SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling.

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.

Linear growth of children with X-linked hypophosphatemia treated with burosumab: a real-life observational study.

To assess the long-term efficacy of burosumab for pediatric patients with X-linked hypophosphatemia, focusing on linear growth. This multi-center retrospective study included 35 pediatric patients who began treatment with burosumab between January 2018 and January 2021. We collected clinical data, anthropometric measurements, laboratory results, and Rickets Severity Score (RSS), from 2 years prior to treatment initiation and up to 4 years after. Burosumab was initiated at a mean age of 7.5 ± 4.4 years (range 0.6-15.9), with a mean initial dose of 0.8 ± 0.3 mg/kg, which was subsequently increased to 1.1 ± 0.4 mg/kg. The patients were followed for 2.9 ± 1.4 years (range 1-4) after initiating burosumab. Serum phosphorus levels increased from 2.7 ± 0.8 mg/dl at burosumab initiation to 3.4 ± 0.6 mg/dl after 3 months and remained stable (p < 0.001). Total reabsorption of phosphorus increased from 82.0 ± 6.8 to 90.1 ± 5.3% after 12 months of treatment (p = 0.041). The RSS improved from 1.7 ± 1.0 at burosumab initiation to 0.5 ± 0.6 and 0.3 ± 0.6 after 12 and 24 months, respectively (p < 0.001). Both height z-score and weight z-score improved from burosumab initiation to the end of the study: from - 2.07 ± 1.05 to - 1.72 ± 1.04 (p < 0.001) and from - 0.51 ± 1.12 to - 0.11 ± 1.29 (p < 0.001), respectively. Eight children received growth hormone combined with burosumab treatment. Height z-score improved among those who received growth hormone (from - 2.33 ± 1.12 to - 1.94 ± 1.24, p = 0.042) and among those who did not (from - 2.01 ± 1.01 to - 1.66 ± 1.01, p = 0.001). CONCLUSION:  Burosumab treatment in a real-life setting improved phosphate homeostasis and rickets severity and enhanced linear growth. WHAT IS KNOWN: • Compared to conventional therapy, burosumab treatment has been shown to increase serum phosphate levels and reduce the severity of rickets. • The effect of burosumab on growth is still being study. WHAT IS NEW: • Height z-score improved between the start of burosumab treatment and the end of the study (-2.07 ± 1.05 vs. -1.72 ± 1.04, p < 0.001). • Eight children received burosumab combined with growth hormone treatment without side effects during the concomitant treatments.

Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction.

PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. At the cellular level, PIK3C2A is critical for the formation of cilia and for receptor mediated endocytosis, among other biological functions. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. In particular, the considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe's syndrome, which is caused by mutations in the PI-5-phosphatase OCRL, highlight the key role of PI metabolizing enzymes in specific developmental processes and demonstrate the unique non-redundant functions of each enzyme. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.

Lessons Learned from Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets Patients on Vitamin D Functions.

We summarize here lessons learned from studies on skeletal and extra-skeletal functions of vitamin D in hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) patients with a mutant, nonfunctioning vitamin D receptor (VDR). During childhood, HVDRR patients are dependent on intestinal VDR, demonstrate low intestinal fraction calcium absorption, and have a bone calcium accretion rate that leads to hypocalcemia and rickets. After puberty, there is recovery in intestinal calcium absorption and in bone calcium accretion and structure. HVDRR monocytes and lymphocytes show impairment in the expression of antimicrobial proteins and demonstrate a proinflammatory cytokine profile. However, HVDRR patients do not exhibit increased rates of infections or inflammatory diseases. Vitamin D deficiency is associated with asthmatic exacerbations. Surprisingly, HVDRR patients do not usually develop asthma. They have normal allergic tests and lung functions and are protected against provoked bronchial hyperactivity. HVDRR patients have decreased IL-5 levels in their exhaled breath condensate. Given that IL-5 is a key cytokine in the development of airway inflammation and hyperactivity and that VDR is important for IL-5 generation, it is plausible that low lung IL-5 protects HVDRR patients from asthma. Vitamin D metabolites have suppressive effects on the renin angiotensin system. However, no HVDRR patient showed hypertension or echocardiographic pathology, and their renin angiotensin metabolites were normal. The VDR is expressed throughout the reproductive system, suggesting a role in reproduction. However, the reproductive history of HVDRR patients is normal despite the lack of a normal VDR. HVDRR patients provide a unique opportunity to study the role of the VDR and the role of vitamin D in various human systems.

Mutations in the mitochondrial ribosomal protein MRPS22 lead to primary ovarian insufficiency.

Primary ovarian insufficiency (POI) is characterized by amenorrhea and loss or dysfunction of ovarian follicles prior to the age of 40. POI has been associated with autosomal recessive mutations in genes involving hormonal signaling and folliculogenesis, however, the genetic etiology of POI most often remains unknown. Here we report MRPS22 homozygous missense variants c.404G>A (p.R135Q) and c.605G>A (p.R202H) identified in four females from two independent consanguineous families as a novel genetic cause of POI in adolescents. Both missense mutations identified in MRPS22 are rare, occurred in highly evolutionarily conserved residues, and are predicted to be deleterious to protein function. In contrast to prior reports of mutations in MRPS22 associated with severe mitochondrial disease, the POI phenotype is far less severe. Consistent with this genotype-phenotype correlation, mitochondrial defects in oxidative phosphorylation or rRNA levels were not detected in fibroblasts derived from the POI patients, suggesting a non-bioenergetic or tissue-specific mitochondrial defect. Furthermore, we demonstrate in a Drosophila model that mRpS22 deficiency specifically in somatic cells of the ovary had no effect on fertility, whereas flies with mRpS22 deficiency specifically in germ cells were infertile and agametic, demonstrating a cell autonomous requirement for mRpS22 in germ cell development. These findings collectively identify that MRPS22, a component of the small mitochondrial ribosome subunit, is critical for ovarian development and may therefore provide insight into the pathophysiology and treatment of ovarian dysfunction.

COG6-CDG: Expanding the phenotype with emphasis on glycosylation defects involved in the causation of male disorders of sex development.

COG6-congenital disorder of glycosylation (COG6-CDG) is caused by biallelic mutations in COG6. To-date, 12 variants causing COG6-CDG in less than 20 patients have been reported. Using whole exome sequencing we identified two siblings with a novel homozygous deletion of 26 bp in COG6, creating a splicing variant (c.518_540 + 3del) and a shift in the reading frame. The phenotype of COG6-CDG includes growth and developmental retardation, microcephaly, liver and gastrointestinal disease, hypohydrosis and recurrent infections. We report two patients with novel phenotypic features including bowel malrotation and ambiguous genitalia, directing attention to the role of glycoprotein metabolism in the causation of disorders of sex development (DSD). Searching the glycomic literature, we identified 14 CDGs including males with DSD, a feature not previously accentuated. This study broadens the genetic and phenotypic spectrum of COG6-CDG and calls for increasing awareness to the central role of glycosylation processes in development of human sex and genitalia.

In Silico Structural and Biochemical Functional Analysis of a Novel CYP21A2 Pathogenic Variant.

Classical congenital adrenal hyperplasia (CAH) caused by pathogenic variants in the steroid 21-hydroxylase gene (CYP21A2) is a severe life-threatening condition. We present a detailed investigation of the molecular and functional characteristics of a novel pathogenic variant in this gene. The patient, 46 XX newborn, was diagnosed with classical salt wasting CAH in the neonatal period after initially presenting with ambiguous genitalia. Multiplex ligation-dependent probe analysis demonstrated a full deletion of the paternal CYP21A2 gene, and Sanger sequencing revealed a novel de novo CYP21A2 variant c.694-696del (E232del) in the other allele. This variant resulted in the deletion of a non-conserved single amino acid, and its functional relevance was initially undetermined. We used both in silico and in vitro methods to determine the mechanistic significance of this mutation. Computational analysis relied on the solved structure of the protein (Protein-data-bank ID 4Y8W), structure prediction of the mutated protein, evolutionary analysis, and manual inspection. We predicted impaired stability and functionality of the protein due to a rotatory disposition of amino acids in positions downstream of the deletion. In vitro biochemical evaluation of enzymatic activity supported these predictions, demonstrating reduced protein levels to 22% compared to the wild-type form and decreased hydroxylase activity to 1-4%. This case demonstrates the potential of combining in-silico analysis based on evolutionary information and structure prediction with biochemical studies. This approach can be used to investigate other genetic variants to understand their potential effects.

Is one diagnosis the whole story? patients with double diagnoses.

One of the goals of evaluating a patient in the genetics clinic is to find the diagnosis that would explain his or her clinical presentation. Sometimes the patient's diagnosis remains undefined or does not explain all of the clinical findings. As clinicians are often guided by a "single disorder" paradigm, diagnosing multiple genetic conditions in the same patient requires a heightened sense of awareness. Over the last few years, we evaluated several patients (n = 14) who were found to have more than one genetic diagnosis. In this paper, we will describe their natural history and diagnoses, and draw on the lessons learned from this phenomenon, which we expect to grow in this era of next-generation diagnostic technologies. To our knowledge, this is by far the largest series of patients with double diagnoses. Based on our findings, we strongly recommend that physicians question every diagnosis to determine whether it indeed explains all of the patients' symptoms, and consider whether they should continue the diagnostic evaluation to look for a more accurate and complete set of diagnoses. © 2016 Wiley Periodicals, Inc.

Evo-devo of Child Growth: The Role of Weaning in the Transition from Infancy to Childhood.

Homo sapiens are unique in having a life history phase of childhood, which follows infancy, as defined by breastfeeding. This review uses evolutionary life history theory in understanding child growth in a broad evolutionary perspective, using the data and theory of evolutionary predictive adaptive growth-related strategies for transition from infancy to childhood. We have previously shown that a delayed infancy-childhood transition has a lifelong impact on stature. Feeding practices during infancy are fundamental elements of nutrition as they program for future growth and body composition. A relationship between the duration of breastfeeding and the nature of weaning has been suggested as a possible cause for later obesity and growth patterns. This review highlights the role that breast milk feeding and variations in the weaning age have on transition to childhood, growth, and body composition.

Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two. METHODS: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays. RESULTS: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling. CONCLUSION: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.

The beneficial effect of growth hormone treatment on islet mass in streptozotocin-treated mice.

BACKGROUND: Type 1 diabetes is an autoimmune disease, characterized by a loss of pancreatic ß-cell mass and function, which results in dramatic reductions in insulin secretion and circulating insulin levels. Patients with type 1 diabetes are traditionally treated with insulin injections and insulin pumps ex vivo or undergo transplantation. Growth hormone (GH) has been shown to be involved in ß-cell function and survival in culture. METHODS: Twelve-week-old female C57BL/6 mice were treated with streptozotocin and monitored for their weight and blood glucose levels. Fourteen days post-initial injection, these mice were separated into two groups at random. One group was treated with GH while the other treated with vehicle for up to 3 weeks. These mice were compared with mice not treated with streptozotocin. RESULTS: Under our experimental conditions, we observed that mice treated with GH had larger islets and higher serum insulin levels than streptozotocin-treated mice treated with saline (0.288 vs. 0.073 ng/mL, p < 0.01). CONCLUSIONS: Our data demonstrate that GH may rescue islets and therefore may possess therapeutic potential in the treatment of type 1 diabetes, although consideration should be made regarding GH's effect on insulin resistance.

Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis.

Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na(+))-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P<0.001). Renal calcifications were also more frequent in het carriers (16%; P=0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (odds ratio [OR], 0.75, 95% confidence interval [95% CI], 0.59 to 0.96; P=0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95% CI, 0.23 to 0.72; P=0.002), and increased serum 1,25(OH)2 vitamin D (OR, 1.22; 95% CI, 1.05 to 1.41; P=0.008). Additional studies are needed to determine whether these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, CKD.

Evidence of ERalpha and ERbeta selectivity and partial estrogen agonism in traditional Chinese medicine.

The use of complementary and alternative medicine and herbal products, especially traditional Chinese medicines, is progressively rising for both adults and children. This increased use is based on the popular belief that these medicines are safe and harmless. In this report, we describe the results of a bedside-to-bench study that involved a short-statured 4-year-old boy with deficiencies in growth hormone, thyroid stimulating hormone, and adrenocorticotropic hormone due to an ectopic posterior pituitary gland and invisible pituitary stalk. Although the boy was given replacement therapy with hydrocortisone and L-thyroxin, the parents refused to treat him with growth hormone and consulted a naturopath who prescribed a traditional Chinese medicine (TCM) to stimulate the boy's growth. From the age of 20 months, the child's growth was regularly monitored while he was being treated with hydrocortisone, thyroxin, and the TCM. Over a 36-month period, the child's growth velocity accelerated (3 cm/year to 8 cm/year), his height increment substantially increased (-2 SD to -0.8 SD), and his bones matured. In the laboratory investigation, estrogen receptor (ER)alpha and ERbeta reporter cell lines were used to characterize the estrogenic activity of the TCM medicine and its 18 components, and the results established that the medicine and some of its components have estrogen receptor ERalpha and ERbeta selectivity and partial estrogen agonism. Partial estrogenic activity of the TCM was confirmed using whole-cell competitive binding, cell proliferation, and endogenous gene expression assays in the ERalpha-positive breast cancer cell lines. Although the presence of evidence is not always evidence of causality, we have concluded that this traditional Chinese medicine contains ingredients with estrogenic activity that can sustain bone growth and maturation without affecting other estrogen-dependent tissues.

Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets.

The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis; for example, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Here, we report presumable loss-of-function mutations in the ENPP1 gene (ectonucleotide pyrophosphatase/phosphodiesterase) in members of four families affected with hypophosphatemic rickets. We provide evidence for the conclusion that ENPP1 is the fourth gene-in addition to PHEX, FGF23, and DMP1-that, if mutated, causes hypophosphatemic rickets resulting from elevated FGF23 levels. Surprisingly, ENPP1 loss-of-function mutations have previously been described in generalized arterial calcification of infancy, suggesting an as yet elusive mechanism that balances arterial calcification with bone mineralization.

The effect of etanercept therapy on adrenal steroid metabolism in juvenile idiopathic arthritis: a steroid metabolomics approach.

OBJECTIVE: To evaluate the impact of anti-tumor necrosis factor-alpha (TNFα: etanercept [Etanercept ®]) therapy on adrenal activity in juvenile idiopathic arthritis (JIA) . METHOD: Eleven JIA patients aged 12 ± 6.2 years with a disease duration of 6.3 ± 5.2 years were enrolled. They were treated once weekly with etanercept (0.8 mg/kg) for 3 ± 2.8 years. Urine samples for gas chromatography-mass spectrometry steroid hormone analysis were collected before, and 1 and 3 days after etanercept injection and compared to age- and sex-matched healthy controls. RESULTS: The levels of 21 of the 31 metabolites were low before etanercept treatment. Those 21 metabolites included 4 C19 steroids (androgens), 5 C C21 steroid hormone intermediates, 10 cortisol metabolites, and 2 corticosterone metabolites. One day after treatment, only 5 of the 21 metabolite levels remained low. They included 2 C19 metabolites, 2 C21 steroid metabolites and 1 cortisol metabolite ß -Cortol (ß-Cl). Three days after treatment, the only metabolites levels that continued to be low were 2 C19 metabolite, 2 C21 steroid hormone intermediates and 1 cortisol metabolite α-Cortol (a-Cl), while the remaining 15 metabolites had already normalized after 1 day. Dehydroepiandrosterone-sulfate and 17-hydroxypregnenolone metabolite levels were the last ones to recover. Urinary metabolite ratios reflecting cytochrome P450 CYP21A2 (21-hydroxylase) and 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) enzymatic activitieswere lower in JIA patients than in controls, although significant was not reached. CONCLUSION: Almost all of the pre-etanercept treatment cortisol urinary metabolite levels were significantly lower than normal, and almost all rose to normal values by 1 day after treatment. The therapeutic effect of anti-TNFα treatment in JIA may be related to its effect on the restoration of adrenal function and cortisol levels.

Identification and characterization of novel parathyroid-specific transcription factor Glial Cells Missing Homolog B (GCMB) mutations in eight families with autosomal recessive hypoparathyroidism.

GCMB is a member of the small transcription factor family GCM (glial cells missing), which are important regulators of development, present in vertebrates and some invertebrates. In man, GCMB encodes a 506 amino acid parathyroid gland-specific protein, mutations of which have been reported to cause both autosomal dominant and autosomal recessive hypoparathyroidism. We ascertained 18 affected individuals from 12 families with autosomal recessive hypoparathyroidism and have investigated them for GCMB abnormalities. Four different homozygous germline mutations were identified in eight families that originate from the Indian Subcontinent. These consisted of a novel nonsense mutation R39X; a missense mutation, R47L in two families; a novel missense mutation, R110W; and a novel frameshifting deletion, I298fsX307 in four families. Haplotype analysis, using polymorphic microsatellites from chromosome 6p23-24, revealed that R47L and I298fsX307 mutations arose either as ancient founders, or recurrent de novo mutations. Functional studies including: subcellular localization studies, EMSAs and luciferase-reporter assays, were undertaken and these demonstrated that: the R39X mutant failed to localize to the nucleus; the R47L and R110W mutants both lost DNA-binding ability; and the I298fsX307 mutant had reduced transactivational ability. In order to gain further insights, we undertook 3D-modeling of the GCMB DNA-binding domain, which revealed that the R110 residue is likely important for the structural integrity of helix 2, which forms part of the GCMB/DNA binding interface. Thus, our results, which expand the spectrum of hypoparathyroidism-associated GCMB mutations, help elucidate the molecular mechanisms underlying DNA-binding and transactivation that are required for this parathyroid-specific transcription factor.

An Expert Perspective on Phosphate Dysregulation With a Focus on Chronic Hypophosphatemia.

Because of their rarity, diseases characterized by chronic hypophosphatemia can be underrecognized and suboptimally managed, resulting in poor clinical outcomes. Moreover, serum phosphate may not be measured routinely in primary care practice. Authors participated in several working sessions to advance the understanding of phosphate homeostasis and the causes, consequences, and clinical implications of chronic hypophosphatemia. Phosphate levels are regulated from birth to adulthood. Dysregulation of phosphate homeostasis can result in hypophosphatemia, which becomes chronic if phosphate levels cannot be normalized. Chronic hypophosphatemia may be underrecognized as serum phosphate measurement is not always part of routine analysis in the primary care setting and results might be misinterpreted, for instance, due to age-specific differences not being accounted for and circadian variations. Clinical consequences of chronic hypophosphatemia involve disordered endocrine regulation, affect multiple organ systems, and vary depending on patient age and the underlying disorder. Signs and symptoms of chronic hypophosphatemic diseases that manifest during childhood or adolescence persist into adulthood if the disease is inadequately managed, resulting in an accumulation of clinical deficits and a progressive, debilitating impact on quality of life. Early identification and diagnosis of patients with chronic hypophosphatemia is crucial, and clinical management should be started as soon as possible to maximize the likelihood of improving health outcomes. Furthermore, in the absence of a universally accepted description for "chronic hypophosphatemia," a definition is proposed here that aims to raise awareness of these diseases, facilitate diagnosis, and guide optimal phosphate management strategies by improving monitoring and assessment of patient response to treatment. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

SERKAL syndrome: an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4.

The WNT-signaling pathway plays a major role during mammalian embryogenesis. We report a novel autosomal-recessive syndrome that consists of female to male sex reversal and renal, adrenal, and lung dysgenesis and is associated with additional developmental defects. Using a candidate-gene approach, we identified a disease-causing homozygous missense mutation in the human WNT4 gene. The mutation was found to result in markedly reduced WNT4 mRNA levels in vivo and in vitro and to downregulate WNT4-dependent inhibition of beta-catenin degradation. Taken together with previous observations in animal models, the present data attribute a pivotal role to WNT4 signaling during organogenesis in humans.

Expanding the spectrum of endocrinopathies identified in Schaaf-Yang syndrome - A case report and review of the literature.

Schaaf-Yang syndrome is a genetic disorder caused by mutations in the paternal allele of the MAGEL2 gene. Developmental delay, feeding difficulties, joint contractures and a high prevalence of autism spectrum disorders are characteristic of the syndrome. Endocrine abnormalities include mostly various pituitary hormonal deficiencies, presenting as hypoglycemia in 48% of reported cases. Persistent hyperinsulinism was only described in two siblings and responded to diazoxide treatment. We describe a unique case of an infant with Schaaf-Yang syndrome that presented with persistent hyperinsulinism unresponsive to diazoxide. Furthermore, we conducted a literature review of the endocrine abnormalities described in MAGEL2 related disorders. The case presented expands the clinical phenotype of Schaaf-Yang syndrome and emphasizes the importance of endocrine follow-up in these patients. Further investigation into the role of MAGEL2 in the regulation of pancreatic beta-cell insulin secretion, will improve our understanding of the abnormalities in glucose regulation in this syndrome.

PI(3,4)P2-mediated cytokinetic abscission prevents early senescence and cataract formation.

Cytokinetic membrane abscission is a spatially and temporally regulated process that requires ESCRT (endosomal sorting complexes required for transport)­dependent control of membrane remodeling at the midbody, a subcellular organelle that defines the cleavage site. Alteration of ESCRT function can lead to cataract, but the underlying mechanism and its relation to cytokinesis are unclear. We found a lens-specific cytokinetic process that required PI3K-C2α (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2α), its lipid product PI(3,4)P2 (phosphatidylinositol 3,4-bisphosphate), and the PI(3,4)P2­binding ESCRT-II subunit VPS36 (vacuolar protein-sorting-associated protein 36). Loss of each of these components led to impaired cytokinesis, triggering premature senescence in the lens of fish, mice, and humans. Thus, an evolutionarily conserved pathway underlies the cell type­specific control of cytokinesis that helps to prevent early onset cataract by protecting from senescence.