DEFINITION
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.The name leprechaunism has been largely abandoned because of the perception of the name by some parents of patients as insulting.
PRESENTATION
Facial features indicative of Donohue syndrome include protuberant and low-set ears, flaring nostrils, and thick lips. Physical features include stunted growth (including during gestation), an enlarged clitoris and breasts in affected females, 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 (DS, OMIM#246200), also known as Leprechaunism, Rabson–Mendenhall syndrome, and type A insulin resistance are autosomal recessive (AR) disorders caused by biallelic mutations in the gene encoding the insulin receptor (INSR, OMIM#147670). These syndromes, sharing phenotype and genotype heterogeneity, are distinguished from one another based on the severity of symptoms, age of onset, and age of death. Donohue Syndrome is considered the most severe syndrome of the group, and is usually lethal within 2 years of life.
The diagnosis is established based on clinical characteristics, and determination of the INSR mutation.
GENETIC
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 pairs, which contain twenty-two exons coding for a protein that consists of 1382 amino acids.
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%.
Diagnosis
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.
Phenotypic heterogeneity has been demonstrated in a number of documentations of DS. For example; One patient who carried a homozygous deletion of the entire INSR gene, and thus absolute lack of insulin receptor activity, survived for 3.5 years before dying from postoperative complications, contrasting with another infant with almost no insulin receptor activity consequent to a nonsense mutation at position 121, who failed to thrive, and died at 16 weeks of age. These two patients present a most striking discrepancy between genotype and phenotype in DS. Both carried what seemed to be complete inactivation of the INSR protein; however, one survived longer than all expectations, whereas the other died after a very short period. It was found that the degree of insulin binding among five patients with defects in the INSR did not correspond to the severity of the clinical phenotype. These data suggest that the absence of the INSR protein is not identical to absence of the gene itself, and that activity of transcriptional factors may also have an important effect.
Moreover, the phenotypic variability might result from various degrees of inactivation of INSR transcription, leading to diverse activation of compensatory pathways, as has been shown in many cases of protein inactivation in transgenic animals. If such a scenario exists in DS, the most likely compensatory pathway might be through the closely related IGF-1 receptor.
DS appears to result from either homozygous or compound heterozygous mutations. Approximately 130 mutations have been reported to be causative of DS so far. As a classic AR trait homozygous or compound heterozygous mutations are expected to cause the phenotype while heterozygous individuals are healthy carriers and free of symptoms.
THERAPY
Management in the neonatal period is largely aimed at minimizing fluctuations in blood glucose levels, and this can best be achieved by continuous nasogastric feeds or intravenous glucose therapy. Subsequent aims of therapy are to improve insulin sensitivity, thereby reducing hyperinsulinaemia, and to promote linear growth and increase longevity. To this end, metformin and/or thiazolidinediones have been used, but there are few data on their effectiveness. Recombinant human IGF-1 (rhIGF-1) has been shown to have modest effectiveness in some cases of Donohue's syndrome and thus is the only therapy with documented efficacy.
The type 1 IGF-1 receptor has a high degree of structural and functional similarities with the insulin receptor, and it is argued that increasing IGF-1 levels therapeutically may improve glucose disposal and reduce high circulating levels of insulin. Supporting this, there appears to be a consistent acute response to rhIGF1, with lowering of both glucose and insulin in the minutes following a bolus dose and variable long-term efficacy. The extent to which this can reduce tissue overgrowth and complications in Donohue's syndrome has yet to be determined in sufficiently large numbers of patients, but several reports suggest sustained improvements in both metabolism and growth. Less response is reported following lower doses of rhIGF-1, while the most impressive responses have been reported with very high doses. Microalbuminuria and retinopathy remain a risk in these patients with or without treatment, and the effect of rhIGF-1 on ovarian and cardiac changes is unknown. Interestingly, despite improved growth, GH levels often remain suppressed, and combination therapy with GH and IGF-1 may be an avenue for future exploration. More data are required relating to the treatment of these infants, and a database is being established through the Department of Paediatrics in Cambridge in collaboration with Ipsen.
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