Farzaneh Abbasi1, Maryam Habibi1, Samaneh Enayati2, Fatemeh Bitarafan2, Maryam Razzaghy-Azar3, Aria Sotodeh1, Sima Parvizi Omran2, Reza Maroofian4, Mahsa M Amoli5. 1. Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran. 2. Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. 3. Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; H. Aliasghar Children's Hospital, Iran University of Medical Sciences, Tehran, Iran. 4. Medical Research, RILD Wellcome Wolfson Centre (Level 4), Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, United Kingdom. 5. Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: amolimm@sina.tums.ac.ir.
Abstract
OBJECTIVE: Wolcott-Rallison syndrome (WRS) is an extremely rare autosomal recessive condition, characterized by permanent neonatal diabetes mellitus (PNDM) associated with skeletal dysplasia, growth retardation and liver dysfunction. WRS is caused by biallelic mutations in the gene encoding eukaryotic translation initiation factor 2alpha kinase 3 (EIF2AK3). METHODS: As part of a comprehensive study on clinical and genetic investigation of neonatal diabetes in an Iranian population, 60 unrelated Iranian subjects referred with PNDM were analyzed. All the probands were screened for KCNJ11, INS, ABCC8 and EIF2AK3 using a polymerase chain reaction-based sequencing approach. RESULTS: We identified 9 different variants in EIF2AK3 in 11 unrelated Iranian probands, of which 5 variants were shown to be novel and not reported previously. The diagnosis of WRS was made by molecular genetic testing and confirmed by clinical re-evaluation of the subjects. Clinical follow up of the affected individuals shows that in at least some of them, PNDM was associated with short stature, failure to thrive, neurodevelopmental delay, epilepsy and hepatic and renal dysfunction. There was a strong family history of neonatal diabetes in the families of the probands with a high mortality rate. CONCLUSION: WRS is a common cause of PNDM in children of consanguineous parents. Furthermore, clinical diagnosis of WRS would have been delayed or possibly missed without genetic testing because this study shows that the associated features of WRS might be obscured by a diagnosis of PNDM. Therefore EIF2AK3 should be considered for any infant and young child with PNDM, particularly if the parents are related.
OBJECTIVE:Wolcott-Rallison syndrome (WRS) is an extremely rare autosomal recessive condition, characterized by permanent neonatal diabetes mellitus (PNDM) associated with skeletal dysplasia, growth retardation and liver dysfunction. WRS is caused by biallelic mutations in the gene encoding eukaryotic translation initiation factor 2alpha kinase 3 (EIF2AK3). METHODS: As part of a comprehensive study on clinical and genetic investigation of neonatal diabetes in an Iranian population, 60 unrelated Iranian subjects referred with PNDM were analyzed. All the probands were screened for KCNJ11, INS, ABCC8 and EIF2AK3 using a polymerase chain reaction-based sequencing approach. RESULTS: We identified 9 different variants in EIF2AK3 in 11 unrelated Iranian probands, of which 5 variants were shown to be novel and not reported previously. The diagnosis of WRS was made by molecular genetic testing and confirmed by clinical re-evaluation of the subjects. Clinical follow up of the affected individuals shows that in at least some of them, PNDM was associated with short stature, failure to thrive, neurodevelopmental delay, epilepsy and hepatic and renal dysfunction. There was a strong family history of neonatal diabetes in the families of the probands with a high mortality rate. CONCLUSION:WRS is a common cause of PNDM in children of consanguineous parents. Furthermore, clinical diagnosis of WRS would have been delayed or possibly missed without genetic testing because this study shows that the associated features of WRS might be obscured by a diagnosis of PNDM. Therefore EIF2AK3 should be considered for any infant and young child with PNDM, particularly if the parents are related.
Authors: Alena Welters; Thomas Meissner; Katja Konrad; Clemens Freiberg; Katharina Warncke; Sylvia Judmaier; Olga Kordonouri; Michael Wurm; Matthias Papsch; Gisela Fitzke; Silke Christina Schmidt; Sascha R Tittel; Reinhard W Holl Journal: Orphanet J Rare Dis Date: 2020-04-22 Impact factor: 4.123