Donohue syndrome

Donohue syndrome (previously known as leprechaunism) is a rare autosomal recessive condition caused by loss of function mutations in the insulin receptor (INSR) gene1,2. Infant’s with Donohue syndrome demonstrate characteristic facial features including low set ears, large mouth, thickened lips, and widely spaced eyes3. Infants are born small for gestational age, and often feature hirsutism, significant acanthosis nigricans, and nail dysplasia. Patients with Donohue syndrome have severe hyperglycemia often requiring extremely high doses of insulin. Unfortunately, life expectancy is very short and patients typically die from severe infections within the first 2 years of life4.

Rabson Mendenhall syndrome

Similar to Donohue syndrome, Rabson-Mendenhall syndrome is due to loss of function mutations in the INSR gene5–7. However, in this case there remains some functional activity of the insulin receptor. Thus, patients with Rabson-Mendenhall syndrome live later into childhood. Key clinical features include precocious puberty and severe acanthosis nigricans. Patients are at risk for infection and diabetic ketoacidosis8.

Type A insulin resistance syndrome

Type A insulin resistance syndrome is an inherited syndrome that is characterized by hyperinsulinemia with or without glucose intolerance, acanthosis nigricans, and ovarian hyperandrogenism9. Classic type A insulin resistance syndrome normally occurs in lean or muscular adolescent girls observed to have hyperandrogenisms such as amenorrhea, hirsutism, and virilization. Similar conditions of severe insulin resistance with acanthosis nigricans may occur in brothers, prepubertal sisters, and fathers of female probands10.

HAIR-AN syndrome

HAIR-AN syndrome consists of hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN) . It is a rare disease which is a subset of polycystic ovarian syndrome (PCOS). HAIR-AN is commonly used to describe women with severe insulin resistance. It can be triggered by blocking antibodies against the insulin receptor or genetically absent/reduced insulin receptor number/function11. All women with HAIR-AN experience increased androgen levels12.

Type B insulin resistance syndrome

In contrast to Type A insulin resistance, Type B insulin resistance is an autoimmune condition caused by polyclonal antibodies against the insulin receptor. Typically, Type B insulin resistance presents in adulthood, primarily in middle-aged women. Patients will experience both hypo- and hyper- glycemia based on antibody mediated activation and subsequent down-regulation of the insulin receptor13. Often, Type B insulin resistance is diagnosed in the setting of other autoimmune conditions such as systemic lupus erythematosus, Sjögren syndrome, or mixed connective tissue disease14. Type B insulin resistance syndrome can also be seen as part of a paraneoplastic syndrome in response to Hodgkin disease or myeloma15.

Lipodystrophy Syndromes

Lipodystrophy is a heterogeneous disorder characterized by adipose tissue deficiency, in which patients have an abnormal accumulation of fat throughout the body (generalized) or one area of the body (partial). The condition might either be inherited or acquired from infection, autoimmune diseases, or pressure/injury on a specific area of the body. Similar symptoms from type A insulin resistance syndrome may occur. Patients with lipodystrophy might observe to have the loss of or abnormal distribution of fat. Patients with total lipoatrophy can demonstrate hypertriglyceridemia with associated hepatosplenomegaly16.

Insulin-mediated pseudoacromegaly

Insulin-mediated pseudoacromegaly (IMPA) is a rare SIR syndrome, with only a handful of cases described in the medical literature. Patients with IMPA develop tall stature, obesity, severe acanthosis nigricans, and acromegalic features. They have extremely elevated insulin levels17. Recent evidence link the genetics of IMPA to mutations in the fibroblast growth factor-21 signaling pathway. This pathway is shared with autosomal dominant forms of Kallman syndrome, a genetic disorder that causes idiopathic hypogonadotropic hypogonadism18.


Familial hyperproinsulinemia is caused specific mutations in the β-chain of the insulin gene. These mutations are linked to a profound increase in circulating plasma proinsulin levels. Serum hyperproinsulinemia is more frequent in type 2 diabetes. It has been attributed to either a direct β-cells defect or an indirect effect of cell dysregulation under sustained elevated blood glucose (hyperglycemia). Some evidence suggests that patients with IMPA experience severe hyperproinsulinemia19,20.

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