Donohue syndrome
Encyclopedia
Donohue syndrome 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.
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 whose growth appeared to have ended in the seventh month of gestation, both born alive but dying before four months of age. Very early death (or spontaneous abortion) is the norm, although sufferers sometimes live longer than a decade.
As the mutation causing the disorder affects insulin receptor
function, those with the disease are also insulin
resistant
, with hypoglycemia and profound hyperinsulinemia (very high levels of insulin in the blood) Another feature of the disease is that the 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. It is caused by a less severe mutation of the same gene.
Donohue syndrome is an autosomal recessive genetic 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. 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. Some of the introns may or may not be spliced out depending on the kind of cell.
Known mutations to the gene which can cause Donohue syndrome include a nonsense mutation
that resulted in a frame shift, a single missense mutation and in the milder form mentioned above, a single codon change that altered isoleucine
to methionine
in the receptor protein.
Some mutations to the gene instead result in insulin resistant diabetes without Donohue syndrome.
Because mutations in the gene are extremely rare, most cases result from consanguineous matings, for example, between cousins. However, the exact mutation need not be the same. Disease can be caused by inheritance of two different mutant alleles, one from each parent, in which case the patient is a compound heterozygote.
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%.
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.
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.
In some patients, particularly those who are longer-lived, unusual bone changes are sometimes seen, and there may be excessive body hair and
velvety hyperpigmentation of the skin
.
The prognosis is quite dire, with early death usual. In fact, most patients die in their first year except in milder forms of the disease, but few are known to have lived longer. The variation is unsurprising given the diversity of mutations causing the disease.
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.
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
. 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
Insulin receptor
In molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors....
with greatly impaired functionality.
Presentation
Facial features indicative of Donohue syndrome include protuberant and low-set earEar
The ear is the organ that detects sound. It not only receives sound, but also aids in balance and body position. The ear is part of the auditory system....
s, flaring nostril
Nostril
A nostril is one of the two channels of the nose, from the point where they bifurcate to the external opening. In birds and mammals, they contain branched bones or cartilages called turbinates, whose function is to warm air on inhalation and remove moisture on exhalation...
s, and thick lips. Physical features include stunted growth (including during gestation
Gestation
Gestation is the carrying of an embryo or fetus inside a female viviparous animal. Mammals during pregnancy can have one or more gestations at the same time ....
), an enlarged clitoris
Clitoris
The clitoris is a sexual organ that is present only in female mammals. In humans, the visible button-like portion is located near the anterior junction of the labia minora, above the opening of the urethra and vagina. Unlike the penis, which is homologous to the clitoris, the clitoris does not...
and breast
Breast
The breast is the upper ventral region of the torso of a primate, in left and right sides, which in a female contains the mammary gland that secretes milk used to feed infants.Both men and women develop breasts from the same embryological tissues...
s in affected female
Female
Female is the sex of an organism, or a part of an organism, which produces non-mobile ova .- Defining characteristics :The ova are defined as the larger gametes in a heterogamous reproduction system, while the smaller, usually motile gamete, the spermatozoon, is produced by the male...
s, and an enlarged penis
Penis
The penis is a biological feature of male animals including both vertebrates and invertebrates...
in affected males.
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. Very early death (or spontaneous abortion) is the norm, although sufferers sometimes live longer than a decade.
As the mutation causing the disorder affects insulin receptor
Insulin receptor
In molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors....
function, those with the disease are also insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
resistant
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
, with hypoglycemia and profound hyperinsulinemia (very high levels of insulin in the blood) Another feature of the disease is that the subcutaneous
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
Adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
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. It is caused by a less severe mutation of the same gene.
Genetics
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
19 (19p13.2) within the coding sequence of the INSR gene (insulin receptor
Insulin receptor
In molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors....
) causing the production of inactive receptor molecules. 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
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
s, which contain twenty-two exons coding for a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that consists of 1382 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s. Some of the introns may or may not be spliced out depending on the kind of cell.
Known mutations to the gene which can cause Donohue syndrome include a nonsense mutation
Nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation...
that resulted in a frame shift, a single missense mutation and in the milder form mentioned above, a single codon change that altered isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
to methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
in the receptor protein.
Some mutations to the gene instead result in insulin resistant diabetes without Donohue syndrome.
Because mutations in the gene are extremely rare, most cases result from consanguineous matings, for example, between cousins. However, the exact mutation need not be the same. Disease can be caused by inheritance of two different mutant alleles, one from each parent, in which case the patient is a compound heterozygote.
A heterozygous individual (i.e. one who is a carrier for the disease, having only one normal allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
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%.
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. The beta cellBeta cell
Beta cells are a type of cell in the pancreas located in the so-called islets of Langerhans. They make up 65-80% of the cells in the islets.-Function:...
s in the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
, which make and store insulin and release it on an as-needed basis, are often found to be very large or numerous.
In some patients, particularly those who are longer-lived, unusual bone changes are sometimes seen, and there may be excessive body hair and
velvety hyperpigmentation of the skin
Acanthosis nigricans
Acanthosis nigricans is a brown to black, poorly defined, velvety hyperpigmentation of the skin. It is usually found in body folds, such as the posterior and lateral folds of the neck, the axilla, groin, umbilicus, forehead, and other areas.-Causes:...
.
The prognosis is quite dire, with early death usual. In fact, most patients die in their first year except in milder forms of the disease, but few are known to have lived longer. The variation is unsurprising given the diversity of mutations causing the disease.
Many of the problems associated with Donohue syndrome may be due to the insulin receptor binding the insulin-like growth factor
Insulin-like growth factor
The insulin-like growth factors are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment...
, regulating the growth of the embryo, in addition to its well-known
role in the regulation of blood sugar.
Eponym
Donohue syndrome was first identified in 1948 by Dr. W.L. Donohue. The name leprechaunism has been largely abandoned because of the perception of the name by some parents of patients as insulting.See also
- Rabson-Mendenhall syndromeRabson-Mendenhall syndromeRabson–Mendenhall syndrome is a rare insulin receptor disorder characterized by severe insulin resistance, developmental abnormalities, and acanthosis nigricans...
- Patterson pseudoleprechaunism syndromePatterson pseudoleprechaunism syndromePatterson syndrome, also called pseudoleprechaunism, is an extremely rare syndrome, first mistaken as Donohue Syndrome .It is named for Dr. Joseph Hanan Patterson. It was described by Patterson and Watkins in 1962...
- Williams syndromeWilliams syndromeWilliams syndrome is a rare neurodevelopmental disorder characterized by a distinctive, "elfin" facial appearance, along with a low nasal bridge; an unusually cheerful demeanor and ease with strangers; developmental delay coupled with strong language skills; and cardiovascular problems, such as...