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Osseous Metaplasia in a Bladder Diverticulum in a Patient with Mosaic Menkes Disease.
Canalichio, KL, Chisholm, KM, Lendvay, TS
Urology. 2020;:238-240
Abstract
Menkes disease, or Kinky Hair Syndrome, is a rare disorder of copper metabolism that causes fatal neurodegenerative disease in infancy. This X-linked disorder results from mutations in the ATP7A gene. Along with neurological decline, characteristic coarse appearance of the hair is seen. Urological issues are prevalent in this patient population, with bladder diverticula being the most common. Herein, we describe a unique male patient with genetic mosaicism and osseous metaplasia found in a ruptured bladder diverticulum.
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A New Multisystem Disorder Caused by the Gαs Mutation p.F376V.
Biebermann, H, Kleinau, G, Schnabel, D, Bockenhauer, D, Wilson, LC, Tully, I, Kiff, S, Scheerer, P, Reyes, M, Paisdzior, S, et al
The Journal of clinical endocrinology and metabolism. 2019;(4):1079-1089
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Abstract
CONTEXT The α subunit of the stimulatory G protein (Gαs) links numerous receptors to adenylyl cyclase. Gαs, encoded by GNAS, is expressed predominantly from the maternal allele in certain tissues. Thus, maternal heterozygous loss-of-function mutations cause hormonal resistance, as in pseudohypoparathyroidism type Ia, whereas somatic gain-of-function mutations cause hormone-independent endocrine stimulation, as in McCune-Albright syndrome. OBJECTIVE We report two unrelated boys presenting with a new combination of clinical findings that suggest both gain and loss of Gαs function. DESIGN AND SETTING Clinical features were studied and sequencing of GNAS was performed. Signaling capacities of wild-type and mutant Gαs were determined in the presence of different G protein-coupled receptors (GPCRs) under basal and agonist-stimulated conditions. RESULTS Both unrelated patients presented with unexplained hyponatremia in infancy, followed by severe early onset gonadotrophin-independent precocious puberty and skeletal abnormalities. An identical heterozygous de novo variant (c.1136T>G; p.F376V) was found on the maternal GNAS allele in both patients; this resulted in a clinical phenotype that differed from known Gαs-related diseases and suggested gain of function at the vasopressin 2 receptor (V2R) and lutropin/choriogonadotropin receptor (LHCGR), yet increased serum PTH concentrations indicative of impaired proximal tubular PTH1 receptor (PTH1R) function. In vitro studies demonstrated that Gαs-F376V enhanced ligand-independent signaling at the PTH1R, LHCGR, and V2R and, at the same time, blunted ligand-dependent responses. Structural homology modeling suggested mutation-induced modifications at the C-terminal α5 helix of Gαs that are relevant for interaction with GPCRs and signal transduction. CONCLUSIONS The Gαs p.F376V mutation causes a previously unrecognized multisystem disorder.
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Identification of a novel mutation of FGFR3 gene in a large Chinese pedigree with hypochondroplasia by next-generation sequencing: A case report and brief literature review.
Yao, G, Wang, G, Wang, D, Su, G
Medicine. 2019;(4):e14157
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Abstract
RATIONALE Hypochondroplasia (HCH) is the mildest form of chondrodysplasia characterized by disproportionate short stature, short extremities, and variable lumbar lordosis. It is caused by mutations in fibroblast growth factor receptor 3 (FGFR3) gene. Up to date, at least thirty mutations of FGFR3 gene have been found to be related to HCH. However, mutational screening of the FGFR3 gene is still far from completeness. Identification of more mutations is particularly important in diagnosis of HCH and will gain more insights into the molecular basis for the pathogenesis of HCH. PATIENT CONCERNS A large Chinese family consisting of 53 affected individuals with HCH phenotypes was examined. DIAGNOSES A novel missense mutation, c.1052C>T, in FGFR3 gene was identified in a large Chinese family with HCH. On the basis of this finding and clinical manifestations, the final diagnosis of HCH was made. INTERVENTIONS Next-generation sequencing (NGS) of DNA samples was performed to detect the mutation in the chondrodysplasia-related genes on the proband and her parents, which was confirmed by Sanger sequencing in the proband and most of other living affected family members. OUTCOMES A novel missense mutation, c.1052C>T, in the extracellular, ligand-binding domain of FGFR3 was identified in a large Chinese family with HCH. This heterozygous mutation results in substitution of serine for phenylalanine at amino acid 351 (p.S351F) and co-segregates with the phenotype in this family. Molecular docking analysis reveals that this unique FGFR3 mutation results in an enhancement of ligand-binding affinity between FGFR3 and its main ligand, fibroblast growth factor 9. LESSONS This novel mutation is the first mutation displaying an increase in ligand-binding affinity, therefore it may serve as a model to investigate ligand-dependent activity of FGF-FGFR complex. Our data also expanded the mutation spectrum of FGFR3 gene and facilitated clinic diagnosis and genetic counseling for this family with HCH.
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MRI findings in pediatric patients with scurvy.
Gulko, E, Collins, LK, Murphy, RC, Thornhill, BA, Taragin, BH
Skeletal radiology. 2015;(2):291-7
Abstract
In modern times scurvy is a rarely encountered disease caused by ascorbic acid (vitamin C) deficiency. However, sporadic cases of scurvy persist, particularly within the pediatric population. Recent individual case reports highlight an increased incidence of scurvy among patients with autism or developmental delay, with isolated case reports detailing the magnetic resonance imaging (MRI) findings of scurvy in these pediatric populations. We present the MRI findings of scurvy in four patients with autism or developmental delay, and review the literature on MRI findings in pediatric patients with scurvy. Despite its rarity, the radiologist must consider scurvy in a pediatric patient with a restricted diet presenting with arthralgia or myalgia.
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Oxalosis in primary hyperoxaluria in infancy : Report of a case in a 3-month-old baby. Follow-up for 3 years and review of literature.
Orazi, C, Picca, S, Schingo, PM, Fassari, FM, Canepa, G
Skeletal radiology. 2009;(4):387-91
Abstract
Primary hyperoxaluria (PH1) is a rare inborn autosomal recessive metabolic disorder due to the deficiency of hepatic alanine-glyoxylate-aminotransferase. This deficiency results in excessive synthesis and urinary excretion of oxalate, inducing renal stone formation and deposition of calcium oxalate in the kidney, bone, myocardium, and vessels (systemic oxalosis, SO) in the most severely affected individuals. We report renal and skeletal changes in a 3-month-old girl with PH1 and SO. Intense cortico-medullary hyperechogenicity and increased homogeneous radiopacity of normal-sized kidneys suggested the diagnosis of SO. Skeletal survey showed osteopenia and characteristic symmetrical metaphyseal transverse bands in long bones, progressively becoming more dense and migrating towards the diaphysis. Multiple pathological and slowly healing fractures of the limbs occurred at the dense band level. A radiopaque rim was then observed in flat bones, epiphyseal nuclei, and vertebral bodies. Inflammatory granulomatous reaction, induced by the presence of oxalate crystals in the marrow spaces, coexisted with progressively evident radiological signs of secondary hyperparathyroidism, with partially overlapping features. The patient was treated by peritoneal dialysis and hemodialysis until combined liver-kidney transplantation. There are no previous reports of infants treated with hemodialysis for more than 2 years.
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An introduction to Na(18)F bone scintigraphy: basic principles, advanced imaging concepts, and case examples.
Bridges, RL, Wiley, CR, Christian, JC, Strohm, AP
Journal of nuclear medicine technology. 2007;(2):64-76; quiz 78-9
Abstract
Na(18)F, an early bone scintigraphy agent, is poised to reenter mainstream clinical imaging with the present generations of stand-alone PET and PET/CT hybrid scanners. (18)F PET scans promise improved imaging quality for both benign and malignant bone disease, with significantly improved sensitivity and specificity over conventional planar and SPECT bone scans. In this article, basic acquisition information will be presented along with examples of studies related to oncology, sports medicine, and general orthopedics. The use of image fusion of PET bone scans with CT and MRI will be demonstrated. The objectives of this article are to provide the reader with an understanding of the history of early bone scintigraphy in relation to Na(18)F scanning, a familiarity with basic imaging techniques for PET bone scanning, an appreciation of the extent of disease processes that can be imaged with PET bone scanning, an appreciation for the added value of multimodality image fusion with bone disease, and a recognition of the potential role PET bone scanning may play in clinical imaging.
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Perspective: cerebral palsy as a model of bone development in the absence of postnatal mechanical factors.
Ward, KA, Caulton, JM, Adams, JE, Mughal, MZ
Journal of musculoskeletal & neuronal interactions. 2006;(2):154-9
Abstract
To ensure optimal skeletal development, mechanical loading is imperative. The consequences of the removal of, or complete absence of, mechanical loading are illustrated by the clinical condition of cerebral palsy (CP). Clinical and radiological evaluation of children with CP provides an insight into how the growing skeleton develops when mechanical loading is reduced due to non-physiological muscle function. The poor bone status or "physiologic osteopenia" that these children suffer is multifactorial compromised of both mechanical and non-mechanical effects; primarily it is the lack of normal loading from the musculature which causes the development of a bone incapable of withstanding daily activities. Fractures occur during daily activities such as dressing and handling. Increased bone resorption during periods of immobilisation after fracture or surgery, also increases bone fragility. Trials of physical, nutritional and pharmacological treatments in CP children result in increased bone mineral density. Trials that include fracture prevention as the primary end point are required in this vulnerable group of children.
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Third case of cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome, further delineating a new malformation syndrome: first report of an affected male and review of literature.
Innes, AM, Chudley, AE, Reed, MH, Shuckett, EP, Hildes-Ripstein, GE, Greenberg, CR
American journal of medical genetics. 2001;(1):44-7
Abstract
CODAS syndrome (MIM# 600373) is a rare multiple congenital anomalies syndrome. The disorder is highly distinctive with characteristic features consisting of developmental delay, cataracts, unusual enamel projections, overfolded and crumpled ears, epiphyseal dysplasia, and dysmorphic features (grooved nose, ptosis). To date, there have been two affected female children reported. The first was a Canadian girl of Mennonite descent, reported by our group, and the second was a girl from Brazil. The etiology and pattern of inheritance of CODAS is unknown. Herein we report a third affected child, a Canadian male infant of Mennonite ancestry. The child, now two years old, exhibits ptosis, cataracts, overfolded ears, grooved nasal tip, dental projections, developmental delay, and characteristic skeletal anomalies. The findings are characteristic for CODAS syndrome. All investigations including karyotype, metabolic screening, peroxisomal studies, and studies of cholesterol biosynthesis were normal. The underlying defect responsible for CODAS syndrome remains unknown. Many of the features suggest a possible underlying collagen gene defect. The fact that this child is the second child from the Manitoba Mennonite community, a genetic isolate, suggests the possibility of autosomal recessive inheritance. To date, there has not been a familial recurrence.
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Chronic hypocalcaemia due to selective skeletal resistance to parathyroid hormone.
Tucci, JR
Clinical endocrinology. 2001;(6):815-8
Abstract
A 71-year-old man was referred for evaluation of asymptomatic hypocalcaemia dating back at least 20 years. There were no somatic abnormalities and Chvostek and Trousseau signs were negative. Serum total calcium varied from 1.88 to 2.03 mmol/l, albumin 37-44 g/l, phosphate 0.54-1.12 mmol/l and ionized calcium 1-1.13 mmol/l. Serum intact PTH levels were 69 and 55 ng/l (10-65), 25-OHD was 40 nmol/l (2.25-107.5) and 1,25-(OH)2D was 54.6 nmol/l (39-156). Serum and urine magnesium and creatinine clearance were normal. Twenty-four-hour urine calcium was 2.15 mmol and calcium/creatinine ratio 0.07. TM phosphate (maximal rate of tubular reabsorption of phosphate in mmol/l glomerular filtrate (GF)) was 0.84 mmol/l GF (0.80-1.34). Bone formation and resorption markers were normal. Bone mineral densities measured by dual-energy X-ray absorptiometry (DEXA) were within normal limits at the hip, forearm and lumbar spine. Infusion of 200 units of synthetic 1-34 PTH was associated with a rise in urinary cyclic AMP from 43 mmol/l GF to 344 mmol/l GF and TM phosphate fell from 0.93 to 0.76 mmol/l GF; 1-34 PTH infusions of 300 units twice daily for 5 days were associated with an increase in serum 1,25-(OH)2D from 80.6 to 114.4 pmol/l but no increase in serum calcium. This is a most unusual case of chronic hypocalcaemia similar to that reported by Frame et al. resulting from isolated skeletal resistance to PTH that is not related to renal insufficiency, osteomalacia or a magnesium-deficient state. These two cases appear to represent a new variant of pseudohypoparathyroidism ?type III.