SHORT COMMUNICATION
Clinical Zinc Deficiency as Early Presentation of Wilson Disease Stephanie Van Biervliet, zSe´bastien Ku¨ry, Ruth De Bruyne, yOlivier M. Vanakker, z Se´bastien Schmitt, Saskia Vande Velde, §Eric Blouin, and zSte´phane Be´zieau
See ‘‘Wilson Disease: A Matter of Copper, But Also of Zinc’’ by Iorio and Ranucci on page 423.
What Is Known
ABSTRACT Wilson disease is a rare autosomal recessive disorder of the copper metabolism caused by homozygous or compound heterozygous mutations in the ATP-ase Cu(2þ) transporting polypeptide (ATP7B) gene. The copper accumulation in different organs leads to the suspicion of Wilson disease. We describe a child with clinical zinc deficiency as presenting symptom of Wilson disease, which was confirmed by 2 mutations within the ATP7B gene and an increased copper excretion.
Wilson disease can be accompanied by subclinical zinc deficiency. Wilson disease has a multitude of clinical disguises, making diagnosis sometimes difficult. Genetic testing can reveal clinically unsuspected diagnoses.
What Is New
Clinical zinc deficiency can be a first symptom of Wilson disease. Association to mutations in the zinc pathway can aggravate the clinical picture.
Key Words: acrodermatitis-like eruption, Wilson disease, zinc deficiency
(JPGN 2015;60: 457–459)
W
ilson disease (MIM #277900) is a rare autosomal recessive disorder (1/30.000–1/100.000 individuals) of the copper metabolism caused by homozygous or compound heterozygous mutations in the ATP-ase Cu(2þ) transporting polypeptide (ATP7B) gene (1,2). Copper accumulation in liver, brain, cornea, and kidneys leads to the most frequent presenting symptoms of progressive liver degeneration (40% of cases), neurological symptoms (35%), Kayser-Fleischer rings, sunflower cataract, and psychiatric problems (10%). Children (>3 years of age) are more likely to present with hepatic symptoms, whereas young adults will more
Received May 6, 2014; accepted November 1, 2014. From the Pediatric Gastroenterology and Hepatology Department, the yCenter for Medical Genetics, Ghent University Hospital, Ghent, Belgium, the zCHU Nantes, Service de Ge´ne´tique Me´dicale, Nantes, Cedex 1, and the §Laboratoire LABCATAL, Montrouge, France. Address correspondence and reprint requests to Stephanie Van Biervliet, MD, PhD, Paediatric Gastroenterology and Nutrition, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium (e-mail: stephanie. [email protected]). The custom high-throughput sequencing, the results of which are presented in the report, was made possible through funding by the laboratory LABCATAL (Montrouge, France). Drs Van Biervliet and Ku¨ry contributed equally to this article. The authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000628
JPGN
Volume 60, Number 4, April 2015
frequently present with neurological symptoms (3). The remaining 15% to 20% of patients have symptoms attributable to involvement of other organs such as the kidney (Fanconi syndrome, renal failure), the heart (cardiac failure), the pancreas (pancreatitis), red blood cells (haemolytic anaemia), and skin (nail, skin discoloration) (4–8). Seven years ago, a 2.5-year-old white boy was referred for a periocular, perioral, and perineal skin eruption since the age of 12 months, which was resistant to local steroids, antifungal and, antibacterial therapy as well as oral antibiotic therapy; he also complained of frequent episodes of diarrhoea. He displayed a sharpedged scaly eruption on the above-mentioned locations with an angular cheilitis (Fig. 1). The lesions were infected with Streptococcus pneumoniae. Because the clinical picture was consistent with acrodermatitis enteropathica (AEZ, MIM #201100), a rare autosomal recessive form of severe zinc deficiency, serum zinc levels were measured and found decreased (41.1 mg/dL [normal values 65–150 mg/dL]). The child having a typical Western diet, rich in meat and low in cereals, had a normal zinc intake as calculated by the dietician, which excluded a nutritional zinc deficiency. Familial history was negative. No aetiology which could lead to secondary zinc deficiency because of maldigestion and malabsorption was found, as the sweat test was normal (chloride 29 mmol/L [normal values 0–40 mmol/L]), coeliac serology was negative, and faecal elastase was normal (>500). Duodenal biopsies collected during gastroduodenoscopy were normal. There was no parasitic infestation. Abdominal ultrasound was normal. Rast tests, total IgE, and skin-prick tests for common food allergens were negative, and no association to the intake could be found using an intake-symptom diary. A zinc acetate supplementation was then started (initially dosed at 4.5 mg elemental zinc/kg body weight a day, tapered until
457
Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Van Biervliet et al
JPGN
Volume 60, Number 4, April 2015
FIGURE 1. Cutaneous lesions around the nose, eyes, and mouth at presentation.
1 mg kg1 day1 based on clinical complaints and serum zinc levels), which normalised serum zinc levels and fully resolved the cutaneous symptoms, although our patient remained susceptible for prolonged gastrointestinal infections, such as rotavirus, giardia lamblia, and adenovirus. An immunological screening including B- and T-lymphocyte, leukocyte transformation test, CD11 and CD8 identification, chemotaxis, immunoglobulins, and reaction on pneumococcal vaccination were all normal. He grew along the 10th percentile for height and the 25th percentile for weight, which was within the expected growth channel based on the parents’ height. During follow-up the serum zinc levels, liver enzymes, serum copper, and ceruloplasmin remained normal. To verify the hypothesis of an AEZ, genomic DNA extracted from the child’s venous blood samples was screened by Sanger sequencing for mutations of SLC39A4, a major intestinal zinc transporter. As this initial testing was negative, the search was expanded to the high-throughput sequencing (using a custom Sureselect library (Santa Clara, CA) on a Genetic Analyzer (Illumina, San Diego, CA) of 50 genes directly involved in cellular zinc ion homeostasis according to the Gene Ontology database AMIGO 2 (http://amigo.geneontology.org/amigo/term/GO:0006882). This approach revealed, 7 years after the initial presentation, the presence of 2 compound heterozygous mutations in the Wilson disease gene ATP7B (NM_000053.3): c.1995G>A (p.Met665Ile) in exon 7 inherited from the father, and c.2804C>T (p.Thr935Met) in exon 12 inherited from the mother; validation and segregation analysis of both mutations were done by Sanger sequencing. The mutation c.1995G>A (p.Met665Ile) is referenced as rs72552259 in the variant public database dbSNP, and it is reported with a minor allele frequency of 0.26% in the white American population of European descent from the Exome Variant Server (National Heart, Lung, and Blood Institute Exome Sequencing Project, Seattle, WA; http://evs.gs.washington.edu/EVS, April 23, 2014). By contrast, the mutation c.2804C>T (p.Thr935Met) is absent from any public variant database. In addition, a third rare heterozygous variant, inherited from the father, was found in the child’s metallothionein gene MT1X (NM_005952.3): c.29–2A>T, reported as rs112485803 in database single-nucleotide polymorphism with a 0.05% minor allele frequency in European American individuals from Exome Variant Server (National Heart, Lung, and Blood Institute Exome Sequencing Project, http://evs.gs.washington. edu/EVS, April 23, 2014). The screening tests for Wilson disease were performed at the age of 10 years during low-dose zinc
458
supplementation (1 mg kg1 day1, 22.5 mg elemental zinc). The 24-hour urinary collection for copper revealed an increased excretion (217 mg/24 h (normal value:
Clinical Zinc Deficiency as Early Presentation of Wilson Disease Stephanie Van Biervliet, zSe´bastien Ku¨ry, Ruth De Bruyne, yOlivier M. Vanakker, z Se´bastien Schmitt, Saskia Vande Velde, §Eric Blouin, and zSte´phane Be´zieau
See ‘‘Wilson Disease: A Matter of Copper, But Also of Zinc’’ by Iorio and Ranucci on page 423.
What Is Known
ABSTRACT Wilson disease is a rare autosomal recessive disorder of the copper metabolism caused by homozygous or compound heterozygous mutations in the ATP-ase Cu(2þ) transporting polypeptide (ATP7B) gene. The copper accumulation in different organs leads to the suspicion of Wilson disease. We describe a child with clinical zinc deficiency as presenting symptom of Wilson disease, which was confirmed by 2 mutations within the ATP7B gene and an increased copper excretion.
Wilson disease can be accompanied by subclinical zinc deficiency. Wilson disease has a multitude of clinical disguises, making diagnosis sometimes difficult. Genetic testing can reveal clinically unsuspected diagnoses.
What Is New
Clinical zinc deficiency can be a first symptom of Wilson disease. Association to mutations in the zinc pathway can aggravate the clinical picture.
Key Words: acrodermatitis-like eruption, Wilson disease, zinc deficiency
(JPGN 2015;60: 457–459)
W
ilson disease (MIM #277900) is a rare autosomal recessive disorder (1/30.000–1/100.000 individuals) of the copper metabolism caused by homozygous or compound heterozygous mutations in the ATP-ase Cu(2þ) transporting polypeptide (ATP7B) gene (1,2). Copper accumulation in liver, brain, cornea, and kidneys leads to the most frequent presenting symptoms of progressive liver degeneration (40% of cases), neurological symptoms (35%), Kayser-Fleischer rings, sunflower cataract, and psychiatric problems (10%). Children (>3 years of age) are more likely to present with hepatic symptoms, whereas young adults will more
Received May 6, 2014; accepted November 1, 2014. From the Pediatric Gastroenterology and Hepatology Department, the yCenter for Medical Genetics, Ghent University Hospital, Ghent, Belgium, the zCHU Nantes, Service de Ge´ne´tique Me´dicale, Nantes, Cedex 1, and the §Laboratoire LABCATAL, Montrouge, France. Address correspondence and reprint requests to Stephanie Van Biervliet, MD, PhD, Paediatric Gastroenterology and Nutrition, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium (e-mail: stephanie. [email protected]). The custom high-throughput sequencing, the results of which are presented in the report, was made possible through funding by the laboratory LABCATAL (Montrouge, France). Drs Van Biervliet and Ku¨ry contributed equally to this article. The authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000628
JPGN
Volume 60, Number 4, April 2015
frequently present with neurological symptoms (3). The remaining 15% to 20% of patients have symptoms attributable to involvement of other organs such as the kidney (Fanconi syndrome, renal failure), the heart (cardiac failure), the pancreas (pancreatitis), red blood cells (haemolytic anaemia), and skin (nail, skin discoloration) (4–8). Seven years ago, a 2.5-year-old white boy was referred for a periocular, perioral, and perineal skin eruption since the age of 12 months, which was resistant to local steroids, antifungal and, antibacterial therapy as well as oral antibiotic therapy; he also complained of frequent episodes of diarrhoea. He displayed a sharpedged scaly eruption on the above-mentioned locations with an angular cheilitis (Fig. 1). The lesions were infected with Streptococcus pneumoniae. Because the clinical picture was consistent with acrodermatitis enteropathica (AEZ, MIM #201100), a rare autosomal recessive form of severe zinc deficiency, serum zinc levels were measured and found decreased (41.1 mg/dL [normal values 65–150 mg/dL]). The child having a typical Western diet, rich in meat and low in cereals, had a normal zinc intake as calculated by the dietician, which excluded a nutritional zinc deficiency. Familial history was negative. No aetiology which could lead to secondary zinc deficiency because of maldigestion and malabsorption was found, as the sweat test was normal (chloride 29 mmol/L [normal values 0–40 mmol/L]), coeliac serology was negative, and faecal elastase was normal (>500). Duodenal biopsies collected during gastroduodenoscopy were normal. There was no parasitic infestation. Abdominal ultrasound was normal. Rast tests, total IgE, and skin-prick tests for common food allergens were negative, and no association to the intake could be found using an intake-symptom diary. A zinc acetate supplementation was then started (initially dosed at 4.5 mg elemental zinc/kg body weight a day, tapered until
457
Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Van Biervliet et al
JPGN
Volume 60, Number 4, April 2015
FIGURE 1. Cutaneous lesions around the nose, eyes, and mouth at presentation.
1 mg kg1 day1 based on clinical complaints and serum zinc levels), which normalised serum zinc levels and fully resolved the cutaneous symptoms, although our patient remained susceptible for prolonged gastrointestinal infections, such as rotavirus, giardia lamblia, and adenovirus. An immunological screening including B- and T-lymphocyte, leukocyte transformation test, CD11 and CD8 identification, chemotaxis, immunoglobulins, and reaction on pneumococcal vaccination were all normal. He grew along the 10th percentile for height and the 25th percentile for weight, which was within the expected growth channel based on the parents’ height. During follow-up the serum zinc levels, liver enzymes, serum copper, and ceruloplasmin remained normal. To verify the hypothesis of an AEZ, genomic DNA extracted from the child’s venous blood samples was screened by Sanger sequencing for mutations of SLC39A4, a major intestinal zinc transporter. As this initial testing was negative, the search was expanded to the high-throughput sequencing (using a custom Sureselect library (Santa Clara, CA) on a Genetic Analyzer (Illumina, San Diego, CA) of 50 genes directly involved in cellular zinc ion homeostasis according to the Gene Ontology database AMIGO 2 (http://amigo.geneontology.org/amigo/term/GO:0006882). This approach revealed, 7 years after the initial presentation, the presence of 2 compound heterozygous mutations in the Wilson disease gene ATP7B (NM_000053.3): c.1995G>A (p.Met665Ile) in exon 7 inherited from the father, and c.2804C>T (p.Thr935Met) in exon 12 inherited from the mother; validation and segregation analysis of both mutations were done by Sanger sequencing. The mutation c.1995G>A (p.Met665Ile) is referenced as rs72552259 in the variant public database dbSNP, and it is reported with a minor allele frequency of 0.26% in the white American population of European descent from the Exome Variant Server (National Heart, Lung, and Blood Institute Exome Sequencing Project, Seattle, WA; http://evs.gs.washington.edu/EVS, April 23, 2014). By contrast, the mutation c.2804C>T (p.Thr935Met) is absent from any public variant database. In addition, a third rare heterozygous variant, inherited from the father, was found in the child’s metallothionein gene MT1X (NM_005952.3): c.29–2A>T, reported as rs112485803 in database single-nucleotide polymorphism with a 0.05% minor allele frequency in European American individuals from Exome Variant Server (National Heart, Lung, and Blood Institute Exome Sequencing Project, http://evs.gs.washington. edu/EVS, April 23, 2014). The screening tests for Wilson disease were performed at the age of 10 years during low-dose zinc
458
supplementation (1 mg kg1 day1, 22.5 mg elemental zinc). The 24-hour urinary collection for copper revealed an increased excretion (217 mg/24 h (normal value:
