Clinical and genetic characterization of a Chanarin Dorfman Syndrome patient born to diseased parents

Clinical and genetic characterization of a Chanarin Dorfman Syndrome patient born to diseased... 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. Keywords: Chanarin-Dorfman Syndrome, Ichthyosis, Lipid disorder, Liver involvement, Myopathy Background identified as a causative gene of CDS [6]. Indeed, different Neutral lipid storage disease with ichthyosis, which is also ABHD5 mutations determine the partial or total loss of known as Chanarin Dorfman Syndrome (CDS; MIM ATGL activation, leading to the accumulation of TG inside 275630), is a rare autosomal recessive disease characterized lipid droplets [2–5]. Lipid droplets are highly dynamic and by the intracellular accumulation of triacylglycerol (TG) in ubiquitous cellular organelles. These droplets are a funda- numerous tissues [1, 2]. The clinical phenotype involves mental component of lipid homeostasis, i.e., a universal multiple organs and systems, including skin, liver, skeletal feature of eukaryotic cells that can ensure a rapidly mobi- muscle, eyes, ears, and the central nervous system. How- lized lipid source for numerous biochemical processes [7]. ever, in this syndrome, the degree of systemic involvement Neutral lipids also accumulate in oocytes and blastomeres is quite variable [2–5]. ABHD5 (α/β hydrolase domain 5), a as lipid droplets, providing energy for mammalian embryo cofactor for adipose triglyceride lipase (ATGL), has been preimplantation, proper growth and development [8]. In the peripheral leukocytes of CDS patients, neutral lipids inside lipid droplets are easily detectable with * Correspondence: daniela.tavian@unicatt.it standard or specific stains, and they are known as Jordan’s Laboratory of Cellular Biochemistry and Molecular Biology-CRIBENS, Catholic University of the Sacred Heart, pz Buonarroti 30, 20145 Milan, Italy anomalies, the most common laboratory findings of the Department of Psychology, Catholic University of the Sacred Heart, Largo disease [9]. Gemelli 1, 20123 Milan, Italy Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Durdu et al. BMC Medical Genetics (2018) 19:88 Page 2 of 5 One hundred and twenty-eight CDS patients have At first examination (at the age of 5), he had lagophthal- been reported worldwide (Additional file 1: Table S1). mos and ectropion. Ophthalmologists did not record For 85 of these patients, clinical diagnosis has been con- lagophthalmos in subsequent examinations, so the condi- firmed by ABHD5 mutation analysis. The highest num- tion was considered a compliance problem. He had ele- ber of CDS patients (27 cases) has been described in vated transaminase (ALT: 75 U/L; normal 5-35 U/L; GGT Turkey, mainly due to the high incidence of consanguin- 31 U/L; normal 5-17 U/L), creatine phosphokinase (CK: eous marriages [10]. Nevertheless, the clinical and genetic 1677 U/L; normal 22-200 U/L), triglyceride (460 mg/dl; description of families in which both parents and children normal 35-130 mg/dl), and total cholesterol levels are affected by CDS has never been reported before. (135 mg/dl; normal 110-200 mg/dl) (Table 1). Systemic examination revealed 2 cm hepatomegaly. Abdominal Case presentation ultrasonography was compatible with hepatosteatosis and Here, we present a CDS Turkish family with four affected hepatomegaly. Electromyographic examination revealed members (Fig. 1a, III-1, III-2, IV-1, IV-2). The child (IV-1) signs of myopathy. was an 8-year-old male born at 38 weeks of gestation and His parents (both 44 years old) were paternal cousins. Both weighing 3400 g. He presented lamellar ichthyosis at birth. presented lamellar ichthyosis, ectropion, hypertriglyceridemia, Fig. 1 Pedigree of CDS family (a). Microphotographs of May-Grünwald-Giemsa buffy coats of patient III-1 showing Jordan’s anomaly (arrows); original magnification 1000× (b). Sequence analysis showing the c594insC (N209X) ABHD5 mutation identified in homozygous status in all family members affected by CDS (c) Durdu et al. BMC Medical Genetics (2018) 19:88 Page 3 of 5 Table 1 Clinical and laboratory features of patients with Chanarin-Dorfman syndrome Clinical feature Child Father Mother Cousin Ichthyosis + + + + Leukocyte vacuoles + + + + Creatinine phosphokinase levels (U/L) 1677 290 219 1145 Electromyographic examination Myopathy Normal Normal Myopathy Triglyceride level (mg/dL) 460 115 74 74 Total cholesterol level (mg/dL) 135 151 115 140 Cataracts –– – – Ectropion + + + – Lagophthalmos + –– – Strabism –– – – Myopia – + –– Hearing loss –– – – Mental retardation –– – – Hepatomegaly + (2 cm) + + + (2 cm) Hepatosteatosis + + + + Microcephaly –– – – Intestinal involvement –– – – hepatomegaly and hepatosteatosis (Table 1). In both amplification conditions were previously reported [2]. parents and the child, dermatological examination re- A few days after molecular diagnosis, the father died of vealed widespread ichthyosis on the facial region, trunk, a heart attack at the age of 44. He had no prior cardiac extensor and flexural regions and scalp. The individual history. However, PNPLA2 gene analysis was performed, scales over the trunk were white, fine, translucent and excluding disease-causing mutations. semi-adherent, whereas those on the limbs and face The CARE guidelines were followed in this case. were grey-brown, larger in size, polygonal and adherent (Fig. 2). No bullous lesions or erosions were noted. The Discussion and conclusions involvement of palms and soles, dental anomaly and The N209X mutation identified in our CDS family is the nail dystrophy was absent. most common in the Turkish CDS population. Nur et al. In the 5-year-old girl (IV-2), ichthyosis was also compared clinical findings between patients carrying this present in flexural regions (Fig. 2). Corrugated appear- mutation with other ABHD5 variations and noted no ance and hyperpigmented scales were detected on foot, significant differences [10]. In CDS patients, skin involve- back, knee, and elbow. Laboratory investigation revealed ment is prevalent and a consistently observed clinical fea- increased ALT (86 U/L) (alanine transaminase), AST ture, consisting of a non-bullous congenital ichthyosiform (aspartate transaminase) (88 U/L) and CK (1145 U/L) erythroderma. Sano et al. demonstrated that the severity levels (Table 1). Electromyographic examination revealed of ichthyosis positively correlates with TG level in the myopathy. Abdominal ultrasonography revealed hepa- scales from patients [11]. In our affected subjects, a wide- tosteatosis causing hepatomegaly. Ophthalmological and spread lamellar ichthyosis detected since birth revealed a audiological examinations were normal. homogeneous CDS phenotype. Notably, skin involvement A peripheral blood smear stained with May-Grünwald- did not appear more severe in the child; however, it is pos- Giemsa revealed lipid vacuoles (Jordan’s anomaly) in leuco- sible to hypothesize increased accumulation of TG in cytes from all patients (Fig. 1b). After obtaining informed ectodermal cells during embryonic development. Liver ab- consent and in accordance with the Declaration of Helsinki normalities can occur in greater than 80% of patients, ran- principles, the coding regions of the ABHD5 gene were se- ging from hepatomegaly or liver steatosis to cirrhosis, and quenced, and a homozygous N209X mutation was identi- can be observed in young children, as occurred in this fied (Fig. 1c). For molecular analysis, oligonucleotides family [4, 6]. Neurological impairment was not detected were selected to amplify and sequence the seven exons in our patients; however, intellectual disability has been of ABHD5, their intron/exon boundaries, and the can- reported in 20% of CDS subjects and in approximately didate promoter regions. The primer sequences and the 40% of those carrying the N209X mutation [10–12]. Durdu et al. BMC Medical Genetics (2018) 19:88 Page 4 of 5 Fig. 2 Dermatological characterization of CDS patients. Lamellar ichthyosis affecting facial region (a, d, e, g), trunk (b, c, f, h), and extremities (i)of child (patient IV-1; a, b, c), father (patient III-2; d), mother (patient III-1; e, f) and cousin (patient IV-2; g, h, i). Prominent eyelid ectropion in father (d) and mother (e) Sensorineural hearing loss was not present in our pregnancy complications were observed. Therefore, the family; however, this condition occurs in 30% of CDS storage of neutral lipids inside lipid droplets did not dra- patients. Muscle involvement was evident only in the matically increase during oocyte maturation. Indeed, two children. Clinically, the children did not exhibit embryo development and foetal growth were not af- significant muscle weakness, fatigue or exercise intoler- fected. To date, the child does not present new symp- ance. However, an electromyographic examination (EMG) toms or an exacerbation of the clinical phenotype even was performed because of an elevation in CK levels and with regard to dermatologic manifestations compared revealed a myopathic pattern. In CDS, muscle abnormali- with the symptoms and phenotypes of his relatives or ties have been detected in 40% of subjects. Myopathy other CDS patients. Instead, a relevant aspect for these typically begins in the thirties, but it has also been three patients seems to be represented by the psycho- described in very young children [2, 13]. genic stress due to isolation from society, colleagues, In conclusion, we describe a family in which all mem- school friends and relatives. Finally, after molecular diag- bers are affected by CDS. When the child was born, his nosis, the two children immediately started a special mother was 36 years old. She did not indicate any infer- diet, poor in fatty acids with medium chain triglycer- tility problems or history of abortion. This paper de- ides (MCT), as hepatic and dermatologic improve- scribes the unique reported case of natural conception ment has been reported in different cases consuming and pregnancy between two CDS patients. No particular such a diet. Durdu et al. BMC Medical Genetics (2018) 19:88 Page 5 of 5 Additional file of chanarin-dorfman syndrome patients: first report of large deletions in the ABHD5 gene. Orphanet J Rare Dis. 2010;5:33. 3. Bruno C, Bertini E, Di Rocco M, Cassandrini D, Ruffa G, De Toni T, et al. Additional file 1: Table S1. Summary of CDS patients reported in the Clinical and genetic characterization of Chanarin-Dorfman syndrome. literature. (DOCX 30 kb) Biochem Biophys Res Com. 2008;369:1125–8. 4. Missaglia S, Valadared ER, Moro L, Faguntes ED, Quintão Roque R, Giardina B, et al. Early onset of Chanarin-Dorfman syndrome with severe liver Abbreviations involvement in a patient with a complex rearrangement of ABHD5 ABHD5: α/β-hydrolase domain-containing protein 5; ALT: Alanine promoter. BMC Med Genet. 2014;15:32. aminotransferase test; AST: Aspartate aminotransferase test; ATGL: Adipose 5. Takeichi T, Sugiura K, Tso S, Simpson MA, McGrath JA, Akiyama M. Bi-allelic triglyceride lipase; CDS: Chanarin-Dorfman syndrome; CK: Creatine kinase; nonsense mutations in ABHD5 underlie a mild phenotype of Dorfman- GGT: Gamma glutamyl transpeptidase; LD: Lipid droplet; MCT: Medium chain Chanarin syndrome. J Dermatol Sci. 2016;81:134–6. triglycerides; NCIE: Non-bullous congenital ichthyosiform erythroderma; 6. Lefevre C, Jobard F, Caux F, Bouadjar B, Karaduman A, Heilig R, et al. NLSDI: Neutral lipid storage disease with ichthyosis; TG: Triacylglicerol Mutations in CGI-58, the gene encoding a new protein of the esterase/ lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome. Am J Hum Acknowledgements Genet. 2001;69:1002–12. The authors are grateful to the patients for their kind cooperation. 7. Welte MA. Expanding roles for lipid droplets. Curr Biol. 2015; https://doi.org/ 10.1016/j.cub.2015.04.004. Funding 8. Prates EG, Nunes JT, Pereira RM. A role of lipid metabolism during cumulus- Università Cattolica del Sacro Cuore (Milan, Italy) sustained the publication of oocyte complex maturation: impact of lipid modulators to improve embryo this article. production. Mediat Inflamm. 2014; https://doi.org/10.1155/2014/692067. 9. Tavian D, Colombo R. Improved cytochemical method for detecting Jordans’ Availability of data and materials bodies in neutral-lipid storage diseases. J Clin Pathol. 2007;60:956–8. Data obtained during this study are included in the article and its additional files. 10. Nur BG, Gencpinar P, Yuzbasioglu A, Emre SD, Mihci E. Chanarin Dorfman syndrome: genotype-phenotype correlation. Eur J Med Genet. 2015;58:238–42. Authors’ contributions 11. Ujihara M, Nakajima K, Yamamoto M, Teraishi M, Uchida Y, Akiyama M, et al. MD performed the clinical characterization of patients and he is taking care Epidermal triglyceride levels are correlated with severity of ichthyosis in of them; SM performed the molecular analysis and critically revised the Dorfman-Chanarin syndrome. J Dermatol Sci. 2010;57:102–7. manuscript; LM supervised the study and critically revised the manuscript; 12. Pennisi EM, Arca M, Bertini E, Bruno C, Cassandrini D. D'amico a et al. DT conceived the study, supervised it and wrote the manuscript. All authors clinical/genetic features and natural history in a large cohort of Italian read and approved the final manuscript. patients. Orphanet J Rare Dis. 2017;12:90. 13. Gupta N, Gothwal S, Satpathy AK, Missaglia S, Tavian D, Das P, et al. Ethics approval and consent to participate Chanarin Dorfman syndrome. A case report with novel nonsense mutation. Informed consent for genetic analysis was obtained from the study participants. Gene. 2016;10:359–62. This manuscript reports the description of a family who presented with CDS clinical symptoms. No experiments were performed and no hypothesis were tested for this study. This case report does not constitute systematic research, therefore no ethics approval was necessary. Consent for publication Written informed consent was obtained from adult patients and the guardians of two young patients for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details Baskent University Faculty of Medicine, Department of Dermatology, Adana Hospital, Adana, Turkey. Laboratory of Cellular Biochemistry and Molecular Biology-CRIBENS, Catholic University of the Sacred Heart, pz Buonarroti 30, 20145 Milan, Italy. Department of Psychology, Catholic University of the Sacred Heart, Largo Gemelli 1, 20123 Milan, Italy. Department of Pharmaceutical Sciences, University of Piemonte Orientale, Lgo Donegani 2, 28100 Novara, Italy. Received: 19 February 2018 Accepted: 18 May 2018 References 1. Schweiger M, Lass A, Zimmermann R, Eichmann TO, Zechner R. Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2 or CGI-58/ABHD5. Am J Physiol Endocrinol Metab. 2009;297: 289–96. 2. Redaelli C, Coleman RA, Moro L, Dacou-Voutetakis C, Elsayed SM, Prati D, Colli A, Mela D, Colombo R, Tavian D. Clinical and genetic characterization http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Medical Genetics Springer Journals

Clinical and genetic characterization of a Chanarin Dorfman Syndrome patient born to diseased parents

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Abstract

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. Keywords: Chanarin-Dorfman Syndrome, Ichthyosis, Lipid disorder, Liver involvement, Myopathy Background identified as a causative gene of CDS [6]. Indeed, different Neutral lipid storage disease with ichthyosis, which is also ABHD5 mutations determine the partial or total loss of known as Chanarin Dorfman Syndrome (CDS; MIM ATGL activation, leading to the accumulation of TG inside 275630), is a rare autosomal recessive disease characterized lipid droplets [2–5]. Lipid droplets are highly dynamic and by the intracellular accumulation of triacylglycerol (TG) in ubiquitous cellular organelles. These droplets are a funda- numerous tissues [1, 2]. The clinical phenotype involves mental component of lipid homeostasis, i.e., a universal multiple organs and systems, including skin, liver, skeletal feature of eukaryotic cells that can ensure a rapidly mobi- muscle, eyes, ears, and the central nervous system. How- lized lipid source for numerous biochemical processes [7]. ever, in this syndrome, the degree of systemic involvement Neutral lipids also accumulate in oocytes and blastomeres is quite variable [2–5]. ABHD5 (α/β hydrolase domain 5), a as lipid droplets, providing energy for mammalian embryo cofactor for adipose triglyceride lipase (ATGL), has been preimplantation, proper growth and development [8]. In the peripheral leukocytes of CDS patients, neutral lipids inside lipid droplets are easily detectable with * Correspondence: daniela.tavian@unicatt.it standard or specific stains, and they are known as Jordan’s Laboratory of Cellular Biochemistry and Molecular Biology-CRIBENS, Catholic University of the Sacred Heart, pz Buonarroti 30, 20145 Milan, Italy anomalies, the most common laboratory findings of the Department of Psychology, Catholic University of the Sacred Heart, Largo disease [9]. Gemelli 1, 20123 Milan, Italy Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Durdu et al. BMC Medical Genetics (2018) 19:88 Page 2 of 5 One hundred and twenty-eight CDS patients have At first examination (at the age of 5), he had lagophthal- been reported worldwide (Additional file 1: Table S1). mos and ectropion. Ophthalmologists did not record For 85 of these patients, clinical diagnosis has been con- lagophthalmos in subsequent examinations, so the condi- firmed by ABHD5 mutation analysis. The highest num- tion was considered a compliance problem. He had ele- ber of CDS patients (27 cases) has been described in vated transaminase (ALT: 75 U/L; normal 5-35 U/L; GGT Turkey, mainly due to the high incidence of consanguin- 31 U/L; normal 5-17 U/L), creatine phosphokinase (CK: eous marriages [10]. Nevertheless, the clinical and genetic 1677 U/L; normal 22-200 U/L), triglyceride (460 mg/dl; description of families in which both parents and children normal 35-130 mg/dl), and total cholesterol levels are affected by CDS has never been reported before. (135 mg/dl; normal 110-200 mg/dl) (Table 1). Systemic examination revealed 2 cm hepatomegaly. Abdominal Case presentation ultrasonography was compatible with hepatosteatosis and Here, we present a CDS Turkish family with four affected hepatomegaly. Electromyographic examination revealed members (Fig. 1a, III-1, III-2, IV-1, IV-2). The child (IV-1) signs of myopathy. was an 8-year-old male born at 38 weeks of gestation and His parents (both 44 years old) were paternal cousins. Both weighing 3400 g. He presented lamellar ichthyosis at birth. presented lamellar ichthyosis, ectropion, hypertriglyceridemia, Fig. 1 Pedigree of CDS family (a). Microphotographs of May-Grünwald-Giemsa buffy coats of patient III-1 showing Jordan’s anomaly (arrows); original magnification 1000× (b). Sequence analysis showing the c594insC (N209X) ABHD5 mutation identified in homozygous status in all family members affected by CDS (c) Durdu et al. BMC Medical Genetics (2018) 19:88 Page 3 of 5 Table 1 Clinical and laboratory features of patients with Chanarin-Dorfman syndrome Clinical feature Child Father Mother Cousin Ichthyosis + + + + Leukocyte vacuoles + + + + Creatinine phosphokinase levels (U/L) 1677 290 219 1145 Electromyographic examination Myopathy Normal Normal Myopathy Triglyceride level (mg/dL) 460 115 74 74 Total cholesterol level (mg/dL) 135 151 115 140 Cataracts –– – – Ectropion + + + – Lagophthalmos + –– – Strabism –– – – Myopia – + –– Hearing loss –– – – Mental retardation –– – – Hepatomegaly + (2 cm) + + + (2 cm) Hepatosteatosis + + + + Microcephaly –– – – Intestinal involvement –– – – hepatomegaly and hepatosteatosis (Table 1). In both amplification conditions were previously reported [2]. parents and the child, dermatological examination re- A few days after molecular diagnosis, the father died of vealed widespread ichthyosis on the facial region, trunk, a heart attack at the age of 44. He had no prior cardiac extensor and flexural regions and scalp. The individual history. However, PNPLA2 gene analysis was performed, scales over the trunk were white, fine, translucent and excluding disease-causing mutations. semi-adherent, whereas those on the limbs and face The CARE guidelines were followed in this case. were grey-brown, larger in size, polygonal and adherent (Fig. 2). No bullous lesions or erosions were noted. The Discussion and conclusions involvement of palms and soles, dental anomaly and The N209X mutation identified in our CDS family is the nail dystrophy was absent. most common in the Turkish CDS population. Nur et al. In the 5-year-old girl (IV-2), ichthyosis was also compared clinical findings between patients carrying this present in flexural regions (Fig. 2). Corrugated appear- mutation with other ABHD5 variations and noted no ance and hyperpigmented scales were detected on foot, significant differences [10]. In CDS patients, skin involve- back, knee, and elbow. Laboratory investigation revealed ment is prevalent and a consistently observed clinical fea- increased ALT (86 U/L) (alanine transaminase), AST ture, consisting of a non-bullous congenital ichthyosiform (aspartate transaminase) (88 U/L) and CK (1145 U/L) erythroderma. Sano et al. demonstrated that the severity levels (Table 1). Electromyographic examination revealed of ichthyosis positively correlates with TG level in the myopathy. Abdominal ultrasonography revealed hepa- scales from patients [11]. In our affected subjects, a wide- tosteatosis causing hepatomegaly. Ophthalmological and spread lamellar ichthyosis detected since birth revealed a audiological examinations were normal. homogeneous CDS phenotype. Notably, skin involvement A peripheral blood smear stained with May-Grünwald- did not appear more severe in the child; however, it is pos- Giemsa revealed lipid vacuoles (Jordan’s anomaly) in leuco- sible to hypothesize increased accumulation of TG in cytes from all patients (Fig. 1b). After obtaining informed ectodermal cells during embryonic development. Liver ab- consent and in accordance with the Declaration of Helsinki normalities can occur in greater than 80% of patients, ran- principles, the coding regions of the ABHD5 gene were se- ging from hepatomegaly or liver steatosis to cirrhosis, and quenced, and a homozygous N209X mutation was identi- can be observed in young children, as occurred in this fied (Fig. 1c). For molecular analysis, oligonucleotides family [4, 6]. Neurological impairment was not detected were selected to amplify and sequence the seven exons in our patients; however, intellectual disability has been of ABHD5, their intron/exon boundaries, and the can- reported in 20% of CDS subjects and in approximately didate promoter regions. The primer sequences and the 40% of those carrying the N209X mutation [10–12]. Durdu et al. BMC Medical Genetics (2018) 19:88 Page 4 of 5 Fig. 2 Dermatological characterization of CDS patients. Lamellar ichthyosis affecting facial region (a, d, e, g), trunk (b, c, f, h), and extremities (i)of child (patient IV-1; a, b, c), father (patient III-2; d), mother (patient III-1; e, f) and cousin (patient IV-2; g, h, i). Prominent eyelid ectropion in father (d) and mother (e) Sensorineural hearing loss was not present in our pregnancy complications were observed. Therefore, the family; however, this condition occurs in 30% of CDS storage of neutral lipids inside lipid droplets did not dra- patients. Muscle involvement was evident only in the matically increase during oocyte maturation. Indeed, two children. Clinically, the children did not exhibit embryo development and foetal growth were not af- significant muscle weakness, fatigue or exercise intoler- fected. To date, the child does not present new symp- ance. However, an electromyographic examination (EMG) toms or an exacerbation of the clinical phenotype even was performed because of an elevation in CK levels and with regard to dermatologic manifestations compared revealed a myopathic pattern. In CDS, muscle abnormali- with the symptoms and phenotypes of his relatives or ties have been detected in 40% of subjects. Myopathy other CDS patients. Instead, a relevant aspect for these typically begins in the thirties, but it has also been three patients seems to be represented by the psycho- described in very young children [2, 13]. genic stress due to isolation from society, colleagues, In conclusion, we describe a family in which all mem- school friends and relatives. Finally, after molecular diag- bers are affected by CDS. When the child was born, his nosis, the two children immediately started a special mother was 36 years old. She did not indicate any infer- diet, poor in fatty acids with medium chain triglycer- tility problems or history of abortion. This paper de- ides (MCT), as hepatic and dermatologic improve- scribes the unique reported case of natural conception ment has been reported in different cases consuming and pregnancy between two CDS patients. No particular such a diet. Durdu et al. BMC Medical Genetics (2018) 19:88 Page 5 of 5 Additional file of chanarin-dorfman syndrome patients: first report of large deletions in the ABHD5 gene. Orphanet J Rare Dis. 2010;5:33. 3. Bruno C, Bertini E, Di Rocco M, Cassandrini D, Ruffa G, De Toni T, et al. Additional file 1: Table S1. Summary of CDS patients reported in the Clinical and genetic characterization of Chanarin-Dorfman syndrome. literature. (DOCX 30 kb) Biochem Biophys Res Com. 2008;369:1125–8. 4. Missaglia S, Valadared ER, Moro L, Faguntes ED, Quintão Roque R, Giardina B, et al. Early onset of Chanarin-Dorfman syndrome with severe liver Abbreviations involvement in a patient with a complex rearrangement of ABHD5 ABHD5: α/β-hydrolase domain-containing protein 5; ALT: Alanine promoter. BMC Med Genet. 2014;15:32. aminotransferase test; AST: Aspartate aminotransferase test; ATGL: Adipose 5. Takeichi T, Sugiura K, Tso S, Simpson MA, McGrath JA, Akiyama M. Bi-allelic triglyceride lipase; CDS: Chanarin-Dorfman syndrome; CK: Creatine kinase; nonsense mutations in ABHD5 underlie a mild phenotype of Dorfman- GGT: Gamma glutamyl transpeptidase; LD: Lipid droplet; MCT: Medium chain Chanarin syndrome. J Dermatol Sci. 2016;81:134–6. triglycerides; NCIE: Non-bullous congenital ichthyosiform erythroderma; 6. Lefevre C, Jobard F, Caux F, Bouadjar B, Karaduman A, Heilig R, et al. NLSDI: Neutral lipid storage disease with ichthyosis; TG: Triacylglicerol Mutations in CGI-58, the gene encoding a new protein of the esterase/ lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome. Am J Hum Acknowledgements Genet. 2001;69:1002–12. The authors are grateful to the patients for their kind cooperation. 7. Welte MA. Expanding roles for lipid droplets. Curr Biol. 2015; https://doi.org/ 10.1016/j.cub.2015.04.004. Funding 8. Prates EG, Nunes JT, Pereira RM. A role of lipid metabolism during cumulus- Università Cattolica del Sacro Cuore (Milan, Italy) sustained the publication of oocyte complex maturation: impact of lipid modulators to improve embryo this article. production. Mediat Inflamm. 2014; https://doi.org/10.1155/2014/692067. 9. Tavian D, Colombo R. Improved cytochemical method for detecting Jordans’ Availability of data and materials bodies in neutral-lipid storage diseases. J Clin Pathol. 2007;60:956–8. Data obtained during this study are included in the article and its additional files. 10. Nur BG, Gencpinar P, Yuzbasioglu A, Emre SD, Mihci E. Chanarin Dorfman syndrome: genotype-phenotype correlation. Eur J Med Genet. 2015;58:238–42. Authors’ contributions 11. Ujihara M, Nakajima K, Yamamoto M, Teraishi M, Uchida Y, Akiyama M, et al. MD performed the clinical characterization of patients and he is taking care Epidermal triglyceride levels are correlated with severity of ichthyosis in of them; SM performed the molecular analysis and critically revised the Dorfman-Chanarin syndrome. J Dermatol Sci. 2010;57:102–7. manuscript; LM supervised the study and critically revised the manuscript; 12. Pennisi EM, Arca M, Bertini E, Bruno C, Cassandrini D. D'amico a et al. DT conceived the study, supervised it and wrote the manuscript. All authors clinical/genetic features and natural history in a large cohort of Italian read and approved the final manuscript. patients. Orphanet J Rare Dis. 2017;12:90. 13. Gupta N, Gothwal S, Satpathy AK, Missaglia S, Tavian D, Das P, et al. Ethics approval and consent to participate Chanarin Dorfman syndrome. A case report with novel nonsense mutation. Informed consent for genetic analysis was obtained from the study participants. Gene. 2016;10:359–62. This manuscript reports the description of a family who presented with CDS clinical symptoms. No experiments were performed and no hypothesis were tested for this study. This case report does not constitute systematic research, therefore no ethics approval was necessary. Consent for publication Written informed consent was obtained from adult patients and the guardians of two young patients for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details Baskent University Faculty of Medicine, Department of Dermatology, Adana Hospital, Adana, Turkey. Laboratory of Cellular Biochemistry and Molecular Biology-CRIBENS, Catholic University of the Sacred Heart, pz Buonarroti 30, 20145 Milan, Italy. Department of Psychology, Catholic University of the Sacred Heart, Largo Gemelli 1, 20123 Milan, Italy. Department of Pharmaceutical Sciences, University of Piemonte Orientale, Lgo Donegani 2, 28100 Novara, Italy. Received: 19 February 2018 Accepted: 18 May 2018 References 1. Schweiger M, Lass A, Zimmermann R, Eichmann TO, Zechner R. Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2 or CGI-58/ABHD5. Am J Physiol Endocrinol Metab. 2009;297: 289–96. 2. Redaelli C, Coleman RA, Moro L, Dacou-Voutetakis C, Elsayed SM, Prati D, Colli A, Mela D, Colombo R, Tavian D. Clinical and genetic characterization

Journal

BMC Medical GeneticsSpringer Journals

Published: May 29, 2018

References

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