, India, mutation
How to cite this article:
Tamhankar P M, Iyer S, Sanghavi S, Khopkar U. Chanarin-Dorfman syndrome: Clinical report and novel mutation in ABHD5 gene. J Postgrad Med 2014;60:332-4 |
How to cite this URL:
Tamhankar P M, Iyer S, Sanghavi S, Khopkar U. Chanarin-Dorfman syndrome: Clinical report and novel mutation in ABHD5 gene. J Postgrad Med [serial online] 2014 [cited 2023 Jun 2];60:332-4. Available from: https://www.jpgmonline.com/text.asp?2014/60/3/332/138826 |
| :: Introduction | |  |
Chanarin-Dorfman syndrome (CDS) is a multisystem, autosomal recessive genetic disorder characterized by congenital non-bullous ichthyosiform erythroderma with accumulation of lipid droplets in granulocytes and basal keratinocytes. Mutations in the ABHD5 gene are responsible for CDS, while a non-ichthyotic, myopathic form of neutral lipid storage disease is caused by mutations in the PNPLA2 gene. [1] Approximately 50 cases of CDS have been reported worldwide with the majority being from the Middle East. Around 30 mutations in the ABHD5 gene have been found to cause CDS. [2] A Pubmed search identified multiple case reports involving Indian patients but none with confirmed mutations.
| :: Case Report | | |
The female patient was born as a collodion baby to non-consanguineous parents from Uttar Pradesh. Other complaints included abdominal distension since one month, recurrent loose motions since 2-3 months and motor developmental delay noticed since 5 months of age. On presentation at 18 months of age, she showed generalized non-bullous ichthyosiform erythroderma with accentuation at the flexures, palms, soles, face, and scalp [Figure 1]. She could sit up by herself but could not stand. Her social, adaptive, and language milestones were normal. Eye exam showed normal results. Liver histopathology revealed micronodular cirrhosis with macrovesicular hepatic steatosis involving up to 40% of the hepatocytes and septae contained lymphocytic infiltrate. In the skin biopsy, stratum corneum showed compact orthohyperkeratosis; stratum spinosum and granulosum were normal, while dermis showed vacuolated eccrine ductal cells of the sweat gland [Figure 2]. Other findings were hemoglobin 7.8 gm% (normal range, 10-14 gm%), microcytic hypochromic anemia, platetet count 350 × 109/L, total leukocyte count 20,900/μl (normal range, 6,000-17,000/μl) (differential count was normal), serum aspartate transaminase 70 IU/L (normal range, 6-34 IU/L), and alanine transaminase 79 IU/L (normal range, 6-34 IU/L); moreover, alkaline phosphatase, serum total proteins and albumin, prothrombin time, activated partial thromboplastin time, random blood sugar, serum cholesterol, triglycerides, HDL, LDL, and VLDL were normal. Eosinophils, basophils, monocytes, and neutrophils were vacuolated (Jordan's anomaly). Informed consent for genetic testing was obtained from parents of the affected child. Mutation analysis of the ABHD5 gene was performed by bidirectional Sanger sequencing of all exons and exon-intron boundaries by previously described methods. [1] Pathogenicity of mutation was verified using MutationTaster software. [3] | Figure 1: Clinical photo showing generalized non-bullous ichthyosiform erythroderma and edema
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 | Figure 2: Histopathology of skin (H and E stain; 1000X) showing compact orthohyperkeratosis of stratum corneum (a), and dermis showing vacuolation in eccrine ductal cells of sweat glands (b)
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| :: Results | | |
The novel mutation g.24947delG (c.773 + 1delG) was found in intron 5 of the ABHD5 gene. Parents were confirmed as carriers for the same mutation [Figure 3]. MutationTaster software predicted this mutation to be pathogenic with a probability of 0.999. The mutation was further not found in 100 control individuals from the same ethnicity. However, further RNA or protein studies could not be carried out.  | Figure 3: Shows the family pedigree (a), and the sequence chromatograms of the mutation in the homozygous (b) and heterozygous forms in the parents (c)
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| :: Discussion | | |
Chanarin-Dorfman syndrome was first described by Rozenszajn et al. (1966) in four members of an Iraqi family and, later, by Dorfman (1975) and Chanarin (1974). [4],[5] Non-bullous ichthyosiform erythroderma or fine scaling on erythematous skin since birth is the characteristic finding. In addition to the skin manifestations, other systems might be affected in the form of myopathy, liver steatohepatitis, sensorineural hearing loss, sub-capsular cataract, and mental retardation. Congenital ichthyosis can occur in several genetic disorders. Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous disorder caused by mutations in any of the following seven genes (TGM1, ALOXE3, ALOX12B, NIPAL4, ABCA12, CYP4F22, and PNPLA1). [6] Possible differential diagnoses of ichthyosis with vacuolated lymphocytes (Jordan anomaly) are multiple sulfatase deficiency and ichthyosis-sclerosing cholangitis syndrome. Jordan anomaly is also present in systemic carnitine deficiency, Refsum disease, and Wolman disease. [7] The presence of liver cirrhosis in our patient ruled out the above differentials.
LeFevre et al. (2001) identified mutations in the ABHD5 gene from CDS patients from the Mediterranean region. This gene encodes the protein Abhydrolase domain containing 5, a member of the esterase/lipase/thioesterase subfamily. [8] Around 30 mutations in the ABHD5 gene have been identified till date in patients with CDS (http://www.hgmd.cf.ac.uk). [2] Most mutations are missense, followed by splicing and deletions. The novel deletion found in our patient involves guanine nucleotide of consensus donor splice site (AAGgtgagg) of intron 5, leading to skipping of exon 5 or generation of aberrant donor splice sites. Splice site mutations previously reported in the ABHD5 gene include c.47 + 1G > A and c.960 + 5G > A. [8] The patient with c.47 + 1G>A had steatohepatitis but was normal neurologically, whereas the patient with c.960 + 5G>A did not have steatohepatitis but had severe neurological impairment. However, another patient with c.960 + 5G>A did have liver involvement. [9] Thus, the genotype-phenotype correlation in CDS is unclear. A previous study from New Delhi, India, has identified a homozygous nonsense mutation g.27606G>T in the ABHD5 gene of an Afghani patient. [10]
There is no specific treatment for CDS. The child was prescribed topical emollient application for ichthyosis and oral hydroxyzine for pruritus. Diet restricted in protein and rich in carbohydrates was prescribed for the liver disease. The role of dietary restriction of fat is controversial and was not found to be useful in some cases. [9] The family was counseled that the recurrence risk of CDS is 25% in each of their future pregnancies. Prenatal diagnosis could be provided by performing a mutation analysis on the fetal DNA obtained from chorionic villus sample or amniotic fluid (around 12 or 16 weeks, respectively). The couple could then choose medical termination of pregnancy if the fetus is diagnosed to be affected (homozygous for the g.24947delG mutation).
| :: Conclusion | | |
Molecular diagnosis in an Indian child led to the identification of a novel mutation in the ABHD5 gene in a patient with CDS. This case highlights that CDS can be diagnosed using clinical and pathology criteria; however, molecular confirmation provides the possibility of prenatal diagnosis for this morbid condition.
| :: Acknowledgment | | |
The authors thank the patient's family for their cooperation. They also thank Dr Lakshmi Vasudevan for critical reading of the manuscript.
| :: References | | |
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| 2. | Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, et al. Human gene mutation database (HGMD): 2003 update. Hum Mutat 2003;21:577-81. |
| 3. | Schwarz JM, Rödelsperger C, Schuelke M, Seelow D. Mutation taster evaluates disease-causing potential of sequence alterations. Nat Methods 2010;7:575-6. |
| 4. | Rozenszajn L, Klajman A, Yaffe D, Efrati P. Jordans' anomaly in white blood cells. Report of case. Blood 1966;28:258-65. [ PUBMED] |
| 5. | Dorfman ML, Hershko C, Eisenberg S, Sagher F. Ichthyosiform dermatosis with systemic lipidosis. Arch Dermatol 1974;110:261-6. [ PUBMED] |
| 6. | Richard G, Bale SJ. Autosomal Recessive Congenital Ichthyosis. In: Pagon RA, Bird TD, Dolan CR, editors. GeneReviews ™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993- 2013 Available from: http://www.ncbi.nlm.nih.gov/books/NBK1420 [Last accessed on 2013 Sep 23]. |
| 7. | Mitra S, Samanta M, Sarkar M, Chatterjee S. Dorfman-Chanarin syndrome: A rare neutral lipid storage disease. Indian J Pathol Microbiol 2010;53:799-801. [ PUBMED] [Full text] |
| 8. | Redaelli C, Coleman RA, Moro L, Dacou-Voutetakis C, Elsayed SM, Prati D, et al. Clinical and genetic characterization of Chanarin-Dorfman syndrome patients: First report of large deletions in the ABHD5 gene. Orphanet J Rare Dis 2010;5:33. |
| 9. | Israeli S, Pessach Y, Sarig O, Goldberg I, Sprecher E. Beneficial effect of acitretin in Chanarin-Dorfman syndrome. Clin Exp Dermatol 2012;37:31-3. |
| 10. | Aggarwal S, Maras JS, Alam S, Khanna R, Gupta SK, Ahuja A. Novel nonsense mutation of ABHD5 in Dorfman-Chanarin syndrome with unusual findings: A challenge for genotype-phenotype correlation. Eur J Med Genet 2012;55:173-7. |
[Figure 1], [Figure 2], [Figure 3]
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