Natural history of Wolcott-Rallison syndrome: A systematic review and follow-up study.

BACKGROUND AND AIMS: To systematically review the literature for reports on Wolcott-Rallison syndrome, focusing on the spectrum and natural history, genotype-phenotype correlations, patient and native liver survival, and long-term outcomes. METHODS: PubMed, Livio, Google Scholar, Scopus and Web of Science databases were searched. Data on genotype, phenotype, therapy, cause of death and follow-up were extracted. Survival and correlation analyses were performed. RESULTS: Sixty-two studies with 159 patients met the inclusion criteria and additional 30 WRS individuals were collected by personal contact. The median age of presentation was 2.5 months (IQR 2) and of death was 36 months (IQR 50.75). The most frequent clinical feature was neonatal diabetes in all patients, followed by liver impairment in 73%, impaired growth in 72%, skeletal abnormalities in 59.8%, the nervous system in 37.6%, the kidney in 35.4%, insufficient haematopoiesis in 34.4%, hypothyroidism in 14.8% and exocrine pancreas insufficiency in 10.6%. Episodes of acute liver failure were frequently reported. Liver transplantation was performed in six, combined liver-pancreas in one and combined liver-pancreas-kidney transplantation in two individuals. Patient survival was significantly better in the transplant cohort (p = .0057). One-, five- and ten-year patient survival rates were 89.4%, 65.5% and 53.1%, respectively. Liver failure was reported as the leading cause of death in 17.9% of cases. Overall survival was better in individuals with missense mutations (p = .013). CONCLUSION: Wolcott-Rallison syndrome has variable clinical courses. Overall survival is better in individuals with missense mutations. Liver- or multi-organ transplantation is a feasible treatment option to improve survival.

Wolcott-Rallison syndrome: a case series of three patients.

INTRODUCTION: Neonatal diabetes is a rare disease with incidence estimated at 1 in 300,000 to 1 in 400,000 live births. Walcott-Rallison syndrome has been identified as the most common cause of permanent neonatal diabetes in consanguineous families caused by mutations in eukaryotic translation initiation factor 2-α kinase 3 (EIF2AK3), characterized by permanent neonatal diabetes associated with liver dysfunction, multiple epiphyseal dysplasia, and developmental delay. We herein report 3 cases of genetically proven Wolcott-Rallison syndrome with variable phenotype presentation. CASE SERIES: All cases presented with high glucose levels and were treated with insulin. EIF2AK3 homozygous mutation was identified in all 3 on genetic analysis. Initial screening testing for associated comorbidities was normal, including X-ray examination, which did not show any signs of epiphyseal dysplasia in all cases. Case 2 and case 3 were both lost to follow-up and were later found to have expired at the ages of 18 months and 2 years, respectively, due to liver failure associated with intercurrent respiratory illness in hospitals in their native towns. Case one is now 2 years old on regular follow-up in paediatric Endocrine and neurology clinics and doing well so far. CONCLUSIONS: Morbidity, as well as mortality, is high among children with WRS neonatal diabetes. It is crucial to screen for gene mutation in patients with diabetes diagnosed before 6 months. Close therapeutic monitoring is recommended in WRS because of the risk of acute episodes of hypoglycaemia and ketoacidosis.

Structural and vascular features in cavitary congenital optic disc anomaly associated with metaphyseal acroscyphodysplasia.

PURPOSE: To evaluate the radial peripapillary vascular plexus of a cavitary congenital optic disc anomaly in a young patient with recessive autosomal metaphyseal acroscyphodysplasia using optical coherence tomography angiography (OCTA). METHODS: Observational case report. RESULTS: A 17-year-old man, with diagnosis of metaphyseal acroscyphodysplasia was referred to Eye Clinic for fundus examination and multimodal imaging for retinal epithelium hypertrophy in the right eye. Clinical examination showed cup-shaped metaphyses, short stature, hyperthelorism, and telecanthus. An optic disc coloboma was detected in the right eye on fundus examination. Wide field en-face Optical Coherence Tomography (OCT) showed a hyporeflective area corresponding to the right optic disc coloboma. At OCTA examination, the whole papillary region revealed a rarefaction of the vascular network, while the ganglion cell complex's and retinal fiber layers' parameters were normal in both eyes. CONCLUSION: The presence of coloboma disc congenital defect linked to embryological abnormalities during the development process could pave the way for a wider understanding of the pathogenesis of metaphyseal acroscyphodysplasia by increasingly framing it as a systemic disease.

Lissencephaly-pachygyria spectrum in a North Indian boy with Wolcott-Rallison syndrome due to homozygous deletion of exon 1 in the EIF2AK3 gene.

BACKGROUND: Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by neonatal diabetes mellitus (NDM), epiphyseal dysplasia, and hepatic and renal dysfunction. Although neuro-psychological features are common in patients with WRS, malformations of cortical development (MCDs) are rarely reported. CASE PRESENTATION: A 3-month-old boy, born to non-consanguineous parents, presented with right focal seizures since two months of age and recently detected diabetes mellitus. He also had a small head and lissencephaly-pachygyria spectrum on brain imaging. Genetic testing confirmed the diagnosis of WRS by identifying a biallelic homozygous deletion of exon 1 in the EIF2AK3 gene. The child achieved reasonable glycemic control on the basal-bolus insulin regimen. CONCLUSIONS: Presentation of WRS may occur with neurological manifestations such as lissencephaly-pachygyria spectrum. Early confirmation of the genetic diagnosis of WRS by screening for pathogenic variants in the EIF2AK3 gene is important in children with NDM and associated syndromic features. Establishing the diagnosis of WRS helps in predicting the development of subsequent clinical features, guides management, and may improve patient outcomes.

Acrocapitofemoral dysplasia: Novel mutation in IHH in two adult patients from the third family in the literature and progression of the disease.

Acrocapitofemoral dysplasia (ACFD) is a rare autosomal recessive skeletal dysplasia characterized by short stature with short limb dwarfism, brachydactyly, and a narrow thorax. Major radiographic features are egg-shaped capital femoral epiphyses with a short femoral neck and cone-shaped epiphyses, mainly in the hands and hips. To date, only four child patients from two families have been reported. We describe two adult patients with ACFD with a novel homozygous c.478C>T (p.Arg160Cys) mutation in IHH in the third family of the literature. The reported cases showed a middle phalanges which fused with distal phalanges in the fifth toes, the typical configuration of metacarpals, radial angulation and extremely short femoral neck. These findings could help the diagnosis of ACFD in adult patients. We hope that this new family will be a helpful guide for predicting and managing the prognosis of diagnosed children.

Long-term follow-up of a child with Wolcott-Rallison syndrome.

Wolcott-Rallison syndrome (WRS), the most common cause of permanent neonatal diabetes mellitus (DM) in consanguineous families, has a poor prognosis, with a mean survival of 5.8 years. Majority of children with WRS succumb to the disease in the first decade of life. We present the long-term follow-up of an 8-year-2-month-old girl with genetically proven WRS who was born to a non-consanguineous parentage. She is on basal bolus regimen of insulin therapy for DM. In addition, she was noted to have features of skeletal dysplasia at 3 years and 3 months of age, which has led to her short stature. Surprisingly, she has had no episodes of hepatitis or liver dysfunction so far, which is frequently seen in children with WRS. To the best of our knowledge, she is the oldest surviving patient with WRS reported in India and South Asia.

Diabetes management in Wolcott-Rallison syndrome: analysis from the German/Austrian DPV database.

BACKGROUND: Wolcott-Rallison syndrome (WRS) is characterized by permanent early-onset diabetes, skeletal dysplasia and several additional features, e.g. recurrent liver failure. This is the first multicentre approach that focuses on diabetes management in WRS. We searched the German/Austrian Diabetes-Patienten-Verlaufsdokumentation (DPV) registry and studied anthropometric characteristics, diabetes treatment, glycaemic control and occurrence of severe hypoglycaemia (SH) and diabetic ketoacidosis (DKA) in 11 patients with WRS. Furthermore, all local treatment centres were personally contacted to retrieve additional information on genetic characteristics, migration background and rate of consanguinity. RESULTS: Data were analysed at diabetes onset and after a median follow-up period of 3 (1.5-9.0) years (time from diagnosis to latest follow-up). Median age at diabetes onset was 0.2 (0.1-0.3) years, while onset was delayed in one patient (aged 16 months). Seventy percent of patients manifested with DKA. At follow-up, 90% of patients were on insulin pump therapy requiring 0.7 [0.5-1.0] IU of insulin/kg/d. More than two third of patients had HbA1c level ≥ 8%, 40% experienced at least one episode of SH in the course of the disease. Three patients died at 0.6, 5 and 9 years of age, respectively. To the best of our knowledge three patients carried novel mutations in EIF2AK3. CONCLUSION: Insulin requirements of individuals with WRS registered in DPV appear to be comparable to those of preschool children with well-controlled type 1 diabetes, while glycaemic control tends to be worse and episodes of SH tend to be more common. The majority of individuals with WRS in the DPV registry does not reach glycaemic target for HbA1c as defined for preschool children (< 7.5%). International multicentre studies are required to further improve our knowledge on the care of children with WRS.

A novel splice site indel alteration in the EIF2AK3 gene is responsible for the first cases of Wolcott-Rallison syndrome in Hungary.

BACKGROUND: Wolcott-Rallison Syndrome (WRS) is a rare autosomal recessive disease that is the most common cause of neonatal diabetes in consanguineous families. WRS is caused by various genetic alterations of the Eukaryotic Translation Initiation Factor 2-Alpha Kinase 3 (EIF2AK3) gene. METHODS: Genetic analysis of a consanguineous family where two children were diagnosed with WRS was performed by Sanger sequencing. The altered protein was investigated by in vitro cloning, expression and immunohistochemistry. RESULTS: The first cases in Hungary, - two patients in one family, where the parents were fourth-degree cousins - showed the typical clinical features of WRS: early onset diabetes mellitus with hyperglycemia, growth retardation, infection-induced multiple organ failure. The genetic background of the disease was a novel alteration in the EIF2AK3 gene involving the splice site of exon 11- intron 11-12 boundary: g.53051_53062delinsTG. According to cDNA sequencing this created a new splice site and resulted in a frameshift and the development of an early termination codon at amino acid position 633 (p.Pro627AspfsTer7). Based on in vitro cloning and expression studies, the truncated protein was functionally inactive. Immunohistochemistry revealed that the intact protein was absent in the islets of pancreas, furthermore insulin expressing cells were also dramatically diminished. Elevated GRP78 and reduced CHOP protein expression were observed in the liver. CONCLUSIONS: The novel genetic alteration causing the absence of the EIF2AK3 protein resulted in insufficient handling of severe endoplasmic reticulum stress, leading to liver failure and demise of the patients.

First European Case of Simultaneous Liver and Pancreas Transplantation as Treatment of Wolcott-Rallison Syndrome in a Small Child.

BACKGROUND: The concept of organ transplantation as treatment for complex genetic conditions, including Wolcott-Rallison syndrome (WRS), continues to show promise. Liver transplantation is essential for survival of patients with WRS, and pancreas transplantation cures their type I diabetes mellitus. METHODS: The recipient, a 3-year-old girl weighing 14 kg at the time of transplantation, suffered from major complications of WRS, including repetitive liver failure episodes and poorly controlled diabetes. The patient underwent a nonacute, combined, simultaneous liver and pancreas transplantation from a pediatric donor without using the en bloc technique. RESULTS: Well-preserved graft functions at 2-year follow-up with normal liver and pancreas function. CONCLUSIONS: This is the first case report of simultaneous liver and pancreas transplantation as treatment of WRS in a small child in Europe. Two-year follow-up demonstrates that organ transplantation can halt life-threating recurrent liver failure episodes and cure type 1 diabetes.

Wolcott-Rallison Syndrome- Endocrinopathy with Recurrent Acute Liver Failure.

A 2-yr-old child with early onset diabetes and hypothyroidism, and diagnosed as Wolcott-Rallison Syndrome, developed two episodes of acute liver failure and recovered, but he remains at high risk of developing another episode of acute liver failure. Autoimmune, metabolic or genetic disorders should be evaluated in children with recurrent acute liver failure and genetic tests needs to be considered.

Dysplasia spondyloepiphysaria and patella dislocation: a case followed over 10 years.

Dysplasia spondyloepiphysaria means altered form and seizure of the vertebral bones and the epiphyseal bone regions. Pathologies related to this disease are: scoliosis, short stature, eye problems, articular deformities. We report a case of tarda form. The main problem was habitual and later fixed dislocation of both patellae together with valgus deformities of the knees. We describe the surgical procedures to gain reduced patellae and correction of the mechanical axis.

The clinical and genetic characteristics of permanent neonatal diabetes (PNDM) in the state of Qatar.

BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare condition that occurs within the first six months of life. Permanent NDM (PNDM) is caused by mutations in specific genes that are known for their expression at early and/or late stages of pancreatic beta- cell development, and are either involved in beta-cell survival, insulin processing, regulation, and release. The native population in Qatar continues to practice consanguineous marriages that lead to a high level of homozygosity. To our knowledge, there is no previous report on the genomics of NDM among the Qatari population. The aims of the current study are to identify patients with NDM diagnosed between 2001 and 2016, and examine their clinical and genetic characteristics. METHODS: To calculate the incidence of PNDM, all patients with PNDM diagnosed between 2001 and 2016 were compared to the total number of live births over the 16-year-period. Whole Genome Sequencing (WGS) was used to investigate the genetic etiology in the PNDM cohort. RESULTS: PNDM was diagnosed in nine (n = 9) patients with an estimated incidence rate of 1:22,938 live births among the indigenous Qatari. Seven different mutations in six genes (PTF1A, GCK, SLC2A2, EIF2AK3, INS, and HNF1B) were identified. In the majority of cases, the genetic etiology was part of a previously identified autosomal recessive disorder. Two novel de novo mutations were identified in INS and HNF1B. CONCLUSION: Qatar has the second highest reported incidence of PNDM worldwide. A majority of PNDM cases present as rare familial autosomal recessive disorders. Pancreas associated transcription factor 1a (PTF1A) enhancer deletions are the most common cause of PNDM in Qatar, with only a few previous cases reported in the literature.

Analysis of Causes for Congenital Ulnar Deviated Thumbs at the Distal Phalanx Level in 157 Thumbs.

PURPOSE: To investigate anatomic abnormalities causing a congenital ulnarly deviated thumb at the distal phalanx. METHODS: A total of 122 children with 157 congenital ulnarly deviated thumbs at the distal phalanges were reviewed, including those with isolated deformity or polydactyly. We analyzed the incidence and characteristics of the underlying anatomic abnormalities as well as the differential diagnoses. RESULTS: Three main causes of an ulnarly deviated thumb were observed. Abnormal hypertrophic epiphyses were found in 96 thumbs. An extra phalanx lying between the normal proximal and distal phalanges was found in 59 thumbs. A previously undescribed cause was found in 2 thumbs with Wassell IV polydactyly, in which an obliquely angled articular surface of the proximal phalanx manifested with ulnar deviation at the interphalangeal joint. Radiographic analysis showed that in cases with abnormal epiphyses, the epiphysis was in good apposition and good alignment with its relevant distal phalanx; the distance from the abnormal epiphysis to the phalanx was usually less than 1 mm. In contrast, in cases of extra phalanges, the distance from the epiphysis to the phalanx averaged more than 2 mm and there was poor apposition between the distal phalanx and the extra bone. CONCLUSIONS: Abnormal hypertrophic epiphysis and triphalangeal thumb are the 2 main causes of a congenital ulnarly deviated thumb. A distance of more than 2 mm between the abnormal bone and the distal phalanx suggests a triphalangeal thumb. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Wolcott-Rallison syndrome in Iran: a common cause of neonatal diabetes.

Background Wolcott-Rallison syndrome is a rare autosomal recessive disorder characterized by neonatal/early-onset non-autoimmune insulin-dependent diabetes, multiple epiphyseal dysphasia and growth retardation. It is caused by mutations in the gene encoding eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3). We aimed to study the clinical characteristics and frequency of the disease in the Iranian population. Methods We recruited 42 patients who referred to the endocrine and metabolism clinic at Mashhad Imam Reza Hospital with neonatal diabetes. Molecular screening of KCNJ11, INS, ABCC8 and EIF2AK3 was performed at the Exeter Molecular Genetics Laboratory, UK. We calculated the frequency of the disease in 124 patients referred from Iran to the Exeter Molecular Genetics Laboratory for genetic screening and compared it to other countries worldwide. Results We identified seven patients as having Wolcott-Rallison syndrome. Genetic testing confirmed the clinical diagnosis and indicated five novel mutations. Only two patients developed clinical features of the syndrome by 6 months of age. Of all 124 cases of Iranian neonatal diabetes referred to the Exeter Molecular Genetics Laboratory for genetic screening, 28 patients (22.58%) had a recessive mutation in EIF2AK3. Conclusions The results of this study raises awareness of the condition and provides further accurate data on the genetic and clinical presentation of Wolcott-Rallison syndrome in the Iranian population. Our study highlights the importance of genetic testing in patients from consanguineous families with diabetes diagnosed within the first 6 months of life.

EIF2AK3 novel mutation in a child with early-onset diabetes mellitus, a case report.

BACKGROUND: Wolcott-Rallison syndrome (WRS) is caused by a biallelic mutation in the gene encoding eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3) on chromosome 2p11.2. This condition is characterized by permanent early-onset diabetes mellitus, epiphyseal dysplasia, and hepatic dysfunction. We report a patient with WRS born to a consanguineous marriage due to a novel biallelic frameshift mutation in the EIF2AK3 gene. CASE PRESENTATION: Our patient was a 2-year-and-6-month-old Yemeni girl born to consanguineous parents who was diagnosed with neonatal diabetes at 20 days of age. She presented with chronic diarrhea and liver dysfunction. The child was normocephalic and exhibited failure to thrive and hepatomegaly with no skeletal deformities. Further investigations revealed microcytic anemia, liver impairment and primary hypothyroidism. Genetic testing confirmed the diagnosis of WRS via identification of a novel biallelic frameshift mutation in the EIF2AK3 gene. During her hospital stay, she went into septic shock and developed multi-organ failure, including fulminant hepatic failure. She unfortunately died within 2 weeks of her hospital stay. CONCLUSIONS: Wolcott-Rallison syndrome is recognized as the most common cause of early-onset diabetes in infants born to consanguineous marriages. Screening for genetic mutations in EIF2AK3 is recommended for establishing early diagnosis, providing genetic counselling, and predicting the development of additional clinical features, most importantly hepatic failure. Hence, this screening is important for guiding optimal management and improving patient outcome.

[A case report of EIF2AK3-related Wolcott-Rallison syndrome and literature review].

The patient was a female infant aged 1 month and 29 days. She was admitted to the hospital due to convulsions for 6 days and increased blood glucose level for 5 days. She had unstable blood glucose levels. The level of glycosylated hemoglobin was too high to measure. Urine glucose was positive (+ - ++++). The levels of fasting C-peptide and insulin were 0.19 ng/mL and 11.68 µIU/mL respectively. High-throughput sequencing of the genetic endocrine disease gene Panel (412 detected genes, including 49 known diabetes-related genes) showed that the EIF2AK3 gene in the infant had two novel compound heterozygous mutations, c.2731_2732delAG and c.2980G>A, both of which were located in the kinase domain. The infant was diagnosed with Wolcott-Rallison syndrome (WRS). As a rare autosomal recessive disease, WRS is characterized by neonatal diabetes, multiple epiphyseal dysphasia and liver disease. Neonatal diabetes is a prerequisite for the diagnosis of WRS. The EIF2AK3 gene is the pathogenic gene of WRS.

The homozygous variant c.797G>A/p.(Cys266Tyr) in PISD is associated with a Spondyloepimetaphyseal dysplasia with large epiphyses and disturbed mitochondrial function.

Spondyloepimetaphyseal dysplasias (SEMD) are a group of genetically heterogeneous skeletal disorders characterized by abnormal vertebral bodies and epimetaphyseal abnormalities. We investigated two families with a new SEMD type with one proband each. They showed mild facial dysmorphism, flat vertebral bodies (platyspondyly), large epiphyses, metaphyseal dysplasia, and hallux valgus as common clinical features. By trio-exome sequencing, the homozygous missense variant c.797G>A/p.(Cys266Tyr) in PISD was found in both affected individuals. Based on exome data analyses for homozygous regions, the two patients shared a single homozygous block on chromosome 22 including PISD, indicating their remote consanguinity. PISD encodes phosphatidylserine (PS) decarboxylase that is localized in the inner mitochondrial membrane and catalyzes the decarboxylation of PS to phosphatidylethanolamine (PE) in mammalian cells. PE occurs at high abundance in mitochondrial membranes. Patient-derived fibroblasts showed fragmented mitochondrial morphology. Treatment of patient cells with MG-132 or staurosporine to induce activation of the intrinsic apoptosis pathway revealed significantly decreased cell viability with increased caspase-3 and caspase-7 activation. Remarkably, ethanolamine (Etn) supplementation largely restored cell viability and enhanced apoptosis in MG-132-stressed patient cells. Our data demonstrate that the biallelic hypomorphic PISD variant p.(Cys266Tyr) is associated with a novel SEMD form, which may be treatable with Etn administration.

An Infant With Neonatal Diabetes and Double Outlet Right Ventricle - Wolcott- Rallison syndrome.

INTRODUCTION: Wolcott-Rallison syndrome (WRS) is a rare, autosomal recessive disorder with infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, osteopenia, mental retardation or developmental delay, and hepatic and renal dysfunction as main clinical findings. Cardiovascular system is very rarely affected and there are a limited number of publications where WRS is associated with congenital heart disease. The aim of this interesting case is to report an infant with Wolcott - Rallison syndrome, type I diabetes mellitus, and complex congenital heart disease, diagnosed in a pre term neonate. CASE REPORT: A case of preterm neonate who presented immediately after delivery with hyperglycemia and heart murmur. Clinical and laboratory investigation showed diabetes mellitus type I and double outlet right ventricle. Genetic examination showed classic mutations in the EIF2AK3 gene - eukaryotic translation initiation factor 2α kinase 3. Conclusion: Diabetes in neonatal age raises doubts about the possibility of association with the syndrome and other diseases.

Wolcott-Rallison Syndrome With Different Clinical Presentations and Genetic Patterns in 2 Infants.

Wolcott-Rallison syndrome is a rare disease presenting with insulin-dependent diabetes mellitus (DM) before 6 months old, skeletal dysplasia after 6 months old, and liver failure. Other manifestations are renal failure, microcephaly, epilepsy, central hypothyroidism, neutropenia, and dental and dermal problems. The cases were 2 patients from 2 different states of Iran (Khoozestan and Fars) who had developed DM before 6 months old. The first one was a 7-month-old infant who was healthy; in the genetic study (screening), autosomal recessive pattern and novel deletion in EIF2AK3 were reported; her sister had died at 5.5 years old due to diabetic ketoacidosis (DKA) that was associated with liver and renal failure. The second patient had developed DKA at 45 days old, which was associated with mild acute tubular necrosis and abnormal coagulation tests at onset clinical presentation, which were then resolved. He was treated with insulin, and at follow-up, the laboratory data are normal; in the genetic study, EIF2AK3 nonsense homozygous mutation was diagnosed. Genetic study of patients with insulin-dependent DM before 6 months old, especially those with DKA and associated with or without other disorders; attention to novel deletion of in EIF2AK3 gene; screening for skeletal dysplasia after 1 year old; and renal, liver, pancreatic, and thyroid function tests are recommended.