Donohue syndrome 252004 222459520 2008-06-29T13:12:21Z DOI bot 6652755 Citation maintenance. Formatted: doi. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. {{Infobox_Disease | Name = Donohue syndrome | Image = PBB Protein INSR image.jpg | Caption = [[insulin receptor]] | DiseasesDB = 30801 | ICD10 = | ICD9 = | ICDO = | OMIM = 246200 | MedlinePlus = | eMedicineSubj = | eMedicineTopic = | MeshID = | }} '''Donohue syndrome''' (also known as '''Leprechaunism''') is an extremely rare and severe [[genetic disorder]]. ''Leprechaunism'' derives its name from the fact that those afflicted with the disease often have elfin features and are smaller than usual. Affected individuals have an [[insulin receptor]] with greatly impaired functionality. ==Presentation== Facial features indicative of Donohue syndrome include protuberant and low-set [[ear]]s, flaring [[nostril]]s, and thick [[lips]]. Physical features include stunted growth (including during [[gestation]]), an enlarged [[clitoris]] and [[breast]]s in affected [[female]]s, and an enlarged [[penis]] in affected males. In the Journal of Pediatric Medicine, Donohue and Uchida described affected sisters who's growth appeared to have ended in the seventh month of gestation, both born alive but dying before four months of age.<ref name="omim246200"><http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=246200</ref> Very early death (or spontaneous abortion) is the norm, although sufferers sometimes live longer than a decade.<ref name="omim246200"/><ref name="pmid12023989">{{cite journal |author=Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D |title=Genotype-phenotype correlation in inherited severe insulin resistance |journal=Hum. Mol. Genet. |volume=11 |issue=12 |pages=1465–75 |year=2002 |pmid=12023989 |url=http://hmg.oxfordjournals.org/cgi/content/full/11/12/1465#DDF143C6 |doi=10.1093/hmg/11.12.1465}}</ref> As the mutation causing the disorder affects [[insulin receptor]] function, those with the disease are also [[insulin]] [[insulin resistance|resistant]], with hypoglycemia and profound hyperinsulinemia (very high levels of insulin in the blood)<ref name="omim246200"/> Another feature of the disease is that the [[skin|subcutaneous]] [[Adipose tissue]] is markedly diminished. (Contributing to the unusual appearance of affected individuals.) A much milder form of the disease, in which there is some insulin resistance but normal growth and subcutaneous fat distribution, is also known.<ref name="pmed8326490">[http://www.ncbi.nlm.nih.gov/portal/query.fcgi?p$site=entrez&cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=8326490 A syndrome of insulin resistance resembling leprec...[J Med Genet. 1993&#93; - PubMed Result<!-- Bot generated title -->]</ref> It is caused by a less severe mutation of the same gene. ==Genetics== [[Image:autorecessive.jpg|thumb|right|Donohue syndrome has an [[autosomal recessive]] pattern of inheritance.]] Donohue syndrome is an [[autosomal]] [[recessive gene]]tic disorder. The mutations responsible for the disorder are found on the short arm [[chromosome]] 19 (19p13.2) within the coding sequence of the ''INSR gene'' ([[insulin receptor]]) causing the production of inactive receptor molecules.<ref name="pmid12023989"/> There are several mutations that can be responsible for the disease, as any mutation that severely impairs the functionality of the insulin receptor will have similar effects. The INSR gene spans over one hundred and twenty thousand [[base pair]]s, which contain twenty-two [[exons]] coding for a [[protein]] that consists of 1382 [[amino acid]]s. <ref>[http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_000199 NCBI Sequence Viewer v2.0<!-- Bot generated title -->]</ref>. Some of the [[introns]] may or may not be spliced out depending on the kind of cell. <ref>[http://www.ncbi.nlm.nih.gov/pubmed/1602013?dopt=Abstract Alternatively spliced variants of the insulin rece...[J Clin Invest. 1992&#93; - PubMed Result<!-- Bot generated title -->]</ref> Known mutations to the gene which can cause Donahue syndrome include a [[nonsense mutation]] that resulted in a [[frame shift mutation|frame shift]]<ref name="pmed8105179">[http://www.ncbi.nlm.nih.gov/portal/query.fcgi?p$site=entrez&cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=8105179 Leprechaunism and homozygous nonsense mutation in ...[Lancet. 1993&#93; - PubMed Result<!-- Bot generated title -->]</ref>, a single missense mutation<ref name="omim147670">[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=147670 Omim - Insulin Receptor; Insr<!-- Bot generated title -->]</ref> and in the milder form mentioned above, a single codon change that altered [[isoleucine]] to [[methionine]] in the receptor protein.<ref name="omim246200"/> Some mutations to the gene instead result in insulin resistant [[diabetes]] without Donahue syndrom.<ref name="omim147670"/> As the mutations are extremely rare, most cases are the result of [[consanguineous]] matings, for instance between cousins.<ref name="omim246200"/>. However, the exact mutation need not be the same: a sufferer may have [[compound heterozygote|two different mutant alleles]].<ref>[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=3883764 Leprechaunism: an inherited defect in a high-affinity insulin receptor<!-- Bot generated title -->]</ref> A heterozygous individual (i.e. one who is a carrier for the disease, having only one normal [[allele]] for the insulin receptor) will not be affected. Two heterozygous parents have, in theory, a one in four chance of having a child with the disease, and two thirds of their unaffected children will be carriers. However, because spontaneous abortion (miscarriage) often results when the fetus has the disease, in actuality the proportion of children born alive with Donahue syndrome will be lower than 25%.<ref name="omim246200"/> It is possible to do a genetic test to identify carriers, but because it is so rare, this is not usually done unless there is reason to suspect that the individual being tested is a carrier, for instance having an affected sibling or cousin. As expected for a genetic disease that can be caused by many different mutations, it is not limited to a specific ethnic group, and has been seen in people of various races. ==Pathophysiology== The cause of the disease is the lack of a fully functional insulin receptor, which has a profound effect during fetal development and thereafter. In one case, it was found (by culturing pancreatic cells) that the receptor produced by the mutant allele is only about 15% as effective as the normal receptor.<ref name="omim246200"/>. The [[beta cell]]s in the [[pancreas]], which make and store insulin and release it on an as-needed basis, are often found to be very large or numerous.<ref name="omim246200"/> In some patients, particularly those who are longer-lived, unusual bone changes are sometimes seen, and there may be excessive body hair<ref name="omim246200"/> and [[acanthosis nigricans|velvety hyperpigmentation of the skin]]. The prognosis is quite dire, with early death usual.<ref name="pmid12023989">{{cite journal |author=Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D |title=Genotype-phenotype correlation in inherited severe insulin resistance |journal=Hum. Mol. Genet. |volume=11 |issue=12 |pages=1465–75 |year=2002 |pmid=12023989 |url=http://hmg.oxfordjournals.org/cgi/content/full/11/12/1465#DDF143C6 |doi=10.1093/hmg/11.12.1465}}</ref> In fact, most patients die in their first year except in milder forms of the disease, but few are known to have lived longer.<ref name="omim246200"/> The variation is unsurprising given the diversity of mutations causing the disease. Many of the problems associated with Donohue syndome may be due to the fact that, in addition to its well-known role in the regulation of blood sugar, the insulin receptor also binds the [[insulin-like growth factor]], regulating the growth of the embryo.<ref>Personal communication with J. Bell, Ph.D.</ref> ==Eponym== Donohue syndrome was first identified in [[1948]] by Dr. [[W.L. Donohue]].<ref>{{cite journal|author=Donohue WL|title=Dysendocrinism|journal= J. Pediat|year=1948|volume=32|pages=739–48|doi=10.1016/S0022-3476(48)80231-3}}</ref> The name leprechaunism has been largely abandoned because of the perception of the name by some parents of patients as insulting.<ref name="omim246200"/> ==See also== * [[Rabson-Mendenhall syndrome]] * [[Patterson pseudoleprechaunism syndrome]] * [[Williams syndrome]] ==References== <!-- ---------------------------------------------------------- See http://en.wikipedia.org/wiki/Wikipedia:Footnotes for a discussion of different citation methods and how to generate footnotes using the <ref>, </ref> and <reference /> tags ----------------------------------------------------------- --> {{reflist}} {{Phakomatoses and other congenital malformations not elsewhere classified}} [[Category:Genetic disorders]] [[Category:Autosomal recessive disorders]] [[Category:Rare diseases]] [[Category:Syndromes]] [[es:Síndrome de Donohue]] [[pl:Leprechaunizm]]