Chanarin-Dorfman syndrome: Shifting out of neutral

By Warren R. Heymann, MD, FAAD
Aug. 27, 2025
Vol. 7, No. 34

This observation by Jordans in 1953 in two brothers with a progressive muscular dystrophy of the Erb type (1) was the seminal discovery in what is now categorized as neutral lipid storage diseases (NLSDs) whose vacuoles are called Jordans’ anomaly. NLSDs are rare autosomal recessive disorders characterized by excessive, non-lysosomal accumulation of neutral lipids in multiple tissues. Clinically, NLSDs cause muscle atrophy, cardiomyopathy, dysfunction of several internal organs as well as ichthyosis.

Pennisi et al. state, “The triglycerides (TG) are involved in the synthesis and degradation pathways of lipids, they are essential for energy production and for the synthesis of important cellular structures. The TG not only contribute to energy production in adipose tissue during fasting, but also in skeletal muscle during physical exercise. Some enzymes allow the release of triglycerides from the lipid droplets in the cytoplasm, two of the most important are adipose triglyceride lipase (ATGL/PNPLA2) and comparative gene identification-58 (CGI-58/ABHD5 [abhydrolase domain-containing gene 5]. Inborn errors affecting ATGL and CGI58 cause two different diseases: Neutral Lipid Storage Disease with Myopathy (NLSD-M, MIM 610717) and Neutral Lipid Storage Disease with Ichthyosis (NLSD-I, Chanarin-Dorfman disease, MIM 604780).” (2) This commentary focuses on Chanarin-Dorfman syndrome (CDS).

Rozenszajn et al. reported persistent lipid-containing vacuoles in the protoplasm of granulocytes, monocytes, and occasional lymphocytes of two sisters suffering from ichthyosis. The sisters immigrated to Israel from Iraq. Their parents were first cousins. (3) Dorfman et al followed up on these two sisters and reported two additional unrelated cases in a 21-year-old-Iraqi man and a 16-year-old Arab boy. The authors noted that the ichthyosiform dermatosis resembled nonbullous ichthyosiform erythroderma. Lipid accumulations were observed in the granulocytes of the peripheral blood, the granulocyte precursors in the bone marrow, and in the liver. Jordans’ anomaly was readily detected in each case when examining a peripheral smear. (4) The following year, Chanarin reported a 22-year-old Ugandan Asian woman with congenital ichthyosis, Jordans’ anomaly, and triglyceride storage in the gastrointestinal epithelium, bone marrow, cultured fibroblasts, and striated muscles. (5)

To date, a total of (at least) 147 patients with CDS have been identified — as expected with an autosomal recessive disorder, males and females are equally affected. Approximately 90% of reported cases are from countries bordering the Mediterranean Sea and Middle Eastern countries, especially Turkey. Of the 147 diagnosed cases, 78 had mutations in ABHD, and the rest of the reported cases were diagnosed based on phenotype only. (6,7) Typically, CDS patients present with ichthyosis, hepatomegaly, cirrhosis, cardiomyopathy, splenomegaly, and myopathy. Less common features include cataracts, keratopathy, hearing loss, and intellectual disability. As stated by Mangukiya et al., “The most common extracutaneous manifestation is hepatomegaly (60% of patients), followed by myopathy (59%), ocular manifestation (bilateral ectropion in 29% and cataract in 22%), neurosensory deafness (17%), and splenomegaly (13%).” (7)

Three recent manuscripts about CDS piqued my interest — one morphologic, the second highlighting a pitfall in (mis)diagnosis, and the third therapeutic.

CDS’s cutaneous features are mostly described as a nonbullous congenital ichthyosiform erythrodema with or without an associated ectropion. Although erythrokeratoderma variablis (EKV)-like ichthyosis was initially reported in a 4-year-old-boy with CDS (8), Çetinarslan et al. reported four patients with CDS presenting with different clinical forms of erythrokeratoderma (three with progressive symmetric erythrokeratoderma [PSE]-like features and one with EKV-like features), including one patient (with PSE) with a novel mutation in ABHD5. (9) There have been reports of CDS presenting as birth with a collodion membrane. (10)

Mallet et al. detailed the case of a female newborn born to nonconsanguineous parents who presented with congenital ichthyosis. Jordans’ anomaly was observed. Molecular analysis did not reveal mutations in the ABHD5 gene involved in CDS, however, next-generation sequencing analysis performed on 32 genes described in other congenital ichthyosis syndromes revealed two heterozygous mutations in ALOX12B. (11) The teaching point is clear — ichthyosis and Jordans’ anomaly may be indicative of CDS but are not pathognomonic. Specific genetic analysis is warranted.

There is no curative treatment for CDS patients. Topical therapy with creams containing cholesterol, urea, or lipids may be beneficial. (9) A diet low in fatty acids along with medium-chain triglyceride supplements may decrease hepatomegaly and normalize hepatic enzymes, especially when initiated early and in combination with vitamin E (10 mg/kg/day) and ursodeoxycholic acid (15-20 mg/kg/day). (10) For skin lesions, acitretin can be an effective therapy; however, its use depends on the severity of the liver involvement. (9, 10) Valette et al. performed a retrospective analysis of 15 patients with CDS who have received oral retinoids (OR, 14 acetretin, 1 etretinate) and were able to conclude, “awaiting future targeted therapy for DCS or prospective monitoring studies, there is no safety signal to contraindicate OR in CDS patients with disabling skin anomalies, on condition that a close monitoring is performed.” (12)

Point to Remember: Lipid vacuoles (Jordans’ anomaly) in white blood cells in patients with ichthyotic disorders (resembling nonbullous congenital erythroderma or the erythrokeratodermas) are indicative — but not pathognomonic — of the Chanarin-Dorfman syndrome. In documented cases of CDS, acitretin may be used with caution.

Our expert’s viewpoint

Juliette Mazereeuw-Hautier
Service de Dermatologie
Coordinatrice du Centre de reference
CHU – hôpitaux de Toulouse

The editorial by Dr. Heymann highlights three recent studies on Chanarin-Dorfman syndrome (CDS), a rare form of syndromic ichthyosis, and provides valuable insights into potential advancements in the field of congenital ichthyosis (CI).

The first paper by Çetinarslan et al. (9) reports four cases of CDS presenting with a skin phenotype of “erythrokeratoderma.” Unlike other forms of CI, such as Netherton syndrome or bathing suit ichthyosis, CDS does not exhibit a distinct skin presentation that differentiates it from other types of CI. Patients with CDS may be born with a collodion membrane and later develop scaling of varying severity and appearance, sometimes accompanied by erythroderma and thickened skin. While erythrokeratoderma is not a typical manifestation of CDS, it is also considered an imprecise term and has been excluded from the new classification of CI, along with eponyms such as CDS (13).

This new classification, unlike the previous CI classification by Oji et al. (14), is no longer based on phenotype but instead focuses on pathogenesis. This shift is justified by recent advances in understanding the genetic and molecular pathways underlying phenotypic manifestations. CI and other inherited disorders of epidermal differentiation have been grouped under the broader term “Epidermal Differentiation Disorders” (EDD). EDDs are now categorized into three subsets: nonsyndromic EDDs (nEDD), syndromic EDDs (sEDD), and EDDs predominantly affecting palmoplantar surfaces (pEDD). The new classification organizes affected genes and disorders according to the function of their protein products, facilitating the identification of potential therapeutic targets. For example, CDS is classified within the functional group of lipid synthesis and transport disorders and is now referred to as ABHD5-sEDD.

The second paper by Mallet et al. (11) highlights the relevance of this new classification. The authors report a case of a female patient with CI caused by two heterozygous variants in ALOX12B, who also exhibited Jordan’s anomaly. This case underscores the importance of identifying the causal gene for accurate classification of CI. In clinical practice, CDS (ABHD5-sEDD) is often suspected when associated anomalies are present, particularly elevated liver enzymes or ocular abnormalities such as cataracts or nystagmus. With the increasing availability of sequencing technologies, the diagnosis of CDS (ABHD5-sEDD) can now be established before the onset of systemic manifestations.

The third paper by our team (12) shifts the focus to therapy. The treatment of CDS (ABHD5-sEDD), like all forms of CI, primarily relies on topical therapies, including emollients and keratolytics. However, if topical treatment proves insufficient or becomes overly burdensome for patients, systemic therapy should be considered. Currently, oral retinoids remain the gold standard, as outlined in our recent updated international guidelines. (15) Four systemic retinoids are available: acitretin, alitretinoin, isotretinoin, and etretinate (now largely unavailable except in Japan and Taiwan). Among them, acitretin is the preferred choice, as it is the only EMA-approved oral retinoid for CI, the most effective at reducing scaling and skin thickening, and supported by the most extensive long-term safety data regarding skeletal effects.

Our retrospective series included 15 patients with CDS (ABHD5-sEDD) followed over the long term, none of whom developed liver toxicity. However, recommendations emphasize the need for close monitoring and lifestyle modifications, including limiting the intake of fatty acids, sugar, hepatotoxic drugs, and alcohol, as well as maintaining a healthy body weight.

The benefits of a low-fat diet, as discussed by Dr. Heymann, remain largely uninvestigated, with evidence limited to two case reports. (16,17) These reports describe children with severe early liver involvement, diagnosed with CDS based on phenotype alone, who exhibited a reduction in liver size while adhering to a low-fat diet. Therefore, this approach cannot be recommended until further well-designed studies provide more conclusive evidence.

Regarding future therapeutic perspectives, biologics (which are not approved for this indication) have demonstrated mild or no effectiveness in most CI patients, with some experiencing transient benefits or worsening symptoms. (18) They should be reserved for CI with an erythrodermic and severe phenotype. It is hoped that the identification of new therapeutic targets will enable the development of pathogenesis-based treatments for CDS (ABHD5-sEDD) and other forms of CI in the future.

References

1. Jordans GH. The familial occurrence of fat containing vacuoles in the leukocytes diagnosed in two brothers suffering from dystrophia musculorum progressiva (ERB.). Acta Med Scand. 1953;145(6):419-23. doi: 10.1111/j.0954-6820.1953.tb07038.x. PMID: 13079655.

2. Pennisi EM, Arca M, Bertini E, Bruno C, Cassandrini D, D'amico A, Garibaldi M, Gragnani F, Maggi L, Massa R, Missaglia S, Morandi L, Musumeci O, Pegoraro E, Rastelli E, Santorelli FM, Tasca E, Tavian D, Toscano A, Angelini C; Italian NLSD Group. Neutral Lipid Storage Diseases: clinical/genetic features and natural history in a large cohort of Italian patients. Orphanet J Rare Dis. 2017 May 12;12(1):90. doi: 10.1186/s13023-017-0646-9. PMID: 28499397; PMCID: PMC5427600.

3. Rozenszajn L, Klajman A, Yaffe D, Efrati P. Jordans' anomaly in white blood cells. Report of case. Blood. 1966 Aug;28(2):258-65. PMID: 5330405.

4. Dorfman ML, Hershko C, Eisenberg S, Sagher F. Ichthyosiform dermatosis with systemic lipidosis. Arch Dermatol. 1974 Aug;110(2):261-6. PMID: 4277517.

5. Chanarin I, Patel A, Slavin G, Wills EJ, Andrews TM, Stewart G. Neutral-lipid storage disease: a new disorder of lipid metabolism. Br Med J. 1975 Mar 8;1(5957):553-5. doi: 10.1136/bmj.1.5957.553. PMID: 1139147; PMCID: PMC1672681.

6. Zoullas S, Morel D, Zafeer F, Borjas-Mendoza P, Angeli S, Zhou Y, Bademci G, Tekin M. Two novel heterozygous exonic deletions lead to Chanarin-Dorfman syndrome in a patient with congenital ichthyosis, sensorineural hearing loss, and liver dysfunction. Am J Med Genet A. 2024 Apr;194(4):e63481. doi: 10.1002/ajmg.a.63481. Epub 2023 Nov 20. PMID: 37984424.

7. Mangukiya NP, Kaleem S, Meghana DR, Ishfaq L, Kochhar G, Mathew B, Pulekar S, Lainingwala AC, Parmar MP, Venugopal V. Chanarin-Dorfman Syndrome (CDS): A Rare Lipid Metabolism Disorder. Cureus. 2023 Aug 21;15(8):e43889. doi: 10.7759/cureus.43889. PMID: 37746493; PMCID: PMC10515467.

8. Pujol RM, Gilaberte M, Toll A, Florensa L, Lloreta J, González-Enseñat MA, Fischer J, Azon A. Erythrokeratoderma variabilis-like ichthyosis in Chanarin-Dorfman syndrome. Br J Dermatol. 2005 Oct;153(4):838-41. doi: 10.1111/j.1365-2133.2005.06828.x. PMID: 16181472.

9. Çetinarslan T, Yazıcı H, Erdoğan KM, Kalkan Uçar S, Dalgıç G, Kaya G, Er E, Bilaç C, Temiz P, Türel Ermertcan A, Fölster-Holst R. Four cases of Chanarin-Dorfman syndrome presenting with different types of erythrokeratoderma. Pediatr Dermatol. 2024 Nov-Dec;41(6):1174-1178. doi: 10.1111/pde.15654. Epub 2024 Jun 17. PMID: 38886172.

10. AlNeyadi R, Abdelhadi S, Ruszczak Z. Chanarin-Dorfman syndrome treatment with acitretin. JAAD Case Rep. 2022 Mar 31;24:11-13. doi: 10.1016/j.jdcr.2022.03.016. PMID: 35518273; PMCID: PMC9062725.

11. Mallet S, Frankel D, Jonca N, Cano A, Roll P, Kaspi E. Leukocytes containing lipid inclusions in congenital ichthyosis without classical Chanarin-Dorfman mutations. Int J Dermatol. 2024 Sep;63(9):1269-1271. doi: 10.1111/ijd.17149. Epub 2024 Apr 5. PMID: 38581117.

12. Valette C, Jonca N, Fischer J, Pernin-Grandjean J, Granier Tournier C, Diociaiuti A, Neri I, Dreyfus I, Furman M, Giehl K, Wollenberg A, Mallet S, Martin L, Martin-Santiago A, Onnis G, Broue P, Leclerc-Mercier S, Schmuth M, Sprecher E, Gruber R, Suessmuth K, Bourrat E, Komlosi K, Hill S, O'Toole EA, Schischmanoff O, Caux F, Mazereeuw-Hautier J; French Pediatric Dermatology Research Group and of the ‘ERN-Skin Network’. A retrospective study on the liver toxicity of oral retinoids in Chanarin-Dorfman syndrome. J Eur Acad Dermatol Venereol. 2023 Oct;37(10):e1237-e1241. doi: 10.1111/jdv.19235. Epub 2023 Jun 20. PMID: 37257069.

13. Ángela Hernández-Martín, Amy S. Paller, Eli Sprecher, Masashi Akiyama, Céline Granier Tournier, Mandy Aldwin-Easton, Christine Bodemer, Keith Choate, Judith Fischer, Antoni Gostynski, Alain Hovnanian, Akemi Ishida-Yamamoto, Edel A. O’Toole, Matthias Schmuth, Janice Schwartz, Gianluca Tadini, Joyce Teng, Juliette Mazereeuw-Hautier. A New Pathogenesis-guided Classification for Inherited Epidermal Differentiation Disorders. Br J Dermatol 2025, in press.

14. Oji V, Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, Coudiere P, DiGiovanna JJ, Elias P, Fischer J, Fleckman P, Gina M, Harper J, Hashimoto T, Hausser I, Hennies HC, Hohl D, Hovnanian A, Ishida-Yamamoto A, Jacyk WK, Leachman S, Leigh I, Mazereeuw-Hautier J, Milstone L, Morice-Picard F, Paller AS, Richard G, Schmuth M, Shimizu H, Sprecher E, Van Steensel M, Taïeb A, Toro JR, Vabres P, Vahlquist A, Williams M, Traupe H. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Soreze 2009. J Am Acad Dermatol. 2010 Oct;63(4):607-41. doi: 10.1016/j.jaad.2009.11.020.

15. Juliette Mazereeuw-Hautier, Amy S Paller, Isabelle Dreyfus, Eli Sprecher, Edel O'Toole, Christine Bodemer, Masashi Akiyama, Andrea Diociaiuti, Maya El Hachem, Judith Fischer, Rogelio Gonzalez-Sarmiento, Carlos Gutiérrez-Cerrajero, Hagen Ott, Cristina Has, Nathalie Jonca, Céline Granier Tournier, Sarah Milesi, Hélène Texier, Ana Martinez, Heiko Traupe, Carmen Maria Salavastru, Matthias Schmuth,Kathrin Giehl,Mandy Aldwin, Ruth Anton Morales, Saturnino Santos, Marie-Anne Morren, Anne Audouze, Raman Malhotra, Karin Veldman, Joanna Narbutt, Kira Süßmuth, Angela Hernandez-Martin, Antoni Gostynski. Management of congenital ichthyoses: Guidelines of care: Part One: 2024 Update. Br J Dermatol 2025, in press

16. Kakourou T, Drogari E, Christomanou H, Giannoulia A, Dacou-Voutetakis C. Neutral lipid storage disease response to dietary intervention. Arch Dis Child. 1997;77(2):184. https: //doi.org/10.1136/adc.77.2.183c

17. Angelini C, Philippart M, Borrone C, Bresolin N, Cantini M, Lucke S. Multisystem triglyceride storage disorder with impaired long chain fatty acid oxidation. Ann Neurol 1980;7:5-10.

18. Mazereeuw-Hautier J, Granier Tournier C, Hernandez-Martin A, Milesi S, Texier H, Severino-Freire M, Bellon N, Bodemer C, Gruber R, Mahé E, Morice Picard F, Hannula-Jouppi K, Murase JE, Barbarot S, Cohen-Barak E, Torres-Pradilla M, Bruckner A, Levy M, Koh MJA, Masson Regnault M, Rossel V, Chiaverini C, Arkin LM, Ott H, Has C, Süβmuth K, Gostynski A, Shourick J, Paller AS. Biologics in congenital ichthyosis: are they effective? Br J Dermatol. 2024 Oct 29:ljae420. doi: 10.1093/bjd/ljae420. Online ahead of print.PMID: 39470394