Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations

Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome.


Patient 2
Patient 2 (P2) is currently 14.5 years old. She was born at term to non-consanguineous parents of European ancestry. Pregnancy was complicated by an amniotic fluid leak and at 30 weeks of gestation intra-uterine growth restriction was noted. Feeding difficulties during infancy were attributed to gastro-oesophageal reflux. Weight remained at or below the 3 rd percentile from infancy. Head circumference followed the 10 th percentile and length was between the 3 rd and 10 th percentile. She had a left duplex kidney and recurrent urinary tract infections secondary to grade 4 urinary reflux, eventually requiring ureteric re-implantation surgery at 5 years. There was no history of nephrocalcinosis.
At two years old, dysmorphic features including a triangular face, wide mouth, thin upper lip, an "unusual" nose with prominent veins on the scalp, face and trunk were noted. The ears were prominent, posteriorly-placed and slightly low-set. There was reduced subcutaneous fat on the head, trunk and over the buttocks, but normal fat coverage on the legs and arms.
At six years old, facial dysmorphism was again noted. Investigation at this age revealed normal lipid and immunoglobulin profiles. At 10.5 years onset of puberty was noted with breast bud development.
At 13.5 years, the age at which the detailed biochemical evaluation is reported, she had narrowed facial features, deep set eyes, prognathism, a pointed chin and nose and over-crowded teeth in the upper and lower jaw. There was widespread acanthosis nigricans, most prominent in the nuchal and periumbilical regions and behind the ears. She was very lean with muscular arms and legs, and very little subcutaneous fat over the face and around her hands. Nails were concave. A deepening voice, hirsutism, and an enlarging laryngeal prominence were noted. Breast development had regressed, and primary amenorrhoea was reported. Pelvic ultrasonography showed numerous small, circumferential ovarian follicles. At 13.8 years, bone age was 15 years. Metformin was started.
No visual problems nor refractive error were reported, however ophthalmological assessment revealed Axenfeld-Rieger anomaly with iris hypoplasia, iridogoniodysgenesis, and posterior embryotoxon (Supplemental Figure 5). On gonioscopy of the angle, iris strands associated with redundant peri-umbilical skin were detected. Ocular pressures and nerves were normal.
Her mother was fit and well. Her father was unavailable for assessment but was said to be 160 cm in height, to be of slight build and to have "fine features", raising the unconfirmed possibility of autosomal dominant inheritance.

Patient 3
Patient 3 (P3) is currently 13 years old, is the second daughter of unrelated Italian parents, and has two healthy siblings. She was born at term after fetal growth was found to be subnormal in the last 2 months of gestation. Birth weight was 2200 g (-2.2 SDS). Facial dysmorphism was noted at birth, including ocular depression, a prominent nose and generalized paucity of adipose tissue. Subsequent psychomotor development was normal. Investigation including brain MRI, LMNA gene sequencing and fasting plasma insulin were said to be normal in infancy.
On endocrine evaluation at age 12 years, height was 144.1 (-1.1 SDS) and weight 28.7 kg (BMI 13.8). Despite well advanced puberty (Tanner stage 4), menarche had not occurred. On physical examination, generalized reduction of adipose tissue, a triangular face with small chin, thin upper lip, and prominent ears were noted. Skin was pale and dry with prominent veins. Severe acanthosis nigricans was present. She did not show joint hyperextensibility.

Patient 4
Patient 4 (P4) is a girl currently aged 14 years old, born at term to unrelated German parents. Intrauterine growth retardation had been observed ultrasonographically during the pregnancy. At birth facial dysmorphism was noted, and she subsequently exhibited poor linear growth, persisting between the 3rd and 10th centiles for height, however development was otherwise normal. At 8 years old she developed a squint and myopia was diagnosed, with raised intraocular pressure later detected at 11 years old. At 13.5 years old glycosuria was detected during an episode of abdominal pain. Further metabolic investigation at that age showed impaired glucose tolerance with extreme hyperinsulinemia during oral glucose tolerance testing.
At 14 years old menarche had not yet occurred although puberty was well established (Tanner A2 B2 P4). There was generalised paucity of subcutaneous adipose tissue, and facial dysmorphism featuring a triangular face with a prominent forehead, deep set eyes, large and low set ears, a narrow nose and dimpled chin. There was no acanthosis nigricans.

Patient 5
Patient 5 (P5) is currently 9 years old. He is the first son of unrelated Bulgarian parents, and was born following an uncomplicated pregnancy at term. He was admitted to the neonatal unit due to small size and poor feeding. Development progressed normally apart from mild speech and language delay, and delay in tooth eruption.
On examination he had fine facial features with prominent eyes and the appearance of megalocornea and ocular depression, although formal ophthalmology assessment was normal. He had a narrow nasal bridge, prominent columella, low set and prominent ears, wide mouth and extensive dental caries of deciduous teeth. He had normal, thick hair. He had generalized lipoatrophy with prominent veins particularly affecting his face and trunk and giving an 'aged appearance'. His hands had wrinkled skin. There was no joint hypermobility. He also had a normal renal ultrasound examination and echocardiogram.
Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations   . Ocular appearance of P2 showing missing pigment layer and visible blood vessels, exposed sphincter muscle seen as a grey rim around the pupil, and the posterior embryotoxon seen as a faint grey rim around the edge of the cornea.