Donohue syndrome
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Donohue syndrome (also known as leprechaunism) is an extremely rare and severe
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome In the fields of molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and li ...
. ''Leprechaunism'' derives its name from the hallmark elvish features (small stature, bulging eyes, thick lips, and upturned nostrils) exhibited by the affected individuals. The disease is caused by a mutation in the
INSR The insulin receptor (IR) is a transmembrane receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental ...
gene, which contains the genetic information for the formation of
insulin receptor The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, Insulin-like growth factor 2, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in th ...

insulin receptor
s. As a result, affected individuals have either a decreased number of insulin receptors, or insulin receptor with greatly impaired functionality. The lack and impairment of insulin receptor functionality leads to an inability to regulate blood glucose levels through severe insulin resistance. This will ultimately lead to affected development of tissues and organs throughout the body. In addition to the physical abnormalities, leprechaunism is also characterized by endocrine system abnormalities that can lead to conditions such as hyperglycemia (high blood glucose levels), hypoglycemia (low blood glucose levels), hyperinsulemia (high blood insulin levels), and the enlargement of certain sex organs such as the penis in males, and the clitoris in females.


Signs and symptoms

Facial features indicative of Donohue syndrome include protuberant and low-set
ear The ear is the organ of hearing and, in mammals, balance. In mammals, the ear is usually described as having three parts—the outer ear The outer ear, external ear, or auris externa is the external part of the ear, which consists ...

ear
s, flaring
nostril A nostril (or naris , plural ''nares'' ) is either of the two orifices of the nose A nose is a protuberance in vertebrates that houses the nostrils, or nares, which receive and expel air for Respiration (physiology), respiration alongside ...
s, unusually large mouth, thick lips, and widely spaced eyes. Physical features include stunted growth (including during
gestation Gestation is the period of development Development or developing may refer to: Arts *Development hell, when a project is stuck in development *Filmmaking#Development, Filmmaking, development phase, including finance and budgeting *Development ...
), lack of subcutaneous adipose tissue, muscle atrophy, hirsutism (excessive body hair growth), and dysplasia (nail malformation). 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 The clitoris ( or ) is a female sex organ present in mammals, ostriches and a limited number of #Other animals, other animals. In humans, the visible portion – the glans – is at the front junction of the labia minora (inner lips), ...

clitoris
and
breast The breast is one of two prominences located on the upper ventral Standard anatomical terms of location deal unambiguously with the of s, including s. Terms used generally derive from or roots and used to describe something in its . Th ...

breast
s, as well as ovarian cysts in affected
female Female (symbol: ♀) is the sex Sex is either of two divisions, typically male Male (♂) is the sex of an organism that produces the gamete known as sperm. A male gamete can fuse with a larger female gamete, or ovum, in the process of ...

female
s, and enlarged
penis A penis (plural ''penises'' or ''penes'' () is the primary sexual organ that male animals use to inseminate females (or hermaphrodites) during Copulation (zoology), copulation. Such organs occur in many animals, both #Vertebrates, vertebrate ...

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. 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. It is caused by a less severe mutation of the same gene.


Cause

Donohue syndrome is an
autosomal An autosome is any chromosome that is not a sex chromosome (an allosome). The members of an autosome pair in a diploid Ploidy () is the number of complete sets of chromosome A chromosome is a long DNA molecule with part or all of the ...
recessive gene In genetics Genetics is a branch of biology concerned with the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) Though heredity had been observed for millennia, Gregor Mendel, Moravia, Moravian scientis ...
tic disorder. The mutations responsible for the disorder are found on the short arm
chromosome 19 Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 58.6 million base pairs, the building material of DNA. Genes Number of genes The following are some ...

chromosome 19
(19p13.2) within the coding sequence of the ''INSR gene'' (
insulin receptor The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, Insulin-like growth factor 2, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in th ...

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 A base pair (bp) is a fundamental unit of double-stranded nucleic acids Nucleic acids are biopolymer Biopolymers are natural polymers produced by the cells of Organism, living organisms. Biopolymers consist of monomeric units that are Covalent_ ...
s, which contain twenty-two
exons An exon is any part of a gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance#History, Mendelian units of heredity..." (Greek language, Greek) meaning ''generation'' or ...
coding for a
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
that consists of 1382
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
s. Some of the
introns An intron (for ''intragenic region'') is any nucleotide sequence A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides Nucleotides are organic molecu ...
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 In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, P ...
that resulted in early termination of the protein, an addition or deletion mutation that resulted in a
frame shift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation Translation is the communication of the meaning of a source-language text by means of a ...
, a single missense mutation and in the milder form mentioned above, a single codon change that altered
isoleucine Isoleucine (symbol Ile or I) is an α-amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bon ...

isoleucine
to
methionine Methionine (symbol Met or M) () is an essential amino acid An essential amino acid, or indispensable amino acid, is an amino acid that cannot be synthesized from scratch by the organism fast enough to supply its demand, and must therefore come ...

methionine
in the receptor protein. Some mutations to the gene instead result in insulin resistant
diabetes Diabetes mellitus, commonly known as just diabetes, is a group of metabolic disorder A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients such as proteins, fats, and carbohydrate ...

diabetes
without Donohue syndrome. Because mutations in the gene are extremely rare, most cases result from
consanguineous Consanguinity ("blood relation", from Latin '':wikt: consanguinitas, consanguinitas'') is the property of being from the same kinship as another person. In that aspect, consanguinity is the quality of being descended from the same ancestor as anot ...
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 In medical genetics, compound heterozygosity is the condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disorders, genetic disease in a heterozygous state; that is, an organism is a compound h ...
. A heterozygous individual (i.e. one who is a carrier for the disease, having only one normal
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is one of two, or more, forms of a given gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance ...
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 cell Beta cells (β cells) are a type of cell found in pancreatic islets The pancreatic islets or islets of Langerhans are the regions of the pancreas The pancreas is an organ Organ may refer to: Biology * Organ (anatomy) An organ is a g ...
s in the
pancreas The pancreas is an Organ (anatomy), organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine ...

pancreas
, which make and store insulin and release it on an as-needed basis, are often found to be very large or numerous. 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 Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to h ...
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 Gluconeogenesis (GNG) is a metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformati ...

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 The insulin-like growth factors (IGFs) are protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John ...
, regulating the growth of the embryo, in addition to its well-known role in the regulation of blood sugar.


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, genetic testing can be performed to diagnose the disease. These genetic tests include
diagnostic testing A medical test is a medical procedure A medical procedure is a course of action intended to achieve a result in the delivery of healthcare. A medical procedure with the intention of determining, measuring, or diagnosing a patient condition or ...
,
carrier testing Carrier testing is a type of genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy ...
, predictive and pre-symptomatic testing, as well as forensic testing. Prenatally,
amniocentesis Amniocentesis (also referred to as an amniotic fluid test or, informally, an "amnio") is a medical procedureThe word ''amniocentesis'' itself indicates precisely the procedure in question, Greek#REDIRECT Greek Greek may refer to: Greece Anythin ...

amniocentesis
can be performed to determine if the child will have Donohue syndrome. Additionally, the disorder can be diagnosed through laboratory testing to measure blood insulin levels and defective insulin receptors.


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. Treatment will often address specific dysfunctions in the patient, such as skin defects, hormonal imbalances, and normal progression of child growth.


Prognosis

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.


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.


Eponym

Donohue syndrome was first identified in 1948 by Canadian
pathologist Pathology is the study of the causesCauses, or causality, is the relationship between one event and another. It may also refer to: * Causes (band), an indie band based in the Netherlands * Causes (company), an online company See also * Ca ...

pathologist
William L. Donohue (1906–1985). The name leprechaunism has been largely abandoned because of the perception of the name by some parents of patients as insulting.


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 Leptin (from Greek#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the Hellenic Republic, is a country located in Southeast Europe. Its population is approxim ...

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. 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


External links

{{Cell surface receptor deficiencies Autosomal recessive disorders Rare diseases Syndromes with craniofacial abnormalities