Fanconi-Bickel syndrome complicated by nephrocalcinosis and GFR decline.

Fanconi-Bickel syndrome (FBS) is a rare genetic disorder of carbohydrate metabolism due to pathogenic variants in SLC2A2, a gene encoding glucose transporter 2 (GLUT2), which leads to accumulation of glycogen in the kidney and liver. While consequential complex proximal tubular dysfunction is well acknowledged in the literature, long-term trajectories of kidney function in patients with FBS have not been well characterized, and kidney biopsy is performed infrequently. Here, we report on a patient with FBS followed from infancy through young adulthood who presented early on with hypercalciuria, phosphaturia, and hypophosphatemia, complicated by chronic kidney disease development during childhood. Kidney biopsy, in addition to a widespread glycogen accumulation in proximal tubular epithelial cells, demonstrated medullary nephrocalcinosis. Screening for nephrocalcinosis may be warranted in pediatric patients with FBS, along with close surveillance of their kidney function.

Clinical features and genetic analysis of 15 Chinese children with dent disease.

OBJECTIVE:  The clinical characteristics, genetic mutation spectrum, treatment strategies and prognoses of 15 children with Dent disease were retrospectively analyzed to improve pediatricians' awareness of and attention to this disease. METHODS:  We analyzed the clinical and laboratory data of 15 Chinese children with Dent disease who were diagnosed and treated at our hospital between January 2017 and May 2023 and evaluated the expression of the CLCN5 and OCRL1 genes. RESULTS:  All 15 patients were male and complained of proteinuria, and the incidence of low-molecular-weight proteinuria (LMWP) was 100.0% in both Dent disease 1 (DD1) and Dent disease 2 (DD2) patients. The incidence of hypercalciuria was 58.3% (7/12) and 66.7% (2/3) in DD1 and DD2 patients, respectively. Nephrocalcinosis and nephrolithiasis were found in 16.7% (2/12) and 8.3% (1/12) of DD1 patients, respectively. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) in 1 patient, minimal change lesion in 5 patients, and small focal acute tubular injury in 1 patient. A total of 11 mutations in the CLCN5 gene were detected, including 3 missense mutations (25.0%, c.1756C > T, c.1166T > G, and c.1618G > A), 5 frameshift mutations (41.7%, c.407delT, c.1702_c.1703insC, c.137delC, c.665_666delGGinsC, and c.2200delG), and 3 nonsense mutations (25.0%, c.776G > A, c.1609C > T, and c.1152G > A). There was no significant difference in age or clinical phenotype among patients with different mutation types (p > 0.05). All three mutations in the OCRL1 gene were missense mutations (c.1477C > T, c.952C > T, and c.198A > G). CONCLUSION:  Pediatric Dent disease is often misdiagnosed. Protein electrophoresis and genetic testing can help to provide an early and correct diagnosis.

Four-month-old with severe PIK3CA-related overgrowth spectrum disorder successfully treated with alpelisb.

PIK3CA-related overgrowth spectrum (PROS) encompasses different clinical entities caused by somatic activating mutations in PIK3CA. Among PROS, CLOVES syndrome represents a severe phenotype with poor survival rate. We present the case of a 4-month-old girl with CLOVES syndrome successfully treated with alpelisib, a PIKC3A inhibitor.

Disease Manifestations and Complications in Dutch X-Linked Hypophosphatemia Patients.

X-linked hypophosphatemia (XLH) is the most common monogenetic cause of chronic hypophosphatemia, characterized by rickets and osteomalacia. Disease manifestations and treatment of XLH patients in the Netherlands are currently unknown. Characteristics of XLH patients participating in the Dutch observational registry for genetic hypophosphatemia and acquired renal phosphate wasting were analyzed. Eighty XLH patients, including 29 children, were included. Genetic testing, performed in 78.8% of patients, showed a PHEX mutation in 96.8%. Median (range) Z-score for height was - 2.5 (- 5.5; 1.0) in adults and - 1.4 (- 3.7; 1.0) in children. Many patients were overweight or obese: 64.3% of adults and 37.0% of children. All children received XLH-related medication e.g., active vitamin D, phosphate supplementation or burosumab, while 8 adults used no medication. Lower age at start of XLH-related treatment was associated with higher height at inclusion. Hearing loss was reported in 6.9% of children and 31.4% of adults. Knee deformities were observed in 75.0% of all patients and osteoarthritis in 51.0% of adult patients. Nephrocalcinosis was observed in 62.1% of children and 33.3% of adults. Earlier start of XLH-related treatment was associated with higher risk of nephrocalcinosis and detection at younger age. Hyperparathyroidism longer than six months was reported in 37.9% of children and 35.3% of adults. This nationwide study confirms the high prevalence of adiposity, hearing loss, bone deformities, osteoarthritis, nephrocalcinosis and hyperparathyroidism in Dutch XLH patients. Early start of XLH-related treatment appears to be beneficial for longitudinal growth but may increase development of nephrocalcinosis.

Research progress on renal calculus associate with inborn error of metabolism. / é—ä¼ æ€§ä»£è°¢ç¼ºé™·æ‰€è‡´è‚¾ç»“çŸ³ç ”ç©¶è¿›å±•.

Renal calculus is a common disease with complex etiology and high recurrence rate. Recent studies have revealed that gene mutations may lead to metabolic defects which are associated with the formation of renal calculus, and single gene mutation is involved in relative high proportion of renal calculus. Gene mutations cause changes in enzyme function, metabolic pathway, ion transport, and receptor sensitivity, causing defects in oxalic acid metabolism, cystine metabolism, calcium ion metabolism, or purine metabolism, which may lead to the formation of renal calculus. The hereditary conditions associated with renal calculus include primary hyperoxaluria, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, Bartter syndrome, primary distal renal tubular acidosis, infant hypercalcemia, hereditary hypophosphatemic rickets with hypercalciuria, adenine phosphoribosyltransferase deficiency, hypoxanthine-guanine phosphoribosyltransferase deficiency, and hereditary xanthinuria. This article reviews the research progress on renal calculus associated with inborn error of metabolism, to provide reference for early screening, diagnosis, treatment, prevention and recurrence of renal calculus.

FAM20A mutations and transcriptome analyses of dental pulp tissues of enamel renal syndrome.

AIM: Biallelic loss-of-function FAM20A mutations cause amelogenesis imperfecta (AI) type IG, better known as enamel renal syndrome (ERS), characterized by severe enamel hypoplasia, delayed/failed tooth eruption, intrapulpal calcifications, gingival hyperplasia and nephrocalcinosis. FAM20A binds to FAM20C, the Golgi casein kinase (GCK) and potentiates its function to phosphorylate secreted proteins critical for biomineralization. While many FAM20A pathogenic mutations have been reported, the pathogeneses of orodental anomalies in ERS remain to be elucidated. This study aimed to identify disease-causing mutations for patients with ERS phenotypes and to discern the molecular mechanism underlying ERS intrapulpal calcifications. METHODOLOGY: Phenotypic characterization and whole exome analyses were conducted for 8 families and 2 sporadic cases with hypoplastic AI. A minigene assay was performed to investigate the molecular consequences of a FAM20A splice-site variant. RNA sequencing followed by transcription profiling and gene ontology (GO) analyses were carried out for dental pulp tissues of ERS and the control. RESULTS: Biallelic FAM20A mutations were demonstrated for each affected individual, including 7 novel pathogenic variants: c.590-5T>A, c.625T>A (p.Cys209Ser), c.771del (p.Gln258Argfs*28), c.832_835delinsTGTCCGACGGTGTCCGACGGTGTC CA (p.Val278Cysfs*29), c.1232G>A (p.Arg411Gln), c.1297A>G (p.Arg433Gly) and c.1351del (p.Gln451Serfs*4). The c.590-5T>A splice-site mutation caused Exon 3 skipping, which resulted in an in-frame deletion of a unique region of the FAM20A protein, p.(Asp197_Ile214delinsVal). Analyses of differentially expressed genes in ERS pulp tissues demonstrated that genes involved in biomineralization, particularly dentinogenesis, were significantly upregulated, such as DSPP, MMP9, MMP20 and WNT10A. Enrichment analyses indicated overrepresentation of gene sets associated with BMP and SMAD signalling pathways. In contrast, GO terms related to inflammation and axon development were underrepresented. Among BMP signalling genes, BMP agonists GDF7, GDF15, BMP3, BMP8A, BMP8B, BMP4 and BMP6 were upregulated, while BMP antagonists GREM1, BMPER and VWC2 showed decreased expression in ERS dental pulp tissues. CONCLUSIONS: Upregulation of BMP signalling underlies intrapulpal calcifications in ERS. FAM20A plays an essential role in pulp tissue homeostasis and prevention of ectopic mineralization in soft tissues. This critical function probably depends upon MGP (matrix Gla protein), a potent mineralization inhibitor that must be properly phosphorylated by FAM20A-FAM20C kinase complex.

Clinical Spectrum of Hereditary Hypophosphatemic Rickets With Hypercalciuria (HHRH).

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) represents an FGF23-independent disease caused by biallelic variants in the solute carrier family 34-member 3 (SLC34A3) gene. HHRH is characterized by chronic hypophosphatemia and an increased risk for nephrocalcinosis and rickets/osteomalacia, muscular weakness, and secondary limb deformity. Biochemical changes, but no relevant skeletal changes, have been reported for heterozygous SLC34A3 carriers. Therefore, we assessed the characteristics of individuals with biallelic and monoallelic SLC34A3 variants. In 8 index patients and 5 family members, genetic analysis was performed using a custom gene panel. The skeletal assessment comprised biochemical parameters, areal bone mineral density (aBMD), and bone microarchitecture. Pathogenic SLC34A3 variants were revealed in 7 of 13 individuals (2 homozygous, 5 heterozygous), whereas 3 of 13 carried monoallelic variants of unknown significance. Whereas both homozygous individuals had nephrocalcinosis, only one displayed a skeletal phenotype consistent with HHRH. Reduced to low-normal phosphate levels, decreased tubular reabsorption of phosphate (TRP), and high-normal to elevated values of 1,25-OH2 -D3 accompanied by normal cFGF23 levels were revealed independently of mutational status. Interestingly, individuals with nephrocalcinosis showed significantly increased calcium excretion and 1,25-OH2 -D3 levels but normal phosphate reabsorption. Furthermore, aBMD Z-score <-2.0 was revealed in 4 of 8 heterozygous carriers, and HR-pQCT analysis showed a moderate decrease in structural parameters. Our findings highlight the clinical relevance also of monoallelic SLC34A3 variants, including their potential skeletal impairment. Calcium excretion and 1,25-OH2 -D3 levels, but not TRP, were associated with nephrocalcinosis. Future studies should investigate the effects of distinct SLC34A3 variants and optimize treatment and monitoring regimens to prevent nephrocalcinosis and skeletal deterioration. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Dent-2 disease with a Bartter-like phenotype caused by the Asp631Glu mutation in the OCRL gene.

BACKGROUND: Dent disease is an X-linked disorder characterized by low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis and chronic kidney disease (CKD). It is caused by mutations in the chloride voltage-gated channel 5 (CLCN5) gene (Dent disease-1), or in the OCRL gene (Dent disease-2). It is associated with chronic metabolic acidosis; however metabolic alkalosis has rarely been reported. CASE PRESENTATION: We present a family with Dent-2 disease and a Bartter-like phenotype. The main clinical problems observed in the proband included a) primary phosphaturia leading to osteomalacia and stunted growth; b) elevated serum calcitriol levels, leading to hypercalcemia, hypercalciuria, nephrolithiasis and nephrocalcinosis; c) severe salt wasting causing hypotension, hyperaldosteronism, hypokalemia and metabolic alkalosis; d) partial nephrogenic diabetes insipidus attributed to hypercalcemia, hypokalemia and nephrocalcinosis; e) albuminuria, LMWP. Phosphorous repletion resulted in abrupt cessation of hypercalciuria and significant improvement of hypophosphatemia, physical stamina and bone histology. Years later, he presented progressive CKD with nephrotic range proteinuria attributed to focal segmental glomerulosclerosis (FSGS). Targeted genetic analysis for several phosphaturic diseases was unsuccessful. Whole Exome Sequencing (WES) revealed a c.1893C > A variant (Asp631Glu) in the OCRL gene which was co-segregated with the disease in male family members. CONCLUSIONS: We present the clinical characteristics of the Asp631Glu mutation in the OCRL gene, presenting as Dent-2 disease with Bartter-like features. Phosphorous repletion resulted in significant improvement of all clinical features except for progressive CKD. Angiotensin blockade improved proteinuria and stabilized kidney function for several years.

SHORT syndrome in an adult Brazilian patient.

We report an individual from Brazil with SHORT syndrome. The term SHORT stands for its common characteristics: short stature (S), hyperextensibility of joints, and/or inguinal hernia (H), ocular depression (O), Rieger anomaly (R), and teething delay (T). In addition to most of the clinical signs previously described in SHORT syndrome, the patient presented here also shows microcephaly and intellectual disability. Diagnosis was confirmed by exome sequencing revealing a novel heterozygous variant c.1456G>A (p.Ala486Thr) at PIK3R1. Human recombinant growth hormone (r-hGH) therapy was administered prior to diagnosis; however, the use of r-hGH may have had a role in anticipating and worsening the glucose metabolic profile in the patient, as previously described. This article contributes to providing a better understanding of the SHORT syndrome genotype and its correlation with the phenotype, by comparing with it other reported cases.

The emerging roles and therapeutic potential of cyclin M/CorC family of Mg2+ transporters.

Cyclin M (CNNM) and its prokaryotic ortholog CorC belong to a family of proteins that function as Mg2+-extruding transporters by stimulating Na+/Mg2+ exchange, and thereby control intracellular Mg2+ levels. The Mg2+-extruding function of CNNM is inhibited by the direct binding of an oncogenic protein, phosphatase of regenerating liver (PRL), and this inhibition is responsible for the PRL-driven malignant progression of cancers. Studies with mouse strains deficient for the CNNM gene family revealed the importance of CNNM4 and CNNM2 in maintaining organismal Mg2+ homeostasis by participating in intestinal Mg2+ absorption and renal reabsorption, respectively. Moreover, CNNM proteins are involved in various diseases, and gene mutations in CNNM2 and CNNM4 cause dominant familial hypomagnesemia and Jalili syndrome, respectively. Genome wide association studies have also revealed the importance of CNNM2 in multiple major diseases, such as hypertension and schizophrenia. Collectively, the molecular and biological characterizations of CNNM/CorC show that they are an intriguing therapeutic target; the current status of drug development targeting these proteins is also discussed.

Pathogenesis of Enamel-Renal Syndrome Associated Gingival Fibromatosis: A Proteomic Approach.

The enamel renal syndrome (ERS) is a rare disorder featured by amelogenesis imperfecta, gingival fibromatosis and nephrocalcinosis. ERS is caused by bi-allelic mutations in the secretory pathway pseudokinase FAM20A. How mutations in FAM20A may modify the gingival connective tissue homeostasis and cause fibromatosis is currently unknown. We here analyzed conditioned media of gingival fibroblasts (GFs) obtained from four unrelated ERS patients carrying distinct mutations and control subjects. Secretomic analysis identified 109 dysregulated proteins whose abundance had increased (69 proteins) or decreased (40 proteins) at least 1.5-fold compared to control GFs. Proteins over-represented were mainly involved in extracellular matrix organization, collagen fibril assembly, and biomineralization whereas those under-represented were extracellular matrix-associated proteins. More specifically, transforming growth factor-beta 2, a member of the TGFß family involved in both mineralization and fibrosis was strongly increased in samples from GFs of ERS patients and so were various known targets of the TGFß signaling pathway including Collagens, Matrix metallopeptidase 2 and Fibronectin. For the over-expressed proteins quantitative RT-PCR analysis showed increased transcript levels, suggesting increased synthesis and this was further confirmed at the tissue level. Additional immunohistochemical and western blot analyses showed activation and nuclear localization of the classical TGFß effector phospho-Smad3 in both ERS gingival tissue and ERS GFs. Exposure of the mutant cells to TGFB1 further upregulated the expression of TGFß targets suggesting that this pathway could be a central player in the pathogenesis of the ERS gingival fibromatosis. In conclusion our data strongly suggest that TGFß -induced modifications of the extracellular matrix contribute to the pathogenesis of ERS. To our knowledge this is the first proteomic-based analysis of FAM20A-associated modifications.

Novel PIK3R1 mutation of SHORT syndrome: A case report with a 6-month follow up.

SHORT syndrome (short stature, hyperextensibility, ocular depression [deeply set eyes], Rieger anomaly and teething delay) is very rare, with a few cases reported in the literature. We report a case of SHORT syndrome with a novel PIK3R1 mutation (c.2008delT) and complicated with severe insulin resistance. Although no treatment guidelines are available to relieve insulin resistance in SHORT syndrome, our treatment plans, including lifestyle intervention combined with metformin and pioglitazone, were carried out for this patient. After the intervention, insulin resistance and hyperinsulinemia in this patient were significantly decreased during a 6-month follow up, which showed the effect of our therapeutic strategies.

Impaired Distal Tubular Acidification, Renal Cysts and Nephrocalcinosis in Monogenic Hypertension.

Monogenic defects in tubular sodium handling contribute a small proportion to hypertension in childhood. Presentation varies from severe hypertension manifesting at birth to asymptomatic hypertension and hypokalemic metabolic alkalosis detected incidentally in adulthood. A 12-y-old girl presenting with polyuria, polydipsia, severe hypertension and seizures, was found to have hypokalemia, renal medullary cysts and nephrocalcinosis. Clinical exome revealed a homozygous variation of unknown significance in exon 5 of the HSD11B2 gene, indicating the diagnosis of apparent mineralocorticoid excess. Therapy with spironolactone was associated with resolution of hypokalemia and normal blood pressure during two-year follow up.

A novel PIK3R1 mutation of SHORT syndrome in a Chinese female with diffuse thyroid disease: a case report and review of literature.

BACKGROUND: SHORT syndrome is a rare genetic disease named with the acronyms of short stature, hyper-extensibility of joints, ocular depression, Rieger anomaly and teething delay. It is inherited in an autosomal dominant manner confirmed by the identification of heterozygous mutations in PIK3R1. This study hereby presents a 15-year-old female with intrauterine growth restriction, short stature, teething delay, characteristic facial gestalts who was identified a novel de novo nonsense mutation in PIK3R1. CASE PRESENTATION: 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*). CONCLUSIONS: 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.

Two new families with enamel renal syndrome: A novel FAM20A gene mutation and review of literature.

Enamel renal syndrome (ERS) or so-called amelogenesis imperfecta type IG is a very rare disorder characterized by the triad of amelogenesis imperfecta, gingival enlargement and nephrocalcinosis. It is caused by biallelic mutations in the FAM20A gene. Herein, we report two unrelated patients with ERS. Our patients presented with the characteristic features of the syndrome, and amelogenesis imperfecta and gingival hyperplasia were the main complaint. Strikingly, they both had long face, thick lips, notched upper central incisors, and thick alveolar ridge which have never been reported before in patients with ERS. Gingival biopsy showed psammomatous calcifications, and renal ultrasound revealed bilateral nephrocalcinosis in the two patients. Mutational analysis of the FAM20A gene identified two homozygous mutations including a novel one (c.915_918delCTTT, p.Phe305Leufs*76 and c.1219 + 3_1219+6delAGGT). Our data expand the phenotypic and mutational spectrum of FAM20A gene and reinforce the importance of kidney examination and follow up for all patients with amelogenesis imperfecta unless FAM20A mutations were ruled out.

APDS2 and SHORT Syndrome in a Teenager with PIK3R1 Pathogenic Variant.

Activated PI3K δ syndrome (APDS) is a primary immunodeficiency caused by heterogeneous germline gain-of-function mutations which ultimately lead to the hyperactivation of the phosphoinositide-3-kinase δ (PI3K δ). PI3K δ exists as a heterodimer composed of a catalytic and a regulatory subunit. APDS type 2 is caused by mutations in the PIK3R1 gene affecting the p85α regulatory subunit. SHORT syndrome is a rare multisystem disorder characterized by short stature, hyperextensible joints, ocular depression, Rieger anomaly, and tooth eruption delay. The primary causes of SHORT syndrome are heterozygous loss-of-function mutations in the PIK3R1 gene. The combination of APDS2 and SHORT syndrome is rare, with few cases reported to date. Here we describe a 17-year-old female with phenotypic features consistent with SHORT syndrome and history of sinopulmonary infections and hypogammaglobulinemia. Invitae immunodeficiency panel genetic testing revealed a pathogenic loss-of-function variant in an intronic splice site in the gene PIK3R1 (c.1425 + 1G > C). This pathogenic variant had been previously associated with APDS2; however, it had not been associated with SHORT syndrome. The exact mechanisms linking both conditions are yet to be identified. This case report emphasizes the importance of screening for comorbidities associated with SHORT syndrome in APDS2 patients and vice versa.

SHORT syndrome in two Chinese girls: A case report and review of the literature.

BACKGROUND: SHORT syndrome is a rare inherited multisystem disease that includes characteristic facial features, growth retardation, and metabolic anomalies and is related to heterozygous mutations in the PIK3R1 gene. However, it is difficult to ascertain the relationship between the phenotype and the genotype quickly and efficiently. METHODS: We report two Chinese girls with SHORT syndrome who presented with growth retardation, dysmorphic features, insulin resistance, and diabetes. Comprehensive medical evaluations were collected, including anthropometric measurements, laboratory measurements, and imaging examinations. Whole exome and Sanger sequencing was performed to detect and confirm the underlying genetic mutations in these patients. We prescribed metformin for the patients. RESULTS: The patients both presented diabetes, insulin resistance, short stature, lipodystrophy, and characteristic facial dysmorphic features. A heterozygous mutation was detected in the PIK3R1 gene (c.1615_1617del) of Patient 1. The analysis of patient 2 revealed another PIK3R1 mutation (c.1945C>T). After family validation, neither their parents nor their brothers had similar clinical presentations or carried the same mutation. CONCLUSION: We identified two de novo heterozygous mutations in PIK3R1 as the cause of SHORT syndrome in two Chinese girls. Additionally, in terms of diabetes control, metformin works well in the early treatment stage.

Contribution of gene mutations to Silver-Russell syndrome phenotype: multigene sequencing analysis in 92 etiology-unknown patients.

BACKGROUND: Silver-Russell syndrome (SRS) is characterized by growth failure and dysmorphic features. Major (epi)genetic causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). However, IGF2, CDKN1C, HMGA2, and PLAG1 mutations infrequently cause SRS. In addition, other imprinting disturbances, pathogenic copy number variations (PCNVs), and monogenic disorders sometimes lead to SRS phenotype. This study aimed to clarify the frequency and clinical features of the patients with gene mutations among etiology-unknown patients with SRS phenotype. RESULTS: Multigene sequencing was performed in 92 out of 336 patients referred to us for genetic testing for SRS. The clinical features of the patients were evaluated based on the Netchine-Harbison clinical scoring system. None of the patients showed 11p15 LOM, upd(7)mat, abnormal methylation levels for six differentially methylated regions (DMRs), namely, PLAGL1:alt-TSS-DMR on chromosome 6, KCNQ1OT1:TSS-DMR on chromosome 11, MEG3/DLK1:IG-DMR on chromosome 14, MEG3:TSS-DMR on chromosome 14, SNURF:TSS-DMR on chromosome 15, and GNAS A/B:TSS-DMR on chromosome 20, PCNVs, or maternal uniparental disomy of chromosome 16. Using next-generation sequencing and Sanger sequencing, we screened four SRS-causative genes and 406 genes related to growth failure and/or skeletal dysplasia. We identified four pathogenic or likely pathogenic variants in responsible genes for SRS (4.3%: IGF2 in two patients, CDKN1C, and PLAG1), and five pathogenic variants in causative genes for known genetic syndromes presenting with growth failure (5.4%: IGF1R abnormality (IGF1R), SHORT syndrome (PIK3R1), Floating-Harbor syndrome (SRCAP), Pitt-Hopkins syndrome (TCF4), and Noonan syndrome (PTPN11)). Functional analysis indicated the pathogenicity of the CDKN1C variant. The variants we detected in CDKN1C and PLAG1 were the second and third variants leading to SRS, respectively. Our patients with CDKN1C and PLAG1 variants showed similar phenotypes to previously reported patients. Furthermore, our data confirmed IGF1R abnormality, SHORT syndrome, and Floating-Harbor syndrome are differential diagnoses of SRS because of the shared phenotypes among these syndromes and SRS. On the other hand, the patients with pathogenic variants in causative genes for Pitt-Hopkins syndrome and Noonan syndrome were atypical of these syndromes and showed partial clinical features of SRS. CONCLUSIONS: We identified nine patients (9.8%) with pathogenic or likely pathogenic variants out of 92 etiology-unknown patients with SRS phenotype. This study expands the molecular spectrum of SRS phenotype.

Truncation of Pik3r1 causes severe insulin resistance uncoupled from obesity and dyslipidaemia by increased energy expenditure.

OBJECTIVE: Insulin signalling via phosphoinositide 3-kinase (PI3K) requires PIK3R1-encoded regulatory subunits. C-terminal PIK3R1 mutations cause SHORT syndrome, as well as lipodystrophy and insulin resistance (IR), surprisingly without fatty liver or metabolic dyslipidaemia. We sought to investigate this discordance. METHODS: The human pathogenic Pik3r1 Y657∗ mutation was knocked into mice by homologous recombination. Growth, body composition, bioenergetic and metabolic profiles were investigated on chow and high-fat diet (HFD). We examined adipose and liver histology, and assessed liver responses to fasting and refeeding transcriptomically. RESULTS: Like humans with SHORT syndrome, Pik3r1WT/Y657∗ mice were small with severe IR, and adipose expansion on HFD was markedly reduced. Also as in humans, plasma lipid concentrations were low, and insulin-stimulated hepatic lipogenesis was not increased despite hyperinsulinemia. At odds with lipodystrophy, however, no adipocyte hypertrophy nor adipose inflammation was found. Liver lipogenic gene expression was not significantly altered, and unbiased transcriptomics showed only minor changes, including evidence of reduced endoplasmic reticulum stress in the fed state and diminished Rictor-dependent transcription on fasting. Increased energy expenditure, which was not explained by hyperglycaemia nor intestinal malabsorption, provided an alternative explanation for the uncoupling of IR from dyslipidaemia. CONCLUSIONS: Pik3r1 dysfunction in mice phenocopies the IR and reduced adiposity without lipotoxicity of human SHORT syndrome. Decreased adiposity may not reflect bona fide lipodystrophy, but rather, increased energy expenditure, and we suggest that further study of brown adipose tissue in both humans and mice is warranted.