INSR-Related Severe Syndromic Insulin Resistance
Shani Ben Harouch, MD, Aharon Klar, MD, and Tzipora C Falik Zaccai, MD.
Author InformationInitial Posting: January 25, 2018.
Estimated reading time: 25 minutes
Summary
Clinical characteristics.
INSR-related severe syndromic insulin resistance comprises a phenotypic spectrum that is a continuum from the severe phenotype Donohue syndrome (DS) (also known as leprechaunism) to the milder phenotype Rabson-Mendenhall syndrome (RMS).
DS at the severe end of the spectrum is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction and postnatal growth failure, hypotonia and developmental delay, characteristic facies, and organomegaly involving heart, kidneys, liver, spleen, and ovaries. Death usually occurs before age one year.
RMS at the milder end of the spectrum is characterized by severe insulin resistance that, although not as severe as that of DS, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and – in the second decade – microvascular complications. Findings can range from severe growth delay and intellectual disability to normal growth and development. Facial features can be milder than those of DS. Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer.
Management.
Treatment of manifestations: DS: No effective treatments for insulin resistance or other manifestations of DS are currently available. Frequent feedings as well as increased protein content of evening feedings can help prevent fasting hypoglycemia.
RMS: Insulin sensitizers are used first to decrease levels of glucose and glycosylated hemoglobin (HbA1c); however, their effect diminishes with time, often requiring dose adjustments and multidrug therapy. When hyperglycemia persists, insulin is started – usually in high doses, especially during the treatment of diabetic ketoacidosis.
Anti-androgen therapies can be used to treat hyperandrogenism. Oophorectomy may be needed.
Surveillance: Routine monitoring of psychomotor development; glucose levels, HbA1c levels, thyroid function for evidence of hypothyroidism; cardiac status; ovarian size by ultrasound examination; urine for hypercalciuria and kidneys for nephrocalcinosis by ultrasound examination.
Agents/circumstances to avoid in DS: Agents that cause hypoglycemia; prolonged fasting; contact with persons with contagious disease.
Pregnancy management: Heterozygotes for an INSR pathogenic variant are at increased risk for gestational diabetes and require monitoring for glucose intolerance before and during pregnancy. Of note, gestational diabetes, which can be hard to control, requires high doses of insulin. A high-resolution fetal ultrasound examination with fetal echocardiogram to screen for malformations is recommended; referral to a maternal-fetal medicine specialist for diabetic management during pregnancy may be considered.
Therapies under investigation: Recombinant human IGF-1(rhIGF-1) shows promise in the treatment of severe insulin resistance; however, its benefit is not well established and it is more likely to be effective in individuals with less severe insulin resistance as the few individuals with prolonged survival with rhIGF-1 treatment had milder phenotypes. Although treatment of RMS with meterleptin (leptin replacement therapy) was beneficial to metabolic control, data to date are insufficient to support its use in patient care.
Genetic counseling.
INSR-related severe syndromic insulin resistance is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the INSR pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
Diagnosis
No formal diagnostic criteria have been published to date for INSR-related severe syndromic insulin resistance, which comprises a phenotypic continuum from the severe phenotype Donohue syndrome to the milder phenotype Rabson-Mendenhall syndrome.
Suggestive Findings
INSR-related severe syndromic insulin resistance should be suspected in individuals with the following clinical, laboratory, and imaging findings of Donohue syndrome or Rabson-Mendenhall syndrome.
Clinical Findings
Donohue syndrome (Note: All findings are prenatal onset.)
Characteristic dysmorphism seen in neonate with DS: gingival overgrowth; large, low-set, posteriorly rotated ears; infraorbital folds; proptosis; thick vermilion of the upper and lower lips Figures 1A and 1C from Falik Zaccai et al [2014]
Hypertrichosis is a feature in all individuals with DS. From Falik Zaccai et al [2014]
Prominent nipples are a typical finding in neonates.
A and B. Abdominal distention B. Labial hypertrophy and clitorimegaly in a girl age four months with DS
Rectal hypertrophy and prolapse
Rabson-Mendenhall syndrome
Laboratory Findings
Donohue syndrome
Rabson-Mendenhall syndrome
Imaging Findings
Donohue syndrome and Rabson-Mendenhall syndrome [al-Gazali et al 1993]
Hypertrophic cardiomyopathy
Enlarged kidneys, liver, and spleen
Nephrocalcinosis
Enlarged polycystic ovaries
Establishing the Diagnosis
The diagnosis of INSR-related severe syndromic insulin resistance is established in a proband with the characteristic findings described above and identification of biallelic INSR pathogenic variants on molecular genetic testing (see ).
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) and comprehensive
genomic testing (genomic sequencing) depending on the phenotype.
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of INSR-related severe syndromic insulin resistance is broad, children with the distinctive findings of Donohue syndrome described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas individuals with milder disease (including Rabson-Mendenhall syndrome), in which the phenotype may not be as distinctive, may be more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of INSR-related severe syndromic insulin resistance (especially Donohue syndrome), molecular genetic testing approaches can include single-gene testing or use of a multigene panel.
A multigene panel that includes
INSR and other genes of interest (see
Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of
uncertain significance and pathogenic variants in genes that do not explain the underlying
phenotype. Note: (1) The genes included in the panel and the diagnostic
sensitivity of the testing used for each
gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview. Of note, given the rarity of
INSR-related severe
syndromic insulin resistance, some panels for diabetes mellitus may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused
exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include
sequence analysis,
deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see ).
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Option 2
When the phenotype of INSR-related severe syndromic insulin resistance is not as distinctive (such as milder Rabson-Mendenhall syndrome), comprehensive
genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in INSR-Related Severe Syndromic Insulin Resistance
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| Gene 1 | Method | Proportion of Probands with Pathogenic Variants 2 Detectable by Method |
|---|
| INSR | Sequence analysis 3 | 58/63 4 |
| Gene-targeted deletion/duplication analysis 5 | 5/63 4 |
- 1.
- 2.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
Clinical Description
INSR-related severe syndromic insulin resistance comprises a phenotypic continuum from the severe phenotype Donohue syndrome to the milder phenotype Rabson-Mendenhall syndrome. In both phenotypes, males and females are affected equally.
Donohue Syndrome
Donohue syndrome (also known as leprechaunism) is characterized by severe insulin resistance manifest as hyperinsulinemia (fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction and postnatal growth failure, hypotonia and developmental delay, characteristic facies, and organomegaly. Death usually occurs during the first year of life.
Birth weight and head circumference are below the third percentile. Failure to thrive is progressive; the average weight at age one year is 4-5 kg [Longo et al 2002].
Most infants have severe global developmental delay, including motor and cognitive impairment [Falik Zaccai et al 2014]. Axial hypotonia and muscle atrophy are also observed [Baqir et al 2012]. Intellectual disability is thought to be a consequence of recurrent, severe hypoglycemic episodes [Ben Abdelaziz et al 2016].
Reduced subcutaneous fat, hypertrichosis, and hyperkeratosis are present at birth in all affected infants. Acanthosis nigricans can be apparent at birth or in early infancy [Musso et al 2004].
Organomegaly can include the following:
Rectal prolapse or hypertrophy, which sometimes requires colostomy [
Weber et al 2014].
Enlargement of the external genitalia in both males (enlargement of the penis) and females (labial hypertrophy and clitoral enlargement).
Ovarian enlargement is characteristic, with multiple follicles in the ovaries. The uterus appears normal.
Other findings that may be seen:
Involvement of the renin-aldosterone system, presenting with hypokalemia, hyperaldosteronism, and hyperreninemia [
Grasso et al 2013]
Nephrocalcinosis [
Simpkin et al 2014] and hypercalciuria, often seen during the first months of life and occasionally detected prenatally
The major causes of death are complications of hypoglycemia, respiratory infections [Elders et al 1982, de Bock et al 2012], and cardiomyopathy [Grasso et al 2013].
Rabson-Mendenhall Syndrome (RMS)
RMS is characterized by severe insulin resistance that, although less severe than that of Donohue syndrome, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and recurrent infections [Tuthill et al 2007]. Findings can range from severe growth delay and intellectual disability to normal growth and development [Musso et al 2004]. Facial features of RMS can be milder than those of Donohue syndrome (DS); advanced dentition and low hair line may be the only unusual features [Jiang et al 2011]. Survival in RMS can be into the third decade [Longo et al 2002, Musso et al 2004].
Often during the first year of life the manifestations of RMS and DS are indistinguishable; however, in other instances, the manifestations of RMS are less severe than those of DS.
Of note, children reported to have Donohue syndrome who have normal psychomotor development and survive beyond the first year of life [de Kerdanet et al 2015] would be considered to be on the RMS end of the spectrum of INSR-related severe syndromic insulin resistance.
Cutaneous changes (hirsutism), genitomegaly, and ovarian enlargement typically appear later in childhood in RMS than in DS.
Morbidity in older individuals with RMS results from prolonged hyperglycemia and hyperinsulinemia, causing early microvascular complications including proliferative retinopathy, peripheral neuropathy, renal vascular complications, and diabetic ketoacidosis [Musso et al 2004, Carrasco de la Fuente et al 2010, Jiang et al 2011]. These complications are also the major causes of death, usually during the second decade of life [Semple et al 2010].
Malignancy, a rare complication of INSR-related severe syndromic insulin resistance, has been reported.
Endometrial carcinoma was reported in a woman age 24 years treated with rhIGF-1 for severe insulin resistance (called Donohue syndrome by the authors, but clinically more likely RMS) [
Jo et al 2013].
Granulosa cell tumor of the ovary was reported in a girl age 35 months with severe insulin resistance treated with rhIGF-1 for 16 months [
Weber et al 2014], and in a young girl who was untreated [
Brisigotti et al 1993].
Because two of these individuals were treated with rhIGF-1, it is possible (though as-yet unconfirmed) that the tumors resulted from an adverse effect of this treatment.
Nomenclature
Donohue syndrome was first described by Donohue & Uchida [1954].
Leprechaunism is a synonym of Donohue syndrome.
Prevalence
Donohue syndrome is extremely rare, estimated at 1:1,000,000 [Desbois-Mouthon et al 1997].
To date 63 individuals with phenotypes of DS and RMS have been molecularly diagnosed and reported [Ardon et al 2014]; about ten other individuals have a clinically based diagnosis.
Differential Diagnosis
The differential diagnosis of INSR-related severe syndromic insulin resistance includes many rare disorders with hirsutism, severe growth failure, and developmental delay with other syndromic features, some of which are summarized in .
Table 2.
Disorders to Consider in the Differential Diagnosis of INSR-Related Severe Syndromic Insulin Resistance
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Differential
Diagnosis
Disorder | Gene(s) | MOI | Clinical Features of the Differential Diagnosis |
|---|
| Overlapping | Distinguishing |
|---|
| Syndromes of congenital hyperinsulinemia |
| Berardinelli-Seip congenital lipodystrophy (BSCL) | AGPAT2
BSCL2
PTRF | AR |
|
|
| Familial hyperinsulinism (FHI) | ABCC8
GCK
GLUD1
HADH
HNF4A
KCNJ11
UCP2 | AD
AR | Hypoglycemia (ranging from severe neonatal-onset disease to childhood-onset disease w/mild symptoms in FHI) 3 |
|
| Syndromes of intrauterine growth restriction |
| Resistance to insulin-like growth factor 1 (OMIM 270450) | IGF1R | AR
AD | Pre- & postnatal growth retardation Mildly impaired glucose tolerance 4 Delayed psychomotor development
|
|
| Silver-Russell syndrome (SRS) | See footnote 5 |
| Dysmorphic features (limb, body, &/or facial asymmetry) unlike those in DS/RMS Hypoglycemia assoc w/fasting only Hyperinsulinemia not a feature
|
- 1.
BSCL. Approximately 25%-35% of affected individuals develop diabetes mellitus between ages 15 and 20 years.
- 2.
BSCL. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals.
- 3.
FHI is characterized by hypoglycemia that ranges from difficult-to-manage severe neonatal-onset disease to childhood-onset disease with mild symptoms and difficult-to-diagnose hypoglycemia. Neonatal-onset disease manifests within hours to two days after birth. In the newborn period, presenting symptoms (including seizures, hypotonia, poor feeding, and apnea) may be nonspecific. In severe cases, serum glucose concentrations are typically extremely low and thus easily recognized. Childhood-onset disease manifests during the first months or years of life, and in milder cases, variable and mild hypoglycemia may make it more difficult to establish the diagnosis.
- 4.
- 5.
- 6.
SRS. The birth weight of affected infants is typically ≥2 SD below the mean, and postnatal growth ≥2 SD below the mean for length or height.
Management
Evaluations Following Initial Diagnosis
To establish the extent of the disease and the needs in an individual diagnosed with INSR-related severe syndromic insulin resistance, the following (if not performed as part of the evaluation that led to diagnosis) are recommended:
Assessment by pediatric endocrinologist including frequent blood glucose monitoring (during fasting and after feeding) or continuous glucose monitoring; measurement of insulin levels and C-peptide; thyroid function tests
Assessment by a nutritionist regarding feeding and diet required to achieve normal glucose levels and optimal growth
Developmental assessment
Evaluation by a pediatric cardiologist including echocardiography for evidence of hypertrophic cardiomyopathy
Evaluation by a pediatric nephrologist including assessment of renal function, measurement of serum electrolytes, measurement of 24-hour urinary excretion of calcium
Evaluation of the liver by pediatric gastroenterologist including liver function tests
Ultrasound examination of the ovaries (in females), kidneys, liver, and spleen
Consultation with a clinical geneticist
Treatment of Manifestations
Insulin Resistance and Hyperglycemia
Donohue syndrome. There are currently no effective treatments for the insulin resistance or other manifestations of DS. Postprandial hyperglycemia does not respond to insulin treatment [Semple et al 2010] or glucose-lowering therapies such as metformin [Musso et al 2004].
Frequent feedings (e.g., breastfeeding, nasogastric tube, and/or intravenous glucose) are used to prevent hypoglycemia [Semple et al 2010].
Rabson-Mendenhall syndrome. The first line of therapy is insulin sensitizers, which decrease the levels of glucose and glycosylated hemoglobin (HbA1c) [Musso et al 2004, Moreira et al 2010]. The effect of these drugs diminishes over time, often requiring dose adjustments and multidrug therapy [Carrasco de la Fuente et al 2010].
When hyperglycemia persists, insulin is started, usually in high doses [Chong et al 2013]. When doses greater than 200 units per day are required, the U500 concentration of soluble human insulin is recommended as part of a multiple-injection regime. In many cases, this is well tolerated and permits large incremental increases in dose without excessive discomfort. U500 can also be administrated continuously by subcutaneous insulin pump [Semple et al 2010].
Although diabetic ketoacidosis is a major cause of morbidity and mortality in RMA, only a few reports have documented its treatment in individual patients. In these instances very high doses of insulin (≤500 U/hr) were required [Chong et al 2013, Moore et al 2017].
Other Treatments for Both DS and RMS
Cardiomyopathy. Treat with beta blockers.
Hyperandrogenism
Treat with oral contraceptives and anti-androgens such as flutamide and spironolactone as well as finasteride, a 5a-reductase inhibitor that reduces the conversion of testosterone to dihydrotestosterone [
Bathi et al 2010,
Wei & Burren 2017].
Use of a GnRH agonist to suppress gonadotrophins is also likely to be beneficial [
Brown et al 2017].
In some cases, removal of the ovaries is necessary to control hyperandrogenism [
Musso et al 2004].
Short stature. Growth does not improve with human growth hormone treatment even when the child's growth hormone levels are low [Musso et al 2004, Kim et al 2012, Brown et al 2013].
Gonadectomy may be considered when enlarged ovaries cause respiratory distress or interfere with development, and/or imaging suggests granulosa cell tumor.
Other
Treatment of hypothyroidism as per routine
Rigorous workup and treatment of intercurrent infections
Psychosocial support and guidance for the families
Surveillance of DS and RMS
The following are appropriate:
Agents/Circumstances to Avoid
In DS:
In RMS:
Pregnancy Management
Heterozygotes for an INSR pathogenic variant are at increased risk for gestational diabetes and require monitoring for glucose intolerance before and during pregnancy [Kleijer et al 2006].
Gestational diabetes, which can be difficult to control, requires high doses of insulin. Adding metformin can lower insulin requirements [Enkhtuvshin et al 2015].
The background risk for birth defects in the general population is approximately 3%-4%. Women who have pre-pregnancy insulin-dependent diabetes are at increased (i.e., ~6%-8%) risk of having a child with a birth defect. Women who develop gestational diabetes during pregnancy may be at increased risk of having a child with a birth defect compared to the background risk, but the risk appears to be less than that for women who have pre-pregnancy insulin-dependent diabetes. Appropriate glycemic control during pregnancy does not eliminate but may reduce the risk of having a child with a birth defect, and may also decrease the risk of having a child with neonatal diabetes-related complications (e.g., macrosomia, hypoglycemia, and electrolyte abnormalities).
Insulin is the preferred medication for treating women with pre-pregnancy diabetes. There are limited data on the fetal effects of metformin exposure during human pregnancy, although such data have been reassuring. Given the risks to the fetus associated with diabetes during pregnancy, aggressive treatment of chronic maternal hyperglycemia is recommended.
To screen for fetal birth defects in pregnant women with diabetes, prenatal high-resolution ultrasound with fetal echocardiogram is recommended; referral to a maternal-fetal medicine specialist may also be considered.
See www.mothertobaby.org for more information on the use of medications during pregnancy.
Therapies Under Investigation
There are no controlled trials of any sort in INSR-related severe syndromic insulin resistance; thus, the two therapies discussed in this section are based on clinical experience, case series, and expert opinion.
Recombinant Human IGF-1 (rhIGF-1)
The rationale for using rhIGF-1 to treat severe insulin resistance syndromes is based on observations of its direct effects on carbohydrate metabolism. In humans, infusion of rhIGF-1 suppresses hepatic glucose production, stimulates peripheral glucose uptake in muscle, and – despite a significant reduction in circulating insulin levels – causes hypoglycemia. The insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor (INSR) share 60% homology and very similar intracellular activity [Weber et al 2014].
Treatment regimen. Although many case reports of severe insulin resistance syndromes describe treatment with rhIGF-1, there is no standard protocol regarding this treatment. In fact, the treatment regimens either differed [McDonald et al 2007, de Kerdanet et al 2015] or were not reported.
Three treatment regimens for rhIGF-1 therapy in children with severe insulin resistance were reported: subcutaneous injections two to four times a day, continuous subcutaneous infusion via insulin pump, and intravenous infusion [Backeljauw et al 1994]. Anecdotal experience suggests that the use of continuous rhIGF-1 infusion is more beneficial than divided doses. Doses ranged from 80 to 1120 µg/kg/day [McDonald et al 2007].
Outcome of treatment. In most treated children:
In some children treated with rhIGF-1, the degree of cardiomyopathy improved and survival was prolonged [McDonald et al 2007, de Kerdanet et al 2015, Carmody et al 2016], whereas in others no improvement was observed [Musso et al 2004, Grasso et al 2013].
Potential side effects include severe hypoglycemia and soft-tissue overgrowth.
Given a lack of evidence it is unclear whether the following two instances were side effects of the treatment or the hyperinsulinemia itself:
Endometrial carcinoma in a woman age 24 years treated with rhIGF-1 for severe insulin resistance (called Donohue syndrome by the authors, but clinically more likely RMS) [
Jo et al 2013]
Granulosa cell tumor of the ovary in a girl age 35 months with severe insulin resistance treated with rhIGF-1 for 16 months [
Weber et al 2014]
To summarize the experience with rhIGF-1 treatment in severe insulin resistance syndromes: (1) its benefit is not well established; and (2) it is more likely to be effective in individuals with less severe insulin resistance, as the few individuals with prolonged survival with rhIGF-1 treatment had milder phenotypes [Carmody et al 2016]. To date, rhIGF-1 appears to be the best treatment option; it is thus reasonable to consider in any patient with severe syndromic insulin resistance.
Metreleptin (Recombinant Human Leptin)
Metreleptin is approved by the FDA for treatment of congenital or acquired generalized lipodystrophy.
Leptin replacement normalized blood lipids (i.e., reduced triglycerides and increased HDL) and reduced insulin and glucose levels in syndromes with leptin deficiency. Syndromes with leptin deficiency are characterized by insulin resistance, hyperglycemia, dyslipidemia, endocrine disruptions, and fatty liver disease [Paz-Filho et al 2015] and include lipodystrophy syndromes, hypothalamic amenorrhea, anorexia nervosa, and congenital leptin deficiency.
After one year of treatment with metreleptin (along with other medications including insulin, metformin, and pioglitazone), individuals with RMS showed improvement in all of the following: serum glucose levels, HbA1c levels, insulinemia, insulin dose required, caloric intake, and body fat mass [Cochran et al 2004, Brown et al 2013].
There are no reports of metreleptin treatment of longer duration in patients with RMS.
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members. This section is not meant to address all personal, cultural, or
ethical issues that individuals may face or to substitute for consultation with a genetics
professional. —ED.
Risk to Family Members
Parents of a proband
Sibs of a proband
At conception, each sib of an
affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic
carrier, and a 25% chance of being unaffected and not a carrier.
Offspring of a proband. Individuals with INSR-related severe syndromic insulin resistance are not known to reproduce.
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an INSR pathogenic variant.
Carrier (Heterozygote) Detection
Carrier testing for at-risk relatives requires prior identification of the INSR pathogenic variants in the family.
Prenatal Testing and Preimplantation Genetic Testing
Once the INSR pathogenic variants have been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
INSR-Related Severe Syndromic Insulin Resistance: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Gene structure.
INSR spans more than 120 kb and has 22 exons [Seino et al 1989]. The longest transcript (NM_000208.3) is 9375 bp with a signal peptide sequence from nucleotides 412 to 492 and coding sequences from nucleotides 493 to 2685 (encoding the insulin receptor subunit alpha) and nucleotides 2698 to 4557 (encoding the insulin receptor subunit beta). For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. More than 70 pathogenic variants causative of INSR-related severe syndromic insulin resistance have been identified. They are distributed throughout the gene and include missense, nonsense, and splicing variants as well as small deletions, insertions, and indels. Exon and multiexon deletions have been reported, including one deletion of the entire gene. The latter was a homozygous complete INSR deletion observed in an infant age one year, thereby demonstrating that absence of INSR is compatible with life [Wertheimer et al 1993].
The prevalence of heterozygotes (carriers) for the pathogenic variant c.167T>C is high among Druze in Israel [Falik Zaccai et al 2014].
Three individuals from two unrelated families of Tunisian origin had the same novel c.3003_3012delinsGGAAG INSR pathogenic deletion/insertion [Siala-Sahnoun et al 2016].
Table 3.
INSR Pathogenic Variants Discussed in This GeneReview
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| DNA Nucleotide Change | Predicted Protein Change
(Alias 1) | Reference Sequences |
|---|
| c.167T>C | p.Ile56Thr | NM_000208.3
NP_000199.2 |
| c.3003_3012delinsGGAAG | p.Ser1001ArgfsTer37
(Ser1001_Asp1004delinsArgGlu) |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions.
Normal gene product. The insulin receptor belongs to the superfamily of transmembrane receptor tyrosine kinases. The INSR preprotein, consisting of 1382 amino acids, is proteolytically processed to generate the alpha and beta subunits of INSR, a heterotetrameric glycoprotein. The 731-amino acid alpha subunit, which is external to the plasma membrane, contains the insulin-binding region. The alpha subunit is linked by disulfide bonds to the 620-amino acid beta subunit, which includes a 194-amino acid extracellular domain, a 23-amino acid membrane-spanning segment, and a 403-amino acid cytoplasmic segment that has intrinsic tyrosine kinase activity [Seino et al 1989].
When insulin binds to the alpha subunit, the beta subunit undergoes autophosphorylation, which activates the insulin-signaling pathway regulating glucose uptake and release as well as the synthesis and storage of carbohydrates, lipids, and protein.
Abnormal gene product.
Taylor et al [1991] described five classes of INSR pathogenic variants that:
Impair synthesis of the receptors;
Impair transport of receptors to the cell membrane;
Decrease receptor affinity for insulin;
Reduce the tyrosine kinase activity of the receptor intracellular
domain; and
In severe insulin resistance, reduced intracellular insulin signaling causes hyperglycemia. The hypoglycemia in INSR-related severe syndromic insulin resistance is thought to be a consequence of late action of IGF-1 [Kawashima et al 2013]. Insulin resistance causes alternations in the expression of genes encoding growth factors and apoptosis [Iovino et al 2014].
References
Literature Cited
Accili D, Barbetti F, Cama A, Kadowaki H, Kadowaki T, Imano E, Levy-Toledano R, Taylor SI. Mutations in the insulin receptor gene in patients with genetic syndromes of insulin resistance and acanthosis nigricans.
J Invest Dermatol. 1992;98:77S–81S. [
PubMed: 1588128]
Ardon O, Procter M, Tvrdik T, Longo N, Mao R. Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.
Mol Genet Metab Rep. 2014;1:71–84. [
PMC free article: PMC5121292] [
PubMed: 27896077]
Backeljauw PF, Alves C, Eidson M. Effect of intravenous insulin-like growth factor I in two patients with leprechaunism.
Pediatr Res. 1994;36:749–54. [
PubMed: 7534902]
Baqir ZS, Al-Lawati TT, Al Hussaini SO, Al-Sinani A, Al-Said K, Al-Rashdi I. A novel leprechaunism mutation, Cys807Arg, in an Arab infant: a rare cause of hypoglycaemia.
Paediatr Int Child Health. 2012;32:183–5. [
PubMed: 22824672]
Bathi RJ, Parveen S, Mutalik S. Rabson-Mendenhall syndrome : two case reports and a brief review of the literature.
Odontology. 2010;98:89–96. [
PubMed: 20155514]
Ben Abdelaziz R, Ben Chehida A, Azzouz H, Boudabbous H, Lascols O, Ben Turkia H, Tebib N. A novel homozygous missense mutation in the insulin receptor gene results in an atypical presentation of Rabson-Mendenhall syndrome.
Eur J Med Genet. 2016;59:16–9. [
PubMed: 26691667]
Brisigotti M, Fabbretti G, Pesce F, Gatti R, Cohen A, Parenti G, Callea F. Congenital bilateral juvenile granulosa cell tumor of the ovary in leprechaunism: a case report.
Pediatr Pathol. 1993;13:549–58. [
PubMed: 8247952]
Carmody D, Ladsaria SS, Buikema RK, Semple RK, Greeley SAW. Successful rhIGF1 treatment for over 5 years in a patient with severe insulin resistance due to homozygous insulin receptor mutation.
Diabet Med. 2016;33:e8–e12. [
PMC free article: PMC4751063] [
PubMed: 26262567]
Carrasco de la Fuente M, Barrio Castellanos R, Alonso Blanco M, de la Calle Blasco H. Long survival in Rabson-Mendenhall syndrome.
Diabetes Res Clin Pract. 2010;89:e17–18. [
PubMed: 20627358]
Cochran E, Young JR, Sebring N, DePaoli A, Oral EA, Gorden P. Efficacy of recombinant methionyl human leptin therapy for the extreme insulin resistance of the Rabson-Mendenhall syndrome.
J Clin Endocrinol Metab. 2004;89:1548–54. [
PubMed: 15070911]
de Bock M, Hayes I, Semple R. Donohue syndrome.
J Clin Endocrinol Metab. 2012;97:1416–17. [
PubMed: 22399506]
de Kerdanet M, Caron-Debarle M, Nivot S, Gaillot T, Lascols O, Fremont B, Bonnaure-Mallet M, Gie S, Massart C, Capeau J. Ten-year improvement of insulin resistance and growth with recombinant human insulin-like growth factor 1 in a patient with insulin receptor mutations resulting in leprechaunism.
Diabetes Metab. 2015;41:331–7. [
PubMed: 25465274]
Desbois-Mouthon C, Girodon E, Ghanem N, Caron M, Pennerath A, Conteville P, Magre J, Besmond C, Goossens M, Capeau J, Amselem S. Molecular analysis of the insulin receptor gene for prenatal diagnosis of leprechaunism in two families.
Prenat Diagn. 1997;17:657–63. [
PubMed: 9249867]
Donohue WL, Uchida I. Leprechaunism: a euphemism for a rare familial disorder.
J Pediatr. 1954;45:505–19. [
PubMed: 13212592]
Elders MJ, Schedewie HK, Olefsky J, Givens B, Char F, Bier DM, Baldwin D, Fiser RH, Seyedabadi S, Rubenstein A. Endocrine-metabolic relationships in patients with leprechaunism.
J Natl Med Assoc. 1982;74:1195–210. [
PMC free article: PMC2561419] [
PubMed: 7154104]
Enkhtuvshin B, Nagashima S, Saito N, Wakabayashi T, Ando A, Takahashi M, Sakai K, Yamamuro D, Nagasaka S, Tamemoto H, Ishibashi S. Successful pregnancy outcomes in a patient with type A insulin resistance syndrome.
Diabet Med. 2015;32:e16–e19. [
PMC free article: PMC5034500] [
PubMed: 25472847]
Falik Zaccai TC, Kalfon L, Klar A, Elisha M, Ben, Hurvitz H, Weingarten G, Chechik E, Fleisher Sheffer V, Haj Yahya R, Meidan G, Gross-Kieselstein E, Bauman D, Hershkovitz S, Yaron Y, Orr-Urtreger A, Wertheimer E. Two novel mutations identified in familial cases with Donohue syndrome.
Mol Genet Genomic Med. 2014;2:64–72. [
PMC free article: PMC3907912] [
PubMed: 24498630]
Geffner ME, Kaplan SA, Bersch N, Lippe BM, Smith WG, Nagel RA, Santulli TV Jr, Li CH, Golde DW. Leprechaunism: in vitro insulin action despite genetic insulin resistance.
Pediatr Res. 1987;22:286–91. [
PubMed: 3309859]
Grasso V, Colombo C, Favalli V, Galderisi A, Rabbone I, Gombos S, Bonora E, Massa O, Meschi F, Cerutti F, Iafusco D, Bonfanti R, Monciotti C, Barbetti F. Six cases with severe insulin resistance (SIR) associated with mutations of insulin receptor: Is a Bartter-like syndrome a feature of congenital SIR?
Acta Diabetol. 2013;50:951–7. [
PubMed: 23824322]
Hovnik T, Bratanič N, Podkrajšek KT, Kovač J, Paro D, Podnar T, Bratina N, Battelino T. Severe progressive obstructive cardiomyopathy and renal tubular dysfunction in Donohue syndrome with decreased insulin receptor autophosphorylation due to a novel INSR mutation.
Eur J Pediatr. 2013;172:1125–9. [
PubMed: 23229189]
Iovino S, Burkart AM, Kriauciunas K, Warren L, Hughes KJ, Molla M, Lee YK, Patti ME, Kahn CR. Genetic insulin resistance is a potent regulator of gene expression and proliferation in human iPS cells.
Diabetes. 2014;63:4130–42. [
PMC free article: PMC4238001] [
PubMed: 25059784]
Jiang S, Fang Q, Zhang F, Wan H, Zhang R, Wang C, Bao Y, Zhang L, Ma X, Lu J, Gao F, Xiang K, Jia W. Functional characterization of insulin receptor gene mutations contributing to Rabson-Mendenhall syndrome - phenotypic heterogeneity of insulin receptor gene mutations.
Endocr J. 2011;58:931–40. [
PubMed: 21869538]
Jo W, Sudo S, Nakamura A, Endo D, Konno Y, Ishizu K, Tajima T. Development of endometrial carcinoma in a patient with leprechaunism (Donohue syndrome).
Clin Pediatr Endocrinol. 2013;22:33–8. [
PMC free article: PMC3756185] [
PubMed: 23990696]
Kawashima Y, Nishimura R, Utsunomiya A, Kagawa R, Funata H, Fujimoto M, Hanaki K, Kanzaki S. Leprechaunism (Donohue syndrome): a case bearing novel compound heterozygous mutations in the insulin receptor gene.
Endocr J. 2013;60:107–12. [
PubMed: 22972224]
Kim D, Cho SY, Sohn YB, Kwon M. Two novel insulin receptor gene mutations in a patient with Rabson-Mendenhall syndrome : the first Korean case confirmed by biochemical and molecular evidence.
J Korean Med Sci. 2012;27:565–8. [
PMC free article: PMC3342552] [
PubMed: 22563226]
Klammt J, Kiess W, Pfäffle R. IGF1R mutations as cause of SGA.
Best Pract Res Clin Endocrinol Metab. 2011;25:191–206. [
PubMed: 21396585]
Kleijer WJ, van der Sterre MLT, Garritsen VH, Raams A, Jaspers NGJ. Prenatal diagnosis of the Cockayne syndrome: survey of 15 years experience.
Prenat Diagn. 2006;26:980–4. [
PubMed: 16941719]
Longo N, Wang Y, Pasquali M. Progressive decline in insulin levels in Rabson-Mendenhall syndrome.
J Clin Endocrinol Metab. 1999;84:2623–9. [
PubMed: 10443650]
Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D. Genotype-phenotype correlation in inherited severe insulin resistance.
Hum Mol Genet. 2002;11:1465–75. [
PubMed: 12023989]
Maassen JA, Tobias ES, Kayserilli H, Tukel T, Yuksel-Apak M, D'Haens E, Kleijer WJ, Féry F, van der Zon GC. Identification and functional assessment of novel and known insulin receptor mutations in five patients with syndromes of severe insulin resistance.
J Clin Endocrinol Metab. 2003;88:4251–7. [
PubMed: 12970295]
McDonald A, Williams RM, Regan FM, Semple RK, Dunger DB. IGF-I treatment of insulin resistance.
Eur J Endocrinol. 2007;157:S51–6. [
PubMed: 17785698]
Moore MM, Bailey AM, Flannery AH, Baum RA. Treatment of diabetic ketoacidosis with intravenous U-500 insulin in a patient with Rabson-Mendenhall syndrome: a case report.
J Pharm Pract. 2017;30:468–75. [
PubMed: 27112737]
Moreira RO, Zagury RL, Nascimento TS. Multidrug therapy in a patient with Rabson-Mendenhall syndrome.
Diabetologia. 2010;53:2454–5. [
PubMed: 20711714]
Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, Taylor S, Gorden P. Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective.
Medicine (Baltimore). 2004;83:209–22. [
PubMed: 15232309]
Nakae J, Kato M, Murashita M, Shinohara N, Tajima T, Fujieda K. Long-term effect of recombinant human insulin-like growth factor I on metabolic and growth control in a patient with leprechaunism.
J Clin Endocrinol Metab. 1998;83:542–9. [
PubMed: 9467572]
Ogilvy-Stuart AL, Soos MA, Hands SJ, Anthony MY, Dunger DB, O'Rahilly S. Hypoglycemia and resistance to ketoacidosis in a subject without functional insulin receptors.
J Clin Endocrinol Metab. 2001;86:3319–26. [
PubMed: 11443207]
Paz-Filho G, Mastronardi CA, Licinio J. Leptin treatment : facts and expectations.
Metabolism. 2015;64:146–56. [
PubMed: 25156686]
Porter JR, Barrett TG. Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and b cell failure.
J Med Genet. 2005;42:893–902. [
PMC free article: PMC1735963] [
PubMed: 15772126]
Siala-Sahnoun O, Dhieb D, Ben Thabet A, Hmida N, Belguith N, Fakhfakh F. First molecular diagnosis of Donohue syndrome in Africa: novel unusual insertion/deletion mutation in the INSR gene.
Mol Biol Rep. 2016;43:165–73. [
PubMed: 26874853]
Semple RK, Cochran EK, Soos MA, Burling KA, Savage DB, Gorden P, O'Rahilly S. Plasma adiponectin as a marker of insulin receptor dysfunction: clinical utility in severe insulin resistance.
Diabetes Care. 2008;31:977–9. [
PubMed: 18299442]
Semple RK, Sleigh A, Murgatroyd PR, Adams CA, Bluck L, Jackson S, Vottero A, Kanabar D, Charlton-Menys V, Durrington P, Soos MA, Carpenter TA, Lomas DJ, Cochran EK, Gorden P, O'Rahilly S, Savage DB. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis.
J Clin Invest. 2009;119:315–22. [
PMC free article: PMC2631303] [
PubMed: 19164855]
Semple RK, Williams RM, Dunger DB. What is the best management strategy for patients with severe insulin resistance?
Clin Endocrinol (Oxf). 2010;73:286–90. [
PubMed: 20455892]
Simpkin A, Cochran E, Cameron F, Dattani M, de Bock M, Dunger DB, Forsander G, Guran T, Harris J, Isaac I, Hussain K, Kleta R, Peters C, Tasic V, Williams R, Yap Kok Peng F, O'Rahilly S, Gorden P, Semple RK, Bockenhauer D. Insulin receptor and the kidney: nephrocalcinosis in patients with recessive INSR mutations.
Nephron Physiol. 2014;128:55–61. [
PMC free article: PMC4369119] [
PubMed: 25358339]
Takahashi Y, Kadowaki H, Momomura K, Fukushima Y, Orban T, Okai T, Taketani Y, Akanuma Y, Yazaki Y, Kadowaki T. A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism.
Diabetologia. 1997;40:412–20. [
PubMed: 9112018]
Taylor SI, Accili D, Cama A, Kadowaki H, Kadowaki T, Imano E, Sierra ML. Mutations in the insulin receptor gene in patients with genetic syndromes of insulin resistance.
Adv Exp Med Biol. 1991;293:197–213. [
PubMed: 1767731]
Tuthill A, Semple RK, Day R, Soos MA, Sweeney E, Seymour PJ, Didi M, O'Rahilly S. Functional characterization of a novel insulin receptor mutation contributing to Rabson-Mendenhall syndrome.
Clin Endocrinol (Oxf). 2007;66:21–6. [
PubMed: 17201797]
Weber DR, Stanescu DE, Semple R, Holland C, Magge SN. Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome.
J Pediatr Endocrinol Metab. 2014;27:1237–41. [
PMC free article: PMC4535795] [
PubMed: 25153212]
Wei C, Burren CP. Diagnostic and management challenges from childhood, puberty through to transition in severe insulin resistance due to insulin receptor mutations.
Pediatr Diabetes. 2017;18:835–8. [
PubMed: 28093873]
Wertheimer E, Lu S, Backeljauw P, Davenport M, Taylor S. Homozygous deletion of the human insulin receptor gene results in leprechaunism.
Nat Genet. 1993;5:71–3. [
PubMed: 7693131]
Chapter Notes
Author Notes
Research interests:
Searching for genes responsible for various rare genetic disorders and investigating the clinical, biochemical, and molecular basis for each disorder by studying the related protein function and biologic pathway. Diseases currently of particular interest include neurogenetic diseases, aplasia of distal phalanges with juvenile breast hypertrophy (MDN), osteogenesis imperfecta, and hereditary spastic paraparesis and cardiomyopathies.
Identification of new pathogenic variants, genes, and proteins involved in NER-type DNA repair mechanisms. Understanding their cellular function and their role in premature aging and cancer. In addition, the establishment of new diagnostic procedures for the screening of causative pathogenic variants in the patient population in Israel and the Middle East.
Development of methods of
genetic counseling tailored to kindreds at high risk for genetic disorders, in an attempt to raise awareness and to prevent and minimize the births of
affected individuals. Also, early identification of affected newborns is critical for provision of prompt and effective treatment.
Genetics of pain: Our interest in this field is manifested in the study of women with vulvodynia (pain during sexual intercourse). This phenomenon is evident within families, and genetic associations have been found. With the collaboration of Professor J Bornstein, we are studying possible genetic associations that relate to biochemical pathways involved in pain regulation among a large cohort of women
affected with vulvodynia.
Dr Falik Zaccai's web page
