Kayser-Fleischer Corneal Ring Research Articles

Wilson Disease: Copper-Mediated Cuproptosis, Iron-Related Ferroptosis, and Clinical Highlights, with Comprehensive and Critical Analysis Update.

Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu2+ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber-Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge.

Clinical manifestations of Wilson disease in organs other than the liver and brain.

Wilson disease (WD) is an inherited genetic disorder that is caused by copper metabolism disturbances with main hepatic, neurological, and psychiatric presentation. Deposits of copper accumulate in different organs and may cause a broad range of clinical manifestations. Patients with WD may present with ophthalmological symptoms, or renal, cardiac and osteoarticular involvement. The most common ophthalmological sign as a result of copper accumulation is the Kayser-Fleischer corneal ring, whereas sunflower cataracts are observed rarely. Retinal degeneration, present in WD patients, may serve as a marker of neurodegeneration. Osteoarticular involvement is quite common and includes osteopenia, osteoporosis and arthropathy, which may lead to bone fractures and joint problems mainly affecting knees and wrists. Renal disturbances include tubular dysfunction and renal calculi. A recent cardiac study has shown a higher risk of atrial fibrillation and heart failure in WD patients than in non-WD patients. Autonomic system dysfunction is also observed, but involvement is subclinical in most cases. Another manifestation of WD concerns endocrine system disturbances, which can lead to recurrent abortions, infertility, growth disruption, and parathyroid failure. However, it is possible to become pregnant for females with mild WD symptoms and for those who are compliant with therapy. Hematologic disturbances are frequent and may include acute hemolytic anemia, leucopenia, anemia and low platelet count. Other observed symptoms include lipomas and characteristic of WD skin changes like hyperpigmentation of the legs, xerosis or azure lunulae of the nails. In this paper, we present some of the less common, but nevertheless, important manifestations of WD.

Hepatic manifestations of Wilson's disease: 12-year experience in a Swiss tertiary referral centre.

Wilson’s disease is an inherited disorder of hepatic copper metabolism, leading to the accumulation of copper in the liver as well as the brain, cornea and other organs. Here, we describe the adult cases of hepatic Wilson’s disease diagnosed at the Division of Gastroenterology and Hepatology of the University Hospital Lausanne, Switzerland between September 2004 and August 2016. Clinical manifestations, results of diagnostic tests, management and outcomes of adult patients with hepatic Wilson’s disease were assessed based on standardised medical records. In addition, liver histology was reviewed and the lesional patterns were recorded. Ten new adult cases of hepatic Wilson’s disease were diagnosed in our centre between September 2004 and August 2016. Male to female ratio was 1:1 and median age at diagnosis was 26 (range 18–56) years. Four patients presented with acute liver failure, four with persistently elevated liver function tests, and two with decompensated cirrhosis; none had neurological manifestations. Only one patient had a Kayser-Fleischer corneal ring. Median ceruloplasmin level at diagnosis was 0.13 (range <0.03–0.30) g/l, median 24-hour urinary copper excretion was 2.8 (range 0.3–77.3) μmol, and median hepatic copper concentration was 789 (range 284–1677) μg/g. At least one mutation in the ATP7B gene was identified in eight patients. Allelic frequency of the common H1069Q mutation was 19%. Leipzig score was ≥5 in all patients. Three patients presenting with acute liver failure and the two with decompensated cirrhosis underwent successful liver transplantation. One patient with acute liver failure recovered under chelation therapy, as predicted by a Dhawan score <11. D-penicillamine was used as first-line chelator treatment, with a subsequent switch to trientine due to adverse effects in three out of six patients. The clinical presentation of hepatic Wilson’s disease is highly variable. Three out of 10 patients were diagnosed at an age >35 years. A high index of suspicion in clinically compatible situations is key.

Living Donor Liver Transplantation for Wilson’s Disease Associated with Fulminant Hepatic Failure: A Case Report

Patient: Female, 17Final Diagnosis: Fulminant Wilson’s diseaseSymptoms: General jaundice • malaise • abdominal painMedication: —Clinical Procedure: ICUSpecialty: TransplantologyObjective:Rare diseaseBackground:Liver transplantation is indicated for patients with Wilson’s disease (WD) who present either with acute liver failure or with end-stage liver disease and severe hepatic insufficiency as the first sign of disease. However, almost all reported cases have been treated with death donor liver transplantation. Here we report the case of a patient with WD associated with fulminant hepatic failure (WD-FHF) who underwent living donor liver transplantation (LDLT).Case Report:A 17-year-old female was diagnosed with WD-FHF based on high uric copper (10 603 μg/day, normal <100 μg/day), low serum ceruloplasmin (15 mg/dL, normal >20 mg/dL) and Kayser-Fleischer (K-F) corneal ring, and acute liver failure (ALF), acute renal failure (ARF) and grade 2 hepatic encephalopathy (HE). The model for end-stage liver disease (MELD) score was 35. Due to her critical condition, the patient underwent LDLT utilizing a right liver graft from her 44-year-old mother. The right hepatic vein (RHV) and inferior right hepatic vein (iRHV) were reconstructed. She developed severe liver dysfunction due to a crooked hepatic vein caused by compression from the large graft. To straighten the bend, a reoperation was performed. During the operation, we tried to relieve the compressed hepatic vein by adjusting the graft location, but the benefits were limited. We therefore performed stenting in both the RHV and iRHV on postoperative day 9. The patient gradually improved, exhibiting good liver and renal functions, and was finally discharged on postoperative day 114.Conclusions:When WD-FHF deteriorates too rapidly for conservative management, LDLT is an effective therapeutic strategy.

Anesthetic Management of a Pediatric Patient With Wilson’s Disease

Wilson’s disease, characterized by cirrhosis, extrapyramidal symptoms and Kayser-Fleischer corneal rings, is a rare hereditary disease of human copper metabolism. Clinical findings in Wilson’s disease are complex and neurological symptoms such as tremor, dysarthria, rigid dystonia, seizures, psychiatric disorders, acute liver failure, chronic hepatitis or cirrhosis may develop. A 4-year-old male patient was operated for traumatic depressed skull fracture and intracerebral hematoma. He was diagnosed with Wilson’s disease at the age of 2.5 years and treated with zinc sulphate and D-penicillamine. General anesthesia was induced with propofol, fentanyl, atracurium, and maintained with isoflurane, and oxygen. No complications were encountered during the operation or in the postoperative period. We concluded that general anesthesia can successfully be given to Wilson’s disease patients using an anesthetic agent, the metabolism of which is least affected by the liver disease, one that induces least hepatic toxicity. By close follow-up of patients clinically and biochemically, it is possible to reduce the complication rates to a minimum. doi:10.4021/jocmr2010.04.292w

Anesthetic Management of a Pediatric Patient With Wilson’s Disease

Wilsons disease, characterized by cirrhosis, extrapyramidal symptoms and Kayser-Fleischer corneal rings, is a rare hereditary disease of human copper metabolism. Clinical findings in Wilsons disease are complex and neurological symptoms such as tremor, dysarthria, rigid dystonia, seizures, psychiatric disorders, acute liver failure, chronic hepatitis or cirrhosis may develop. A 4-year-old male patient was operated for traumatic depressed skull fracture and intracerebral hematoma. He was diagnosed with Wilsons disease at the age of 2.5 years and treated with zinc sulphate and D-penicillamine. General anesthesia was induced with propofol, fentanyl, atracurium, and maintained with isoflurane, and oxygen. No complications were encountered during the operation or in the postoperative period. We concluded that general anesthesia can successfully be given to Wilsons disease patients using an anesthetic agent, the metabolism of which is least affected by the liver disease, one that induces least hepatic toxicity. By close follow-up of patients clinically and biochemically, it is possible to reduce the complication rates to a minimum.KeywordsWilson's Disease; Craniocerebral trauma; Thoracic injuries; General anesthesia; Surgery

Morbus Wilson: eine klinische und molekularbiologische Kasuistik

Wilson's disease is a rare autosomal recessively inherited disorder of copper metabolism resulting in accumulation of copper in many organs. The Kayser-Fleischer corneal ring represents a typical symptom in Wilson patients. ATP7B, the gene product of the Wilson's disease gene, is expressed in hepatocytes and plays a critical role in copper transport and secretion. Mutations encompassing this gene leading to amino acid substitutions reduce the affinity of the ATPase enzyme to copper and prevent the transport of copper through the hepatocytes into the bile duct. More than 200 mutations in the 21 coding exons of the Wilson's disease gene ATP7B have been described, the most common European one being Hisl069Gln (30-60% in European patients). Wilson's disease may present with various clinical symptoms, commonly as liver and neuropsychiatric disease. The diagnosis of Wilson's disease (prevalence 1:30000) is based on a combination of clinical and neurological symptoms (Kayser-Fleischer corneal ring, MRI), a multi-parametric clinical chemistry panel (ceruloplasmin, 24 h-copper excretion in urine, serum copper) and molecular genetic analysis of ATP7B gene mutations. Symptomatic patients are treated with the chelating agents D-penicillamine or trientine, and in a second phase often with zinc. Lifelong therapy is required and provides life expectancy near to normal. Here, we report on the long-term follow-up of a 30-year-old Wilson patient displaying a compound heterozygosity of His1069Gln -Asnl270Ser mutations in the ATP7B gene as diagnosed by LightCycler real time polymerase chain reaction and DNA sequencing of exon 18. Molecular family-pedigree analysis over four generations revealed seven additional heterozygous mutation carriers. Treatment of the index patient with high doses of chelating agent D-penicillamine (1500 mg/d) in combination with zinc (150 mg/d) could reverse copper encephalopathy to normal and markedly reduced neurological symptoms. Kayser-Fleischer corneal ring was persistent. Wilson's disease should be taken into consideration in case of any liver disease of unknown origin or neuropsychiatric symptoms. Current diagnostic panels (international scoring system) encompassing clinical chemistry and molecular genetics for screening and confirmation of Wilson's disease are discussed.

Wilson Disease

Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism, resulting in pathological accumulation of copper in many organs and tissues. The hallmarks of the disease are the presence of liver disease, neurologic symptoms, and Kayser-Fleischer corneal rings. The leading neurologic symptoms in WD are dysathria, dyspraxia, ataxia, and Parkinsonian-like extrapyramidal signs. Changes in the basal ganglia in brain magnetic resonance imaging (MRI) are characteristic features of the disease. In presence of liver cirrhosis, some features may resemble hepatic encephalopathy. Symptoms and MRI abnormalities may be fully reversible on treatment with zinc or copper chelators. Improvement can be monitored by serial recording of brain-stem-evoked responses. The basic defect is an impaired trafficking of copper in hepatocytes. ATP7B is the gene product of the WD gene located on chromosome 13 and resides in hepatocytes in the trans-Golgi network, transporting copper into the secretory pathway for incorporation into apoceruloplasmin and excretion into the bile. While about 40% of patients preset with neurologic symptoms, little is known about the role of copper and ATP7B in the central nervous system. In some brain areas, like in the pineal gland, ATP7B is expressed and functionally active. Increasing evidence supports an important role for metals in neurobiology. Two proteins related to neurodegeneration are copper-binding proteins (1) the amyloid precursor protein (APP), a protein related to Alzheimer's disease, and (2) the Prion protein, related to Creutzfeldt-Jakob disease. A major source of free-radical production in the brain derives from copper. To prevent metal-mediated oxidative stress, cells have evolved complex metal transport systems. APP is a major regulator of neuronal copper homeostasis and has a copper-binding domain (CuBD). The surface location of this site, structural homology of CuBD to copper chaperones, and the role of APP in neuronal copper homeostasis are consistent with the CuBD acting as a neuronal metallotransporter. There are several copper-containing enzymes in the brain, like dopamine beta hydroxylase or Cu/Zn superoxide dismutase (SOD1). Their function may be altered because of copper overload. WD appears to be associated with a dopaminergic deficit. Mutations in the SOD1gene cause familial amyotrophic lateral sclerosis. Survival of transgenic mice with a mutant SOD1 which fails to incorporate Cu((2+)) in its active site was improved by copper depletion. Wilson disease (WD) is an autosomal recessive inherited disorder in which copper pathologically accumulates primarily within the liver and subsequently in the neurologic system and many other organs and tissues. Presence of liver disease, neurologic symptoms, and Kayser-Fleischer corneal rings are the hallmarks of the disease.

Wilson's Disease

THE TALENTS of S. A. Kinnier Wilson (1878 to 1937) were most apparent at the bedside and in the lecture hall. 1,2 He had little interest in experimentation and confined his attention to clinical matters. Thus, during his long professional career at the National Hospital, Queen Square, London, 3-5 Wilson wrote on a variety of clinical topics, ending with a two-volume textbook of neurology that was edited and published after his death. 6 Perhaps the best of these many contributions was a lengthy masterpiece that Wilson prepared for the MD degree at the University of Edinburgh. 7 In it, he reviewed a few previous reports and added four personal cases, crystallizing all of this information into a classic description of a distinct disease. But Wilson did not recognize the existence of the Kayser-Fleischer corneal ring 8-11 in his patients, and this sign was not appreciated as a manifestation of progressive

Outcome of liver transplantation in Wilson's disease: A demonstrative case

A Wilson's disease (WD) patient developed a progressive liver cirrhosis and a disabling 'rubral' tremor, despite decoppering therapy, and subsequently underwent orthotopic liver transplantation (OLT). This case illustrates the outcome of OLT in WD, by demonstrating: (a) correction of the metabolic syndrome without further deposition of copper in the transplanted liver, (b) improvement of the neurological condition, (c) concomitant mobilization of copper deposits, as suggested by the fading of the Kayser-Fleischer corneal rings, (d) fading of brain MRI signal abnormalities on T2 weighted images. This case illustrates that OLT can be considered in WD, but only with caution because of the significant morbidity of the procedure.

Paediatric liver transplantation: a 10 year experience in Taiwan.

Between March 1984 and August 1994, 13 orthotopic liver transplantations were performed in 13 patients < or = 25 years of age. The indications included Wilson's disease (n = 7), biliary atresia (n = 4), choledochal cyst (n = 1) and hepatitis C cirrhosis (n = 1). Technical variants included full-size (n = 11), reduced-size (n = 1) and living-related (n = 1) liver transplantation. These recent technical innovations have offered an expanded donor pool for earlier transplantation, shorter waiting times and excellent quality grafts. Surgical complications occurred in six patients; all required additional surgery. Biliary complications were encountered more commonly in our earlier patients. Our actuarial patient and graft survival rate is 92% at 2 years. The long-term follow-up of our liver-transplanted Wilson's disease patients provides confirmatory evidence that orthotopic liver transplantation cures the underlying metabolic defect with complete normalization of biochemical abnormalities of copper metabolism, reversal of neurological impairments and the disappearance of Kayser-Fleischer corneal rings. The high rate of patient survival and excellent rehabilitation indicate that with prudent clinical judgement, liver transplantation can be achieved with an acceptable rate of morbidity, mortality and cost in a setting where manpower and donor organs are very limited.

Wilson''s Disease in the Adult

We reported three cases of Wilson's disease in the adult. Onset of Wilson's disease occurs between 4 and 40 years of age, but is relatively rare in adults. In a typically progressed stage the disease may easily be diagnosed from findings of Kayser-Fleischer's corneal ring in addition to the clinical features as neurologic manifestation and liver involvement, but there still remain many unknown problems concerning abnormal copper metabolism in Wilson's disease. The retention of radioactive copper (64Cu) was measured with a whole body counter in three patients with Wilson's disease, four of their family members and two control subjects. The 64Cu retained in the body showed high value in the patients with Wilson's disease, which may reflect a larger copper pool than in normal subjects. The applicability of retention measurement with 64Cu as a screening test is discussed. Study of the body retention of 64Cu may be useful as a screening test to differentiate the carrier from normal individuals in the family of Wilson's disease. In Wilson's disease, excretion of urinary copper and body retention of radiocopper increased. Urinary copper in Wilson's disease may be excreted via the copper pool, rather than directly after absorption through the intestine.

The Characterisation of Individuals with Respect to Wilson's Disease

In the case of heredo-familial diseases it is desirable to identify the abnormal genotype, the homozygously abnormal individual, if possible while still asymptomatic, and the carrier of the abnormal gene or allele, the heterozygote.So far as Wilson's disease is concerned, it is possible to diagnose individuals as presymptomatic homozygotes by finding Kayser-Fleischer corneal rings on slit-lamp microscopy, or by demonstrating increased liver-copper on needle biopsy.False-negative results are common, however, and more reliable identification of the presymptomatic homozygote as well as the heterozygote can be achieved by studies of the physiology of copper, using tracer doses of radioactive copper, 67copper, which has a physical half life of about 61 hours. Using this method it can be shown:1. That there is prolonged retention of copper in the whole body in both homozygotes and heterozygotes, the former showing more prolonged retention than the latter.2. In both there is retention of copper in the liver, again more marked in the homozygote than in the heterozygote.3. There is decreased intestinal excretion of copper in both cases as manifested by decreased biliary radiocopper and decreased stool radiocopper, and again this is most marked in the homozygote.4. Urinary excretion of radiocopper is usually increased significantly in the homozygote, but is usually normal or only very slightly increased in the heterozygote.5. The additional finding of impaired ceruloplasmin biosynthesis is sufficient usually to distinguish with certainty between the presymptomatic homozygote and the heterozygote.

Neurological classics XXXVI. Wilson's disease (S.A. Wilson).

THE TALENTS of S. A. Kinnier Wilson (1878 to 1937) were most apparent at the bedside and in the lecture hall. 1,2 He had little interest in experimentation and confined his attention to clinical matters. Thus, during his long professional career at the National Hospital, Queen Square, London, 3-5 Wilson wrote on a variety of clinical topics, ending with a two-volume textbook of neurology that was edited and published after his death. 6 Perhaps the best of these many contributions was a lengthy masterpiece that Wilson prepared for the MD degree at the University of Edinburgh. 7 In it, he reviewed a few previous reports and added four personal cases, crystallizing all of this information into a classic description of a distinct disease. But Wilson did not recognize the existence of the Kayser-Fleischer corneal ring 8-11 in his patients, and this sign was not appreciated as a manifestation of progressive

HEPATOLENTICULAR DEGENERATION; CLINICAL AND BIOCHEMICAL STUDY OF THREE CASES.

Após reverem os marcos fundamentais da história da moléstia de Wilson, os autores relatam 3 casos desta afecção. Dois pacientes faleceram, tendo o exame necroscópico confirmado o diagnóstico clínico-laboratorial. Entre as particularidades do quadro neurológico, sobressaía, em um caso, a existência de espasticidade em flexão e de sinais cerebelares. O anel corneano de Kayser-Fleischer apresentou-se sempre completo e bilateral. Entre os caracteres inconstantes do proteinograma do líquido cefalor-raqueano são salientadas a ausência de pré-albumina e os baixos níveis de globulinas 1 e 2. Provàvelmente pela primeira vez, foi observada redução dos valôres de fósforo e magnésio no sôro sangüíneo. O estudo das funções hepática e renal foi realizado por meio dos testes convencionais, tendo-se verificado que o comprometimento do fígado era discreto, em nítida desproporção com o grau de lesão histológica do órgão (cirrose pós-necrótica). Em relação aos rins, foi comprovada hiperaminacidúria em dois casos, associada a discreta diminuição da excreção tubular, em um deles. A análise genética pôde ser mais aprofundada em um dos casos, incluindo a pesquisa, nos seus familiares, do anel de Kayser-Fleischer, a determinação dos valôres de cobre no sangue e urina, e da ceruloplasminemia, além do estudo citogenético do paciente. O anel corneano foi comprovado em uma irmã assintomática, ocorrendo nela e em outros parentes nítidas alterações do metabolismo do cobre. O estudo do conteúdo de cobre nos tecidos confirmou os dados da literatura quanto ao acúmulo desse metal no pancreas, rins, supra-renais, fígado, substâncias branca e cinzenta do cérebro, tálamo, córtex cerebelar e núcleo lentículo-caudado, assim como níveis normais nas unhas e baixos nos cabelos. Verificação provàvelmente inédita foi o achado de acúmulo de cobre na substância negra e núcleo rubro, assim como nas glândulas submandibulares e no cerume. No líquido cefalorraqueano os valôres do cobre total se encontravam dentro dos limites normais e muito próximos dos do cobre de reação direta. Na bile, de acordo com as referências da literatura, observamos concentração de cobre normal na bile total e na fração B, e valôres diminuídos nas biles A e C. Em todos os casos verificou-se diminuição da concentração de cobre e ceruloplasmina no sangue e elevação dos valores na urina e saliva. O cobre de reação direta do soro, determinado em um caso, mostrou-se em nível relativamente alto. O estudo dos balanços metabólicos demonstrou positividade para o cobre nos períodos de contrôle, e discreta negatividade do balanço do fósforo. Após o emprego do BAL, e particularmente da D-penicilamina, o balanço do cobre se negativou e o do fósforo tornou-se mais acentuadamente negativo. Dieta hipocúprica, resinas permutadoras de cations ou sulfeto de potássio foram associados aos agentes complexantes. A melhora clínica, embora nítida no caso 3 após o uso de D-penicilamina e estrógenos, não correspondeu ao excelente resultado bioquímico.

Metabolic balance studies in hepatolenticular degeneration treated with diethyldithiocarbamate

Metabolic balance studies carried out on a thirty-four year old woman with Wilson's disease who was treated with sodium diethyldithiocarbamate (“dithiocarb”) during a period of five months are described. Intravenous administration of dithiocarb in daily dosages of 10 and 20 mg. per kg. of body weight resulted in clinical improvement and increased excretion of copper in the urine but did not reverse the pre-existing positive copper balance. Oral administration of dithiocarb in daily dosage of 30 mg. per kg. of body weight produced a threefold increase in the fecal excretion of copper and thereby resulted in negative copper balance. Measurements of nickel revealed that the patient maintained a positive nickel balance. Administration of dithiocarb intravenously in dosage of 20 mg. per kg. of body weight, or orally, in dosage of 30 mg. per kg., resulted in a negative metabolic balance for nickel. Treatment with dithiocarb was accompanied by a striking clinical response. The patient's neurologic involvement had been so severe that she had been unable to walk, to feed herself or to speak intelligibly. Following dithiocarb therapy she became able to speak clearly and to return to light housework. The Kayser-Fleischer corneal rings became less intense, and measurements of hepatic function returned to the normal ranges.

Abnormal copper metabolism and Kayser-Fleischer corneal ring associated with schistosoma infection. Report of a case.

Abnormal copper metabolism and Kayser-Fleischer corneal ring associated with schistosoma infection. Report of a case.