Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.0
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: ATP7B
• Condition: Wilson Disease
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• ATP7B ⇔ 0010200 (wilson disease): Definitive Actionability

Actionability Rationale

All experts agreed with upgrading the assertion from the generated assertion of strong to an assertion of definitive. Though there are not studies of individuals identified in the absence of personal or family history, there are a number of reports of individuals managed presymptomatically due to family history.

Final Consensus Scores

Gene Condition Pairs: ATP7B ⇔ 0010200 (OMIM:277900)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity and mortality from copper deposition / Copper chelation and zinc therapy	2	3C	3A	3	11CA

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The prevalence of Wilson disease is usually reported as one in 30,000 in most populations. A meta-analysis of genetic studies of Wilson disease prevalence gave a global estimate of 12.7 per 100,000. Prevalence may vary by population. Wilson disease accounts for 6–12% of all patients with acute liver failure (ALF) who are referred for emergency transplantation. [1, 2, 3, 4, 5, 6, 7, 8]

Clinical Features

Wilson disease is a disorder of copper metabolism that manifests with varying combinations of hepatic, neurologic, psychiatric, and ocular findings. Liver disease includes recurrent jaundice, cirrhosis, and acute episodes of hemolysis often in association with acute liver failure. Neurologic presentations include movement disorders or rigid dystonia. Psychiatric manifestations include depression, phobias, compulsive behaviors, aggression, or antisocial behavior. Kayser-Fleischer rings (deposits of copper in the cornea) do not cause ocular difficulties and are often present in patients with neurologic symptoms but can also be found in those without neurologic symptoms. Less common features of Wilson disease include renal abnormalities including aminoaciduria and nephrolithiasis, skeletal abnormalities such as premature osteoporosis and arthritis, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis of skeletal muscle, pancreatitis, hypoparathyroidism, and infertility or repeated miscarriages. Hepatocellular carcinoma rarely develops in Wilson disease. [1, 2, 3, 4, 5, 6, 7, 9]

Natural History

Wilson disease may present at any age. The majority of patients present between ages 5 and 35 years of age but patients have been diagnosed in their early 70s. The youngest patient reported with cirrhosis and ALF due to Wilson disease was 3 years old and 5 years old, respectively. Symptoms at any age are frequently nonspecific and the spectrum of disease at presentation is highly variable. After a presymptomatic period, approximately 40% of clinically diagnosed patients present acutely with liver failure, hemolytic anemia, or both, or more chronically with liver conditions such as hepatitis, portal hypertension, or cirrhosis. Wilson disease presents with liver disease more often in children and young adults than in older adults. In other patients, liver disease remains subclinical and neuropsychiatric symptoms develop, reflecting ongoing copper deposition in other organs. Clinically evident liver disease may precede neurologic manifestations by as much as 10 years, and most patients with neurologic symptoms have some degree of liver disease. However, neurological, behavioral, and/or psychiatric signs are present in almost 50% of clinically diagnosed patients at any one time, and present before motor signs in 20% of cases. Neuropsychiatric presentation can be extremely subtle, and intermittent for many years, but may also develop very rapidly, leading within a few months to complete disability. In children with Wilson disease, initial symptoms are frequently misdiagnosed as behavioral problems associated with puberty. Additionally, children can become unable to perform activities requiring hand-eye coordination, handwriting may deteriorate, and micrographia may develop. Wilson disease is uniformly fatal without treatment, with most patients dying from liver disease and a minority from complications of progressive neurologic disease. Acute liver disease and hemolysis as a presenting symptom can occur during delivery, mimicking HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome. ALF occurs predominantly in young females (female: male ratio 4:1). [1, 3, 4, 5, 6, 7, 8]

2. How effective are interventions for preventing harm?

Patient Management

To establish the extent of the disease and treatment needs of an individual diagnosed with Wilson disease, the following evaluations are recommended:
•Liver biopsy or biochemical testing and imaging of the liver
•Upper GI endoscopy to exclude or confirm esophageal varices
•Assessment of kidney function
•Consultation with clinical geneticist and/or genetic counselor (Tier 4) [5]

Neurologic evaluation should be performed for all patients with Wilson disease. (Tier 2) [6, 7]

Radiologic imaging of the brain, preferably by MRI, should be part of the evaluation of any patient presenting with neurological symptoms consistent with Wilson disease and should be considered prior to treatment in all patients with neurologic symptoms. (Tier 2) [6, 7]

High-quality evidence is lacking to estimate the optimal first-line treatment choice in Wilson disease. Treatment of presymptomatic patients (as soon age 2-3 years) can be accomplished with a copper chelating agent or with zinc. Several drugs are available as copper chelation agents with the most evidence for D-penicillamine and trientine. Given its safety profile, zinc appears to be preferable for pre-symptomatic children under the age of 3 years. Treatment is lifelong and should not be discontinued (including during pregnancy, though dosage may need to be reduced, especially with D-penicillamine and trientine), unless liver transplantation is performed. Initial treatment for symptomatic patients should include a chelating agent. Children with signs of significant liver disease, such as cirrhosis or abnormal INR should be preferably treated with chelating agents. Children with decompensated liver cirrhosis should be treated with a chelating agent or a combination of zinc and a chelating agent that may preclude the need for liver transplantation. (Tier 2) [4, 6, 7]

A systematic review of 13 studies of D-penicillamine or zinc monotherapy in presymptomatic and symptomatic patients included 199 patients treated with D-penicillamine (mean age at diagnosis 14 years, range 1.5-52 years) and 85 treated with zinc (mean age at diagnosis 12.5 years, range 3-39 years). Clinical effectiveness was defined as the ability of the interventional drug to prevent or reverse clinical symptoms related to Wilson disease over the mean evaluation periods of 64 months (range 3-228) and 81 months (range 3-323) for D-penicillamine and zinc, respectively. Overall, treatment of presymptomatic, hepatic and neurological patients with D-penicillamine was effective in respectively 70/70 (100%), 42/57 (73.7%) and 58/72 (80.6%) of patients, whereas zinc therapy had a positive effect on clinical status in respectively 66/66 (100%), 5/9 (55.6%) and 9/10 (90%) of patients treated. A recent systematic review and meta-analysis of 23 studies reporting on 2055 patients (age range 1 to 66 years and at any stage of Wilson disease) found that when compared to no treatment, D-penicillamine was associated with a lower mortality (odds ratio 0.013; 95% CI 0.0010 to 0.17). When D-penicillamine was compared to zinc, there was no evidence for a difference in mortality, clinical symptoms, liver transplant, side effects, and neurologic deterioration. When compared to no treatment, D-penicillamine was associated with a lower mortality (OR 0.013, 95% CI 0.0010 to 0.17). When compared to zinc, there was no association with mortality (OR 0.73; 95% CI 0.16 to 3.40) and prevention or amelioration of clinical symptoms (OR 0.84; 95% CI 0.48-1.48). However, D-penicillamine may have a higher frequency of side effects and treatment discontinuation than zinc. Study quality was stated as low, warranting cautious interpretation of findings. (Tier 1) [8, 9]

Liver transplantation (LT) is recommended for ALF due to Wilson disease when certain criteria are met (using King’s Wilson index). Children should be monitored for prognostic assessment and timely decision for LT. Adults with decompensated cirrhosis, unresponsive to chelation treatment, should be evaluated promptly for LT. Patient survival rates post-LT were 87% at 5, 10, and 15 years in a French series of 75 adults (median age: 29 years, range 18-66) and 46 children (median age: 14 years, range 7–17 years) transplanted between 1985 and 2009 for ALF (53%), decompensated cirrhosis (41%), or severe neurological disease (6%). (Tier 2) [4, 6, 7]

A recent review, including 290 children (mean age at time of LT was 12.6 years) with Wilson disease from six studies (including the above French series with 46 children), found the average 1-year survival rate was 91.9%, while the average 5-year survival rate was 88.2%. Re-transplantation was performed in 16 patients due to transplant rejection. The main indications for LT were chronic liver failure and fulminant liver failure. (Tier 5) [10]

One guideline states that only spermicide and barrier contraceptives and progesterone-only preparations can be safely prescribed. (Tier 4) [6]

Surveillance

All children should be closely followed-up during the first month following initiation of therapy, then every 1 to 3 months until remission, and every 3 to 6 months thereafter. Monitoring includes physical examination, biochemical tests (i.e., blood cell count, liver function tests, urea, creatinine, proteinuria), serum copper, and 24-hour urinary copper to assess efficacy, overdosage, or non-adherence to therapy and adverse events. (Tier 2) [4]

For routine monitoring, serum copper and ceruloplasmin, liver biochemistries and international normalized ratio, complete blood count and urinalysis (especially for those on chelation therapy), as well as physical and neurological examination should be performed regularly, at least twice annually. Patients receiving chelation therapy require a complete blood count and urinalysis regularly, no matter how long they have been on treatment. (Tier 2) [4, 6, 7]

The 24-hour urinary excretion of copper while on medication should be measured yearly, or more frequently if there are questions on compliance or if dosage of medications is adjusted. (Tier 2) [6, 7]

Circumstances to Avoid

Patients should avoid intake of both water and foods with high concentrations of copper (such as shellfish, nuts, chocolate, mushrooms, and organ meats) especially during the first year of treatment. (Tier 2) [4, 6, 7]

Patients must avoid alcohol consumption and potential hepatotoxic drug therapy. (Tier 4) [4]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive [1, 2, 3, 4, 5, 6, 7, 8, 9]

Prevalence of Genetic Variants

A recent systematic review of known disease-causing pathogenic variants in ATP7B calculated the global genetic prevalence of Wilson disease to be 13.9 per 100,000 (95% CI: 12.9–14.9), or 1 per 7194. The genetic prevalence of Wilson disease is much higher than epidemiological estimates, potentially indicating incomplete penetrance, underdiagnosis, or the existence of less severe phenotypes. (Tier 1) [2]

Molecular genetic testing identifies biallelic pathogenic variants in the ATP7B gene in about 98% of affected individuals. (Tier 3) [5]

Penetrance

Reported rates of presenting clinical findings for those with Wilson disease include:
•Liver disease (40%), typical age of onset 6-45 years (range 3-70 years)
•Neurologic disease (40%), typical age of onset mid-teen to mid-adult (range 6-50 years)
•Psychiatric disturbance (20%), typical age of onset adolescent to young adult (Tier 3) [5]

Reported clinical symptoms in patients with Wilson disease presenting with liver disease include:
•Jaundice, anorexia, vomiting (14-44%)
•Ascites/edema (14-50%)
•Variceal hemorrhage (3-10%)
•Hemorrhagic diathesis (3-8%)
•Hemolysis (5-20%)
•Hepatomegaly/splenomegaly (15-49%)
•ALF (17%)
•Hepatocellular carcinoma (<1%) (Tier 3) [4, 6]

Kayser-Fleischer rings are present in 95% of patients with neurologic symptoms and over 50% of patients without neurological symptoms. In children presenting with liver disease, Kayser-Fleischer rings are usually absent. (Tier 3) [6, 7]

Relative Risk

No information on relative risk was found.

Expressivity

Phenotypic expression is variable, even within families. Age of onset is highly variable. The phenotypic spectrum has further expanded through molecular genetic testing. (Tier 4) [1, 5]

Pathogenic variants that abolish ATP7B function tend to result in a more severe phenotype than some missense variants. Several studies have found a mean age of onset of 20 to 22 years in individuals homozygous for the common p.His1069Gln
pathogenic variant, although earlier onset also occurs. (Tier 3) [5, 11]

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions include noninvasive surveillance, lifelong pharmacologic treatment and rarely (less than 1%) LT. All pharmacologic treatment is associated with a risk of neurological deterioration (up to 15-20%) during initial phase of treatment. D-penicillamine in particular is associated with severe early (e.g. sensitivity reactions, fever, proteinuria) and late side effects requiring the drug to be discontinued in approximately 30% of patients. Trientine is rarely associated with side effects and is the usual second-line treatment for individuals who cannot tolerate D-penicillamine. It is gaining acceptance as a first-line drug because of good efficiency and better tolerance than D-penicillamine; however, it is still not generally available in all countries. Zinc has few side effects, though gastric irritation is a common problem and may be dependent on the salt employed. A systematic review of 13 studies of D-penicillamine and zinc monotherapy in presymptomatic and symptomatic individuals evaluated side effects in 205 and 224 patients, respectively. Side effects were observed in 50/205 (24.4%) of those who were on D-penicillamine. In half of these patients (26/205, 12.7%), the side effects were severe, making withdrawal of D-penicillamine therapy necessary. On zinc therapy, 28/224 (12.5%) of patients experienced side effects, but in only 2/224 (0.9%) patients the therapy had to be discontinued. [4, 5, 6, 7, 8]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Clinical features of Wilson disease overlap with other liver diseases such as autoimmune liver diseases, and with neurologic symptoms characteristic of a variety of other neurologic disorders, resulting in potential for misdiagnosis. Diagnosis of Wilson disease is difficult in children because they are often asymptomatic, with hepatic enlargement or abnormal serum aminotransferases found only incidentally, and the conventional criteria established for adults may not be appropriate for children. Additionally, about half of patients presenting with liver disease do not possess two of the three conventional criteria and pose a challenge in trying to establish the diagnosis Acute or chronic hepatitis with Wilson disease presents similarly to any other acute or chronic cases of hepatitis. A delay in diagnosing Wilson disease in patients with neuropsychiatric presentations is frequent. In children with Wilson disease, initial symptoms are frequently misdiagnosed as behavioral problems associated with puberty. Patients with Wilson disease may present with important extra hepatic manifestations apart from neurologic or psychiatric disease. (Tier 3) [4, 6, 7]

Date of Search: 02.14.2022

Reference List

1. Wilson disease. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=905

2. Gao J, Brackley S, Mann JP. The global prevalence of Wilson disease from next-generation sequencing data. Genet Med. (2019) 21(1530-0366):1155-1163.

3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. WILSON DISEASE; WND. MIM: 277900: 2020 Mar 25. World Wide Web URL: http://omim.org.

4. Socha P, Janczyk W, Dhawan A, Baumann U, D'Antiga L, Tanner S, Iorio R, Vajro P, Houwen R, Fischler B, Dezsofi A, Hadzic N, Hierro L, Jahnel J, McLin V, Nobili V, Smets F, Verkade HJ, Debray D. Wilson's Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. (2018) 66(1536-4801):334-344.

5. KH Weiss. Wilson Disease. 1999 Oct 22 [Updated 2013 May 16]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1512

6. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol. Journal of hepatology. (2012) 56(3):671-85.

7. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology. (2008) 47(6):2089-111.

8. Wiggelinkhuizen M, Tilanus ME, Bollen CW, Houwen RH. Systematic review: clinical efficacy of chelator agents and zinc in the initial treatment of Wilson disease. Aliment Pharmacol Ther. (2009) 29(9):947-58.

9. Appenzeller-Herzog C, Mathes T, Heeres MLS, Weiss KH, Houwen RHJ, Ewald H. Comparative effectiveness of common therapies for Wilson disease: A systematic review and meta-analysis of controlled studies. Liver Int. (2019) 39(1478-3231):2136-2152.

10. Garoufalia Z, Prodromidou A, Machairas N, Kostakis ID, Stamopoulos P, Zavras N, Fouzas I, Sotiropoulos GC. Liver Transplantation for Wilson's Disease in Non-adult Patients: A Systematic Review. Transplant Proc. (2019) 51(1873-2623):443-445.

11. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. ATPase, Cu(2+)-TRANSPORTING, BETA POLYPEPTIDE; ATP7B. MIM: 606882: 2020 Mar 26. World Wide Web URL: http://omim.org.