Table 3.

Selected Disorders of Interest in the Differential Diagnosis of INSR-Related Severe Insulin Resistance Syndrome

Gene(s) / Genetic MechanismDisorderMOIClinical Features of Disorder
Overlapping w/INSR-SIRSDistinguishing from INSR-SIRS
11p15.5 hypomethylation,
maternal UPD7, & other causes 1		Silver-Russell syndrome (SRS)See footnote 1.
  • IUGR & postnatal growth deficiency 2
  • ↑ risk for hypoglycemia
  • Dysmorphic features unlike those in DS/RMS
  • Limb, body, &/or facial asymmetry
  • Hypoglycemia assoc w/fasting only
  • Hyperinsulinemia is not a feature in SRS.
ABCC8
CACNA1D
GCK
GLUD1
HADH
HK1
HNF1A
HNF4A
KCNJ11
PMM2
SLC16A1
UCP2 		Familial hyperinsulinism (FHI)AD
AR
  • Congenital hyperinsulinemia
  • Hypoglycemia (ranging from severe neonatal-onset disease to childhood-onset disease w/mild symptoms in FHI) 3
  • Dysmorphism & growth deficiency are not characteristic of FHI.
  • Insulin levels are usually much higher in DS/RMS.
AGPAT2
BSCL2
CAV1
CAVIN1 (PTRF)		Berardinelli-Seip congenital lipodystrophy (BSCL) (OMIM PS608594)AR
  • Congenital hyperinsulinemia
  • Insulin resistance 4
  • Hepatomegaly (due to hepatic steatosis & skeletal muscle hypertrophy in BSCL)
  • Hypertrophic cardiomyopathy 5
  • Dysmorphic features (due to absence of subcutaneous fat) in BSCL are unlike those in DS/RMS.
  • Hyperlipidemia & liver steatosis in BSCL
IGF1R Resistance to insulin-like growth factor 1 (OMIM 270450)AR
AD
  • IUGR & postnatal growth deficiency
  • Mildly impaired glucose tolerance 6
  • Delayed psychomotor development
  • Mild dysmorphic features
  • No hyperinsulinemia
  • Only mildly impaired glucose tolerance

AD = autosomal dominant; AR = autosomal recessive; DS = Donohue syndrome; INSR-SIRS = INSR-related severe insulin resistance syndrome; IUGR = intrauterine growth restriction; MOI = mode of inheritance; RMS = Rabson-Mendenhall syndrome; UPD = uniparental disomy

1.

Silver-Russell syndrome (SRS) is a genetically heterogeneous condition. Genetic testing confirms clinical diagnosis in ~60% of affected individuals. Accurate assessment of SRS recurrence requires identification of the causative genetic mechanism in the proband.

2.

The birth weight of infants with SRS is typically ≥2 standard deviations (SD) below the mean, and postnatal growth ≥2 SD below the mean for length or height.

3.

Familial hyperinsulinism (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 FHI, 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 FHI, diagnosis may be difficult to establish due to variable and/or mild hypoglycemia.

4.

Approximately 25%-35% of affected individuals develop diabetes mellitus between ages 15 and 20 years.

5.

Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals.

6.

From: INSR-Related Severe Insulin Resistance Syndrome

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