Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 111307005; ORPHA: 508; DO: 0050470;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.2 | Donohue syndrome | 246200 | Autosomal recessive | 3 | INSR | 147670 |
A number sign (#) is used with this entry because Donohue syndrome is caused by homozygous or compound heterozygous mutation in the insulin receptor gene (INSR; 147670) on chromosome 19p13.
Among the children of second cousins once removed, Donohue and Uchida (1954) observed 2 sisters with the following features: apparent cessation of growth at about the seventh month of gestation, peculiar facies creating a gnomelike appearance and leading to the designation, and severe endocrine disturbance indicated by emaciation, enlargement of breasts and clitoris, and histologic changes in the ovaries, pancreas and breasts. Three abortions (1 child at 4 months, the others earlier) had been experienced by this mother. The patients died at 46 and 66 days of age, respectively.
Two affected sisters were reported by Lakatos et al. (1963). Salmon and Webb (1963) observed a patient with consanguineous parents. Dekaban (1965) found normal chromosomes. Der Kaloustian et al. (1971) described 2 unrelated patients born of consanguineous parents.
Schilling et al. (1979) found a defect in insulin receptors in a Canadian Indian infant, the son of first cousins once removed. Emaciation, absence of subcutaneous fat, decreased muscle mass, hirsutism, and low-set, poorly developed ears were features. Sudden death occurred at age 47 days. Profound hyperinsulinemia and insulin receptor function in cultured fibroblasts. At autopsy, marked hypertrophy of pancreatic beta cells was noted. Epidermal growth factor, although chemically related to insulin, showed normal binding.
Bier et al. (1980) concluded that hypoglycemia in leprechaunism is due to an accelerated fasting state. Elfin facial appearance, growth retardation, severely diminished subcutaneous adipose tissue stores, decreased muscle mass, hypertrichosis, pachyderma, and acanthosis nigricans were cited as notable clinical features. See Seip syndrome (269700).
Elsas et al. (1985) stated that 31 patients with leprechaunism had been reported since the original description by Donohue (1948). They summarized the phenotype as follows: severe intrauterine growth retardation; small, elfin-like face with protuberant ears; distended abdomen; relatively large hands, feet, and genitalia; and abnormal skin with hypertrichosis, acanthosis nigricans, and decreased subcutaneous fat. At autopsy, patients have shown cystic changes in membranes of gonads and hyperplasia of pancreatic islet cells.
Taylor et al. (1981) studied cultured lymphocytes from a patient with leprechaunism and extreme insulin resistance previously attributed to a postreceptor defect (Kobayashi et al., 1978). They found that in fact the patient had an inborn error affecting insulin receptor function. Receptor binding was abnormal in having decreased sensitivity to alterations in temperature and pH. However, the level of insulin binding to cells from the patient was within normal limits. Thus, insulin resistance probably resulted from a decreased ability of the receptor to couple insulin binding to insulin action.
From studies of an infant with leprechaunism and the parents, Elsas et al. (1985) concluded that the family had 2 different recessive mutations that impair high-affinity insulin-receptor binding and that the proband was a genetic compound. The 2 mutations produced structural changes in the receptor that altered subunit interaction and resulted in loss of high-affinity binding and cellular responsiveness. After oral glucose, the proband showed marked hyperinsulinism, the father showed mild hyperinsulinism, and the mother had a normal response. The proband's fibroblasts had no high-affinity binding of insulin but normal low-affinity binding. Cells from the mother had 60% and those from the father 20% of high-affinity binding and normal low-affinity binding. The patient studied by Elsas et al. (1985), a black female, was 8 years old at the time of report. Most patients have died by the age of 10 months. The same patient, designated 'Arkansas I,' was studied by Kobayashi et al. (1978), Taylor et al. (1981), and others. In studies of probands and parents from 3 unrelated families, Endo et al. (1987) demonstrated heterogeneity of a defect in insulin receptor. One of the 3, 'Arkansas I,' showed defective alpha-subunit interaction.
Geffner et al. (1987) studied a female patient with very high levels of insulin. There was evidence of residual insulin activity in the form of cystic ovarian enlargement with gonadotropin-independent steroid secretion and persistent, severe myocardial hypertrophy. Geffner et al. (1987) concluded that the response to supraphysiologic concentrations of insulin was mediated via the insulin-like growth factor receptor mechanism which remained intact.
Cantani et al. (1987) reviewed 49 published cases.
Reddy et al. (1988) studied insulin receptor function in cultured skin fibroblasts from 3 patients with leprechaunism. The cell lines in all 3 patients showed insulin binding less than 15% of control values. In 1 cell line this was primarily due to reduced affinity of the receptor; in the other 2, it was due to a reduced number of receptors. When expressed as a fraction of total insulin bound, the percentage of cell-associated insulin internalized and degraded did not differ between the patient cell lines and the controls. Reddy et al. (1989) characterized a second family of leprechaunism (Ark-2) and found defects of insulin receptor phosphorylation in the phenotypically normal parents.
Reddy and Kahn (1989) demonstrated a functional abnormality of the epidermal growth factor receptor (131550), as well as of the insulin receptor, in 3 unrelated patients with leprechaunism. The abnormality was due to a decrease in receptor affinity in 2 of the cases and to a decrease in receptor number in the third. In all 3 cell lines studied, EGF-stimulated receptor autophosphorylation was also decreased, whereas EGF internalization and degradation were normal. The type A syndrome of insulin resistance and acanthosis nigricans showed no abnormality of EGF receptor. Reddy and Kahn (1989) proposed that 'a more fundamental defect beyond the insulin receptor alone is the probable cause of leprechaunism.'
Psiachou et al. (1993) reported a female infant with leprechaunism who was homozygous for a mutation in the INSR gene. Both parents, who were first cousins, were heterozygous for the mutant allele and phenotypically and clinically normal. The patient, who died at 4 months of age, had grossly retarded bone age, with the distal femoral epiphysis not being evident at 3 months of age. She had high fasting growth hormone (GH) values without a rise in IGF-I concentrations as well as an inadequate response to exogenously administered GH, implying growth hormone resistance. Psiachou et al. (1993) suggested that this resistance was a secondary effect caused by downregulation of GH receptor activity in the presence of high concentrations of insulin proximal to the cell membrane, with consequent limitation of IGF-I formation and cellular growth. Thus, although the primary defect in leprechaunism is in the insulin receptor gene, a secondary defect is probably responsible for an impaired response to endogenous GH and growth failure.
In a Yemeni family, Al-Gazali et al. (1993) observed what they considered to be a mild form of leprechaunism in 4 males and 1 female out of 8 offspring of second-cousin parents. The patients had insulin resistance with paradoxical hypoglycemia and acanthosis nigricans. However, unlike infants with classic leprechaunism who die in the first year of life, all the children were alive, the oldest being 11 years of age; furthermore, all had normal subcutaneous tissue and some showed a normal growth pattern. Ultrasound studies showed thickened myocardium and enlarged kidneys, and the female had ovarian enlargement.
The transmission pattern of Donohue syndrome in the families reported by Psiachou et al. (1993) and Hone et al. (1994) was consistent with autosomal recessive inheritance.
Psiachou et al. (1993) reported a female infant with leprechaunism who was homozygous by descent for a null allele of the insulin receptor gene. The mutation involved replacement of a 13-bp sequence in exon 13 by an unrelated 5-bp sequence. The net deletion of 8 bp shifted the reading frame and introduced a premature chain termination downstream. Both parents, who were first cousins, were heterozygous for the mutant allele and phenotypically and clinically normal.
In affected members of a Yemeni family segregating Donahue syndrome, Hone et al. (1994) identified homozygosity for a substitution of methionine for isoleucine at codon 119 (exon 2) in the INSR gene (147670.0033).
Fernhoff (2004) noted that Donohue syndrome is a more appropriate designation for this disorder because 'leprechaunism' may be viewed as pejorative by families.
Patterson and Watkins (1962) described a probable case in a male. The 4 previously described cases had been female. Follow-up observations (Patterson, 1969) suggest that this may have been a different disorder. There were clinical signs of Cushing disease and at autopsy the adrenals were found to be much enlarged. Before the patient died at the age of almost 8 years, severe changes in the bones, of an unusual type, had developed. Serum alkaline phosphatase was always low, but no phosphoethanolamine was demonstrated in the urine.
Al-Gazali, L. I., Khalil, M., Devadas, K. A syndrome of insulin resistance resembling leprechaunism in five sibs of consanguineous parents. J. Med. Genet. 30: 470-475, 1993. [PubMed: 8326490] [Full Text: https://doi.org/10.1136/jmg.30.6.470]
Bier, D. M., Schedewie, H., Larner, J., Olefsky, J., Rubenstein, A., Fiser, R. H., Craig, J. W., Elders, M. J. Glucose kinetics in leprechaunism: accelerated fasting due to insulin resistance. J. Clin. Endocr. Metab. 51: 988-994, 1980. [PubMed: 6999010] [Full Text: https://doi.org/10.1210/jcem-51-5-988]
Cantani, A., Ziruolo, M. G., Tacconi, M. L. A rare polydysmorphic syndrome: leprechaunism--review of forty-nine cases reported in the literature. Ann. Genet. 30: 221-227, 1987. [PubMed: 3322162]
Dekaban, A. S. Metabolic and chromosomal studies in leprechaunism. Arch. Dis. Child. 40: 632-636, 1965. [PubMed: 5844952] [Full Text: https://doi.org/10.1136/adc.40.214.632]
Der Kaloustian, V. M., Kronfol, N. M., Takla, R. J., Habash, A., Khazin, A., Najjar, S. S. Leprechaunism: a report of two new cases. Am. J. Dis. Child. 122: 442-445, 1971. [PubMed: 5129536]
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Elsas, L. J., Endo, F., Strumlauf, E., Elders, J., Priest, J. H. Leprechaunism: an inherited defect in a high-affinity insulin receptor. Am. J. Hum. Genet. 37: 73-88, 1985. [PubMed: 3883764]
Endo, F., Nagata, N., Priest, J. H., Longo, N., Elsas, L. J., II. Structural analysis of normal and mutant insulin receptors in fibroblasts cultured from families with leprechaunism. Am. J. Hum. Genet. 41: 402-417, 1987. [PubMed: 3631076]
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Fernhoff, P. M. 50 years ago in the Journal of Pediatrics. J. Pediat. 145: 697 only, 2004.
Geffner, M. E., Kaplan, S. A., Bersch, N., Lippe, B. M., Smith, W. G., Nagel, R. A., Santulli, T. V., Jr., Li, C. H., Golde, D. W. Leprechaunism: in vitro insulin action despite genetic insulin resistance. Pediat. Res. 22: 286-291, 1987. [PubMed: 3309859] [Full Text: https://doi.org/10.1203/00006450-198709000-00010]
Hone, J., Accili, D., Al-Gazali, L. I., Lestringant, G., Orban, T., Taylor, S. I. Homozygosity for a new mutation (ile119-to-met) in the insulin receptor gene in five sibs with familial insulin resistance. J. Med. Genet. 31: 715-716, 1994. [PubMed: 7815442] [Full Text: https://doi.org/10.1136/jmg.31.9.715]
Kaplowitz, P. B., D'Ercole, A. J. Fibroblasts from a patient with leprechaunism are resistant to insulin, epidermal growth factor, and somatomedin C. J. Clin. Endocr. Metab. 55: 741-748, 1982. [PubMed: 6286709] [Full Text: https://doi.org/10.1210/jcem-55-4-741]
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Kuhlkamp, F., Helwig, H. Das Krankheitsbild des kongenitalen Dysendokrinismus oder Leprechaunismus. Z. Kinderheilk. 109: 50-63, 1970. [PubMed: 4991281]
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Psiachou, H., Mitton, S., Alaghband-Zadeh, J., Hone, J., Taylor, S. I., Sinclair, L. Leprechaunism and homozygous nonsense mutation in the insulin receptor gene. (Letter) Lancet 342: 924 only, 1993. [PubMed: 8105179] [Full Text: https://doi.org/10.1016/0140-6736(93)91970-w]
Reddy, S. S.-K., Kahn, C. R. Epidermal growth factor receptor defects in leprechaunism: a multiple growth factor-resistant syndrome. J. Clin. Invest. 84: 1569-1576, 1989. [PubMed: 2808704] [Full Text: https://doi.org/10.1172/JCI114334]
Reddy, S. S.-K., Lauris, V., Kahn, C. R. Insulin receptor function in fibroblasts from patients with leprechaunism: differential alterations in binding, autophosphorylation, kinase activity, and receptor-mediated internalization. J. Clin. Invest. 82: 1359-1365, 1988. [PubMed: 3049675] [Full Text: https://doi.org/10.1172/JCI113739]
Reddy, S. S.-K., Muller-Wieland, D., Kriauciunas, K., Kahn, C. R. Molecular defects in the insulin receptor in patients with leprechaunism and in their parents. J. Lab. Clin. Med. 114: 165-170, 1989. [PubMed: 2569023]
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Roth, S. I., Schedewie, H. K., Bier, D. M., Conaway, H. H., Olefsky, J., Rubenstein, A., Elders, M. J. Hepatic ultrastructure in leprechaunism: hepatic ultrastructural evidence suggesting a syndrome with defective hepatic glucose release. Virchows Arch. A Path. Anat. Histol. 397: 121-130, 1982. [PubMed: 7179734] [Full Text: https://doi.org/10.1007/BF00442383]
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Schilling, E. E., Rechler, M. M., Grunfeld, C., Rosenberg, A. M. Primary defect of insulin receptors in skin fibroblasts cultured from an infant with leprechaunism and insulin-resistance. Proc. Nat. Acad. Sci. 76: 5877-5881, 1979. [PubMed: 293690] [Full Text: https://doi.org/10.1073/pnas.76.11.5877]
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Taylor, S. I., Roth, J., Blizzard, R. M., Elders, M. J. Qualitative abnormalities in insulin binding in a patient with extreme insulin resistance: decreased sensitivity to alterations in temperature and pH. Proc. Nat. Acad. Sci. 78: 7157-7161, 1981. [PubMed: 7031672] [Full Text: https://doi.org/10.1073/pnas.78.11.7157]