Wolcott–Rallison syndrome

Wolcott–Rallison syndrome
Classification and external resources
OMIM 226980

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. Patients with WRS have mutations in the EIF2AK3 gene, which encodes the pancreatic eukaryotic translation initiation factor 2-alpha kinase 3.[1]

[2] Other disease names include multiple epiphyseal dysplasia and early-onset diabetes mellitus.[3] Most patients do not survive to adult hood with this disease.[4] The majority of these WRS patients die from fulminant hepatitis during childhood.[5] There are few reported cases for this disease. Of the 54 families worldwide with reported cases of WRS, 22.2% of them are from the Kingdom of Saudi Arabia.[5] Of the 23 WRS patients in Saudi Arabia, all but one is the result of consanguineous marriages.[5] Another country where WRS cases have been found is Kosovo. Here, the Albanian population is also known for consanguineous marriages, but there were some cases involving patients from non-consanguineous parents that were carriers for the same mutant allele.[4]

Radiograph of a WRS child presenting with dysplastic bone growth in various regions of the body.

Genetics

The main focus for this autosomal recessive disease is mutations to the EIF2AK3 gene. This gene is located on chromosome 2 p11.2.[3] In unrelated families, different mutations have been observed in the EIF2AK3 gene, including missense and nonsense mutations.[3] For some cases for unrelated families, identical mutations were observed, although these cases are rare.

The EIKF2AK3 gene codes for PERK (pancreatic endoplasmic reticulum kinase), an explanation for the spectrum symptoms. PERK is associated with the activity of beta cells in the pancreas. Beta cells are needed for the proper release of insulin into the blood stream after an increase in blood glucose.[4] This kinase is needed for the control of protein levels in the endoplasmic reticulum and is linked to ribosome activity.[6] The endoplasmic reticulum is a major protein sorting and processing center in every cell of the body. A broad range of bodily systems is affected because of the lack of post-translational modifications of to proteins. These proteins are coming from the endoplasmic reticulum can be in the cells of the various organ systems effected, such as urinary and central nervous system. EIKF2AK3 is also involved in bone cells.[4] This is part of the reason why patients suffer from multiple epiphyseal dysplasia and osteopenia.

Symptoms and Diagnosis

Initially, patients with neonatal or early-childhood onset diabetes are possible candidates for having Wolcott–Rallison syndrome.[1] The other symptoms include the multiple epiphyseal dysplasia, osteopenia, intellectual disability, and hepatic and renal dysfunction.[1] Patients with the symptoms that line up with Wolcott–Rallison syndrome can be suggested for genetics testing. The key way to test for this disease specifically is through genetic testing for the EIKF2AK3 mutation.[7] Molecular genetic analysis can be done for the patient and the parents to test for de novo mutations or inherited. It can also show whether the patient's parents are heterozygotes or homozygotes for the normal phenotype.[4] X-Rays can show bone age in relation to actual age. Typically the bond age is a few years less than the actual in the patients with WRS.[4][5][8][9] Hypothyroidism is rare is WRS patients but can occur.[4]

Therapies

The most common method to manage hypoglycemia and diabetes is with an insulin pump.[9] As soon as parent knows Walcott-Rallison syndrome is the source, treatment or therapy plans need to be drawn up along with frequent check ins to make sure kidney and liver functions are around normal and insulin therapy are working.[4] If needed, the patient can undergo thyroxin therapy in order to maintain proper thyroid stimulating hormone levels. This has only been needed in a few cases were hypothyroidism was present in the patient.[4]

References

  1. 1 2 3 Søvik O, Njølstad PR, Jellum E, Molven A (May 2008). "Wolcott-Rallison syndrome with 3-hydroxydicarboxylic aciduria and lethal outcome". J. Inherit. Metab. Dis. 31: 293–297. doi:10.1007/s10545-008-0866-1. PMID 18500571.
  2. ↑ Durocher F, Faure R, Labrie Y, Pelletier L, Bouchard I, Laframboise R (July 2006). "A novel mutation in the EIF2AK3 gene with variable expressivity in two patients with Wolcott-Rallison syndrome". Clin. Genet. 70 (1): 34–8. doi:10.1111/j.1399-0004.2006.00632.x. PMID 16813601.
  3. 1 2 3 McKusick, Victor. "Epiphyseal Dysplasia, Multiple, with Early-Onset Diabetes". Online Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 14 October 2015.
  4. 1 2 3 4 5 6 7 8 9 Uroić, Anita Špehar; Kotori, Vjosa Mulliqi; Putarek, Nataša Rojnić; Kušec, Vesna; Dumić, Miroslav (2013-11-06). "Primary hypothyroidism and nipple hypoplasia in a girl with Wolcott–Rallison syndrome". European Journal of Pediatrics. 173 (4): 529–531. doi:10.1007/s00431-013-2189-y. ISSN 0340-6199.
  5. 1 2 3 4 Habeb, Abdelhadi M. (June 2013). "Frequency and spectrum of WolcottRallison syndrome in Saudi Arabia: a systematic review" (PDF). Libyan J Medicine. 8: 21137. doi:10.3402/ljm.v8i0.21137. PMC 3679509Freely accessible. PMID 23759358.
  6. ↑ Porter, J R (12 April 2005). "Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and cell failure" (PDF). Journal of Medical Genetics. 42 (12): 893–902. doi:10.1136/jmg.2005.030791. Retrieved 14 October 2015.
  7. ↑ Senée, Valérie; Vattem, Krishna M.; Delépine, Marc; Rainbow, Lynn A.; Haton, Céline; Lecoq, Annick; Shaw, Nick J.; Robert, Jean-Jacques; Rooman, Raoul (2004-07-01). "Wolcott-Rallison Syndrome Clinical, Genetic, and Functional Study of EIF2AK3 Mutations and Suggestion of Genetic Heterogeneity". Diabetes. 53 (7): 1876–1883. doi:10.2337/diabetes.53.7.1876. ISSN 0012-1797. PMID 15220213.
  8. ↑ Hawkes, C. P.; McGlacken-Byrne, S. M.; Murphy, N. P. (2013-05-05). "Short stature in child with early-onset diabetes". European Journal of Pediatrics. 172 (9): 1255–1257. doi:10.1007/s00431-013-2007-6. ISSN 0340-6199.
  9. 1 2 Julier, Cécile; Nicolino, Marc (2010). "Wolcott-Rallison syndrome". Orphanet Journal of Rare Diseases. 5 (1): 29. doi:10.1186/1750-1172-5-29. PMC 2991281Freely accessible. PMID 21050479.
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