PMID: 37758162

Gene: PIK3R1

HGNC: 8979

Case#: 15-year-old boy

DiseaseAssertion: SHORT syndrome and Immunodeficiency 36

FamilyInfo: Table2 Father is wild type, mother was unavailable for testing. Consanguinity was reported at Table 4. No affected family members Table4.

CasePresentingHPOs: HP:0001511(Intrauterine growth retardation) HP:0004322(Short stature) HP:0000325(Triangular face) HP:0010751(Dimple chin) HP:0000684(Delayed eruption of teeth) HP:0000347(micrognathia) HP:0100750(Atelectasis) HP:0004469(chronic bronchitis) HP:0002110(bronchiectasis) HP:0002720(Decreased circulating IgA level) HP:0011342(Mild global developmental delay) HP:0004279(short hands) HP:0000954(Single transverse palmar crease) HP:0002205(Recurrent respiratory infections)

CaseHPOFreeText:

CaseNotHPOs: Height -5.5 to -6.1 SDS

CaseNotHPOFreeText: N/A

CasePreviousTesting: CMA and MS-MLPA for chromosomes 6,14,20 was performed.

GenotypingMethod: Whole-exome sequencing was performed on the patient’s whole blood sample.

PreviouslyPublished: No

Variant: NM_001242466.2:c.68G > A p.Arg23Gln

ClinVar: 1361868

CAID: CA3290343

gnomAD: 0.00005439 https://gnomad.broadinstitute.org/variant/5-67589169-G-A

PMID: 37600808

Gene: PIK3CD Gene: PIK3R1

HGNC: 8977 HGNC: 8979

Case#: P1, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000490 (Deeply set eye/Ocular depression), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000540 (Hypermetropia/Hyperopia), HP:0000483 (Astigmatism), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia), HP:0100678 (Premature skin wrinkling/Thin, wrinkled skin), HP:0001256 (Intellectual disability, mild/Mild impairment),

CaseHPOFreeText: Proband was noted to have readily visible veins and delayed bone age.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1615_1617del (p.Ile539del).

ClinVar: 60761.

CAID: CA344796.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P2, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000490 (Deeply set eye/Ocular depression), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia), HP:0100678 (Premature skin wrinkling/Thin, wrinkled skin), HP:0001256 (Intellectual disability, mild/Mild impairment),

CaseHPOFreeText: Proband was noted to have readily visible veins and delayed bone age.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A..

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1465G>A (p.Glu489Lys).

ClinVar: 60762.

CAID: CA344798.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P3, F, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0001382 (Joint hypermobility/Hyperextensibility of joints), HP:0000490 (Deeply set eye/Ocular depression), HP:0000558 (Rieger anomaly), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000540 (Hypermetropia/Hyperopia), HP:0000483 (Astigmatism), HP:0000565 (Esotropia), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia), HP:0000138 (Ovarian cyst), HP:0001256 (Intellectual disability, mild/Mild impairment), HP:0003100 (Slender long bone/Gracile long bones)

CaseHPOFreeText: Proband was noted to have delayed bone age and mild impairment and/or speech delay

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A..

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P4, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0004322 (Short stature), HP:0004325 (Decreased body weight), HP:0040195 (Decreased head circumference), HP:0000490 (Deeply set eye/Ocular depression), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000540 (Hypermetropia/Hyperopia), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia), HP:0100678 (Premature skin wrinkling/Thin, wrinkled skin),

CaseHPOFreeText: Proband was noted to readily visible veins, normal mental development.

Proband was not evaluated for insulin resistance, ovarian cysts, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have hyperextensibility of joints, inguinal hernia, Rieger anomaly, astigmatism, myopia, esotropia, diabetes, frequent illnesses, mild impairment and/or speech delay.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P5, F, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0001382 (Joint hypermobility/Hyperextensibility of joints), HP:0000490 (Deeply set eye/Ocular depression), HP:0000558 (Rieger anomaly), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000545 (Myopia), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia),

CaseHPOFreeText: Proband was noted to have insulin resistance, frequent illnesses, ovarian cysts, normal mental development,

Proband was not evaluated for delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have inguinal hernia, hyperopia, astigmatism, esotropia, thin, wrinkled skin, readily visible veins, mild impairment and/or speech delay.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P6, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000490 (Deeply set eye/Ocular depression), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), (Micrognathia),

CaseHPOFreeText: Proband was not evaluated for inguinal hernia, Rieger anomaly, teeth delay, hyperopia, astigmatism, myopia, esotropia, lack of subcutaneous fat, insulin resistance, diabetes, thin, wrinkled skin, readily visible veins, frequent illnesses, ovarian cysts, normal mental development, mild impairment and/or speech delay, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have hyperextensibility of joints,

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P7, F, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000483 (Astigmatism), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0000347 (Micrognathia),

CaseHPOFreeText: : Proband was noted to have insulin resistance, ovarian cysts, normal mental development,

Proband was not evaluated for hyperextensibility of joints, ocular depression, hyperopia, myopia, esotropia, Triangular face, Mild midface hypoplasia, frequent illnesses, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have inguinal hernia, Rieger anomaly, thin, wrinkled skin, readily visible veins, mild impairment and/or speech delay,

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P8, F, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia),

CaseHPOFreeText: Proband was noted to have insulin resistance, thin, wrinkled skin, readily visible veins, frequent illnesses, normal mental development,

Proband was not evaluated for hyperextensibility of joints, teeth delay, hyperopia, astigmatism, myopia, esotropia, ovarian cysts, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have inguinal hernia, Rieger anomaly, mild impairment and/or speech delay.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1943dup (p.Arg649ProfsTer5).

ClinVar: 60764.

CAID: CA344800.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P9, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0004325 (Decreased body weight), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0000347 (Micrognathia),

CaseHPOFreeText: Proband was noted to have insulin resistance, normal mental development, mild impairment and/or speech delay,

Proband was not evaluated for height/length, occipitofrontal circumference, hyperextensibility of joints, teeth delay, hyperopia, astigmatism, myopia, esotropia, thin, wrinkled skin, readily visible veins, frequent illnesses, ovarian cysts, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have inguinal hernia, ocular depression, Rieger anomaly, Prominent forehead, Mild midface hypoplasia,

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1892G>A (p.Arg631Gln).

ClinVar: 126459.

CAID: CA347796.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: 15-year-old female, F, Age of Report: 15 y.o., Ethnicity: From China.

CasePresentingHPOs: HP:0001511 (Intrauterine growth retardation/Intrauterine growth restriction), HP:0004322 (Short stature), HP:0000684 (Delayed eruption of teeth/teething delay), HP:0000858 (Irregular menstruation/irregular menstrual cycle), HP:0001007 (Hirsutism), HP:0000820 (Abnormality of the thyroid gland/thyroid disease), HP:0005328 (Progeroid facial appearance/Progeroid facial appearance), HP:0000545 (Myopia), HP:0000678 (Dental crowding/overcrowded teeth), HP:0000855 (Insulin resistance)

CaseHPOFreeText: Proband was noted to have "characteristic facial gestalts/"characteristic facial dysmorphim", low weight at birth,

The proband was admitted to our department due to irregular menstrual cycle and hirsutism with short stature, who had a history of intrauterine growth restriction and presented with short stature, teething delay, characteristic facial gestalts, hirsutism, and thyroid disease. Whole-exome sequencing and Sanger sequencing revealed c.1960C > T, a novel de novo nonsense mutation, leading to the termination of protein translation (p. Gln654*).

This is the first case report of SHORT syndrome complicated with thyroid disease in China, identifying a novel de novo heterozygous nonsense mutation in PIK3R1 gene (p. Gln654*).

The phenotypes are mildly different from other cases previously described in the literature, in which our patient presents with lipoatrophy, facial feature, and first reported thyroid disease. Thyroid disease may be a new clinical symptom of patients with SHORT syndrome.

The patient was a girl born to a physically healthy and non-consanguineous couple by spontaneous delivery at the 37th week. Birth weight was 2150 g (− 3.39SD) and birth length was 44 cm (− 3.41SD), indicating that the patient had intrauterine growth restriction (IUGR). The proband also had teething delay, getting the first tooth at 1 year old. During childhood, the patient was bothered by short stature. Psychomotor and speech development was normal. The height of proband’s father and mother was 168 cm and 155 cm respectively. The patient also had a healthy 20-month-old brother.

At the age of 15 years and 4 months, the proband was referred to our department due to irregular menstrual cycle and hirsutism with a height of 149 cm (− 2.04SD), weight of 43 kg (− 1.22SD) and body mass index (BMI) of 19.4 kg/m2. The height of the proband had remained 149 cm, ever since 13 years old. Physical examination showed a triangular-shaped face, small chin, large low-set ears, thin lip, downturned mouth, obvious beard and bushy eyebrows (Fig. 1a,b,c,d). Oral examination showed overcrowded and irregular teeth, hypodontia, and severe dental caries (Fig. 1g). Pubertal development was assessed according to the Tanner stage, with pubic hair at PH5 stage and breast at B2 stage. The second phalanx of little finger in the left hand was short and thicken, which was confirmed with X-ray (Fig. 1e,f). Ultrasound of neck showed diffuse thyroid disease. Ultrasound biomicroscopy of the eyes, examination of ocular fundus, abdominal ultrasound, reproductive system ultrasound, and chest X-ray were normal. The cranial magnetic resonance imaging (MRI) indicated a small posterior pituitary.

Not evaluated on the proband: OFC at birth, thin, wrinkled skin with readily visible veins, inguinal hernia,

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have: Hyperextensibility of joints, ocular depression, Riegar anomaly, lipoatrophy, glaucoma, hyperopia, astigmatism, delayed bone age, intellectual deficiency, speech delay, diabetes, hearing loss, frequent infections, congenital heart diseases, pulmonary stenosis and ovarian cysts.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Whole-exome sequencing and Sanger sequencing.

Variant: NM_181523.3:c.1960C>T (p.Gln654Ter).

ClinVar: N/A.

CAID: CA359884699.

gnomAD: N/A.

VariantEvidence: A novel de novo heterozygous nonsense mutation in the PIK3R1 gene (p. Gln654*) was found in the proband.

WES was performed to make a clear clinical diagnose. The candidate variants were first screened by a minor allele frequency < 3% against the 1000 Genomes Project, the NHLBI exome variant server or in 50 HapMap control exomes. Then, short stature, facial abnormalities were selected as the filtering clinical symptoms to analyze the screened candidate variants. According to the guidelines recommended by the American College of Medical Genetics and Genomics, a pathogenic variant of PIK3R1 gene was identified to contribute to the patient’s conditions. Sequencing result indicated c.1960C > T of PIK3R1 gene a novel nonsense mutation, leading to the termination of protein translation (p. Gln654*), which was confirmed by sanger sequencing (Fig. 2). In addition, direct sequencing results showed the genotypes of proband’s parents were wild-type, suggesting it was a de novo mutation.

CaseAddInfo: The height of proband’s father and mother was 168 cm and 155 cm respectively. The patient also had a healthy 20-month-old brother.

CasePMIDs: N/A.

Case#: patient, M, Age of Report: newborn, Ethnicity: Korean.

CasePresentingHPOs: HP:0004322 (Short stature), HP:0004325 (Decreased body weight), HP:0040195 (Decreased head circumference), HP:0003074 (Hyperglycemia), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000490 (Deeply set eye/Ocular depression), HP:0009125 (Lipodystrophy), HP:0000023 (Inguinal hernia), HP:0001642 (Pulmonic stenosis), HP:0001684 (Secundum atrial septal defect/ASD secundum), HP:0000684 (Delayed eruption of teeth)

CaseHPOFreeText: To the best of our knowledge, this is the first case report of SHORT syndrome with TNDM.

The patient was a newborn male and the only child of a healthy non-consanguineous Korean couple with a non-contributory family history. The height of his father and mother was 170 cm (−0.70 SD score) and 160 cm (−0.04 SD score), respectively. They had no dysmorphic features. The mother had regular antenatal check-up and did not have any history of medical and obstetric problems during pregnancy. He was born at 38 weeks of gestation but displayed features of IUGR during pregnancy. His birth weight was 1.8 kg (<3rd percentile), length 44 cm (<3rd percentile), and head circumference 31 cm (<3rd percentile) according to the Korean reference for birth weight based on gestational age and sex. The initial blood glucose level was 70 mg/dl. The baby was exclusively breastfed starting on day 3 and was in generally good condition. However, blood glucose level was between 218 and 263 mg/dl at 5 day of age. At the age of 20 day, his blood glucose level was still high (205–260 mg/dl), and the infant was referred to the endocrine clinic for persistent hyperglycemia assessment. On physical examination, several dysmorphic features (triangular-shaped face, prominent forehead, ocular depression, lipodystrophy at the lumbar region) and inguinal hernia were present. The systolic and diastolic blood pressure measurements were 74 and 42 mmHg, respectively. The serum c-peptide and insulin levels were 2.83 ng/ml (normal: 1.0–3.5) and 120 μU/ml (normal: 2.8–13.5), respectively. Baseline chemistry including serum blood urea nitrogen was 15.3 mg/dl (normal: 7.0–20.0), creatinine 0.9 mg/dl (normal: 0.6–1.2), aspartate aminotransferase 38 U/L (normal: 14–40), and alanine aminotransferase 16 U/L (normal: 9–45), as well as complete blood count profile were within normal range. Urinalysis showed no glucose or ketones. There was no sign of ketoacidosis and the patient had no type 1 diabetes autoantibodies (antibodies against glutamic acid decarboxylase, islet cell, islet antigen-2, and insulin). The liver and pancreas ultrasonography revealed no structural abnormality. Echocardiography at the age of 1 month confirmed mild pulmonary stenosis and ASD secundum (2 mm) which did not require surgical intervention. Neonatal diabetes mellitus (NDM) was suspected on the basis of hyperglycemia occurring within the first month of life that lasted for >2 weeks and required insulin therapy. At age of 25 day, clinical exome sequencing was performed to identify the genetic cause of NDM.

To monitor the glycemic level, his blood glucose was measured at the beginning of each feeding session. The patient was treated with subcutaneous insulin, and blood glucose level gradually stabilized. The blood glucose levels ranged from 110–250 mg/dl during the next 10 days. An adequate glucose level was achieved at 6 weeks of age without insulin treatment. His body weight was 4.4 kg (<3rd percentile) and his length was 61.6 cm (<3rd percentile) at 10 months of age. The patient experienced no hyperglycemic episode and the glycated hemoglobin was 5.0% and insulin level 2.8 μU/ml. At 10 months of age, the patient had no teeth erupted in the oral cavity.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Urinalysis showed no glucose or ketones. There was no sign of ketoacidosis and the patient had no type 1 diabetes autoantibodies (antibodies against glutamic acid decarboxylase, islet cell, islet antigen-2, and insulin). The liver and pancreas ultrasonography revealed no structural abnormality.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: TruSight One sequencing panel and Sanger sequencing.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: Segregation analysis could not be performed due to the unavailability of parental samples.

CasePMIDs: N/A.

Case#: proband, M, Age of Report: 8 y.o., Ethnicity: British.

CasePresentingHPOs: HP:0008846 (Severe intrauterine growth retardation), HP:0004322 (Short stature), HP:0004325 (Decreased body weight), HP:0040195 (Decreased head circumference), HP:0001510 (Growth delay), HP:0011968 (Feeding difficulties/behavioral feeding difficulties), HP:0001263 (Global developmental delay/psychomotor development delay), HP:0000252 (Microcephaly), HP:0000684 (Delayed eruption of teeth/Dentition), HP:0100543 (Cognitive impairment/delayed intellectual development), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000582 (Upslanted palpebral fissure/upward-slanting palpebral fissures), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0100678 (Premature skin wrinkling/Thin, wrinkled skin), HP:0001187 (Hyperextensibility of the finger joints), HP:0010485 (Hyperextensibility at elbow), HP:0009125 (Lipodystrophy)

CaseHPOFreeText:The proband, 8 years of age, is the first child of non-consanguineous Caucasian parents. There are no manifestations of SHORT syndrome in the family. There is no family history of microcephaly or intellectual disability. Following an otherwise uneventful pregnancy, delivery was induced at 38 weeks of gestation on discovery of severe intrauterine growth restriction. His birth weight was 1.97 kg (<0.4th centile, −3.7 SD).

Despite adequate nutritional intake, the patient's growth was significantly delayed. At 12 months of age, his weight was 6.88 kg (<0.4th centile, −3.2 SD), length was 69.5 cm (1st centile, −2.98 SD) and head circumference was 39.5 cm (<0.4th centile, −5.26 SD). Enteral tube feeding was initiated at 9 months of age, which the patient continues to remain dependent on today. Despite extensive investigation of the proband's feeding disorder, no organic cause was identified, and he was diagnosed with behavioral feeding difficulties. Follow-up consultations revealed a persistent development delay and sustained striking microcephaly. Dentition did not start until the age of 2.5 years. At 6 years of age, his weight was 16.2 kg (1st centile, −2.39SD), length was 105.4 cm (1st centile, −2.47 SD) and head circumference was 43.8 cm (<0.4th centile, −6.16 SD). Skeletal survey and extensive endocrine investigation did not find any abnormalities. The patient has not been formally diagnosed with diabetes and is awaiting an oral glucose tolerance test.

Intellectual and psychomotor development is moderate to severely delayed. The patient first walked at 20 months, first smiled at 3 months and spoke his first words aged 3 years. At his current age of 8 years, he attends a special needs school and requires substantial multidisciplinary support. Magnetic resonance imaging of the brain and electroencephalogram performed at 12 months of age was normal. Neurometabolic investigation was also normal. Recurrent ophthalmology investigations revealed a myopic left eye and hypermetropic right eye at 4 years of age. No anterior chamber defects were noted and his ocular pressure was reported as normal. His hearing was formally assessed and reported as normal.

Facial dysmorphic features are subtle but present (see Figure 2): triangular face, prominent forehead, broad eyebrows, slight upward-slanting palpebral fissures, and hypoplastic alae nasi leading to an impression of low columnella nasi. The patient has thin, wrinkled skin with visible veins, most prominently seen on his chest wall. He has hyperextensibility in his finger and elbow joints. Of note, local lipodystrophy of his proximal finger phalanges is also observed.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Skeletal survey and extensive endocrine investigation did not find any abnormalities. The patient has not been formally diagnosed with diabetes and is awaiting an oral glucose tolerance test.

No anterior chamber defects were noted and his ocular pressure was reported as normal.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Chromosome breakage studies, Angelman methylation studies and a 60 gene developmental delay and epilepsy panel were normal. Comparative genomic hybridization microarray identified a likely benign maternally inherited Xp11.4 duplication (GRch X:38646145-38687854). Trio-exome sequencing revealed a de novo heterozygous missense variant, c.1456G>A (p.Ala486Thr) in PIK3R1 (NM_181523.3).

Variant: NM_181523.3:c.1456G>A (p.Ala486Thr).

ClinVar: N/A.

CAID: CA359881414.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo:N/A.

CasePMIDs: N/A.

Case#: 17-year-old female, F, Age of Report:17 y.o., Ethnicity: Cuban descent.

CasePresentingHPOs: HP:0001510 (Growth delay), HP:0004322 (Short stature), HP:0000696 (Delayed eruption of permanent teeth/secondary tooth eruption delay), HP:0000858 (Irregular menstruation/irregular menses), HP:0100607 (Dysmenorrhea), HP:0012384 (Rhinitis), HP:0002099 (Asthma), HP:0001025 (Urticaria), HP:0031796 (Recurrent), HP:0000403 (Recurrent otitis media), HP:0010606 (Hordeolum/hordeolums), HP:0031796 (Recurrent), HP:0012204 (Recurrent vulvovaginal candidiasis/vaginal candidiasis), HP:0032168 (Clostridium difficile colitis), HP:0004315 (Decreased circulating IgG concentration/low IgG levels), HP:0045082 (Decreased body mass index/low BMI), HP:0001382 (Joint hypermobility/hyperextensible joints), HP:0011220 (Prominent forehead), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0009765 (Low hanging columella), HP:0000219 (Thin upper lip vermilion/thin upper lip), HP:0007495 (Prematurely aged appearance/aged appearance), HP:0010976 (B lymphocytopenia/low absolute B cells), HP:0410376 (Increased proportion of naive CD8 T cells/elevated CD8 T cell),

CaseHPOFreeText: This is a 17-year-old female of Cuban descent, born to nonconsanguineous parents at 36 weeks gestational age to an uncomplicated pregnancy. Her birth weight and length were average for gestational age (7 pounds, 18 in.). She presented with a history of growth delay, short stature, and secondary tooth eruption delay. She measured below her growth curve at 1 year of age. She had growth hormone testing which resulted normal; however, she received growth hormone therapy from 3 to 10 years of age with a good response. At that time, she underwent genetic testing for short stature; however, no genetic causes of short stature were found. She has a history of irregular menses and dysmenorrhea with work-up for possible etiologies, including polycystic ovarian syndrome (PCOS), resulting negative. She has met all developmental milestones appropriately and has normal cognition.

She has nonallergic rhinitis, mild intermittent asthma, and acute recurrent urticaria. Her history of infections includes recurrent episodes of otitis media since she was toddler requiring placement of 3 sets of ear tubes and tonsillectomy and adenoidectomy. She has a history of recurrent hordeolums and frequent episodes of vaginal candidiasis attributed to the many courses of antibiotics she has received for her various infections. She had one episode of Clostridium difficile colitis 6 months prior to presentation to our clinic. Prior immunologic evaluation at a different institution at 9 years of age was remarkable for low IgG levels, which ranged from 435 to 511 mg/dL [ref 759–1549 mg/dL]. A skin prick test to aeroallergens resulted negative. She did not receive intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin therapy at that time.

Her physical exam was relevant for short stature (1 percentile, z = − 2.33), low weight for age (< 1 percentile, z = − 2.69), low BMI (15 percentile), and hyperextensible joints. Her facial features were significant for a prominent forehead, triangular face, low-hanging columella, thin upper lip, and aged appearance. Given concern for immune deficiency, a complete immune evaluation was obtained. Her results revealed hypogammaglobulinemia (IgG of 610 mg/dL [ref 694–1618 mg/dL]), with IgM and IgA within the reference range. The lymphocyte subset panel revealed remarkably low absolute B cells (34 cells/μL [ref 130–800 cells/μL]) and percentage (1% [ref 9–30%]). CD4 T cells were within the reference range, and CD8 T cell counts (1091 cells/μL [ref 240–890 cells/μL]) and percentage (40% [ref 17–36%]) were elevated. She had low CD4:CD8 ratio (0.84 [ref 1.00–2.90]). Follow-up B cell panel corroborated the finding of low absolute B cells (70 cells/μL [ref 100–500 cells/μL]) and revealed increased transitional B cells (6.6% CD19 + CD27-CD21-IgM+ [ref 0.5–2.8%]) and naïve B cells (5.9% CD19 + CD27-CD21-CD38- [ref 0.3–2.3%]). ImmunoCAP IgE to aeroallergens was negative, and total IgE was 2 kU/L [ref < 114 kU/L]. Vaccine boosters to S. pneumoniae, H. influenzae, diphtheria, and tetanus were given. Subsequent titers revealed protective antibodies to S. pneumoniae, H. influenzae, and diphtheria and absent response to tetanus. Her lymphocyte mitogen proliferation showed normal lymphocyte responses to phytohaemagglutinin, concanavalin A, and pokeweed mitogen. Viral testing was not performed. At this time, the decision was made to start amoxicillin prophylaxis and monthly IVIG replacement therapy.

After initiating treatment with IVIG, our patient did not have new episodes of ear or sinus infections. IgG levels have remained within normal limits with monthly IVIG therapy. Given the finding of a PIK3R1 pathogenic variant and its known associations with SHORT syndrome, she was referred to ophthalmology and endocrinology. Of note, she started complaining of frequent headaches, not associated with administration of IVIG. Brain and cervical spine MRI revealed a Chiari I malformation for which she is being evaluated by neurosurgery.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: She did not have protective titers to tetanus, diphtheria, pneumococcus, or influenzae.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Invitae primary immunodeficiency 207-gene panel was obtained.

Variant: NM_181523.3:c.1425+1G>C (n.336+1G>C).

ClinVar: 156009.

CAID: CA170736.

gnomAD: N/A.

VariantEvidence: Results revealed a heterozygous “pathogenic variant” in PIK3R1 (c.1425 + 1G > C) with an autosomal dominant mode of inheritance in association with APDS2. This variant is a missense point mutation affecting a donor splice site in intron 11, resulting in exclusion of exon 11 (Fig. 1). Her parents are not carriers of this pathogenic variant, indicating this is a de novo mutation.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Table S1 lists two additional INSR variants identified in the proband during whole exome sequencing:

1. NM_000208.3:c.*104A>G – a 3′ UTR variant, homozygous, annotated as benign in ClinVar (rs1051690).
2. NM_000208.3:c.2666G>A (p.Arg889Gln) – a heterozygous missense variant, classified as a variant of uncertain significance in ClinVar (rs187282966).

PMID: 40971032

Gene: PIK3R1 HGNC: 8979

Gene: PIK3CD HGNC: 8977

Case#: Female, age of onset: 56, age at testing: 69, age of last documented clinical stability: 74

DiseaseAssertion: suspected hyperactivation of the PI3K pathway; implied earlier in the paper as "activated PI3Kδ syndrome (APDS)"

FamilyInfo: no relevant family history

CasePresentingHPOs: HP:0001878, HP:0012735, HP:0000975, HP:0002716, HP:0012387, HP:0001744, HP:6000143, HP:0004313, HP:0002721, HP:0006530, HP:0002788 (hemolytic anemia, cough, diaphoresis, lymphadenopathy, bronchitis, splenomegaly, perforated appendicitis, hypogammaglobulinemia, immunodeficiency, interstitial lung disease, recurrent upper respiratory tract infections)

CaseHPOFreeText: asthenia, sarcoidosis due to chronic granulomatous sarcoid-type inflammation without necrosis, bronchiectasis with bronchiolitis, wound infection, abdominal wall dehiscence, common variable immunodeficiency (CVID) with immune dysregulation, CVID-associated interstitial lung disease, granulomatous-lymphocytic interstitial lung disease

CaseNotHPOs: HP:0012759 (neurodevelopmental abnormalities)

CaseNotHPOFreeText: dysmorphic features, learning difficulties

CasePreviousTesting: clinical exome sequencing targeting genes associated with primary immunodeficiencies

GenotypingMethod: sequencing

PreviouslyPublished: No prior article is known to contain information on the same proband.

Variant: NM_181504.3(PIK3R1):c.5A > T (p.Tyr2Phe)

ClinVar: not found

CAID:CA3290217

gnomAD: 0.3004% https://gnomad.broadinstitute.org/variant/5-67586561-A-T?dataset=gnomad_r2_1

SupplementalData: There is no supplemental data, clinical timeline and schematic with noted variants are in Figure 2 and Figure 3

PMID: 40420664

GENE: PIK3R1

HGNC: 8979

Case#: 10-month‐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: Her father has SHORT syndrome, with the same variant of PIK3R1, NM_181523.3:c.1957A>T, further described in Case 4. Her paternal grandmother "also manifests some facial characteristics of SHORT syndrome as well as a hearing impairment."

CasePresentingHPOs: HP:0001511, HP:0011220, HP:0000325, HP:0000430, HP:0004322, HP:0000490, HP:0000684, HP:0000331, HP:0000963, HP:0007392

CaseHPOFreeText: Born at 37 weeks of gestation with a birth length of 40.0 cm (−2.9 SD relative to the average for this gestational age) and birth weight of 1,676 g (−3.1 SD relative to the average for this gestational age) (Table 1). Her height and weight were 60.3 cm (−4.0 SD relative to the average for her age) and 4.01 kg (−7.6 SD relative to the average for her age), respectively, at the time of evaluation for the present study. Her fasting plasma glucose, serum IRI concentrations, and serum C‐peptide were 83 mg/dL, 2.6 μIU/mL, and 1.34 ng/mL, respectively, with an HbA1c level of 4.6%. Her HOMA‐IR was 0.53, and her HOMA‐β was 46.8%.

CaseNotHPOs: HP:0000819, HP:0000855, HP:0001382, HP:0000023, HP:0000558, HP:0000400, HP:0000369, HP:0000233, HP:0002714, HP:0005328, HP:0000540, HP:0000483, HP:0000545, HP:0000593, HP:0000501, HP:0100578, HP:0001249, HP:0000750, HP:0000365

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.1957A>T

ClinVar: 3767319

gnomAD: NR

SupplementalData: Table 1, Figure 1c,d

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 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: His daughter has SHORT syndrome, with the same variant of PIK3R1, NM_181523.3:c.1957A>T, further described in Case 3. His mother also manifests some facial characteristics of SHORT syndrome as well as a hearing impairment.

CasePresentingHPOs: HP:0008619, HP:0000365, HP:0000501, HP:0000819, HP:0001511, HP:0004322, HP:0000023, HP:0000490, HP:0000558, HP:0000325, HP:0011220, HP:0000430, HP:0000331, HP:0000400, HP:0005328, HP:0100578

CaseHPOFreeText: He was born at 36 weeks of gestation with a birth weight of 1,970 g. Weight at time of diagnosis was 44.2 kg (-2.4 SD), height 154 cm (-3.00SD) , body mass index 18.6 kg/m2 (-1.5 SD). He had been treated with a DPP‐IV (dipeptidyl peptidase‐IV) inhibitor and an SGLT2 inhibitor and manifesting an HbA1c level of 7.4% at the time of the current evaluation. His blood glucose and serum IRI levels at baseline and at 30, 60, 90, and 120 min after the glucose load were 130, 220, 238, 243, and 252 mg/dL and 8.0, 15.5, 25.6, 27.1, and 24.6 μIU/mL, respectively. His HOMA‐IR, HOMA‐β, and insulinogenic index were 2.57, 43.0%, and 0.083, respectively.

CaseNotHPOs: HP:0000855, HP:0001382, HP:0000684, HP:0000369, HP:0000233, HP:0002714, HP:0000540, HP:0000483, HP:0000545, HP:0000593, HP:0000963, HP:0007392, HP:0001249, HP:0000750

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.1957A>T

ClinVar: 3767319

gnomAD: NR

SupplementalData: Table 1, Figure 1e,f

PMID: 40860302

Interesting SHORT syndrome article requiring annotation.

PMID: 39735640

Gene: PIK3R1

HGNC: 8979

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

Case#: male, onset at or before age 12 months, ethnicity not specified DiseaseAssertion: Patient is asserted to have both "SHORT syndrome" and "X-linked agammaglobulinemia (XLA)" due to "absence of peripheral B cells" and "features of SHORT syndrome such as hyperextensibility, vision abnormalities, lack of fat tissue, triangular face, extroverted ears, ocular depression, [and] developmental and teething delay" CasePresentingHPOs: HP:0000974 (Hyperextensible skin), HP:0000504 (Abnormality of vision), HP:0005320 (Lack of facial subcutaneous fat), HP:0000325 (Triangular face), HP:0000430 (Underdeveloped nasal alae), HP:0000490 (Deeply set eye), HP:0000750 (Delayed speech and language development), HP:0002719 (Recurrent infections), HP:0030084 (Clinodactyly), HP:0045075 (Sparse eyebrow), HP:0000540 (Hypermetropia), HP:0000696 (Delayed eruption of permanent teeth) CaseHPOFreeText: A current 9 year old was diagnosed with XLA with SHORT at age 15 months after presenting with skin lesions, scrotal swelling and ulcers along with recurring upper and lower tract infections after 6 months of age. Evaluations for immunodeficiencies were performed. Basic immunoglobulin levels and lymphocyte subsets were measured, which suggested an XLA diagnosis. Delays in developmental milestones observed by the mother and physical examination suggested SHORT syndrome. CaseNotHPOs: HP:0000558 (Rieger anomaly), HP:0000364 (Hearing abnormality) GenotypingMethod: Genotyping was performed by whole exome sequencing, whivh revealed a novel pathogenic homozygous frameshift mutation in the PIK3R1 gene. PreviouslyPublished: No prior article is known to contain information on the same proband. Variant: The patient harbors NM_181523.3:c.244dup(p.(lle82Asnfs24) chr5:67522740) variant in the homozygous state. ClinVar: This variant was not found in ClinVar CAID: This variant was not found in the ClinGen Allele Registry. gnomAD:* The variant was not found in gnomAD v4.1.0.

PMID: 39044864 Gene: PIK3R1 HGNC: 8979