Children presenting with ALF without hepatic encephalopathy can be treated with chelation agents; however, the response to medication may take time given it can take at least 1 month for the improvement of prothrombin time and 312 months for normalization. The challenge of recognising WD early in the disease course, particularly in the context of much more prevalent mimics, is exacerbated by the incomplete sensitivity of the various diagnostic tests. Machado et al. A lack or dysfunction of this enzyme results in a progressive accumulation of copper in several organs, especially in the liver, the nervous system, corneas, kidneys, and heart. Clinical presentations of Wilson disease in children. In a large cohort of 308 consecutive patients presenting with ALF to tertiary care centers, WD accounted for eight cases (2.6%), of which one, five and two were hyperacute, acute and subacute, respectively (38). WD can occur at any age but most . Several different classifications of neurologic presentations have previously been proposed and this reflects the complexity of the features seen in WD. Consensus Paper: Revisiting the Symptoms and Signs of Cerebellar Syndrome. What Is the Life Expectancy of a Person With Wilson's Disease? Scheinberg IH, Sternlieb I. Wilson's disease. Roy-Chowdhury J, Schilsky ML. Evaluation of the scoring system for the diagnosis of Wilson's disease in children. Zinc increases fecal copper excretion by inducing enterocyte metallothionein to complex with copper and inhibiting the entry of this complex into the portal circulation. In those seen during the episode, the features were of anemia, a raised reticulocyte count, negative direct antiglobulin (Coombs) test and hyperbilirubinemia, with conjugated versus unconjugated bilirubin around 5070%, presumably because of concomitant liver disease. Normally, your liver gets rid of extra copper by sending it out in bile. Motor impairment in Wilson's disease, II: Slowness of speech. However, these findings are not seen in all cases (48). Show full text. Yener S, Akarsu M, Karacanci C, Sengul B, Topalak O, Biberoglu K, et al. However, ruling out WD before making the diagnosis of NAFLD in a child or adult is considered very important (55) because of the implications for management. Long term urinary copper excretion on Chelation therapy in children with Wilson disease. Dhawan et al. Oculogyric crisis as an initial manifestation of Wilson's disease. Wilson disease | Nature Reviews Disease Primers If the serum ceruloplasmin is low, slit lamp examination for KF rings and a urine collection to measure copper excretion, are performed. The importance of recognising and promptly investigating Wilson disease at the initial presentation should be understood by all those who assess patients with hepatic or neurologic disorders and/or train others in their specialty. ULN, upper limit of normal; WD, Wilson disease. Revisiting the topic of histochemically detectable copper in various liver diseases with special focus on venous outflow impairment. Aggarwal A, Bhatt M. Neurological Wilsons disease. It may reveal itself through poor performance at school or work, and was one of the initial symptoms in 26% of children in one cohort (23). These core movement disorders often occur in combination and may initially be subtle. Wilson disease is a disorder of copper metabolism that affects men and women; about 1 person in 30,000 has the disorder. Neurologic manifestations may be subtle and easily missed by patients presenting to hepatologists, and vice versa. Cognitive functioning in neurologically symptomatic and asymptomatic forms of Wilson's disease. [17,20,29] Associated hemolysis due to free copper could lead to a high total bilirubin. Roberts EA, Cox DW. Secondly, KF rings may be visible at the bedside. A recurring theme is that a combination of hepatic, neurologic, psychiatric and hemolytic manifestations can be identified at presentation but may be subtle and easily missed. In: Kerkar N, Roberts EA. . ATP7B also facilitates copper excretion into the bile by forming vesicles that traffic to the biliary canaliculi and excreted in stool [Figure 2]. Mounajjed T, Oxentenko AS, Qureshi H, Smyrk TC. Tang NL, Hui J, Huang D, Tang MF, Wang X, Wu J, et al. The copper deposits in the liver, brain, kidneys, and the eyes. [63] Zinc therapy has been used as first-line monotherapy in patients with neurological WD. Zaccherini G, Weiss E, Moreau R. Acute-on-chronic liver failure: Definitions, pathophysiology and principles of treatment. The dosage of penicillamine and trientine can be decreased to the minimum necessary to maintain clinical and biochemical stability,[43] especially during the first trimester, as the risk of fetal teratogenicity is high in the first trimester, and the last trimester to avoid insufficient copper supply to the fetus and/or insufficient wound healing after caesarean section or episiotomy. Socha P, Janczyk W, Dhawan A, Baumann U, D'Antiga L, Tanner S, et al. Wenisch E, De Tassigny A, Trocello JM, et al. Wilson Disease - Nutritional Disorders - MSD Manual Professional Edition Neurological improvement is observed in 50%60% of patients over a longer time course of 13 years if early and correct pharmacological treatment has been introduced.[43]. Most people with Wilson's disease are diagnosed between the ages of 5 and 35, but it can affect younger and older people, as well. PDF Wilson'sdisease: clinical presentation prognosticindex - Gut Diverse functional properties of Wilson disease ATP7B variants. Manolaki N, Nikolopoulou G, Daikos GL, Panagiotakaki E, Tzetis M, Roma E, et al. Diagnosis of Wilson's disease: an experience over three decades Received 2021 Sep 21; Accepted 2021 Sep 25. Design: Retrospective cohort study with a mean follow-up period of 14.2 years. [21] In the muscle, copper induces the inhibition of Na+/K+-ATPase activity, leading to rhabdomyolysis. The frequency of mutations in the ATP7B gene in Russia. In 2001, a WD diagnostic score [Table 2] was developed by the Working Group at the 8th International Meeting on Wilson's disease in Leipzig. Wilson disease is a disorder of copper metabolism that, when untreated, can present with hepatic, neurologic, or psychiatric disturbances - or a combination of these - in individuals ages three years to older than 70 years. Other features of parkinsonism include rest tremor, rigidity, postural instability, an abnormal gait, hypomimia (reduced facial expression) and micrographia. 1Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology, London, UK; 2UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, London, UK. Tremor can be divided into postural, rest or kinetic on the basis of activating conditions. Currently, its practical application still requires further investigation, although good outcomes have been reported in experimental animal models by using an infusion of recombinant adeno-associated virus bearing ATP7B cDNA. Neuropsychiatric symptoms are rarely seen in children, especially in those younger than 10 years; however, 5%15% of children with hepatic manifestations could also have neurological symptoms. While WD can mimic other diseases, and vice versa, clinicians should be aware of the possibility of multiple diagnoses. (A) A circumferential ring of discoloration can be seen at the periphery of the cornea due to the deposition of copper in Descemets membrane. Handbook of Clinical Neurology. The asymptomatic patient with compensated cirrhosis may have features of chronic liver disease with spider naevi, splenomegaly and thrombocytopenia due to portal hypertension. The literature has drawn attention to the fact that the clinical picture including liver biopsy may suggest an autoimmune hepatitis (50), presenting at a similar age with jaundice, raised transaminases and gamma globulins, although autoantibodies are negative. Again, serum caeruloplasmin analysis should be requested but may be normal, and other tests for WD may be required, particularly with a positive family history, previous episodes of hemolysis or unexplained neurologic or psychiatric symptoms. Wilson's disease is a rare autosomal recessive disease, caused by impaired secretion of copper into bile due to a defective function of the ATPase 7B enzyme. The signs and symptoms of Wilson disease usually first appear between the ages of 6 and 45, but they most often begin during the teenage years. ATP7B transports copper through the trans-Golgi network in hepatocytes before it is incorporated into apoceruloplasmin which is secreted as holoceruloplasmin. . Wang JS, Lu Y, Wang XH, Zhu QR. A recent study proposed a promising method to directly measure the level of ATP7B peptides; this method could provide direct evidence of the consequences of the detected variants even if no second mutation was detected. [69] A recent study prospectively re-evaluated the WD index and proposed that patients with an index of 810 within the first 2 weeks of admission require close monitoring for at least 2 months, as the disease could progress and LT may become necessary (Chanpong and Dhawan. Ryan A, Nevitt SJ, Tuohy O, Cook P. Biomarkers for diagnosis of Wilson's disease. Guillaud O, Brunet AS, Mallet I, Dumortier J, Pelosse M, Heissat S, et al. Wilson disease has a range of clinical manifestations, from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurologic, and psychiatric. The amount of NCC is relatively calculated from total serum copper and ceruloplasmin concentrations with the following equation[38]: NCC (g/L) = Serum copper (g/L) [3.15 g/mg ceruloplasmin x ceruloplasmin (mg/L)]. Photographs courtesy of Mr. Fion Bremner, Consultant Neuro-ophthalmologist. Genetics Co. Committee opinion No 690: carrier screening in the age of genomic medicine. Relative exchangeable copper (REC) is the ratio between CuEXC and total serum copper, representing the toxic blood copper fraction. Wilson's disease presentation by Milan Marshall Wilson's disease is traditionally considered a disease of children and young adults. It presents in childhood, adolescence or adulthood with a wide range of clinical manifestations. Age,sex, but not ATP7B genotype effectively influences the clinical phenotype of Wilson disease. It is absorbed from food into the body through intestinal mucosa by using ATP7A transporter and transported via the portal system to the liver. Before [1] If the sibling carries homozygous ATP7B gene variants or the same compound heterozygous of the index patient, other diagnostic tests could be omitted.[53]. Counseling in young adults regarding fertility and therapeutic management during pregnancy and lactation is also essential. Anyone presenting with parkinsonism that is subacute or progressing over months or with concomitant dystonia or prominent dysarthria should also be promptly investigated. Liver transplantation for Wilson's disease: The burden of neurological and psychiatric disorders. The aims of treatment are to reduce copper levels and prevent its accumulation in the liver and other organs, especially in the central nervous system. Schilsky ML, Blank RR, Czaja MJ, Zern MA, Scheinberg IH, Stockert RJ, et al. Wilson's disease in patients presenting with liver disease: a diagnostic challenge. Once the disease progresses, patients may present with signs and symptoms of chronic liver disease (e.g., hepatosplenomegaly), or complications from cirrhosis (e.g., ascites and variceal bleeding). 27. report minimal changes or normal appearances in 310% of their series of patients (52). It is. Wilson disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. [43,64] In a randomized control trial, tetrathiomolybdate appeared to work more efficiently as compared to trientine in terms of neurologic preservation in adult WD patients with neurological involvement.[65]. If doubt exists over the significance of any subtle features then early input from the relevant specialist can be invaluable. Frontiers | Late-Onset Wilson's Disease 8600 Rockville Pike Wilson's disease with superimposed autoimmune features: report of two cases and review. Epidemiology and natural history of Wilson's disease in the Chinese: A territory-based study in Hong Kong between 2000 and 2016. [82,83] Ideally, a hepatologist with experience in WD should supervise on the treatment during pregnancy. Barnes and Hurst subsequently reported in 1925 that WD can present with symptomatic liver disease in the absence of neurologic features (11). Psychiatric features of WD are covered in more detail in another contribution but may be observed or easily assessed during a hepatic or neurologic consultation and are therefore only briefly mentioned here. [1,17,43] LT in patients with neurologic WD is still controversial. Genetic defects in Indian Wilson disease patients and genotype-phenotype correlation. Some physicians may be over-reliant on specific tests, for example serum ceruloplasmin levels, which may be normal in 40% of hepatic and 15% of neurologic presentations (Table 1) (24). The acute haemolytic syndrome in Wilson's disease--A review of 22 patients. [18] Of note, holoceruloplasmin is the major copper-containing protein with six copper atoms per molecule. People with untreated Wilson's disease may have a life expectancy of 40 years; however, early diagnosis and treatment can increase life span. Walshe and Marsden separately described the third category, which they referred to as parkinsonian (23,61,62). Wilson disease is present at birth (congenital), but the symptoms don't appear until copper builds up in your liver, brain, eyes or other organs. Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation. Hepatic failure and liver cell damage in acute Wilson's disease involve CD95 (APO-1/Fas) mediated apoptosis. have reported that pure parkinsonism occurred in less than 2% of neurologic presentations but that parkinsonism in combination with other movement disorders is seen in the majority; bradykinesia was reported in 58% of their cohort (66). In: Weiss KH, Schilsky M, editors. Wilson's disease with coexisting autoimmune hepatitis. The delay from first symptom to diagnosis is still 1-2 years and of concern with this progressing disease. Geographic distribution of ATP7B mutations in Wilson disease. Wilson's disease (WD) is an autosomal recessive in- herited disorder of hepatic copper metabolism re- sulting in accumulation of copper in many organs and tissues. EASL Clinical Practice Guidelines: Wilsons disease. Patients may have difficulties with attention, impulsivity, emotional lability or executive function, for example planning or decision-making (87). Indications for liver transplantation (LT)[67] in patients with WD are those with ALF, as defined by the rapid development of severe hepatic insufficiency with coagulopathy and with hepatic encephalopathy, with progression of liver dysfunction to liver failure despite drug therapy, and those with acute on chronic liver failure due to WD. Wilson's disease (WD) is an autosomal recessive disease affecting the copper metabolism resulting in various clinical presentations. reported that decrease in scholastic performance, behavioural problems, affective disorders and psychosis, typically with persecutory delusions, were the most common psychiatric features at onset (26). A study of brain MRI characteristics and clinical features in 76 cases of Wilson's disease. reported cerebellar dysfunction in 28% of cases (66). We strongly advocate a multi-disciplinary approach to the investigation and workup of suspect WD, including those patients diagnosed through family screening who often show neurologic and/or hepatic features. Neurological manifestations in Wilson's disease: Report of 119 cases. Age and sex but Not ATP7B genotype effectively influence the clinical phenotype of Wilson disease. Gene therapy of Wilson disease: A golden opportunity using rAAV on the 50th anniversary of the discovery of the virus. However, it is important to differentiate these from HE, which is defined as brain dysfunction caused by liver insufficiency and/or porto-systemic shunting manifesting with a wide spectrum of neurologic or psychiatric abnormalities ranging from subclinical alterations to coma (49). Wilson disease: clinical presentation, treatment, and survival Amsterdam: Elsevier, 1976:379-414. Common features across all presentations were jaundice, abdominal pain, ascites and hepatosplenomegaly. World J Gastroenterol 2015; 21:8981-8984. Reilly M, Daly L, Hutchinson M. An epidemiological study of Wilson's disease in the Republic of Ireland. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease. The key features of Wilson disease are liver disease and cirrhosis, neuropsychiatric disturbances, Kayser-Fleischer rings, and acute episodes of hemolysis, often in association with acute liver failure. Wilson's disease: clinical presentation and use ofprognostic index frontal headache, diarrhoea, andlethargy butbythe time of admission he had deteriorated to grade II Long term results of liver transplantation for Wilson's disease: experience in France. Roberts EA, Yap J. Nonalcoholic Fatty Liver Disease (NAFLD): Approach in the adolescent patient. As mentioned earlier, neurological or psychiatric disease is more prevalent in older children and young adults (aged 2030 years old)[1,17] and could be misdiagnosed as psychosis. As a library, NLM provides access to scientific literature. Swallowing dysfunction in Wilson's disease: a scintigraphic study. Gomes A, Dedoussis GV. Federal government websites often end in .gov or .mil. While immunologic assays measure both apoceruloplasmin and holoceruloplasmin, which could overestimate serum ceruloplasmin,[1,51] current WD guidelines[1,24,43] suggest a cut-off level (<0.2 g/L) indicative of WD that is measured by immunologic methods. Facts To Know About Wilson Disease < Yale School of Medicine Wilson disease in children and young adults - State of the art Gitlin D, Janeway CA. Heterozygous carriers, who constitute about 1.1% of the population, are asymptomatic. Philadelphia: WB Saunders, 1984. A working party at the 8th International Meeting on WD in Leipzig in 2001 revised the phenotypic classification and differentiated cases into neurologic (N), hepatic (H) or other (O) presentations (28). [52] In asymptomatic children with elevated liver enzymes, a level of <0.2 g/L provided sensitivity and specificity of 95% and 85%, respectively. assessed drooling in 10 consecutive symptomatic patients and identified problems with reduced swallow frequency, longer swallow latency and poor swallowing capacity. Other unusual presentations include muscle cramps, undulating tongue movements, oculogyric crises, optic neuropathy and an unusual cough due to involuntary respiratory muscle contraction (80-84). Late-Onset Wilson's Disease - ScienceDirect [1] (Reproduced from Ref, 1 with permission). Czonkowska A, Litwin T, Dusek P, Ferenci P, Lutsenko S, Medici V, et al. [53] In this case, WD is highly likely if the laboratory tests are suggestive[7] and the diagnosis can be reached according to WD diagnostic score [Table 2]. Guillaud O, Dumortier J, Sobesky R, et al. Merle et al. showed that this delay is greater in neurologic than hepatic presentations (44 vs. 14 months). Wilson's disease with severe hepatic insufficiency: beneficial effects of early administration of D-penicillamine. Wilson Disease in Infancy through Adolescence. Apart from serum ceruloplasmin, a serum copper, 24-hour urinary copper output, slit lamp examination (by an experienced ophthalmologist), brain MRI, liver biopsy with copper quantification (histology may suggest but does not rule out WD) and ATP7B genotyping may be required (27). The severity and presentation of Wilson disease varies among patients; the reason for this variation in expression of symptoms and clinical manifestations is still unknown. Definition and classification of hyperkinetic movements in childhood. Muller T, Koppikar S, Taylor RM, Carragher F, Schlenck B, Heinz-Erian P, et al. The relative frequency of neurologic and hepatic presentations has been examined in several large cohorts over the last three decades. Diagnosis and phenotypic classification of Wilson disease. A very important ophthalmologic feature of WD is the Kayser-Fleischer (KF) ring (Figure 1). Marcellini M, Di Ciommo V, Callea F, et al. The patient-reported experience of living with Wilson disease High prevalence of the H1069Q mutation in East German patients with Wilson disease: Rapid detection of mutations by limited sequencing and phenotype-genotype analysis. Chelating agents, such as D-penicillamine and trientine dihydrochloride, and zinc salts usually improve symptoms and prevent disease progression and death (18-21). A genetic study of Wilson's disease in the United Kingdom. Clinical manifestations of WD are varied and other causes of liver disease can mimic WD. We are very grateful to the patient who provided the photographs in the picture. reported that it occurred in 30% of pediatric cases presenting with ALF that required transplantation and 60% of those who died prior to transplantation (40). Trientine was introduced in 1969 as a second-line chelating agent for WD patients, especially in those who experienced side effects from penicillamine. However, iron supplement should be given at a different time from trientine because trientine-iron complex is nephrotoxic. [1,2,3,4,5] ATP7B encodes an enzyme called transmembrane copper-transporting ATPase, which is essential for copper incorporation into ceruloplasmin and for copper excretion into the bile [Figure 1]. described dystonia in 69% of a series of patients with neurologic presentations (66). in more severe adult patients and in pediatric populations to comprehensively describe the presentation and impact of Wilson disease across patient age groups and . WD, Wilson disease; KF, Kayser-Fleischer; AST, aspartate aminotransferase; ALT, alanine aminotransferase. The average age at diagnosis reported in pediatric WD cohorts is 10 years . [27] Some children may have a past history of acute self-limited hepatitis-like illness, recurrent jaundice, hemolytic anemia, or elevated transaminases. The most recent definitions require the presence of limb bradykinesia, a specific type of slowness associated with decrement in the amplitude or speed, or progressive hesitations, as movements are continued (75). [80] This incidence becomes higher as the duration of follow-up increases. Mrs. Treloar, Period 2. Drug administration and monitoring. Tremor - 22 to 55 percent. Wilson disease in children: Analysis of 57 cases. Difficulty in performing alternating lateral tongue movements (and dysarthria) may provide supportive evidence of oromandibular dystonia. Genetic testing allows even earlier detection. It was then called progressive hepatolenticular degeneration, better known by its eponym, Wilson disease (WD). . used a cluster analysis to provide supportive evidence for these four subgroups in a combined cohort of 400 cases in 1989 (29). We will describe bulbar symptoms, tremor, dystonia and parkinsonism in presentations of WD before summarising additional neurologic features, including cognitive impairment, and psychiatric features. Wilson Disease - GeneReviews - NCBI Bookshelf Hepatic presentations are subdivided into acute (H1) or chronic (H2) depending on the presence of acute jaundice due to hepatitis and/or hemolysis in a previously healthy subject (H1), or any type of chronic liver disease, with or without symptoms (H2). EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. [20], WD in children may present at any age with the reported median age of 13 years[20,23]; however, symptomatic disease is uncommon before the age of 3 years. 8600 Rockville Pike Any patients in whom neurologic and/or psychiatric symptoms are present at the time of diagnosis are classified as a neurologic presentation. Neurologic Wilson disease: case series on a diagnostic and therapeutic This binding can be detected with special staining (rhodanine and orcein) on liver histology. Wilson's disease and other neurological copper disorders. Wilson's disease: the problem of delayed diagnosis. Copper is deposited in Descemets membrane within the cornea and may be visible as a greenish-brown opacity at the periphery of each iris (13). According to the definition above, 17 of the 57 patients presented with ALF (with encephalopathy) and 10 presented with ALI (without encephalopathy). Koppikar S, Dhawan A. [39] However, the availability of this test is limited given its high analytic cost; therefore, it is mainly used in research facilities. WD is rare and the initial manifestations in the majority of cases have numerous mimics that are much more prevalent. Untreated or poorly controlled female WD patients can have menstrual and ovulatory dysfunction due to liver dysfunction and copper intoxication of specific enzymes that are involved in the normal menstrual cycle and ovulatory mechanism. The clinical features of patients with both chronic hepatitis B and C infections and WD have been described (56). Malik A, Khawaja A, Sheikh L. Wilson's disease in pregnancy: Case series and review of literature. Wilson Disease | Johns Hopkins Medicine The clinical features of both hepatic and neurologic presentations are highly variable: Walshe and Yealland explained that no two patients are ever the same, even in a sibship (, KF rings are absent in up to 45% of hepatic and 10% of neurologic presentations and may only be visible with slit lamp examination (. The serum copper level, which represents both ceruloplasmin-bound and non-ceruloplasmin-bound copper, is usually low at the time of diagnosis in non-acute presentations of WD but is likely to be high in WD-related ALF as non-ceruloplasmin-bound copper is released from the failing liver. Serum ceruloplasmin, which is an acute phase reactant, may be normal or raised and a low serum ceruloplasmin has a sensitivity of 2156% and specificity of 6384% for the diagnosis of WD in the context of ALF (46). Additionally, some patients may require further molecular analysis, including multiplex ligation-dependent probe amplification (MLPA) to search for large gene defects such as whole-exome deletions or duplications, which are not easily identified by direct DNA sequencing. Neurologic symptoms or signs can occur in parallel with ALF due to WD or emerge while patients are being considered for transplantation. official website and that any information you provide is encrypted A diagnosis of WD has been reported in a 3-year-old child and in two individuals in their eighth decade of life (33,34). A hemolytic anemia with a negative direct antiglobulin (Coombs) test can provide a vital clue to the diagnosis. HHS Vulnerability Disclosure, Help A borderline low serum ceruloplasmin should lead to a full screen for WD as serum ceruloplasmin may be normal in hepatic WD. Advances in the diagnosis and treatment of Wilson disease are discussed, with the emphasis that this is a disease of children, adolescents, and young adults. Li LT, Qiu YL, et al. movement disorder or unexplained haemolytic anaemia should have routine investigations and a wider screen for Wilson's disease: 4: 1.5 All patients between the age of 5 years and 50 years who develop a progressive . Ferenci P. Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: Impact on genetic testing. Diagnosis and treatment of Wilson disease: An update. Penicillamine could also interfere with pyridoxine metabolism (pyridoxine antagonist); thus, supplementation of pyridoxine should be given orally at the dosage of 2550 mg/day.[24]. Diagnosis of Wilson disease in young children: Molecular genetic testing and a paradigm shift from the laboratory diagnosis. Diagnostic algorithms have been derived from this (2). Wilson disease: Canadian perspectives on presentation and outcomes from an adult ambulatory setting. Brewer GJ, Hedera P, Kluin KJ, Carlson M, Askari F, Dick RB, et al. Wing-beating tremor refers to a large amplitude postural tremor in the upper limbs that emerges as the elbows are flexed. Pfeiffenberger J, Beinhardt S, Gotthardt DN, Haag N, Freissmuth C, Reuner U, et al.
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