Case#: 20‐year‐old Japanese male

DiseaseAssertion: Patients are asserted to have “SHORT syndrome” and “harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins.”

FamilyInfo: No relevant family history

CasePresentingHPOs: HP:0001511, HP:0000819, HP:0000855, HP:0040063, HP:0000484, HP:0000540, HP:0000483, HP:0000646, HP:0000684, HP:0000325, HP:0011220, HP:0000430, HP:0000331, HP:0000233, HP:0002714, HP:0100578

CaseHPOFreeText: Born at 39 weeks of gestation with a birth length of 45 cm and a birth weight of 1,990 g (−3.0 SD relative to the average for this gestational age). Weight at time of diagnosis was 38.5 kg (−1.2 SD), height 163.4 cm (−2.7 SD), body mass index 14.4 kg/m2 (−2.1 SD). He was found to have glycosuria during a school urine test at the age of 12 years and started treatment with metformin for diabetes at 15 years. Fasting plasma glucose, serum immunoreactive insulin (IRI) concentrations, and serum C‐peptide at evaluation were 161 mg/dL, 35.8 μIU/mL, and 5.20 ng/mL, respectively. HOMA‐IR was 14.2, and his HOMA‐β was 131.5%. Patient has facial characteristics of SHORT syndrome and adipose tissue atrophy in the upper body.

CaseNotHPOs: HP:0004322, HP:0001382, HP:0000023, HP:0000490, HP:0000558, HP:0000369, HP:0005328, HP:0000545, HP:0000593, HP:0000501, HP:0000963, HP:0007392, HP:0001249, HP:0000750, HP:0000365, HP:0000400

CaseNotHPOFreeText: Readily visible veins

CasePreviousTesting: NR

GenotypingMethod: Initially, comprehensive sequencing analysis was conducted on all 22 exons of the INSR gene using the Sanger sequencing method, confirming the absence of pathogenic variants. Subsequently, sequencing was extended to encompass all 16 exons of the PIK3R1 gene.

PreviouslyPublished: No

Variant: NM_181523.3:c.1945C>T

ClinVar: 60763

gnomAD: NR

SupplementalData: Table 1

Case#: 6‐year‐old Japanese female

DiseaseAssertion: Patients are asserted to have “SHORT syndrome” and “harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins.”

FamilyInfo: No relevant family history

CasePresentingHPOs: HP:0001511, HP:0000855, HP:0004322, HP:0000490, HP:0000684, HP:0000325, HP:0000430, HP:0000400, HP:0000369, HP:0005328, HP:0000545, HP:0000963, HP:0007392, HP:0000365

CaseHPOFreeText: Born with a birth length of 43.1 cm (−1.3 SD relative to the average for this gestational age) and birth weight of 1,544 g (−2.7 SD relative to the average for this gestational age). Her height was 104.0 cm and weight 12.6 kg at the time of evaluation for this study, indicating no apparent short stature (−1.0 SD relative to the average for this age). Her fasting plasma glucose, serum IRI concentrations, and serum C‐peptide were 108 mg/dL, 56.4 μIU/mL, and 6.95 ng/mL, respectively, with an HbA1c level of 5.2%. Her HOMA‐IR was 15.0, and her HOMA‐β was 451.2%. She had a hearing threshold of 30 and 50 dB in the right and left ears, respectively. Otitis media was apparent in the right ear, but not in the left. Patient had readily visible veins.

CaseNotHPOs: HP:0000819, HP:0001382, HP:0000023, HP:0011220, HP:0000331, HP:0000233, HP:0002714, HP:0000540, HP:0000483, HP:0000593, HP:0000501, HP:0100578, HP:0001249, HP:0000750

CaseNotHPOFreeText: N/A

CasePreviousTesting: NR

GenotypingMethod: Initially, comprehensive sequencing analysis was conducted on all 22 exons of the INSR gene using the Sanger sequencing method, confirming the absence of pathogenic variants. Subsequently, sequencing was extended to encompass all 16 exons of the PIK3R1 gene.

PreviouslyPublished: No

Variant: NM_181523.3:c.1945C>T

ClinVar: 60763

gnomAD: NR

SupplementalData: Table 1, Figure 1a,b

Case#: 33-year-old Chinese adult female

DiseaseAssertion: Patient is asserted to have “SHORT syndrome due to a PIK3R1 gene variant (c.1945C > T).”

FamilyInfo: Both parents were healthy and non-consanguineous. Her father was 167 cm tall and her mother was 160 cm tall. The patient had a younger brother, aged 29, who was 175 cm tall and weighed 60 kg.

CasePresentingHPOs: HP:0000684, HP:0000750, HP:0040270, HP:0000855, HP:0004322, HP:0001382, HP:0000858, HP:0000558, HP:0011220, HP:0000430, HP:0000331, HP:0000233, HP:0000369, HP:0005328, HP:0007392, HP:0000963, HP:0100578, HP:0001952, HP:0000819, HP:0000147, HP:0000325

CaseHPOFreeText: Patient has a spontaneous full-term vaginal delivery without birth trauma or asphyxia. At birth, the patient weighed 2000 g (< 3rd percentile), though her length was unknown. Her first primary tooth emerged at 9 months and her ability to say “mom” and “dad” developed at 10 months. Throughout childhood, the patient consistently lagged in growth and development compared with their peers. At 5 years of age, her height was only 99.7 cm (−3 SD) and her weight 11.5 kg(< 3rd percentile). By age 9, her height was 116.5 cm (−3 SD) and her weight was 15.0 kg(< 3rd percentile). Her test results revealed a fasting blood glucose (FBG) level of 5.48 mmol/L and 2-hour postprandial blood glucose level of 8.04 mmol/L. Notably, her postprandial 2-hour insulin level exceeded the upper detection limit (> 2152.5 pmol/L), while her postprandial 2-hour C-peptide level was 0.4 nmol/L. Her glycosylated hemoglobin (HbA1c) was 5.78%. Consequently, she was prescribed long-term voglibose monotherapy. The patient exhibited distinctive facial features. The patient also exhibited visible veins and had polycystic ovarian syndrome. Height: 147.50 cm, Weight: 37.50 kg, BMI: 17.24 kg/m2, Lean mass: 23.90 kg, Fat mass: 9.30 kg, VFA: 35.3 cm2, Total cholesterol: 4.20 mmol/L, HDL-c: 1.09 mmol/L, LDL-c: 2.92 mmol/L, Triglyceride: 1.47 mmol/L, Calcium: 2.19 mmol/L, Phosphorous: 1.25 mmol/L, 25-hydroxyvitamin D3: 14.5 ng/ml, TSH: 1.97 mIU/L, Free T4: 11.47 pmol/L, Total testosterone: 1.47 nmol/L

CaseNotHPOs: HP:0001249, HP:0000956, HP:0002240, HP:0001397,<br /> HP:0000501, HP:0000488, HP:0009830

CaseNotHPOFreeText: Elevated plasma triglycerides, ocular hypotension, diabetic kidney disease, lower extremity arterial disease. The patient exhibited no lipid dysregulation, with fat mass and visceral fat area falling below the normal range, accompanied by a reduction in lean body mass.

CasePreviousTesting: NR

GenotypingMethod: Whole-exome sequencing

PreviouslyPublished: No

Variant: NM_181523.3:c.1945C>T

ClinVar: 60763

gnomAD: NR

SupplementalData: Table 1, 2, 3, 4