(from OMIM) By examining the critical region for triglyceride storage disease with impaired long-chain fatty acid oxidation, a rare autosomal recessive form of NCIE (242100), on chromosome 3p21, Lefevre et al.(2001) identified several candidate genes, one of which, designated comparative gene identification-58 (human-ABHD5).In 9 families from the Mediterranean basin segregating triglyceride storage disease with impaired long-chain fatty acid oxidation, Lefevre et al. (2001) identified 8 different haplotypes and mutations in the human-ABHD5 gene. Many more mutations have been described since then (see below). The Family in ESTHER id CGI-58_ABHD5_ABHD4. The disease locus was designated NLSDI (neutral lipid storage disease with ichtyosis). Symptoms are close to NLSMD (neutral lipid storage disease with myopathy) which is due to mutations in patatin-like phospholipase domain-containing protein-2 (adipose triglyceride lipase; ATGL (PNPLA2); not an alpha beta hydrolase Fischer et al.). But NLSMD do not show ichtyolisis and in NLSDI myopathy is milder. However ABDH5 interacts and activates ATGL (Yamaguchi et al.). Two highly conserved ABHD5 amino acids (R299 and G328) enabled ABHD4 (ABHD4 N303R/S332G) to activate ATGL. The corresponding ABHD5 mutations (ABHD5 R299N and ABHD5 G328S) selectively disrupted lipolysis without affecting ATGL lipid droplet translocation or ABHD5 interactions with perilipin proteins and ABHD5 ligands (Sanders et al.)
References
Title: Chanarin-Dorfman Syndrome: A comprehensive review Cakmak E, Bagci G Ref: Liver Int, 41:905, 2021 : PubMed
The Chanarin-Dorfman syndrome (CDS) is a rare, autosomal recessively inherited genetic disease. This syndrome is associated with a decrease in the lipolysis activity in multiple tissue cells because of recessive mutations in the abhydrolase domain containing 5 (ABHD5) gene, which leads to the accumulation of lipid droplets in multiple types of cells. Major clinical symptoms in patients with CDS include ichthyosis and intracytoplasmic lipid droplets. The variability of clinical symptoms in patients with CDS depends on a large number of mutations involved. In this syndrome, liver involvement is an important cause of mortality and morbidity. This review aims to summarize the demographic characteristic, clinical symptoms, liver involvement and mutations in CDS patients in the literature to date.
Title: Two cases of Chanarin-Dorfman syndrome with novel and recurrent mutations in the ABHD5 gene Jiang X, Zhong W, Yu B, Lin Z, Wang H Ref: Int J Dermatol, :, 2021 : PubMed
ABHD5 protein is widely involved in lipid and energy homeostasis. Mutations in the ABHD5 gene are associated with the onset of Neutral Lipid Storage Disease with Ichthyosis (NLSDI), historically known as Chanarin Dorfman Syndrome (CDS). CDS is a rare autosomal recessive lipid storage disease, characterized by non-bullous congenital ichthyosiform eritrhoderma (NCIE), hepatomegaly and liver steatosis. Myopathy, neurosensory hearing loss, cataracts, nystagmus, strabismus, and mental impairment are considered additional findings. To date, 151 CDS patients have been reported all over the world. Here we described two additional families with patients affected by CDS from Turkey. Our patients were a 42 and 22-years old men, admitted to the Hospital for congenital ichthyosis. Hepatic steatosis and myopathy were also detected in both patients. ABHD5 molecular analysis revealed the presence of N209* mutation. Our data enlarge the cohort of CDS patients and provide a revision of muscle clinical findings for this rare inborn error of neutral lipid metabolism.
Title: Chanarin-Dorfman syndrome: a novel homozygous mutation in the ABHD5 gene Al-Hage J, Abbas O, Nemer G, Kurban M Ref: Clinical & Experimental Dermatologyatol, 45:257, 2020 : PubMed
Title: A novel mutation of ABHD5 gene in a Chanarin Dorfman patient with unusual dermatological findings Eskiocak AH, Missaglia S, Moro L, Durdu M, Tavian D Ref: Lipids Health Dis, 18:232, 2019 : PubMed
BACKGROUND: Chanarin Dorfman Syndrome (CDS) is a rare autosomal recessive disorder characterized by the multisytemic accumulation of neutral lipids inside the cytoplasmic lipid droplets. This condition is caused by mutations in the abhydrolase domain containing 5 gene (ABHD5). In CDS the skin involvement is the prevalent and always observed clinical feature, consisting of a non-bullous congenital ichthyosiform erythroderma (NCIE). Moreover, a variable involvement of the liver and neuromuscular system can be also observed. In this report, we aimed to perform the clinical and genetic characterization of a patient affected by CDS with atypical dermatological findings, considering this rare inborn error of neutral lipid metabolism. METHODS: Genomic DNA samples obtained from patient and his parents were used to perform the sequencing of the ABHD5 exons and their intron/exon boundaries. Bioinformatic analyses were performed to investigate the possible effect of the identified mutation on protein structure. RESULTS: Here we present the case of a 29-year-old male patient with CDS, who, for long time, has been misdiagnosed as pityriasis rubra pilaris (PRP). He has a history of increasing hyperlipidemia; hepatomegaly associated with hepatosteatosis was also detected. ABHD5 molecular analysis revealed a novel missense mutation, the c.811G > A (p.G271R). Bioinformatic investigations showed that the variant has a deleterious effect on ABHD5 function, probably causing an incorrect folding of the mutant protein. CONCLUSIONS: These results highlihts the importance of genetic testing for ABHD5 in unresolved cases of patients presenting unusual skin lesions, that resemble PRP, associated with a history of hyperlipidemia and nonalcoholic fatty liver.
BACKGROUND: Chanarin-Dorfman syndrome (CDS) is a rare syndromic disease related to an accumulation of triacylglycerol in most organs. The aim of our study was to investigate various organs in a large series of CDS patients. RESULTS: We report for the first time thyroid function impairment in CDS. Among 12 investigated patients, 7 showed thyroid function impairment. All of them were over 30 of age. The 5 remaining investigated patients with normal thyroid function were under 30. Thyroid loss of function is an unknown clinical feature of CDS that could gradually develop with age. Thyroid ultrasound showed an abnormal aspect in all investigated patients (6 with thyroid impairment and 3 with normal thyroid function). Cervical MRI done in 2 patients with thyroid impairment showed fat infiltration of thyroid parenchyma. Audiogram carried out in 8 of our patients showed sensorineural hearing impairment in all patients, although only 2 patients suffered from clinical hypoacusia. We also demonstrated that kidney could be a more commonly involved organ than previously reported in the literature. A poorly differentiated kidney parenchyma is a common feature in our series. One patient showed cerebellar atrophy and T2 hypersignal of brain's white matter in MRI. All patients carried the same founder mutation c.773(- 1)G > A in the ABDH5 gene. DISCUSSION: Aside from the congenital ichthyosiform erythroderma, the most common symptom of CDS, in addition to other organs involvement frequently reported in the literature, we described thyroid dysfunction, an unreported feature, probably related to the lipid infiltration of the thyroid parenchyma. The association found between age and hypothyroidism in CDS patients could explain the gradually development of thyroid disease with age. CONCLUSION: We reported a thyroid dysfunction and unreported ultrasonographic aspects of kidneys and cerebral MRI in CDS patients. METHODS: We performed clinical analyses in 15 patients in whom thyroid, liver, ocular, kidney, skeletal muscle and neurological involvement were explored. Genetic and molecular explorations were performed by direct sequence analysis. Software SPSS, Fisher's exact test and ANOVA were used for statistical analyses.
Neutral lipid storage disease with myopathy (NLSDM) and with ichthyosis (NLSDI) are rare autosomal recessive disorders caused by mutations in the PNPLA2 and in the ABHD5/CGI58 genes, respectively. These genes encode the adipose triglyceride lipase (ATGL) and alpha-beta hydrolase domain 5 (ABHD5) proteins, which play key roles in the function of lipid droplets (LDs). LDs, the main cellular storage sites of triacylglycerols and sterol esters, are highly dynamic organelles. Indeed, LDs are critical for both lipid metabolism and energy homeostasis. Partial or total PNPLA2 or ABHD5/CGI58 knockdown is characteristic of the cells of NLSD patients; thus, these cells are natural models with which one can unravel LD function. In this review we firstly summarize genetic and clinical data collected from NLSD patients, focusing particularly on muscle, skin, heart, and liver damage due to impaired LD function. Then, we discuss how NLSD cells were used to investigate and expand the current structural and functional knowledge of LDs.
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition and the most common liver disease worldwide, affecting more than one-third of the population. So far there have been no reports on mendelian inheritance in families with NAFLD. METHODS: We performed whole-exome or targeted next-generation sequencing on patients with autosomal dominant NAFLD. RESULTS: We report a heritable form of NAFLD and/or dyslipidemia due to monoallelic ABHD5 mutations, with complete clinical expression after the fourth decade of life, in 7 unrelated multiplex families encompassing 39 affected individuals. The prevalence of ABHD5-associated NAFLD was estimated to be 1 in 1,137 individuals in a normal population. CONCLUSION: We associate a Mendelian form of NAFLD and/or dyslipidemia with monoallelic ABHD5 mutations. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is a common multifactorial disorder with a strong genetic component. Inherited forms of NAFLD have been suspected but, their molecular pathogenesis has not been disclosed. Here we report a heritable form of NAFLD with clinical expression after 40 years of age, associated with monoallelic ABHD5 mutations.
Title: Clinical and genetic characterization of a Chanarin Dorfman Syndrome patient born to diseased parents Durdu M, Missaglia S, Moro L, Tavian D Ref: BMC Med Genet, 19:88, 2018 : PubMed
BACKGROUND: Chanarin Dorfman Syndrome (CDS) is a rare autosomal recessive disorder characterized by ichthyosiform non-bullous erythroderma and variable involvement of the liver and the neuromuscular system. In CDS patients, the accumulation of neutral lipids inside cytoplasmic lipid droplets has been demonstrated in different tissues. To date, ninety families with this disease have been described worldwide; most of them are from Mediterranean countries. CASE PRESENTATION: In this report, we describe a consanguineous Turkish family with typical features of CDS. The parents are first cousins and are both diseased. At the age of eight, their child presented CDS with non-bullous congenital ichthyosiform erythroderma, hepatosteatosis, hepatomegaly and ectropion. Electromyographic examination is compatible with myopathy. A five-year-old cousin of the child is also affected by CDS. She was born to non-affected consanguineous parents. Mutation analysis of the ABHD5 gene revealed the previously reported mutation, N209X, which is the most frequent in Turkish patients. Lipid vacuoles, also known as Jordan's anomaly, are detectable in their leucocytes. CONCLUSIONS: To the best of our knowledge, this is the first report of a CDS family in which both parents and their child are affected by CDS. To date, the child does not present a more severe clinical phenotype compared with those of his relatives or other CDS patients of the same age. These findings suggest that high levels of triacylglycerol accumulation, that may be supposed to be present in high amount inside the ooplasm, did not affect embryo development and foetal growth.
Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive metabolic disorder caused by mutations in gene encoding the domain-5 of alpha/beta-hydrolase enzyme (ABHD5). It is known as a natural lipid storage disorder arising from impaired lipid metabolism often characterized by hepatomegaly, myopathy, ataxia, non-bullous ichthyosiform erythroderma, hearing loss, and mental retardation. In the present study, we report two affected 28-month-old monozygotic twin boys as new cases of CDS. Genetic analysis was performed in patients, and the results showed a homozygote deletion in exon 4 of ABHD5. According to the the American College of Medical Genetics and Genomics, this variant is categorized as a pathogenic variant.
Clinical and biochemical manifestations of lecithin-cholesterol acyltransferase (LCAT) deficiency include an abnormal lipid profile (characterized by hypercholesterolemia with markedly decreased high-density lipoprotein cholesterol [HDL-C] and hypertriglyceridemia), corneal opacities, hematologic abnormalities (normochromic anemia of varying intensity), splenomegaly, variable early coronary artery disease and nephropathy (initially proteinuria followed by progressive deterioration of renal function). We presented a patient with nephrotic syndrome, which renal biopsy revealed classic features of LCAT deficiency. To our knowledge, the present case is the first reported case of LCAT deficiency presenting with symptoms related to nephrotic syndrome in a patient with no obvious family history without any corneal deposits and normal HDL-C levels.
BACKGROUND: A small number of patients affected by Neutral Lipid Storage Diseases (NLSDs: NLSD type M with Myopathy and NLSD type I with Ichthyosis) have been described in various ethnic groups worldwide. However, relatively little is known about the progression and phenotypic variability of the disease in large specific populations. The aim of our study was to assess the natural history, disability and genotype-phenotype correlations in Italian patients with NLSDs. Twenty-one patients who satisfied the criteria for NLSDs were enrolled in a retrospective cross-sectional study to evaluate the genetic aspects, clinical signs at onset, disability progression and comorbidities associated with this group of diseases. RESULTS: During the clinical follow-up (range: 2-44 years, median: 17.8 years), two patients (9.5%, both with NLSD-I) died of hepatic failure, and a further five (24%) lost their ability to walk or needed help when walking after a mean period of 30.6 years of disease. None of the patients required mechanical ventilation. No patient required a heart transplant, one patient with NLSD-M was implanted with a cardioverter defibrillator for severe arrhythmias. CONCLUSION: The genotype/phenotype correlation analysis in our population showed that the same gene mutations were associated with a varying clinical onset and course. This study highlights peculiar aspects of Italian NLSD patients that differ from those observed in Japanese patients, who were found to be affected by a marked hypertrophic cardiopathy. Owing to the varying phenotypic expression of the same mutations, it is conceivable that some additional genetic or epigenetic factors affect the symptoms and progression in this group of diseases.
Alpha-beta hydrolase domain-containing 5 (ABHD5), the defective gene in human Chanarin-Dorfman syndrome, is a highly conserved regulator of adipose triglyceride lipase (ATGL)-mediated lipolysis that plays important roles in metabolism, tumor progression, viral replication, and skin barrier formation. The structural determinants of ABHD5 lipolysis activation, however, are unknown. We performed comparative evolutionary analysis and structural modeling of ABHD5 and ABHD4, a functionally distinct paralog that diverged from ABHD5 ~500 million years ago, to identify determinants of ABHD5 lipolysis activation. Two highly conserved ABHD5 amino acids (R299 and G328) enabled ABHD4 (ABHD4 N303R/S332G) to activate ATGL in Cos7 cells, brown adipocytes, and artificial lipid droplets. The corresponding ABHD5 mutations (ABHD5 R299N and ABHD5 G328S) selectively disrupted lipolysis without affecting ATGL lipid droplet translocation or ABHD5 interactions with perilipin proteins and ABHD5 ligands, demonstrating that ABHD5 lipase activation could be dissociated from its other functions. Structural modeling placed ABHD5 R299/G328 and R303/G332 from gain-of-function ABHD4 in close proximity on the ABHD protein surface, indicating they form part of a novel functional surface required for lipase activation. These data demonstrate distinct ABHD5 functional properties and provide new insights into the functional evolution of ABHD family members and the structural basis of lipase regulation.
BACKGROUND: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study. METHODS: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families. RESULTS: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718 + 2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes. CONCLUSION: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders.
Chanarin Dorfman syndrome (CDS) is a very rare neutral lipid metabolism disorder with multisystem involvement. It is inherited as an autosomal recessive manner. It is characterized with congenital ichthyosiform erythroderma and involvement of liver, muscle, and central nervous system. Demonstration of lipid vacuoles in neutrophils from peripheral blood smears in patients with ichthyosiform erythroderma leads to the diagnosis. We report a novel ABHD5 truncating variant in a twenty nine month old female child, who presented with icthyosiform erythroderma.
Autosomal recessive congenital ichthyosis (ARCI) represents a heterogeneous group of rare disorders of cornification with 3 major subtypes: harlequin ichthyosis (HI), lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). A 4th subtype has also been proposed: pleomorphic ichthyosis (PI), characterized by marked skin changes at birth and subsequently mild symptoms. In nationwide screenings of suspected cases of ARCI in Denmark and Sweden, we identified 132 patients (age range 0.1-86 years) classified as HI (n = 7), LI (n = 70), CIE (n = 17) and PI (n = 38). At birth, a collodion membrane or similar severe hyperkeratosis was reported in almost all patients with HI and LI, and in nearly half of patients with CIE and PI. Persistent ectropion was more common in HI (85%) and LI (57%), than in CIE (35%) and PI (5%). Anhidrosis was a frequent problem in all 4 groups (58-100%). A scoring (0-4) of ichthyosis/ery-thema past infancy showed widely different mean values in the subgroups: HI (3.2/3.1), LI (2.4/0.6), CIE (1.8/1.6), PI (1.1/0.3). Novel or recurrent mutations were found in 113 patients: TGM1 (n = 56), NIPAL4 (n = 15), ALOX12B (n = 15), ABCA12 (n = 8), ALOXE3 (n = 9), SLC27A4 (n = 5), CYP4F22 (n = 3), PNPLA1 (n = 1) and ABHD5 (n = 1). In conclusion, by performing a deep phenotyping and gene screening, ARCI can be definitely diagnosed in 85% of cases in Scandinavia, with a prevalence of 1:100,000 and > 8 different aetiologies.
Hepatitis C virus (HCV) particles closely mimic human very-low-density lipoproteins (VLDL) to evade humoral immunity and to facilitate cell entry. However, the principles that govern HCV association with VLDL components are poorly defined. Using an siRNA screen, we identified ABHD5 (alpha/beta hydrolase domain containing protein 5, also known as CGI-58) as a new host factor promoting both virus assembly and release. ABHD5 associated with lipid droplets and triggered their hydrolysis. Importantly, ABHD5 Chanarin-Dorfman syndrome mutants responsible for a rare lipid storage disorder in humans were mislocalised, and unable to consume lipid droplets or support HCV production. Additional ABHD5 mutagenesis revealed a novel tribasic motif that does not influence subcellular localization but determines both ABHD5 lipolytic and proviral properties. These results indicate that HCV taps into the lipid droplet triglyceride reservoir usurping ABHD5 lipase cofactor function. They also suggest that the resulting lipid flux, normally devoted to VLDL synthesis, also participates in the assembly and release of the HCV lipo-viro-particle. Altogether, our study provides the first association between the Chanarin-Dorfman syndrome protein and an infectious disease and sheds light on the hepatic manifestations of this rare genetic disorder as well as on HCV morphogenesis.
Chanarin-Dorfman syndrome is a rare, genetically determined autosomal recessive disorder, characterised by the presence of lipid droplets in the cytoplasm of multiple tissues of the body, particularly in the blood leukocytes and congenital non-bullous icthyosiform erythroderma. In this paper, we report one-year child who presented with skin lesions since birth and hepatomegaly. Liver biopsy showed steatohepatitis; and peripheral blood smear confirmed Jordan`s anomaly, which is a permanent feature of Chanarin-Dorfman syndrome.
Title: [Chanarin-Dorfman syndrome in a 7-year-old child: when myophathy and skin involvement are all but one] Barnerias C, Bassez G, Schischmanoff O Ref: Med Sci (Paris), 31 Spec No 3:11, 2015 : PubMed
UNLABELLED: Chanarin-Dorfman syndrome, a "neutral lipid storage disease with ichthyosis," is a multisystem inherited metabolic disorder associated with congenital ichthyosis and accumulation of lipid droplets in various types of cells. CASE REPORT: A 3-year-old male presented to the Pediatric Hepatology Unit, Cairo University Children's Hospital, Cairo, Egypt, with accidentally discovered hepatomegaly. He had generalised ichthyosis with dark skin pigmentation and bilateral ectropion. Abdominal examination revealed generalised abdominal distention with firm nontender hepatomegaly. His liver functions were deranged. Blood film showed many vacuolated neutrophils. Serum triglyceride and creatine kinase levels were elevated. Abdominal ultrasound showed a moderately enlarged liver with a bright echo pattern. Liver biopsy revealed marked diffuse macrovesicular fatty changes. The diagnosis of Chanarin-Dorfman Syndrome was made based on the dermatological, haematological, and liver biopsy findings.
Chanarin-Dorfman syndrome is an autosomal recessive lipid storage disease characterized by non-bullous congenital ichthyosiform erythroderma, and involvement of the liver, muscles and central nervous system due to a multisystemic accumulation of neutral lipids in various types of cells. Less than 100 affected individuals have been reported worldwide, the majority from the Mediterranean and Middle-East countries, especially Turkey. We present clinical and molecular data of four affected relatives with Chanarin-Dorfman syndrome homozygous for a N209X mutation in ABHD5, and provide a short review by comparing patients with N209X homozygous mutations to patients with other ABHD5 mutations. No major clinical differences exist between individuals with an N209X mutation and those with other mutations, which argues against a genotype/phenotype correlation.
Chanarin-Dorfman syndrome (CDS) is an autosomal recessive disorder, characterized by intracellular accumulation of lipid droplets in most tissues. It is very difficult to find a correlation between the phenotypic and genotypic features due to the occurrence of novel ABHD5 [ alpha/beta hydrolase domain-containing protein-5; originally called CGI-58 (comparative gene identification-58)] mutations and the fact that there are only a few cases in the literature. The protein encoded by this gene is a cofactor for adipose triglyceride lipase (ATGL), which promotes the catabolism of stored fat. The clinical phenotype involves multiple organs and systems. Ichthyosis, nonbullous congenital ichthyosiform erythroderma and cytoplasmic accumulation of lipid droplets in granulocytes (Jordans' bodies) are always present. Peripheral blood smear is an easy method for diagnosing CDS; its use can also avoid unnecessary further testing. Herein, we report a patient with a homozygous mutation in ABHD5 that has never previously been described. Moreover, the case was diagnosed as Chanarin-Dorfman syndrome with only a peripheral blood smear.
BACKGROUND: alpha/beta-hydrolase domain-containing protein 5 (ABHD5) plays an important role in the triacylglycerols (TAG) hydrolysis. Indeed, ABHD5 is the co-activator of adipose triglyceride lipase (ATGL), that catalyses the initial step of TAG hydrolysis. Mutations in ABHD5 gene are associated with the onset of Chanarin-Dorfman syndrome (CDS), a rare autosomal recessive lipid storage disorder, characterized by non-bullous congenital ichthyosiform erythroderma (NCIE), hepatomegaly and liver steatosis. CASE PRESENTATION: We describe here a 5-years-old Brazilian child who presented with NCIE at birth and diffuse micro and macro-vesicular steatosis on liver biopsy since she was 2 years old. Molecular analysis of coding sequence and putative 5' regulatory region of ABHD5 gene was performed. A homozygous novel deletion, affecting the promoter region and the exon 1, was identified, confirming the suspected diagnosis of CDS for this patient. RT-PCR analysis showed that the genomic rearrangement completely abolished the ABHD5 gene expression in the patient, while only a partial loss of expression was detected in her parents. This is the first report describing the identification of a large deletion encompassing the promoter region of ABHD5 gene. The total loss of ABHD5 expression may explain the early onset of CDS and the severe liver involvement. After molecular diagnosis, the patient started a special diet, poor in fatty acids with medium chain triglycerides (MCT), and showed hepatic and dermatologic improvement in spite of severe molecular defect. CONCLUSIONS: This case report extends the spectrum of disease-causing ABHD5 mutations in CDS providing evidence for a novel pathogenic mechanism for this rare disorder. Moreover, our preliminary data show that early diagnosis and prompt treatment of neutral lipid accumulation might be useful for CD patients.
Chanarin-Dorfman syndrome (CDS) is a rare nonlysosomal neutral lipid storage disorder characterized by congenital ichthyosis, lipid vacuoles in leukocytes (Jordan's anomaly), and hepatomegaly. The authors herein report an 18-month-old boy with ichthyosis and hepatomegaly diagnosed with CDS and confirmed to have a novel c.506-3C>G mutation in the ABHD5/CGI-58 gene. Our case also illustrates that retinoids such as acitretin could be useful in the treatment of skin manifestations in CDS even in the presence of liver derangement.
Title: Dorfman-Chanarin syndrome without mental retardation caused by a homozygous ABHD5 splice site mutation that skips exon 6 Sugiura K, Suga Y, Akiyama M Ref: J Dermatol Sci, 75:199, 2014 : PubMed
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.
UNLABELLED: Chanarin-Dorfman syndrome (CDS) is a very rare autosomal recessive inherited neutral lipid metabolism disorder associated with congenital ichthyosis and multi-system involvement. Observation of lipid vacuoles in neutrophils (Jordan's anomaly) in peripheral blood smears in patients with ichthyosiform erythroderma is diagnostic. Herein we present 2 siblings with CDS that were referred to Dokuz Eylul University School of Medicine Department of Pediatrics due to ichthyosis. They had hepatomegaly, cataract, growth retardation, and sensorineural hearing loss. Some lipid vacuoles in neutrophils were noted in peripheral blood smear evaluation. Genetic analysis showed homozygous N209X mutation in both patients. They were put on a low-fat high-carbohydrate diet supplemented with medium-chain fatty acids. During 6 months of follow-up, no improvement was observed in both patients. In conclusion, although CDS is a rare lipid storage disease, it should always be a consideration in patients with congenital ichthyosis, especially those with extracutaneous symptoms or signs. The diagnosis of CDS is made based on a very simple test-peripheral blood smear. CONFLICT OF INTEREST: None declared.
Title: Novel nonsense mutation of ABHD5 in Dorfman-Chanarin syndrome with unusual findings: a challenge for genotype-phenotype correlation. Aggarwal S, Maras JS, Alam S, Khanna R, Gupta SK, Ahuja A Ref: Eur Journal of Medical Genetics, 55:173, 2012 : PubMed
Dorfman-Chanarin syndrome is a rare neutral lipid disorder characterised by icthyosis, hepatic steatosis and multisystemic involvement of varying magnitude. It is an autosomal recessive disease caused by mutations in the ABHD5 gene. We report a consanguineous family of Afgani origin, with four affected siblings who were found to have a novel homozygous nonsense mutation g. [27606 G > T]; [27606 G > T]. The clinical findings were unusual in the form of early cirrhosis and hepatic decompensation in one sibling, presence of corneal opacities in male siblings and tessellated fundus in all affected children. Steatosis was minimal in liver biopsy specimens and all children had low vitamin D levels. Genotype-phenotype correlations have not been possible in Dorfman-Chanarin syndrome and the present report raises further challenges for the same.
Chanarin-Dorfman syndrome (CDS) is an autosomal recessive neutral lipid storage disease. It is very rare and characterized by ichtiosis, intracellular fat droplets in leucocytes (Jordan anomaly) and involvement of multiple tissues (skeletal muscle, central nervous system, bone marrow, eye and ear) mainly the liver. Our patients were diagnosed as CDS because they had ichtiosis, Jordon anomaly of leucocytes in peripheral blood smear, liver involvement and presence of homozygous 88 insertion C frame shift mutation on exon 4 of ABHD5/CGI-58 gene in genetic analysis. Our cases were two sisters. One of them developed severe steatohepatitis on age 19 and the other one was diagnosed as decompensated cirrhosis when she was 26 years old. We report here a new mutation in comparative gene identification-58 (CGI-58) gene causing syndactyly and steatohepatitis induced early cirrhosis.
Chanarin-Dorfman syndrome (CDS) is an autosomal recessive metabolic disorder characterized by congenital ichthyosis and visceral complications due to accumulation of neutral lipids. CDS is caused by mutations in the ABHD5 (previously termed CGI-58) gene. In the present study, we assessed a young child presenting with ichthyosis and hepatomegaly, suggesting a diagnosis of CDS. We identified an intronic mutation, c.960 + 5G>A, which was found to result in skipping of exon 6. Abnormal results on liver function tests led us to treat the child with acitretin, which resulted in satisfactory clinical and laboratory responses. The present case illustrates the beneficial effect of acitretin treatment in CDS even in the presence of compromised liver function.
Mutations of comparative gene identification 58 (CGI-58) in humans cause Chanarin-Dorfman syndrome, a rare autosomal recessive disease in which excess triacylglycerol (TAG) accumulates in multiple tissues. CGI-58 recently has been ascribed two distinct biochemical activities, including coactivation of adipose triglyceride lipase and acylation of lysophosphatidic acid (LPA). It is noteworthy that both the substrate (LPA) and the product (phosphatidic acid) of the LPA acyltransferase reaction are well-known signaling lipids. Therefore, we hypothesized that CGI-58 is involved in generating lipid mediators that regulate TAG metabolism and insulin sensitivity. Here, we show that CGI-58 is required for the generation of signaling lipids in response to inflammatory stimuli and that lipid second messengers generated by CGI-58 play a critical role in maintaining the balance between inflammation and insulin action. Furthermore, we show that CGI-58 is necessary for maximal TH1 cytokine signaling in the liver. This novel role for CGI-58 in cytokine signaling may explain why diminished CGI-58 expression causes severe hepatic lipid accumulation yet paradoxically improves hepatic insulin action. Collectively, these findings establish that CGI-58 provides a novel source of signaling lipids. These findings contribute insight into the basic mechanisms linking TH1 cytokine signaling to nutrient metabolism.
Title: An exceptional mutational event leading to Chanarin-Dorfman syndrome in a large consanguineous family Samuelov L, Fuchs-Telem D, Sarig O, Sprecher E Ref: Br J Dermatol, 164:1390, 2011 : PubMed
Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive metabolic disorder featuring congenital ichthyosis combined with pleiomorphic visceral manifestations associated with tissue accumulation of cytoplasmic lipid droplets. Mutations in the ABHD5 gene, encoding a crucial cofactor for adipose triglyceride lipase, have been found to underlie all CDS cases reported to date. The purposed of this study was to ascertain the genetic defect underlying CDS in a large multigenerational family. We used a combination of direct sequencing, reverse transcriptase-polymerase chain reaction (RT-PCR) and microsatellite marker genotyping to identify a novel CDS-causing mutation in ABHD5. Although no pathogenic mutation could be identified in the coding sequence of the ABHD5 gene, polymorphic marker genotyping analysis supported linkage to this gene locus. Accordingly, direct sequencing of RT-PCR amplification products generated from patient skin-derived total RNA, revealed in all four patients the presence of a 101 bp insertion between exon 3 and exon 4. Bioinformatic analysis and direct sequencing indicated that this insertion resulted from an exceptional mutational event, namely, the insertion of a LINE element into intron 3 of the ABHD5 gene, leading to aberrant splicing out of the mutant intron 3. Our results confirm genetic homogeneity in CDS and underscore the importance of RNA studies in the molecular diagnosis of genodermatoses.
Title: Liver cirrhosis in an infant with Chanarin-Dorfman syndrome caused by a novel splice-site mutation in ABHD5 Cakir M, Bruno C, Cansu A, Cobanoglu U, Erduran E Ref: Acta Paediatr, 99:1592, 2010 : PubMed
UNLABELLED: We described a Turkish girl with Chanarin-Dorfman syndrome who developed liver cirrhosis in the early infancy. She had all the clinical features of Chanarin-Dorfman syndrome such as ichthyosis, Jordan's anomaly, fatty liver disease and mild ectropion. The diagnosis was confirmed with a novel ABHD5 mutation. Liver steatosis or steatohepatitis with or without hepatomegaly is the predominant finding of Chanarin-Dorfman syndrome. Cirrhosis has been reported in patients with long-duration disease. CONCLUSION: Local factors or dysfunction of local proteins such as mutations or polymorphisms in hepatic microsomal lipase and arylacetamide deacetylase may contribute the severity of liver involvement, and steatosis may progress to cirrhosis in the early infancy in Chanarin-Dorfman syndrome.
Chanarin-Dorfman syndrome (CDS) is an autosomal recessive metabolic disorder associated with congenital ichthyosis and a multisystemic accumulation of neutral lipids in various types of cells. Recently, mutations of the ABHD5 gene were identified as the cause of CDS. In this work, we carried out molecular analysis of the ABHD5 gene in 6 unrelated patients. We identified one previously reported mutation, N209X and two novel genetic alterations; a nonsense mutation (p.Y50X) and missense mutation (p.S73A).
BACKGROUND: Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive disorder characterized by nonbullous congenital ichthyosiform erythroderma (NCIE) and an intracellular accumulation of triacylglycerol (TG) droplets in most tissues. The clinical phenotype involves multiple organs and systems, including liver, eyes, ears, skeletal muscle and central nervous system (CNS). Mutations in ABHD5/CGI58 gene are associated with CDS. METHODS: Eight CDS patients belonging to six different families from Mediterranean countries were enrolled for genetic study. Molecular analysis of the ABHD5 gene included the sequencing of the 7 coding exons and of the putative 5' regulatory regions, as well as reverse transcript-polymerase chain reaction analysis and sequencing of normal and aberrant ABHD5 cDNAs. RESULTS: Five different mutations were identified, four of which were novel, including two splice-site mutations (c.47+1G>A and c.960+5G>A) and two large deletions (c.898_*320del and c.662-1330_773+46del). All the reported mutations are predicted to be pathogenic because they lead to an early stop codon or a frameshift producing a premature termination of translation. While nonsense, missense, frameshift and splice-site mutations have been identified in CDS patients, large genomic deletions have not previously been described. CONCLUSIONS: These results emphasize the need for an efficient approach for genomic deletion screening to ensure an accurate molecular diagnosis of CDS. Moreover, in spite of intensive molecular screening, no mutations were identified in one patient with a confirmed clinical diagnosis of CDS, appointing to genetic heterogeneity of the syndrome.
A 27-year-old Japanese man underwent liver transplantation because of uncompensated cirrhosis due to Dorfman-Chanarin syndrome (DCS). At birth, the patient displayed ichthyosis and liver dysfunction. Moreover, mental retardation appeared and intracytoplasmic vacuoles were observed within peripheral blood neutrophils. A fatty liver was also noticed, leading to the diagnosis of DCS. When he was referred to our hospital, his American Society of Anesthesiologists score was 3. The findings of computed tomography showed liver atrophy, splenomegaly, and ascites. The Child-Pugh score was B, and the Model for End-stage Liver Disease score was 14. The pathophysiology was DCS with uncompensated liver cirrhosis. Therefore, living donor liver transplantation (LDLT) was performed from the patient's brother. The histological appearance of the resected liver revealed macrovesicular steatosis in most hepatocytes with excess fibrous tissue in the portal areas. These findings were compatible with nonalcoholic steatohepatitis. Although the patient's mental retardation and characteristic appearance have not improved, good liver function has been maintained since LDLT. An outpatient protocol liver biopsy performed at 12 months after LDLT did not show recurrence of macrovesicular steatosis.
Title: Chanarin-Dorfman syndrome: deficiency in CGI-58, a lipid droplet-bound coactivator of lipase Yamaguchi T, Osumi T Ref: Biochimica & Biophysica Acta, 1791:519, 2009 : PubMed
Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive disease of lipid metabolism; it is associated with congenital ichthyosis typed as non-bullous congenital ichthyosiform erythroderma (NCIE). CDS is characterized by the presence of an abnormally large number of cytosolic lipid droplets containing triacylglycerol (TG) in various tissues such as the skin, liver, and leukocytes. Mutations in the CGI-58 (also called ABHD5) gene encoding a 39-kDa protein of the alpha/beta hydrolase domain subfamily have been shown to be responsible for this disorder. In adipocytes, CGI-58 is involved in TG degradation on lipid droplets; in doing so, it coordinates with several lipolytic factors including perilipin, a member of the PAT protein family, and ATGL, a putative rate-limiting lipase in adipocytes. In quiescent adipocytes, CGI-58 interacts with perilipin on the surfaces of lipid droplets. Upon hormonal stimulation, CGI-58 facilitates massive lipolysis by activating ATGL. Some CGI-58 mutations found in CDS patients cancel the ability to interact with perilipin or activate ATGL, indicating that the loss of these interactions is physiologically important. However, based on the tissue distributions of these lipolytic factors, there are likely multiple molecular targets of CGI-58 actions. This in turn gives rise to the multiple phenotypes of CDS, such as ichthyosis, liver steatosis, or neurosensory diseases.
We describe the clinical features, muscle pathology features, and molecular studies of seven patients with Chanarin-Dorfman syndrome (CDS) or neutral lipid storage disease and ichthyosis (NLSDI), a multisystem triglyceride storage disease with massive accumulation of lipid droplets in muscle fibers. All patients presented with congenital ichthyosiform erythroderma, cytoplasmic lipid droplets in blood cells, mild to severe hepatomegaly, and increased serum CK levels and liver enzymes. Three patients showed muscle symptoms and three had steathorrea. Molecular analysis identified five mutations, three of which are novel. These findings expand the clinical and mutational spectrum and underline the genetic heterogeneity of this disease.
Chanarin-Dorfman disease (CDD) is a rare genetic disorder characterized by ichthyosis, myopathy, central nervous system disturbances, and intracellular lipid storage in muscle fibers, hepatocytes, and granulocytes. We describe skeletal muscle magnetic resonance imaging findings in a case of CDD, outlining the potential role of GE T1-weighted opposed-phase sequence (chemical shift imaging) in the evaluation of lipid storage myopathies.
Fatty liver disease is mainly caused by alcohol consumption, excessive body weight, dyslipidemia and impaired glucose tolerance, but inherited disorders can sometimes be involved. We report the case of a 40-year-old woman with steatohepatitis and severe portal hypertension, associated with ichthyosis, cataract and hypoacusia. The clinical, pathological and genetic findings were consistent with a diagnosis of Chanarin-Dorfman syndrome (CDS), a rare autosomal recessive inherited neutral lipid storage disorder, and genetic analysis showed that a novel ABHD5 mutation is responsible.
Adipose triglyceride lipase (ATGL) was recently identified as an important triacylglycerol (TG) hydrolase promoting the catabolism of stored fat in adipose and nonadipose tissues. We now demonstrate that efficient ATGL enzyme activity requires activation by CGI-58. Mutations in the human CGI-58 gene are associated with Chanarin-Dorfman Syndrome (CDS), a rare genetic disease where TG accumulates excessively in multiple tissues. CGI-58 interacts with ATGL, stimulating its TG hydrolase activity up to 20-fold. Alleles of CGI-58 carrying point mutations associated with CDS fail to activate ATGL. Moreover, CGI-58/ATGL coexpression attenuates lipid accumulation in COS-7 cells. Antisense RNA-mediated reduction of CGI-58 expression in 3T3-L1 adipocytes inhibits TG mobilization. Finally, expression of functional CGI-58 in CDS fibroblasts restores lipolysis and reverses the abnormal TG accumulation typical for CDS. These data establish an important biochemical function for CGI-58 in the lipolytic degradation of fat, implicating this lipolysis activator in the pathogenesis of CDS.
Title: Severe oily ichthyosis in monozygotic twins mimicking Chanarin-Dorfman syndrome but not associated with a mutation of the CGI58 gene Solomon C, Bernier L, Germain L, Dufour R, Davignon J Ref: Arch Dermatol, 142:402, 2006 : PubMed
Neutral lipid storage disease (Chanarin-Dorfman syndrome) is an autosomal recessive metabolic disorder associated with congenital ichthyosis and a multisystemic accumulation of neutral lipids (lipid droplets) in various types of cells. The clinical presentation has been reported to correspond to that of nonbullous congenital ichthyosiform erythroderma. We report a 4-year-old boy presenting a generalized ichthyosiform disorder manifested by migrating scaly plaques alternating with areas of normal-looking skin, showing erythematous borders with sharp margins, clinically suggestive of erythrokeratoderma variabilis (EKV). A peripheral blood smear revealed cytoplasmic vacuoles in most granulocytes. Genetic studies from the patient and his parents revealed that the patient carried two different and novel mutations of the ABHD5 gene: a nonsense mutation in exon 6 (transmitted by the father) and an insertion/deletion in exon 4 (transmitted by the mother). Our observation demonstrates the clinical heterogeneity of the ichthyosiform dermatoses observed in Chanarin-Dorfman syndrome and widens the clinical range of conditions presenting migrating scaly plaques mimicking EKV.
Mutation in ABHD5 causes Dorfman-Chanarin syndrome (DCS), a multisystem triglyceride storage disorder. Ultrastructural study of leukocytes confirmed DCS in a child homozygous for a novel ABHD5 mutation, with ichthyosis, developmental delay, and steatohepatitis with cirrhosis, manifest only as elevated aminotranferase levels. We recommend early assessment for liver disease in DCS.
Title: CGI-58 interacts with perilipin and is localized to lipid droplets. Possible involvement of CGI-58 mislocalization in Chanarin-Dorfman syndrome Yamaguchi T, Omatsu N, Matsushita S, Osumi T Ref: Journal of Biological Chemistry, 279:30490, 2004 : PubMed
Lipid droplets (LDs) are a class of ubiquitous cellular organelles that are involved in lipid storage and metabolism. Although the mechanisms of the biogenesis of LDs are still unclear, a set of proteins called the PAT domain family have been characterized as factors associating 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. In this study, we used a yeast two-hybrid system to examine the potential function of perilipin. We found direct interaction between perilipin and CGI-58, a deficiency of which correlated with the pathogenesis of Chanarin-Dorfman syndrome (CDS). Endogenous CGI-58 was distributed predominantly on the surface of LDs in differentiated 3T3-L1 cells, and its expression increased during adipocyte differentiation. Overexpressed CGI-58 tagged with GFP gathered at the surface of LDs and colocalized with perilipin. This interaction seems physiologically important because CGI-58 mutants carrying an amino acid substitution identical to that found in CDS lost the ability to be recruited to LDs. These mutations significantly weakened the binding of CGI-58 with perilipin, indicating that the loss of this interaction is involved in the etiology of CDS. Furthermore, we identified CGI-58 as a binding partner of ADRP, another PAT domain protein expressed ubiquitously, by yeast two-hybrid assay. GFP-CGI-58 expressed in non-differentiated 3T3-L1 or CHO-K1 cells was colocalized with ADRP, and the CGI-58 mutants were not recruited to LDs carrying ADRP, indicating that CGI-58 may also cooperate with ADRP.
Title: Truncation of CGI-58 protein causes malformation of lamellar granules resulting in ichthyosis in Dorfman-Chanarin syndrome Akiyama M, Sawamura D, Nomura Y, Sugawara M, Shimizu H Ref: Journal of Investigative Dermatology, 121:1029, 2003 : PubMed
Dorfman-Chanarin syndrome is a rare autosomal recessive inherited lipid storage disease characterized by ichthyosis, leukocyte lipid vacuoles, and involvement of several internal organs. Recently, CGI-58 mutations were identified as the cause of Dorfman-Chanarin syndrome. The physiologic roles of the CGI-58 protein and the pathomechanisms of Dorfman-Chanarin syndrome still remain to be clarified, however. The patient, a 16-y-old male, demonstrated ichthyosis, small ears, lipid vacuoles in his leukocytes, liver dysfunction, and mental retardation. Sequencing of CGI-58 revealed that the patient was homozygous for a novel nonsense mutation R184X, in exon 4. The putative truncated protein was 52.4% of the length of the normal CGI-58 polypeptide and lacked approximately 60% of the lipid binding region, 66.4% of the alpha/beta hydrolase folding segment of the polypeptide, and two of the CGI-58 catalytic triads, resulting in a significant loss of lipase/esterase/thioesterase activity. Electron microscopy revealed a large number of abnormal lamellar granules, a disturbed intercellular lamellar structure, and lipid vacuoles in the epidermis. These results suggested that CGI-58 protein is involved in the lipid metabolism of lamellar granules and that defective lipid production in lamellar granules caused by a CGI-58 protein deficiency is involved in the pathogenesis of ichthyosis in Dorfman-Chanarin syndrome.
Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive form of nonbullous congenital ichthyosiform erythroderma (NCIE) that is characterized by the presence of intracellular lipid droplets in most tissues. We previously localized a gene for a subset of NCIE to chromosome 3 (designated "the NCIE2 locus"), in six families. Lipid droplets were found in five of these six families, suggesting a diagnosis of CDS. Four additional families selected on the basis of a confirmed diagnosis of CDS also showed linkage to the NCIE2 locus. Linkage-disequilibrium analysis of these families, all from the Mediterranean basin, allowed us to refine the NCIE2 locus to an approximately 1.3-Mb region. Candidate genes from the interval were screened, and eight distinct mutations in the recently identified CGI-58 gene were found in 13 patients from these nine families. The spectrum of gene variants included insertion, deletion, splice-site, and point mutations. The CGI-58 protein belongs to a large family of proteins characterized by an alpha/beta hydrolase fold. CGI-58 contains three sequence motifs that correspond to a catalytic triad found in the esterase/lipase/thioesterase subfamily. Interestingly, CGI-58 differs from other members of the esterase/lipase/thioesterase subfamily in that its putative catalytic triad contains an asparagine in place of the usual serine residue.
Title: Dorfman-Chanarin syndrome in a Turkish kindred: conductor diagnosis requires analysis of multiple eosinophils Wollenberg A, Geiger E, Schaller M, Wolff H Ref: Acta Derm Venereol, 80:39, 2000 : PubMed
Dorfman-Chanarin syndrome is a rare, autosomal recessive inherited lipid storage disease with congenital ichthyotic erythroderma due to an acylglycerol recycling defect. Demonstration of lipid vacuoles in neutrophils from peripheral blood smears (Jordans' anomaly) in patients with ichthyotic erythroderma leads to the diagnosis. In spite of frequent liver, muscle, ear, eye and central nervous system involvement, Dorfman-Chanarin syndrome may present clinically as monosymptomatic ichthyosis. Here, we report clinical and laboratory investigations in a consanguineous family from Turkey with 3 affected family members, and demonstrate the lipid vacuoles in epidermal Langerhans' cells for the first time. Langerhans' cell phenotyping suggests that the skin inflammation is due to the gene defect and not to underlying atopic dermatitis. Microscopic examination of eosinophils for lipid vacuoles to identify conductors revealed variable percentages of normal and vacuolized eosinophils in conductors, suggesting the microscopic analysis of at least 10 eosinophils for conductor identification.
BACKGROUND: Dorfman-Chanarin syndrome is an uncommon condition characterized by non-bullous congenital ichtyosiform erythrodermia and lipid vacuoles in circulating leukocytes. CASE REPORT: We report an unusual presentation in a child who had a dry congenital ichtyosiform erythroderma. Blood smears revealed lipid vacuoles in granulocyte cytoplasm, leading to the diagnosis of Dorfman-Chanarin syndrome. The child also had liver and ophthalmologic involvement. DISCUSSION: Dorfman-Chanarin syndrome is a rare autosomic recessive hereditary disease (27 cases reported in the literature) related to the accumulation of neutral lipids in organ tissues. Clinical manifestations are dry congenital ichtyosiform erythroderma and lipid vacuoles in circulating granulocytes. The syndrome may be expressed more or less severely in several organs. Diagnosis is confirmed on blood smears. The vacuoles can also be observed in smears of heterozygous subjects and can serve as a screening test. The pathogenesis of Dorfman-Chanarin syndrome is poorly understood but appears to be related to perturbed intracellular triglyceride catabolism. Treatment is symptomatic.
Title: Dorfman-Chanarin syndrome: morphologic studies and presentation of new cases Srebrnik A, Brenner S, Ilie B, Messer G Ref: Am J Dermatopathol, 20:79, 1998 : PubMed
Dorfman-Chanarin syndrome, or neutral lipid storage disease with ichthyosis, is a rare inherited metabolic disorder characterized by accumulation of neutral lipids in different tissues. Variability in dermatologic severity is not understood. We report two new cases, compare their features with other reported cases, and examine the possible relationship between the severity of the dermatologic condition and lipid accumulation in various types of skin cells. The localization of lipid droplets was determined in various dermal and epidermal cells by light microscopy of epoxy resin semithin sections and electron microscopy in four cases of Dorfman-Chanarin syndrome. Lipid droplets in the dermis were detected in fibroblasts, Schwann cells in both myelinated and unmyelinated nerves, smooth muscle cells, and sweat gland cells, but not in endothelial cells of blood capillaries. The droplets were not surrounded by a membrane. Findings indicate that there is no correlation between the clinical severity of the disease and the microscopic findings.
Dorfman-Chanarin syndrome is a rare, autosomal recessive inherited lipid storage disease with skin manifestations in form of congenital ichthyotic erythroderma. Demonstration of lipid vacuoles in neutrophils from peripherals blood smears in patients with ichthyotic erythroderma leads to the diagnosis. Other organ systems, such as CNS, liver, muscle, ears and eyes, are frequently involved. Since Dorfman-Chanarin syndrome may present with just skin findings, it should be included in the differential diagnosis of the congenital ichthyoses. Microscopic examination of peripheral blood smears is recommended in all patients with ichthyosis. We summarize the current data on the pathogenesis, diagnosis, differential diagnosis, and therapeutic options in Dorfman-Chanarin syndrome, give an overview of the clinical manifestations of the 23 patients affected with this rare disease.
BACKGROUND/AIMS: Dorfman-Chanarin syndrome is a very rare condition determined by an autosomal recessive inherited disorder of neutral lipid metabolism. The syndrome is defined by the association of ichthyosiform nonbullous erythroderma, vacuoles in the leukocytes and variable involvement of liver, muscle and central nervous system. Only 19 cases have been described worldwide. METHODS: We studied a 16-year-old patient with congenital ichthyosis, liver and spleen enlargement and abnormal gamma-glutamyltransferase. Liver biopsy, skin biopsy and blood smear showed abnormal intracellular neutral lipid storage. RESULTS/CONCLUSION: On the basis of clinical and histological findings, the patient was diagnosed as having Dorfman-Chanarin syndrome. This is the fourth reported Italian case, with a prominent skin and hepatic involvement. Liver biopsy, performed in the first instance, was of great importance in reaching a diagnosis.
We describe the case of a woman from a small town in the south of Spain, with consanguineous parents, who presented with the complete syndrome. The main clinicopathological characteristics are discussed.
A four-year-old boy presented with hepatomegaly, vacuolized granulocytes (Jordans' anomaly) and slightly progressive myopathy as signs of multisystem triglyceride storage disease. The nine-year-old sister of the patient also showed Jordans' anomaly and early fatigability, but no overt weakness. Biochemical analysis revealed normal values for carnitines, carnitine palmityl transferase in serum and striated muscle, and beta-oxidation enzymes in striated muscles. Distribution of non-membrane-bound lipids in granulocytes, fibroblasts, smooth muscle cells and striated muscle was compatible with Chanarin-Dorfman syndrome. In contrast to Chanarin-Dorfman syndrome, our patients lacked congenital ichthyosis.
Neutral lipid storage disease (NLSD) (Chanarin-Dorfman Syndrome) is an autosomal recessive disorder of multisystem triacylglycerol (TAG) storage. Previous work has pointed to a defect in intracellular TAG metabolism. In the studies reported here, the lipid metabolism of three lines of NLSD fibroblasts were compared to normal skin fibroblasts. When pulsed with [3H]oleic acid, the earliest observed abnormality in NLSD cell lines was increased incorporation into phosphatidylethanolamine, followed by accumulation of radiolabel in TAG. Activities of several glycerolipid synthetic enzymes were comparable in NLSD and normal fibroblast lines, excluding oversynthesis of glycerolipid. The proportion of plasmalogen and neutral ether lipid synthesized was normal and alkylglycerols did not accumulate, excluding a defect in ether lipid metabolism. Activities of both acid lipase and Mn2(+)-sensitive lipase within the particulate fractions of NLSD and normal fibroblasts were comparable. These studies are most consistent with functional deficiency of a TAG lipase with activity against a pool of TAG that are normally utilized for phospholipid biosynthesis.
A boy with a lipid storage disease characterized by lamellar ichthyosis, cataracts, hepatosplenomegaly, and leukocyte vacuoles has been identified in a Sicilian family. This patient shows all the characteristics of ichthyosis and neutral lipid storage disease (Chanarin-Dorfman syndrome). Family data confirm an autosomal recessive inheritance; the heterozygotes may be detected by the presence of vacuoles in circulating eosinophils.
Ichthyosis and neutral lipid storage disease (INLSD) is a nonlysosomal, multisystemic, triglyceride storage disorder. It is characterized by nonbullous congenital ichthyosiform erythroderma (NBCIE), leukocyte vacuoles, and variable involvement of the liver, muscles, eyes, and central nervous system. In our patient fat-containing vacuoles were also demonstrated in the epidermis. In patients with NBCIE, the diagnosis of INLSD is readily made by direct examination of a peripheral blood smear demonstrating cytoplasmic lipid vacuoles within most granulocytes and monocytes.
Title: Value of looking at leukocytes in every case of ichthyosis Wolf R, Zaritzky A, Pollak S Ref: Dermatologica, 177:237, 1988 : PubMed
A three-year old patient had ichthyosis and neutral lipid storage disease (Chanarin-Dorfman syndrome), characterized by congenital ichthyosiform erythroderma and leukocyte vacuoles. He did not show any of the internal system involvement that was found in previously described cases. Patients with this syndrome demonstrate a great variability of clinical involvement. The affliction may be very mild as in our case or it may lead to rapid death, as with the patient's brother born a Harlequin baby, who only survived 5 days. Because of this wide spectrum of clinical variability mild cases might escape diagnosis. It is, therefore, suggested that every case of ichthyosis should have a peripheral blood smear evaluation with special attention to the morphology of the leukocytes. Our case clearly demonstrates the value of such a screening examination. Although the patient had been under treatment for almost 3 years, only screening examination of blood smears of all the patients with ichthyosis finally led to the correct diagnosis.
Dorfman-Chanarin syndrome in two sisters of Jewish Iraqi origin is reported. This heritable disorder of the metabolism of neutral lipids was manifested by congenital ichthyosis, vacuoles in the leukocytes, and variable involvement of liver, muscle, central nervous system, and the auditory system. In two asymptomatic members of the family leukocyte vacuoles were found as the only sign of the syndrome. Clinical, pathologic, ultrastructural, and biochemical findings are described. Previous reported cases are reviewed.
Title: Neutral lipid storage disease with ichthyosis. Defective lamellar body contents and intracellular dispersion Elias PM, Williams ML Ref: Arch Dermatol, 121:1000, 1985 : PubMed
Although the link between epidermal lamellar body lipids and stratum corneum barrier function is well established, a role for lamellar body lipids in desquamation remains unproved. We examined skin biopsy material from three family members of a Palestinian kindred with a multisystem disorder of altered lipid metabolism, ichthyosis, and deposition of fat droplets in multiple tissues (Chanarin-Dorfman syndrome, neutral lipid storage disease). Thin-section and freeze-fracture ultrastructural studies revealed a distinctive lamellar body abnormality: multilaminated spherules that distorted and displaced the normal internal disk structure of these organelles. Whereas these spherules remained interspersed with secreted lamellar body contents within the intercellular spaces of the outer epidermis, at the stratum granulosum-stratum corneum interface they apparently dispersed into electron-lucent "slits." These studies therefore provide strong support for the concept that lamellar body-derived lipids influence stratum corneum desquamation and further suggest that abnormalities of neutral lipid-alkane metabolism influence normal epidermal shedding.
