Donohue syndrome
Donohue syndrome | |
---|---|
Other names | Leprechaunism |
Infant with Donohue syndrome | |
Specialty | Endocrinology, rheumatology, medical genetics |
Prognosis | poor[1] |
Donohue syndrome (also known as leprechaunism) is an extremely rare and severe
Signs and symptoms
Facial features indicative of Donohue syndrome include protuberant and low-set ears, flaring nostrils, unusually large mouth, thick lips, and widely spaced eyes. Physical features include stunted growth (including during gestation), lack of subcutaneous adipose tissue, muscle atrophy, hirsutism (excessive body hair growth), and dysplasia (nail malformation).[3] Additionally, a condition known as acanthosis nigricans is present in affected individuals. In acanthosis nigricans, patches of skin darken and thicken to gain a velvet-like appearance. Gender specific features also include enlarged clitoris and breasts, as well as ovarian cysts in affected females, and enlarged penis in affected males.[3] In the Journal of Pediatric Medicine, Donohue and Uchida described affected sisters whose growth appeared to have ended in the seventh month of gestation, both born alive but dying before four months of age.[4] Very early death (or spontaneous abortion) is typical, although affected individuals sometimes live longer than a decade.[4]
Endocrine related abnormalities as a result of insulin receptor malfunction include insulin resistance, hypoglycemia and hyperglycemia (depending on whether or not the individual has eaten) and hyperinsulemia.
A much milder form of the disease, in which there is some insulin resistance but normal growth and subcutaneous fat distribution, is also known.[5] It is caused by a less severe mutation of the same gene.
Cause
Donohue syndrome is an
Known mutations to the gene which can cause Donohue syndrome include a
Because mutations in the gene are extremely rare, most cases result from
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 Donohue syndrome will be lower than 25%.[4]
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.[citation needed]
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.[4] The beta cells 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.[4]
The role of insulin in the body is to facilitate the entrance of glucose into the cell. Once insulin binds to the insulin receptors on the cell surface, the insulin receptors will send a signal that will ultimately bring the glucose transporter protein GLUT4 to attach to the cell membrane. Additionally, once insulin is bound to the insulin receptors, it will also initiate several signaling cascades that will promote cell growth and differentiation, protein synthesis, glucose synthesis, and the inhibition of gluconeogenesis through several metabolic pathways. A malfunctioning insulin receptor would thus not be able to properly initiate the signaling cascades for the aforementioned cellular processes. Many of the problems associated with Donohue syndrome may be due to the insulin receptor binding the insulin-like growth factor, regulating the growth of the embryo, in addition to its well-known role in the regulation of blood sugar.[10]
Diagnosis
There are a few ways to diagnose Donohue syndrome. Due to the nature of the disorder, Donohue syndrome can be diagnosed either genetically, symptomatically, or both. Because Donohue syndrome is a genetic disorder,
Treatment
While there currently is no cure for Donohue syndrome, treatments for those with the disease are tailored specifically to the symptoms present in each individual. It is often that a team of medical professionals will come together to treat a patient with this condition in their specific realm of practice such as pediatrics, endocrinology, and dermatology.[3] Treatment will often address specific dysfunctions in the patient, such as skin defects, hormonal imbalances, and normal progression of child growth.[citation needed]
Prognosis
The prognosis is quite dire, with early death usual.[1] In fact, most patients die in their first year except in milder forms of the disease, but few are known to have lived longer.[4] The variation is unsurprising given the diversity of mutations causing the disease.
Epidemiology
Donohue syndrome is an extremely rare disorder that occurs in one of every million births worldwide. Several dozen cases have been reported in the medical community, and in the reported cases of the disorder, it has been found that the females are twice as likely to have the disorder as men.[citation needed]
Eponym
Donohue syndrome was first identified in 1948 by Canadian
Future research
The National Institute of Diabetes and Digestive Kidney Diseases sponsored a phase 2 clinical study in 2001 that would look at the effectiveness of leptin to treat severe insulin resistance. In the study, two children with severe insulin resistance of ages 11 and 13 with known a known defect in the insulin receptor. The goal for the study was to see if leptin could overcome insulin receptor defects by initiating molecules in the insulin-signal cascade.[12] While no outcomes have yet been reported to date, the direction in which this clinical trial is heading is promising.
See also
- Patterson pseudoleprechaunism syndrome
- Rabson–Mendenhall syndrome
- Williams syndrome
References
- ^ PMID 12023989.
- ^ a b Reference, Genetics Home. "Donohue syndrome". Genetics Home Reference. Retrieved 2019-11-19.
- ^ a b c "Leprechaunism". NORD (National Organization for Rare Disorders). Retrieved 2019-11-19.
- ^ a b c d e f g h i j k Online Mendelian Inheritance in Man (OMIM): Insulin Receptor - 147670
- PMID 8326490.
- ^ NCBI Sequence Viewer v2.0
- PMID 1602013.
- S2CID 8869552.
- PMID 3883764.
- ^ Personal communication with J. Bell, Ph.D.
- PMID 18866943.
- ^ "Search of: "Leprechaunism" - List Results - ClinicalTrials.gov". www.clinicaltrials.gov. Retrieved 2019-11-24.