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INSR-Related Severe Syndromic Insulin Resistance

, MD, , MD, and , MD.

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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.

Diagnosis/testing.

The diagnosis of INSR-related severe syndromic insulin resistance is established in a proband with characteristic clinical findings and identification of biallelic INSR pathogenic variants on molecular genetic testing.

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, prenatal testing for a pregnancy at increased risk for INSR-related severe syndromic insulin resistance, and preimplantation genetic diagnosis are possible.

GeneReview Scope

INSR-Related Severe Syndromic Insulin Resistance: Included Phenotypes 1
  • Donohue syndrome
  • Rabson-Mendenhall syndrome

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

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.)

  • Progressive intrauterine growth restriction (IUGR) from the early third trimester and postnatal failure to thrive
  • Dysmorphic facial features (Figure 1) characterized by proptosis; infra-orbital folds; large, low-set, posteriorly rotated ears; thick vermilion of the upper and lower lips; and gingival hypertrophy [Grasso et al 2013]
  • Hypotonia
  • Developmental delay
  • Other:
    • Dry skin and reduced subcutaneous fat
    • Hypertrichosis (Figure 2)
    • Acanthosis nigricans (Figure 2)
    • Prominent nipples (Figure 3)
    • Abdominal distention (Figure 4)
    • Organomegaly
    • Genital enlargement (males and females) (Figure 4B)
    • Rectal hypertrophy and prolapse (Figure 5)
Figure 1.

Figure 1.

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]

Figure 2. . Hypertrichosis is a feature in all individuals with DS.

Figure 2.

Hypertrichosis is a feature in all individuals with DS. From Falik Zaccai et al [2014]

Figure 3. . Prominent nipples are a typical finding in neonates.

Figure 3.

Prominent nipples are a typical finding in neonates.

Figure 4. A and B.

Figure 4

A and B. Abdominal distention B. Labial hypertrophy and clitorimegaly in a girl age four months with DS

Figure 5.

Figure 5.

Rectal hypertrophy and prolapse

Rabson-Mendenhall syndrome

Laboratory Findings

Donohue syndrome

  • Severe hyperinsulinemia: extremely high plasma insulin and C-peptide levels with fluctuating blood glucose levels (typically fasting hypoglycemia and postprandial hyperglycemia)
  • Ketoacidosis not reported [Ogilvy-Stuart et al 2001]

Rabson-Mendenhall syndrome

  • Laboratory findings in the first year of life are the same as in Donohue syndrome.
  • After age one year insulin levels decline steadily:

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 Table 1).

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.

  • Single-gene testing. Sequence analysis of INSR detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
  • 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 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 Table 1).
    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

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
INSRSequence analysis 358/63 4
Gene-targeted deletion/duplication analysis 55/63 4
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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 that may be used 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:

  • Hypertrophic cardiomyopathy. Present in 30% of infants, it is a major cause of death [Geffner et al 1987, Hovnik et al 2013, Falik Zaccai et al 2014].
  • Enlarged kidneys. Kidney function as measured by glomerular filtration rate (GFR) and plasma creatinine concentration is normal [Grasso et al 2013, Simpkin et al 2014].
  • Hepatomegaly without liver dysfunction. Cholestasis is common in the neonatal period [Kawashima et al 2013, Hovnik et al 2013].
  • 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:

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.

Genotype-Phenotype Correlations

There are no known genotype-phenotype correlations in INSR-related severe syndromic insulin resistance.

Nomenclature

Donohue syndrome was first described by Donohue and 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.

Table 2.

Disorders to Consider in the Differential Diagnosis of INSR-Related Severe Syndromic Insulin Resistance

DisorderGene(s)MOIClinical Features
OverlappingDistinguishing
Syndromes of congenital hyperinsulinemia
Berardinelli-Seip congenital lipodystrophy (BSCL)AGPAT2
BSCL2
PTRF
AR
  • Insulin resistance 1
  • Hepatomegaly (due to hepatic steatosis & skeletal muscle hypertrophy in BSCL)
  • Hypertrophic cardiomyopathy 2
  • Dysmorphic features (due to absence of subcutaneous fat) in BSCL unlike those in DS/RMS
  • Hyperlipidemia & liver steatosis in BSCL
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
  • Dysmorphism & failure to thrive not characteristic of FHI
  • Insulin levels usually much higher in DS/RMS
Syndromes of intrauterine growth restriction
Resistance to insulin-like growth factor 1 (OMIM 270450)IGF1RAR
AD
  • Pre- & postnatal growth retardation
  • Mildly impaired glucose tolerance 4
  • Delayed psychomotor development
  • Mild dysmorphic features
  • No hyperinsulinemia
  • Only mildly impaired glucose tolerance
Russell-Silver syndrome (RSS)See footnote 5
  • IUGR accompanied by postnatal growth deficiency 6
  • Increased risk for hypoglycemia
  • Dysmorphic features (limb, body, and/or facial asymmetry) unlike those in DS/RMS
  • Hypoglycemia associated w/fasting only
  • Hyperinsulinemia not a feature

IUGR = intrauterine growth restriction

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.

RSS has multiple etiologies including: epigenetic changes that modify expression of genes in the imprinted region of chromosome 11p15.5, maternal uniparental disomy 7, and (infrequently) AD or AR inheritance.

6.

RSS. 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:

  • Close supervision by a pediatrician
  • Evaluation of psychomotor development every three months
  • Monitoring of:
    • Capillary glucose levels before every feeding or when clinically indicated
    • HbA1c levels for the evaluation of glycemic control, every three months
    • Thyroid function every six months
    • Cardiac status every three months
    • Ovarian size every three months until age two years, then every six months
    • Urine for hypercalciuria
    • Kidneys for nephrocalcinosis by ultrasound examination every six months
  • Gynecologic evaluation when there is an abnormal vaginal bleeding, which could be a manifestation of endometrial cancer

Agents/Circumstances to Avoid

In DS:

  • Agents that cause hypoglycemia
  • Prolonged fasting
  • Contact with persons with a contagious disease

In RMS:

  • Agents that cause hyperglycemia
  • High-carbohydrate diet
  • Contact with persons with a contagious disease

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

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:

  • The metabolic state improved and levels of glucose, insulin, and glycosylated hemoglobin decreased.
  • Growth parameters improved [Nakae et al 1998].
  • Renal tubular dysfunction improved [Hovnik et al 2013].

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 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.

Mode of Inheritance

INSR-related severe syndromic insulin resistance is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

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.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the INSR pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for INSR-related severe syndromic insulin resistance 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 decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
INSR19p13​.2Insulin receptorINSR databaseINSRINSR

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.

Table B.

OMIM Entries for INSR-Related Severe Syndromic Insulin Resistance (View All in OMIM)

147670INSULIN RECEPTOR; INSR
246200DONOHUE SYNDROME
262190PINEAL HYPERPLASIA, INSULIN-RESISTANT DIABETES MELLITUS, AND SOMATIC ABNORMALITIES

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

DNA Nucleotide ChangePredicted Protein Change
(Alias 1)
Reference Sequences
c.167T>Cp.Ile56ThrNM_000208​.3
NP_000199​.2
c.3003_3012delinsGGAAGp.Ser1001ArgfsTer37
(Ser1001_Asp1004delinsArgGlu)

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: 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
  • Accelerate receptor degradation [Porter & Barrett 2005].

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

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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

Revision History

  • 25 January 2018 (bp) Review posted live
  • 14 March 2016 (sbh) Original submission
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