Clinical Guidance

There are no known genotype-phenotype correlations in INSR-SIRS.

Source: GeneReviews — "INSR-Related Severe Insulin Resistance Syndrome"

Diagnostic Criteria

Suggestive Findings

INSR-related severe insulin resistance syndrome (INSR-SIRS) should be suspected in individuals with the following , , and findings of Donohue syndrome or Rabson-Mendenhall syndrome (RMS).

Clinical Findings

Donohue syndrome

Source: GeneReviews — "INSR-Related Severe Insulin Resistance Syndrome"

Differential Diagnosis

The differential diagnosis of INSR-related severe insulin resistance syndrome (INSR-SIRS) includes many rare disorders with hirsutism, severe growth deficiency, and developmental delay with other syndromic features, some of which are summarized in . Table 3. Selected Disorders of Interest in the Differential Diagnosis of INSR-Related Severe Insulin Resistance Syndrome

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with INSR-related severe insulin resistance syndrome (INSR-SIRS), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

INSR-Related Severe Insulin Resistance Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Endocrine

| • Assessment by pediatric endocrinologist

• Blood glucose monitoring (during fasting after feeding) or continuous glucose monitoring

• Measurement of insulin C-peptide levels

• Thyroid function tests

• Ovarian ultrasound (in females)

|

Nutrition/Feeding

| Assessment by nutritionist | To assess feeding diet required to achieve normal glucose levels optimal growth

Development

| Developmental assessment |

Cardiac

| • Eval by pediatric cardiologist

• Echocardiography

• Cardiac MRI if indicated

| • To assess for hypertrophic cardiomyopathy

• Note: Novel blood biomarkers incl BNP, NT-proBNP, hs-CRP, hs-cTnT, uric acid are currently being evaluated.

Renal

| • Eval by pediatric nephrologist

• Serum electrolytes

• 24-hour urinary calcium

• Renal ultrasound

| To assess for abnormal renin-aldosterone system for nephrocalcinosis

Liver/GI function

| • Liver function tests per gastroenterologist

• Abdominal ultrasound to assess liver/spleen

• Eval by pediatric gastroenterologist

| To assess for cholestatic liver disease

Assess for rectal prolapse. |

Dental

| Consider eval by oral maxillofacial sp...

Source: GeneReviews — "INSR-Related Severe Insulin Resistance Syndrome"

Clinical Guidance

In individuals with Donohue syndrome, avoid the following:

• Agents that cause hypoglycemia

• Prolonged fasting

• Contact with persons with a contagious disease

In individuals with RMS, avoid the following:

• Agents that cause hyperglycemia

• High-carbohydrate diet

• Contact with persons with a contagious disease

Source: GeneReviews — "INSR-Related Severe Insulin Resistance Syndrome"

Therapies Under Investigation

There are no controlled trials in INSR-SIRS; thus, the two therapies discussed in this section are for individuals with INSR pathogenic variants based on clinical experience, case series, and expert opinion.

Recombinant Human Insulin-like Growth Factor 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 . Treatment regimen.

Source: GeneReviews — "INSR-Related Severe Insulin Resistance Syndrome"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended [, , , ]. Table 6. INSR-Related Severe Insulin Resistance Syndrome: Recommended Surveillance

Source: GeneReviews — "INSR-Related Severe Insulin Resistance Syndrome"