Variable phenotype in five patients with Wolcott-Rallison syndrome due to the same EIF2AK3 (c.1259delA) mutation

Al-Shawi, Manal; Mutair, Angham Al; Ellard, Sian; Habeb, Abdelhadi

doi:10.1515/jpem-2012-0071

Cited by 12 publications

(13 citation statements)

References 5 publications

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“…In agreement with previous reports [3,4,16,17], we found a variation in the phenotype between patients with the same mutation. The exact cause of this phenomenon is still unclear; however, it seems likely that other genetic and environmental factors influence the tissue response to the mutant PERK protein.…”

Section: Discussionsupporting

confidence: 93%

“…Both were located close to each other on the first kinase domain of PERK protein residue, and the p.N656K mutation was shown to have a residual kinase activity, which may explain the delayed onset in that patient [3]. However, the other 2 mutations (p.W164X and p.N42Tfs*14) were reported in other patients with early-onset WRS [3,4,16]. The mean survival age in our cohort was 5.8 years, which is similar to the figure reported by Ozbek et al [5].…”

Section: Discussionmentioning

confidence: 99%

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Liver Disease and Other Comorbidities in Wolcott-Rallison Syndrome: Different Phenotype and Variable Associations in a Large Cohort

Habeb

Deeb²,

Johnson³

et al. 2015

Horm Res Paediatr

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Background: Wolcott-Rallison syndrome (WRS) is caused by recessive EIF2AK3 mutations and characterized by early-onset diabetes and skeletal dysplasia. Hepatic dysfunction has been reported in 60% of patients. Aims: To describe a cohort of WRS patients and discuss the pattern and management of their liver disease. Methods: Detailed phenotyping and direct sequencing of EIF2AK3 gene were conducted in all patients. Results: Twenty-eight genetically confirmed patients (67% male; mean age 4.6 years) were identified. 17 different EIF2AK3 mutations were detected, of which 2 were novel. The p.S991N mutation was associated with prolonged survival and p.I650T with delayed onset. All patients presented before 25 months with diabetes with variation in the frequency and severity of 10 other features. Liver disease, first manifested as non-autoimmune hepatitis, was the commonest extra-pancreatic feature identified in 85.7% (24/28). 22/24 had at least one episode of acute hepatic failure which was the cause of death in all deceased patients (13/28). One child was treated by liver transplantation and had no liver disease and better diabetes control for the following 6 years. Conclusions: Liver disease in WRS is more frequent than previously described and carries high mortality. The first experience with liver transplantation in WRS is encouraging.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Liver Disease and Other Comorbidities in Wolcott-Rallison Syndrome: Different Phenotype and Variable Associations in a Large Cohort

Habeb

Deeb²,

Johnson³

et al. 2015

Horm Res Paediatr

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“…Of the original articles, two papers reported Saudi patients as part of an international WRS cohort (3, 4), one provided data on the frequency and spectrum of WRS in one KSA region (14), and two described studies to define the genetic causes of Saudi subjects with a clinical phenotype of WRS (15, 16). The five case reports (17–21) were on patients; most of them had been or were subsequently duplicated elsewhere (Table 1). Seven of the published Saudi patients with WRS were reported in more than one article (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Frequency and spectrum of Wolcott–Rallison syndrome in Saudi Arabia: a systematic review

Habeb

2013

Libyan Journal of Medicine

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BackgroundWolcott–Rallison syndrome (WRS) is caused by recessive EIF2AK3 gene mutations and characterized by permanent neonatal diabetes (PNDM), skeletal dysplasia, and recurrent hepatitis. The frequency of this rare syndrome is largely unknown.ObjectivesTo define the frequency and spectrum of WRS in the Kingdom of Saudi Arabia (KSA) based on published data.MethodsThe Medline database was searched for published articles on WRS. The number of reported cases from KSA was compared to the total number of WRS cases reported worldwide. The genotype and phenotype of WRS patients from KSA were reviewed.ResultsTen articles describing 23 WRS patients from 12 Saudi families from 1995 to 2012 were identified. This figure accounts for 27.7% (23/83) of the patients and 22.2% (12/54) of the families with WRS reported worldwide until January 2013. All Saudi patients with WRS presented with PNDM, and they represent 59% of all PNDM cases from WRS. At reporting, 73% of patients experienced recurrent hepatitis, 56.5% had skeletal abnormalities, and 39.1% of them were dead. There was a variation in the phenotype even between affected siblings. Genetic diagnosis was confirmed in all 12 families with no correlation between the genotype and phenotype. Eight of the nine EIF2AK3 mutations were only reported in these families, and one was shared with a patient from Qatar, a neighboring Arab state.ConclusionsNo study on the frequency of WRS has been published. However, the available data indicate that KSA has the largest collection of patients with WRS worldwide, and nine of the identifiable EIF2AK3 mutations appear to be confined to Arabs. Establishing a national or international registry for WRS would provide more reliable data on this rare condition.

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“…[1][2][3][4][5]. По мнению зарубежных исследова-телей [20,21], у большинства пациентов с WRS от-сутствует корреляция генотип-фенотип, что может быть связано с индивидуальной скоростью клеточ-ного апоптоза или с влиянием внешних факторов. В частности, описаны семьи пациентов с идентич-ной мутацией в гене EIF2AК3 и различными клини-ческими проявлениями заболевания.…”

Section: Discussionunclassified

Rare form of Permanent Neonatal Diabetes Mellitus (PNDM) due to novel mutation in EIF2AK3 gene (Wolcott—Rallison syndrome)

Тихонович¹,

Стотикова²,

Rubtsov³

et al. 2015

Probl Endokrinol (Mosk)

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Wolcott—Rallison syndrome (WRS) is a rare genetic disease inherited in autosomal recessive way. Сlinical manifestations develop in early infancy with symptoms of permanent neonatal diabetes mellitus (PNDM), skeletal dysplasia, short stature and hepatic dysfunction. The condition has poor prognosis and most patients die at a young age due to episodes of acute liver or renal failure. To date about 60 genetically proved cases of WRS have been reported worldwide. The disease is most common in countries where consanguineous marriages are frequent, such as the Saudi Arabia (60% cases of PNDM patients), India, Turkey, Pakistan and North Africa. In Russian Federation WRS patients have not been described earlier.

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Variable phenotype in five patients with Wolcott-Rallison syndrome due to the same EIF2AK3 (c.1259delA) mutation

Cited by 12 publications

References 5 publications

Liver Disease and Other Comorbidities in Wolcott-Rallison Syndrome: Different Phenotype and Variable Associations in a Large Cohort

Liver Disease and Other Comorbidities in Wolcott-Rallison Syndrome: Different Phenotype and Variable Associations in a Large Cohort

Frequency and spectrum of Wolcott–Rallison syndrome in Saudi Arabia: a systematic review

Rare form of Permanent Neonatal Diabetes Mellitus (PNDM) due to novel mutation in EIF2AK3 gene (Wolcott—Rallison syndrome)

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