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Wolcott-Rallison Syndrome


Presentation

Short Stature
  • Short stature and walking difficulties become evident in the 2 nd year of life when the child starts to walk. These skeletal changes are progressive with age.[ncbi.nlm.nih.gov]
  • WRS should be suspected in any child who presents with permanent, nonimmune neonatal/infantile diabetes associated with skeletal dysplasia, short stature, episodes of acute liver failure, or pancytopenia, diabetes associated with skeletal dysplasia, short[abstracts.eurospe.org]
Euthyroid
  • Thyroid dysfunction in WRS is a transient phenomenon reflecting euthyroid sickness.[ncbi.nlm.nih.gov]
  • Euthyroid sick syndrome is thought to be an energy saving mechanism during stress conditions [ 13 ]. Neutropenia has been reported in some patients [ 6, 9 ], and is often associated with recurring infections.[doi.org]
Turkish
  • This report presents an 8-year-old WRS case who is found to have W522X mutation in EIF2AK3 gene which was only found in two other unrelated Turkish families.[ncbi.nlm.nih.gov]
  • In particular, it was observed in four out of four patients studied from two Turkish families with the W522X mutation, three out of three French/Tunisian siblings with the Fs346X346 mutation, one child with a Fs910X956 in a single-affected family, and[doi.org]
Recurrent Bacterial Infection
  • Neonatal diabetes mellitus because of pancreatic agenesis with dysmorphic features and recurrent bacterial infections. Pediatr Diabetes. 2008 ; 9: 240 – 4.[doi.org]
Failure to Thrive
  • 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.[ncbi.nlm.nih.gov]
  • Other features such as renal dysfunction, failure to thrive, neutropenia, exocrine pancreatic insufficiency, hypothyroidism, recurrent infection, and developmental delay have been reported in some patients ( 3 Senee V, Vattem KM, Delepine M, Rainbow LA[doi.org]
  • […] to thrive Craniofacial Triangular face NO Furrowed tongue NO Prominent metopic ridge Eye Defects Hyperopic astigmatism NO Alacrima NO Progressive external ophthalmoplegia NO Ophthalmoplegia NO Anisocoria Cutaneous Hyperpigmentation of the skin Hypopigmentation[playground.phenotips.org]
  • Other features of the syndrome include renal dysfunction, failure to thrive, neutropenia, exocrine pancreatic insufficiency, hypothyroidism, recurrent infection and developmental delay.[edmcasereports.com]
  • Further reports extended the phenotype to recurrent hepatitis, renal dysfunction, failure to thrive, developmental delay, neutropenia and hypothyroidism [ 2, 3, 4, 5, 6, 7 ].[karger.com]
Lordosis
  • There is usually a short trunk, excessive lordosis, a short and broad chest, and genu valgum. This report presents a case of Wolcott-Rallison syndrome in a 10 year old child.[ncbi.nlm.nih.gov]
  • The vertebral involvement is more common in the dorsolumbar region and leads to thoracic kyphosis and/or lumbar lordosis. Hand involvement of carpal and metacarpal bones leads to short and thick metacarpals.[docksci.com]
  • Regarding vertebrae, changes are especially marked at the dorsolumbar level with a consequent appearance of thoracic kyphosis and/or lumbar lordosis. Difficulty in walking is frequent.[journals.lww.com]
  • Changes are especially marked at the dorso-lumbar level with a consequent appearance of thoracic kyphosis and/or lumbar lordosis.[doi.org]
Arthralgia
  • Affected individuals also experience early onset pain and stiffness in affected joints (early-onset arthritis) that can develop in chronic joint pain (arthralgia) and damage to the joints. The hips and the knees are commonly affected.[rarediseases.org]
Platyspondyly
  • 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 ).[doi.org]
Coxa Vara
  • 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.[doi.org]

Workup

  • Clinical Testing and Workup Basic x-rays (radiographs) can help to establish a diagnosis of rMED by revealing abnormal epiphyses, brachydactyly, and a double patella.[rarediseases.org]

Treatment

  • Management and treatment Close therapeutic monitoring of diabetes should be considered and treatment with an insulin pump is recommended, especially in the first months of life, due to the risk of acute episodes of hypoglycemia.[orpha.net]
  • We report on primary hypothyroidism, which has not been previously described, of a patient with Wolcott-Rallison syndrome due to novel mutation (W521X), who showed improved growth after thyroid hormone treatment.[ncbi.nlm.nih.gov]
  • Liver, pancreas and kidney transplantation for the treatment of Wolcott-Rallison syndrome. American Journal of Transplantation, 15 (2), 565-567. Liver, pancreas and kidney transplantation for the treatment of Wolcott-Rallison syndrome. / Tzakis, A.[miami.pure.elsevier.com]
  • Make the best clinical decisions with an enhanced emphasis on evidence-based practice and expert opinions on treatment strategies. Zero in on the most relevant and useful references with the aid of a more focused, concise bibliography.[books.google.de]

Prognosis

  • Prognosis Prognosis is poor and most patients die at a young age from multiple-organ failure with predominant liver and renal dysfunction. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • Prognosis - Wolcott-Rallison syndrome Not supplied. Treatment - Wolcott-Rallison syndrome Not supplied. Resources - Wolcott-Rallison syndrome Not supplied.[checkorphan.org]
  • Prognosis is poor and most patients die at a young age. Intervention strategies targeting ER dysfunction provide hope for future therapy and prevention.[ncbi.nlm.nih.gov]
  • We noticed a variation in the age at onset, frequency, and prognosis of hepatitis between patients.[karger.com]
  • A long-term follow-up study would provide more insight into the clinical phenotype and prognosis of WRS.[doi.org]

Etiology

  • Etiology WRS is caused by mutations in the EIF2AK3 gene encoding eukaryotic translation initiation factor 2-alpha kinase 3 (PKR-like endoplasmic reticulum kinase; PERK), which plays a key role in translation control during unfolded protein response.[orpha.net]
  • […] pancreati anomalies severe pancreatic hypoplasia neonatal diabetes mellitus laryngeal stenosis isolated central hypothyroidism ( 12210348 ) epiphyseal dysplasia central nervous system arrhinencephaly cerebellar cortical dysplasia mental retardation Etiology[humpath.com]
  • Investigating the siblings for cystic kidneys or testing for cystic kidney disease in a gene panel could shed some light on the etiology of the disease in the index case. The renal involvement in WRS is well known ( 3 ).[edmcasereports.com]
  • Etiology Genetics WRS is a rare autosomal recessive disease.[doi.org]

Epidemiology

  • Summary Epidemiology Fewer than 60 cases have been reported to date. Most patients are from consanguineous families. Prevalence may therefore vary significantly between countries.WRS may be underdiagnosed because of early death before diagnosis.[orpha.net]
  • Although genetic components in these diseases are clearly present, the lack of obvious and homogeneous modes of transmission has slowed progress by prevent ing the full exploitation of classical genetic epidemiologic techniques.[books.google.de]
  • Bappal B, Raghupathy P, de Silva V, Khusaiby SM (1999) Permanent neonatal diabetes mellitus: clinical presentation and epidemiology in Oman. Arch Dis Child Fetal Neonatal Ed 80:F209–F212 PubMed CrossRef Google Scholar 3.[doi.org]
  • Relevant External Links for EIF2AK3 Genetic Association Database (GAD) EIF2AK3 Human Genome Epidemiology (HuGE) Navigator EIF2AK3 Atlas of Genetics and Cytogenetics in Oncology and Haematology: EIF2AK3 No data available for Genatlas for EIF2AK3 Gene Characterization[genecards.org]
Sex distribution
Age distribution

Pathophysiology

  • This is the first case in which the pathophysiological role of EIF2AK3 deficiency in WRS is confirmed at the molecular level.[ncbi.nlm.nih.gov]
  • […] include: Homeostasis and migration of neutrophil granulocytes,Granulocyte-colony Stimulating Factor (G-CSF) receptor signaling,New Granulocyte-colony Stimulating Factor (G-CSF) Receptor Signaling Pathways ,Neutrophil elastase (ELANE) – Genetics and Pathophysiology[books.google.de]
  • This demonstrates that EIF2AK3 gene plays a major role in the pathophysiology of WRS. In addition, EIF2aK3 kinase activity appears to be essential for pancreatic islet cell function and bone development in humans. References 1.[annsaudimed.net]
  • [ Download the entire slideshow to play on your pc ] Click here for the The Pathophysiology Underlying Cardiovascular Mortality Results in a Worsening of Glycemic Control SlideShow Click here for the Sulfonylurea Dose-Responsive and Sulfonylurea-Metformin[diabetes-mellitus.org]
  • These mice models have proven very useful to dissect the pathophysiology of WRS.[doi.org]

Prevention

  • Furthermore, Os Odontoideum needs to be actively screened for in WRS patients to prevent neurological and respiratory compromise.[ncbi.nlm.nih.gov]
  • Wolcott-Rallison Syndrome 1 Department of Pediatric and Preventive Dentistry, Faculty of Dentistry, Jamia Millia Islamia, New Delhi, India 2 Department of Pedodontics and Preventive Dentistry, Jodhpur Dental College General Hospital, Boranara, Jodhpur[jisppd.com]
  • Future episodes of liver failure, the main contributor to the increased mortality in WRS, may be prevented through timely liver transplantation.[miami.pure.elsevier.com]
  • At any age, hypoglycemia should be prevented because the disease can decompensate, even if this requires maintaining the level of glucose above the objectives generally recommended in diabetic children.[orpha.net]

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