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Wolcott-Rallison syndrome.

Julier C, Nicolino M - Orphanet J Rare Dis (2010)

Bottom Line: Molecular genetic testing confirms the diagnosis.Prognosis is poor and most patients die at a young age.Intervention strategies targeting ER dysfunction provide hope for future therapy and prevention.

View Article: PubMed Central - HTML - PubMed

Affiliation: Inserm UMR-S 958, Faculté de Médecine Denis-Diderot, Paris, France. cecile.julier@inserm.fr

ABSTRACT
Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disease, characterized by neonatal/early-onset non-autoimmune insulin-requiring diabetes associated with skeletal dysplasia and growth retardation. Fewer than 60 cases have been described in the literature, although WRS is now recognised as the most frequent cause of neonatal/early-onset diabetes in patients with consanguineous parents. Typically, diabetes occurs before six months of age, and skeletal dysplasia is diagnosed within the first year or two of life. Other manifestations vary between patients in their nature and severity and include frequent episodes of acute liver failure, renal dysfunction, exocrine pancreas insufficiency, intellectual deficit, hypothyroidism, neutropenia and recurrent infections. Bone fractures may be frequent. WRS is caused by mutations in the gene encoding eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3), also known as PKR-like endoplasmic reticulum kinase (PERK). PERK is an endoplasmic reticulum (ER) transmembrane protein, which plays a key role in translation control during the unfolded protein response. ER dysfunction is central to the disease processes. The disease variability appears to be independent of the nature of the EIF2AK3 mutations, with the possible exception of an older age at onset; other factors may include other genes, exposure to environmental factors and disease management. WRS should be suspected in any infant who presents with permanent neonatal diabetes associated with skeletal dysplasia and/or episodes of acute liver failure. Molecular genetic testing confirms the diagnosis. Early diagnosis is recommended, in order to ensure rapid intervention for episodes of hepatic failure, which is the most life threatening complication. WRS should be differentiated from other forms of neonatal/early-onset insulin-dependent diabetes based on clinical presentation and genetic testing. Genetic counselling and antenatal diagnosis is recommended for parents of a WRS patient with confirmed EIF2AK3 mutation. Close therapeutic monitoring of diabetes and treatment with an insulin pump are recommended because of the risk of acute episodes of hypoglycaemia and ketoacidosis. Interventions under general anaesthesia increase the risk of acute aggravation, because of the toxicity of anaesthetics, and should be avoided. Prognosis is poor and most patients die at a young age. Intervention strategies targeting ER dysfunction provide hope for future therapy and prevention.

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Radiographs of a WRS patient (age 13 years). A. Hand: the carpal bones are small and irregular with dysplastic distal radial and ulnar epiphyses; several phalanges are dysplastic with abnormal metaphyseal cupping at the proximal ends. B. Spine: dorsal region of spine shows flattening of the vertebral bodies with defects at the anterior edges. C. Pelvis: the acetabular roofs are hypoplastic with dysplastic capital femoral epiphyses.
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Figure 1: Radiographs of a WRS patient (age 13 years). A. Hand: the carpal bones are small and irregular with dysplastic distal radial and ulnar epiphyses; several phalanges are dysplastic with abnormal metaphyseal cupping at the proximal ends. B. Spine: dorsal region of spine shows flattening of the vertebral bodies with defects at the anterior edges. C. Pelvis: the acetabular roofs are hypoplastic with dysplastic capital femoral epiphyses.

Mentions: WRS is characterized by multiple epiphyseo-metaphyseal dysplasia whose major features affect the long bones, pelvis and vertebrae, while the skull is usually normal. Dysplastic changes on knee radiographs are illustrated by enlarged and irregular metaphyses with prominent beaks. Femoral and tibial epiphyses are flattened. On the hand, the carpal bones and phalanges show tubulation defects and appear short and enlarged. The carpal centres are small and irregular, the proximal phalanges show especially dense and cone-shaped epiphyses (Figure 1A) [5]. Interestingly, bone mineralization is affected, as was noted in the early descriptions of the syndrome [6]. Osteopenia is associated with thin cortices and poorly calcified epiphyses which are undeveloped. Multiple and frequent fractures can be observed. Blood calcium and phosphorus values are normal. At the spine, the characteristics correspond to those of mild platyspondyly. Vertebrae show irregular upper and lower plates with frequent ossification defects at the anterior edge (Figure 1B). Changes are especially marked at the dorso-lumbar level with a consequent appearance of thoracic kyphosis and/or lumbar lordosis. Clinically, the chest is rather broad and flattened in the antero-posterior direction (dwarfism with short trunk) (Figure 2A). At the pelvic level, the radiographs usually show abnormal iliac wings and dysplastic acetabular roofs (Figure 1C). Dislocation or subluxation of the femoral heads is a common complication. Femoral epiphyses are flattened with coxa vara. Clinically, difficulty in walking or running is frequent, with a "duck-like" gait related to stiff hips and limited abduction. In some cases, the extreme skeletal condition may manifest with severe cervical spine instability, which may result in spinal cord compression and motor neuropathy in arms and legs (T. Barrett, pers. communication).


Wolcott-Rallison syndrome.

Julier C, Nicolino M - Orphanet J Rare Dis (2010)

Radiographs of a WRS patient (age 13 years). A. Hand: the carpal bones are small and irregular with dysplastic distal radial and ulnar epiphyses; several phalanges are dysplastic with abnormal metaphyseal cupping at the proximal ends. B. Spine: dorsal region of spine shows flattening of the vertebral bodies with defects at the anterior edges. C. Pelvis: the acetabular roofs are hypoplastic with dysplastic capital femoral epiphyses.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2991281&req=5

Figure 1: Radiographs of a WRS patient (age 13 years). A. Hand: the carpal bones are small and irregular with dysplastic distal radial and ulnar epiphyses; several phalanges are dysplastic with abnormal metaphyseal cupping at the proximal ends. B. Spine: dorsal region of spine shows flattening of the vertebral bodies with defects at the anterior edges. C. Pelvis: the acetabular roofs are hypoplastic with dysplastic capital femoral epiphyses.
Mentions: WRS is characterized by multiple epiphyseo-metaphyseal dysplasia whose major features affect the long bones, pelvis and vertebrae, while the skull is usually normal. Dysplastic changes on knee radiographs are illustrated by enlarged and irregular metaphyses with prominent beaks. Femoral and tibial epiphyses are flattened. On the hand, the carpal bones and phalanges show tubulation defects and appear short and enlarged. The carpal centres are small and irregular, the proximal phalanges show especially dense and cone-shaped epiphyses (Figure 1A) [5]. Interestingly, bone mineralization is affected, as was noted in the early descriptions of the syndrome [6]. Osteopenia is associated with thin cortices and poorly calcified epiphyses which are undeveloped. Multiple and frequent fractures can be observed. Blood calcium and phosphorus values are normal. At the spine, the characteristics correspond to those of mild platyspondyly. Vertebrae show irregular upper and lower plates with frequent ossification defects at the anterior edge (Figure 1B). Changes are especially marked at the dorso-lumbar level with a consequent appearance of thoracic kyphosis and/or lumbar lordosis. Clinically, the chest is rather broad and flattened in the antero-posterior direction (dwarfism with short trunk) (Figure 2A). At the pelvic level, the radiographs usually show abnormal iliac wings and dysplastic acetabular roofs (Figure 1C). Dislocation or subluxation of the femoral heads is a common complication. Femoral epiphyses are flattened with coxa vara. Clinically, difficulty in walking or running is frequent, with a "duck-like" gait related to stiff hips and limited abduction. In some cases, the extreme skeletal condition may manifest with severe cervical spine instability, which may result in spinal cord compression and motor neuropathy in arms and legs (T. Barrett, pers. communication).

Bottom Line: Molecular genetic testing confirms the diagnosis.Prognosis is poor and most patients die at a young age.Intervention strategies targeting ER dysfunction provide hope for future therapy and prevention.

View Article: PubMed Central - HTML - PubMed

Affiliation: Inserm UMR-S 958, Faculté de Médecine Denis-Diderot, Paris, France. cecile.julier@inserm.fr

ABSTRACT
Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disease, characterized by neonatal/early-onset non-autoimmune insulin-requiring diabetes associated with skeletal dysplasia and growth retardation. Fewer than 60 cases have been described in the literature, although WRS is now recognised as the most frequent cause of neonatal/early-onset diabetes in patients with consanguineous parents. Typically, diabetes occurs before six months of age, and skeletal dysplasia is diagnosed within the first year or two of life. Other manifestations vary between patients in their nature and severity and include frequent episodes of acute liver failure, renal dysfunction, exocrine pancreas insufficiency, intellectual deficit, hypothyroidism, neutropenia and recurrent infections. Bone fractures may be frequent. WRS is caused by mutations in the gene encoding eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3), also known as PKR-like endoplasmic reticulum kinase (PERK). PERK is an endoplasmic reticulum (ER) transmembrane protein, which plays a key role in translation control during the unfolded protein response. ER dysfunction is central to the disease processes. The disease variability appears to be independent of the nature of the EIF2AK3 mutations, with the possible exception of an older age at onset; other factors may include other genes, exposure to environmental factors and disease management. WRS should be suspected in any infant who presents with permanent neonatal diabetes associated with skeletal dysplasia and/or episodes of acute liver failure. Molecular genetic testing confirms the diagnosis. Early diagnosis is recommended, in order to ensure rapid intervention for episodes of hepatic failure, which is the most life threatening complication. WRS should be differentiated from other forms of neonatal/early-onset insulin-dependent diabetes based on clinical presentation and genetic testing. Genetic counselling and antenatal diagnosis is recommended for parents of a WRS patient with confirmed EIF2AK3 mutation. Close therapeutic monitoring of diabetes and treatment with an insulin pump are recommended because of the risk of acute episodes of hypoglycaemia and ketoacidosis. Interventions under general anaesthesia increase the risk of acute aggravation, because of the toxicity of anaesthetics, and should be avoided. Prognosis is poor and most patients die at a young age. Intervention strategies targeting ER dysfunction provide hope for future therapy and prevention.

Show MeSH
Related in: MedlinePlus