Severe insulin resistance has been linked to some of the most globally prevalent disorders

such as diabetes mellitus

nonalcoholic fatty liver disease

polycystic ovarian syndrome

and hypertension. Hereditary severe insulin resistance syndrome (H-SIRS) is a rare disorder classified into four principal categories: primary insulin receptor defects

lipodystrophies

complex syndromes

and obesity-related H-SIRS. Genes such as

INSR

AKT2

TBC1D4

AGPAT2

BSCL2

CAV1

PTRF

LMNA

PPARG

PLIN1

CIDEC

LIPE

PCYT1A

MC4R

LEP

POMC

SH2B1

RECQL2

RECQL3

ALMS1

PCNT

ZMPSTE24

PIK3R1

and

POLD1

have been linked to H-SIRS. Its clinical features include insulin resistance

hyperglycemia

hyperandrogenism

severe dyslipidemia

fatty liver

abnormal topography of adipose tissue

and low serum leptin and adiponectin levels. Diagnosis of H-SIRS is based on the presence of typical clinical features associated with the various H-SIRS forms and the identification of mutations in H-SIRS-linked genes by genetic testing. Diet therapy

insulin sensitization

exogenous insulin therapy

and leptin replacement therapy have widely been adopted to manage H-SIRS. The rarity of H-SIRS

its highly variable clinical presentation

refusal to be tested for genetic mutations by patients’ family members who are not severely sick

unavailability of genetic testing

and testing expenses contribute to the delayed or underdiagnoses of H-SIRS. Early diagnosis facilitates early management of the condition

which results in improved glycemic control and delayed onset of diabetes and other complications related to severe insulin resistance. The use of updated genetic sequencing technologies is recommended

and long-term studies are required for genotype–phenotype differentiation and formulation of diagnostic and treatment protocols.