DOCSLIB.ORG

HPP Flashcard

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
HPP Flashcard Do you see any of the following signs/ symptoms in neonates?1,2 Slender ribs and metaphyseal “tongues” of radiolucency (arrows) in the upper chest in a 3-week-old girl who died with Hypophosphatasia (HPP)1 Clinical Radiographic • Vitamin B6-responsive seizures • Shortening, bowing, and/or angulation • Respiratory insufficiency/failure of the long bones • Widened sutures and fontanelles • Small/narrow thorax • Osteochondral spurs (Bowdler spurs) • Fractures • Metaphyseal irregularities • Lucencies (“cupping” or “tongues”) • Thin ribs • Deficient/absent ossification of bones • Polyhydramnios Alexion® is a registered trademark of Alexion Pharmaceuticals, Inc. Copyright ©2019, Alexion Pharmaceuticals, Inc. All rights reserved. US/UNB-H/0033 HPP should be in your differential diagnosis1,2 • HPP is a progressive, systemic, inherited metabolic disorder2 • In HPP, a loss-of function mutation in the ALPL gene leads to deficient alkaline phosphatase (ALP) enzyme activity, the biochemical hallmark of HPP2 • ALP is an essential enzyme for bone mineralization; infants with HPP have poorly mineralized bones and usually require ventilatory support due to rachitic chest3 • Infants with HPP are critically ill and have a high mortality rate1 Skeletal Features That Can Differentiate HPP, OI, and ACG/HCG4 HPP OI Type II ACG/HCG Low bone density +++ +++ - Underossification of cranial vault +++ +++ + Unossified vertebral bodies Cervical and lumbosacral Thoracic - (typical location) (whole spine in ACG) Sharp demarcation between +++ - + (tapering) ossified and unossified vertebrae Fractures + +++ - Bowed legs ++ +++ + Shortened long bones Thin Broad Normal width Cupped metaphyses (Y shaped) +++ - + Osteochondral Bowdler spurs1,2 + - - Cleft palate - - ++ +++, very highly associated; ++, often associated; +, sometimes associated; -, not associated. HPP-differentiating features shown in yellow. ACG/HCG, achondrogenesis/hypochondrogenesis; OI, osteogenesis imperfecta. Additional considerations for diagnosis of HPP1 • Assess for low age- and sex-adjusted ALP activity in patients with suspicion of HPP1 • Normal range in infants younger than 14 days of age is 90 to 273 U/L5,a • Normal range in infants 15 days and younger than 1 year of age is 134 to 518 U/L5,a • Genetic testing for ALPL mutations is helpful in cases of diagnostic uncertainty and is essential for family genetic counseling1 aBased on Canadian Laboratory Initiative in Pediatric Reference Intervals (CALIPER) data.5 EARLY DIAGNOSIS AND THE INVOLVEMENT OF A MULTIDISCIPLINARY TEAM MAY HELP PROVIDE THE BEST MANAGEMENT OPTIONS FOR INFANTS WITH HPP1 References: 1. Offiah AC, et al.Pediatr Radiol. 2019;49(1):3-22. 2. Rockman-Greenberg C. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388. 3. Bishop N. Clin Cases Miner Bone Metab. 2015;12(2):170-173. 4. Zankl A, et al. Am J Med Genet A. 2008;146A(9):1200-1204. 5. Colantonio DA, et al. Clin Chem. 2012;58(5):854-868. The information on this page is intended as educational information for healthcare professionals. It does not replace a healthcare professional’s judgment or clinical diagnosis. US/UNB-H/0033.
Load more

Recommended publications
  • Blueprint Genetics Comprehensive Skeletal Dysplasias and Disorders
    Comprehensive Skeletal Dysplasias and Disorders Panel Test code: MA3301 Is a 251 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of disorders involving the skeletal system. About Comprehensive Skeletal Dysplasias and Disorders This panel covers a broad spectrum of skeletal disorders including common and rare skeletal dysplasias (eg. achondroplasia, COL2A1 related dysplasias, diastrophic dysplasia, various types of spondylo-metaphyseal dysplasias), various ciliopathies with skeletal involvement (eg. short rib-polydactylies, asphyxiating thoracic dysplasia dysplasias and Ellis-van Creveld syndrome), various subtypes of osteogenesis imperfecta, campomelic dysplasia, slender bone dysplasias, dysplasias with multiple joint dislocations, chondrodysplasia punctata group of disorders, neonatal osteosclerotic dysplasias, osteopetrosis and related disorders, abnormal mineralization group of disorders (eg hypopohosphatasia), osteolysis group of disorders, disorders with disorganized development of skeletal components, overgrowth syndromes with skeletal involvement, craniosynostosis syndromes, dysostoses with predominant craniofacial involvement, dysostoses with predominant vertebral involvement, patellar dysostoses, brachydactylies, some disorders with limb hypoplasia-reduction defects, ectrodactyly with and without other manifestations, polydactyly-syndactyly-triphalangism group of disorders, and disorders with defects in joint formation and synostoses. Availability 4 weeks Gene Set Description
    [Show full text]
  • REVIEW ARTICLE Genetic Disorders of the Skeleton: a Developmental Approach
    Am. J. Hum. Genet. 73:447–474, 2003 REVIEW ARTICLE Genetic Disorders of the Skeleton: A Developmental Approach Uwe Kornak and Stefan Mundlos Institute for Medical Genetics, Charite´ University Hospital, Campus Virchow, Berlin Although disorders of the skeleton are individually rare, they are of clinical relevance because of their overall frequency. Many attempts have been made in the past to identify disease groups in order to facilitate diagnosis and to draw conclusions about possible underlying pathomechanisms. Traditionally, skeletal disorders have been subdivided into dysostoses, defined as malformations of individual bones or groups of bones, and osteochondro- dysplasias, defined as developmental disorders of chondro-osseous tissue. In light of the recent advances in molecular genetics, however, many phenotypically similar skeletal diseases comprising the classical categories turned out not to be based on defects in common genes or physiological pathways. In this article, we present a classification based on a combination of molecular pathology and embryology, taking into account the importance of development for the understanding of bone diseases. Introduction grouping of conditions that have a common molecular origin but that have little in common clinically. For ex- Genetic disorders affecting the skeleton comprise a large ample, mutations in COL2A1 can result in such diverse group of clinically distinct and genetically heterogeneous conditions as lethal achondrogenesis type II and Stickler conditions. Clinical manifestations range from neonatal dysplasia, which is characterized by moderate growth lethality to only mild growth retardation. Although they retardation, arthropathy, and eye disease. It is now be- are individually rare, disorders of the skeleton are of coming increasingly clear that several distinct classifi- clinical relevance because of their overall frequency.
    [Show full text]
  • Whole Exome Sequencing Gene Package Skeletal Dysplasia, Version 2.1, 31-1-2020
    Whole Exome Sequencing Gene package Skeletal Dysplasia, Version 2.1, 31-1-2020 Technical information DNA was enriched using Agilent SureSelect DNA + SureSelect OneSeq 300kb CNV Backbone + Human All Exon V7 capture and paired-end sequenced on the Illumina platform (outsourced). The aim is to obtain 10 Giga base pairs per exome with a mapped fraction of 0.99. The average coverage of the exome is ~50x. Duplicate and non-unique reads are excluded. Data are demultiplexed with bcl2fastq Conversion Software from Illumina. Reads are mapped to the genome using the BWA-MEM algorithm (reference: http://bio-bwa.sourceforge.net/). Variant detection is performed by the Genome Analysis Toolkit HaplotypeCaller (reference: http://www.broadinstitute.org/gatk/). The detected variants are filtered and annotated with Cartagenia software and classified with Alamut Visual. It is not excluded that pathogenic mutations are being missed using this technology. At this moment, there is not enough information about the sensitivity of this technique with respect to the detection of deletions and duplications of more than 5 nucleotides and of somatic mosaic mutations (all types of sequence changes). HGNC approved Phenotype description including OMIM phenotype ID(s) OMIM median depth % covered % covered % covered gene symbol gene ID >10x >20x >30x ABCC9 Atrial fibrillation, familial, 12, 614050 601439 65 100 100 95 Cardiomyopathy, dilated, 1O, 608569 Hypertrichotic osteochondrodysplasia, 239850 ACAN Short stature and advanced bone age, with or without early-onset osteoarthritis
    [Show full text]
  • A Case of Achondrogenesis Type 2/ Hypochondrogenesis Due to Ade
    J Clin Res Pediatr Endocrinol 2015;7(Suppl 2):77-92 A Case of Achondrogenesis Type 2/ Seven Cases of Williams-Beuren Syndrome: Hypochondrogenesis Due to a De Novo Mutation Endocrine Evaluation and Long-Term Follow-Up in the COL2A1 Gene Ayla Güven Gönül Çatlı1, Ayhan Abacı1, Ahmet Anık1, Ranad Shaneen2, Hale Ünver Tuhan1, Medeniyet University, Faculty of Medicine Göztepe Education Derya Erçal3, Ece Böber1, Niema A. Ibrahim2, and Research Hospital, Clinic of Pediatric Endocrinology, İstanbul, Turkey Mais O. Hashem2, Fowzan Sami Alkuraya2 Objectives: Hypercalcemia, hypothyroidism, and early 1 Dokuz Eylül University Faculty of Medicine, Department of puberty are the most common endocrine disorders defined Pediatric Endocrinology, İzmir, Turkey in Williams-Beuren syndrome (WBS). Here, the endocrine 2King Faisal Specialist Hospital and Research Center, Clinic of Genetics, Riyadh, Saudi Arabia evaluation and long-term follow-up of seven patients with 3Dokuz Eylül University Faculty of Medicine, Department of WBS are given. Pediatric Genetics, İzmir, Turkey Methods: Data were obtained from patients’ medical records. WBS was diagnosed by demonstration of the Achondrogenesis type 2/hypochondrogenesis is a rare deletion on chromosome 7 by using FISH method (7q11.23). cause of micromelic dwarfism in the neonatal period. Anthropometric measurements and growth velocities Severe short stature, narrow chest, increased lordosis, (GV) of patients during L-thyroxine (L-T4) treatment were protuberant abdomen, and characteristic facies are the evaluated. Thyroid ultrasonography was performed and typical clinical findings. A 13-month-old boy was referred to thyroid volume was calculated. L-T4 was started in patients our clinic for severe short stature and dysmorphic features.
    [Show full text]
  • COL2A1 Mutations with Analysis of Genotype-Phenotype J Med Genet: First Published As 10.1136/Jmg.37.4.263 on 1 April 2000
    J Med Genet 2000;37:263–271 263 Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype J Med Genet: first published as 10.1136/jmg.37.4.263 on 1 April 2000. Downloaded from correlation in patients with a lethal type II collagen disorder Geert R Mortier, MaryAnn Weis, Lieve Nuytinck, Lily M King, Douglas J Wilkin, Anne De Paepe, Ralph S Lachman, David L Rimoin, David R Eyre, Daniel H Cohn Abstract osteoarthrosis and little or no skeletal growth Achondrogenesis II-hypochondrogenesis abnormality.2 Achondrogenesis II-hypochond- and severe spondyloepiphyseal dysplasia rogenesis and lethal spondyloepiphyseal dys- congenita (SEDC) are lethal forms of plasia congenita (SEDC) represent the more dwarfism caused by dominant mutations severe end of the spectrum.1 5–7 These entities in the type II collagen gene (COL2A1). To are characterised by severe disproportionate identify the underlying defect in seven short stature of prenatal onset. The distinction cases with this group of conditions, we between these phenotypes is mainly based used the combined strategy of cartilage upon clinical, radiographic, and morphological protein analysis and COL2A1 mutation features but considerable phenotypic overlap 1 6–8 analysis. Overmodified type II collagen often hampers proper classification. and the presence of type I collagen was All of the previously reported cases of found in the cartilage matrix of all seven achondrogenesis II-hypochondrogenesis in which the molecular defect was found were Department of cases. Five patients were heterozygous for Medical Genetics, a nucleotide change that predicted a heterozygous for a mutation in the COL2A1 University Hospital of glycine substitution in the triple helical gene resulting in a glycine substitution in the Gent, De Pintelaan triple-helical domain of the proá1(II) collagen domain (G313S, G517V, G571A, G910C, 9–16 185, B-9000 Gent, G943S).
    [Show full text]
  • Skeletal Dysplasia Panel Versie V1 (345 Genen) Centrum Voor Medische Genetica Gent
    H9.1-OP2-B40: Genpanel Skeletal dysplasia, V1, in voege op 14/02/2020 Skeletal_dysplasia panel versie V1 (345 genen) Centrum voor Medische Genetica Gent Associated phenotype, OMIM phenotype ID, phenotype Gene OMIM gene ID mapping key and inheritance pattern Atrial fibrillation, familial, 12, 614050 (3), Autosomal dominant; ABCC9 601439 Cardiomyopathy, dilated, 1O, 608569 (3); Hypertrichotic osteochondrodysplasia, 239850 (3), Autosomal dominant Congenital heart defects and skeletal malformations syndrome, 617602 (3), Autosomal dominant; Leukemia, Philadelphia ABL1 189980 chromosome-positive, resistant to imatinib, 608232 (3), Somatic mutation Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, 165800 (3), ACAN 155760 Autosomal dominant; Spondyloepimetaphyseal dysplasia, aggrecan type, 612813 (3), Autosomal recessive; ?Spondyloepiphyseal dysplasia, Kimberley type, 608361 (3), Autosomal dominant Spondyloenchondrodysplasia with immune dysregulation, 607944 ACP5 171640 (3), Autosomal recessive Fibrodysplasia ossificans progressiva, 135100 (3), Autosomal ACVR1 102576 dominant Weill-Marchesani syndrome 1, recessive, 277600 (3), Autosomal ADAMTS10 608990 recessive Weill-Marchesani 4 syndrome, recessive, 613195 (3), Autosomal ADAMTS17 607511 recessive ADAMTSL2 612277 Geleophysic dysplasia 1, 231050 (3), Autosomal recessive AFF4 604417 CHOPS syndrome, 616368 (3), Autosomal dominant AGA 613228 Aspartylglucosaminuria, 208400 (3), Autosomal recessive Rhizomelic chondrodysplasia punctata,
    [Show full text]
  • Achondrogenesis
    Achondrogenesis Authors: Doctors Laurence Faivre1 and Valérie Cormier-Daire Creation Date: July 2001 Update: May 2003 Scientific Editor: Doctor Valérie Cormier-Daire 1Consultation de génétique, CHU Hôpital d'Enfants, 10 Boulevard Maréchal de Lattre de Tassigny BP 7908, 21079 Dijon Cedex, France. [email protected] Abstract Keywords Disease name and synonyms Prevalence Diagnosis criteria / Definition Clinical description Differential diagnosis Diagnostic methods Etiology Genetic counseling Antenatal diagnosis Management including treatment Unresolved questions References Abstract Achondrogenesis is a lethal disorder characterized by deficient endochondral ossification, abdomen with disproportionately large cranium, and anasarca. Radiological features are characteristic, with virtual absence of ossification of the vertebral column, sacrum and pelvic bones. There are 2 types of achondrogenesis, and differentiation between those types is possible through clinical and radiological andhistological studies. Type I achondrogenesis is of autosomal recessive inheritance with the subtype IB caused by mutations in the diastrophic dysplasia sulfate transporter DTDST gene, and type II achondrogenesis caused by de novo dominant mutations in the collagen type II-1 COL2A1 gene. Keywords endochondral ossification deficiency, lethol disorder, anasarca, absence of ossification in vertebral column, DTDST gene, COL2A1 gene Disease name and synonyms Diagnosis criteria / Definition According to the current classification, there are Association of:
    [Show full text]
  • Connective Tissue Disorder NGS Panel
    Connective Tissue Disorder Next Generation Sequencing (NGS) Rev 1.00 Panels: Information for Ordering Providers Background Heritable connective tissue disorders are a group of conditions caused by genetic variants that impact the development and maintenance of the extracellular matrix, which provides support and structure throughout the body. Connective tissue represents the most abundant tissue type in the body, and is comprised of proteins such as collagen and elastin. Due to the widespread role of connective tissue in most organs and body systems, connective tissue disorders can present with a diverse array of cutaneous, ocular, skeletal, cardiovascular, and craniofacial features.1 The panels listed below include genes related to aortopathies and other groups of heritable connective tissue disorders. Associated clinical features or genetic conditions are listed for each gene and the inheritance pattern for each condition (AD – autosomal dominant, AR – autosomal recessive, XL – X-linked). Please be advised that order restrictions apply for the following panels. Carrier testing/presymptomatic testing is currently restricted to Clinical Genetics. Testing for symptomatic patients is restricted based on clinical specialty. Please refer to the APL Test Directory for specific ordering restrictions for each panel. Aortopathy Panels (Core and Extended) Aortopathies are a group of disorders that affect the structure of the aorta, conferring an increased susceptibility to aortic dilation, aneurysm, and/or dissection. An aortic aneurysm is defined as localized dilation of the aorta to a diameter that is 50% greater than normal, while an aortic dissection refers to a tear in the inner layer of the aorta, which can lead to aortic rupture and sudden cardiac death.2 Aortic aneurysms and dissections can occur in the thoracic aorta or in the abdominal aorta.
    [Show full text]
  • Blueprint Genetics Cleft Lip/Palate and Associated Syndromes Panel
    Cleft Lip/Palate and Associated Syndromes Panel Test code: MA3701 Is a 22 gene panel that includes assessment of non-coding variants. Is ideal for patients with cleft lip and/or cleft palate, particularly those who have a positive family history for clefts or who are suspected to have an associated genetic syndrome. About Cleft Lip/Palate and Associated Syndromes Clefts of the lip and/or palate are common birth defects. Cleft lip (CL) with or without cleft palate is found in 1/700 – 1/1,000 births and cleft palate (CP) is found in about 1/1,500 births. In most cases CL and/or CP occur as an isolated malformation but they can be part of several genetic syndromes or chromosomal anomalies. The etiology of the non-syndromic clefts remains poorly understood and multifactorial inheritance is suspected but in some families predisposition to clefts may follow autosomal dominant inheritance with varying penetrance. There are many syndromes that can have clefts as a feature. Van der Woude syndrome (VWS) is caused by a pathogenic mutation in IRF6 or GRHL3 and is characterized by cleft lip with or without cleft palate or isolated cleft palate and lower-lip paramedian pits. It follows autosomal dominant inheritance, but penetrance is incomplete. Cleft palate can be a feature of Stickler syndrome, also known as hereditary arthro- ophthalmopathy, an inherited vitreoretinopathy characterized by the association of ocular signs with abnormalities affecting head and face, bone disorders, and sensorineural deafness. Stickler syndrome caused by mutations in COL2A1, COL11A1 or COL11A2 is inherited in an autosomal dominant manner.
    [Show full text]
  • Vitreoretinopathy with Phalangeal Epiphyseal Dysplasia, a Type II
    661 SHORT REPORT J Med Genet: first published as 10.1136/jmg.39.9.661 on 1 September 2002. Downloaded from Vitreoretinopathy with phalangeal epiphyseal dysplasia, a type II collagenopathy resulting from a novel mutation in the C-propeptide region of the molecule A J Richards, J Morgan,PWPBearcroft, E Pickering, M J Owen, P Holmans, N Williams, C Tysoe, F M Pope, M P Snead, H Hughes ............................................................................................................................. J Med Genet 2002;39:661–665 quadrant of some patients. Although the vitreous did not A large family with dominantly inherited rhegmatogenous exhibit the congenital membraneous anomaly characteristic retinal detachment, premature arthropathy, and develop- of Stickler syndrome type 1,15–17 the architecture was strikingly ment of phalangeal epiphyseal dysplasia, resulting in abnormal, with absence of the usual lamellar array. Affected brachydactyly was linked to COL2A1, the gene encoding subjects had a spherical mean refractive error of –1.46 diopt- α pro 1(II) collagen. Mutational analysis of the gene by res (SD 1.5), which was not significantly greater than that in exon sequencing identified a novel mutation in the unaffected subjects (mean refractive error –0.71, SD 0.99, C-propeptide region of the molecule. The glycine to aspar- p=0.13, Mann-Whitney test). The axial length was slightly tic acid change occurred in a region that is highly greater in affected eyes (mean 24.6 mm, SD 0.73) compared conserved in all fibrillar collagen molecules. The resulting with unaffected eyes (mean 23.8 mm, SD 1.1, p=0.008, t test). phenotype does not fit easily into pre-existing subgroups of A single affected subject, whose axial length had increased to the type II collagenopathies, which includes spondyloepi- 33.5 mm, following retinal detachment surgery, distorted any physeal dysplasia, and the Kniest, Strudwick, and Stickler apparent variation in myopia between affected and unaffected dysplasias.
    [Show full text]
  • JCRPE Ic Sayfalar 2011-4X-Son:Layout 1
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central J Clin Res Pediatr En docrinol 2011;3(4):163-178 DO I: 10.4274/jcrpe.463 Review A Review of the Principles of Radiological Assessment of Skeletal Dysplasias Yasemin Alanay1, Ralph S. Lachman2,3 1Pediatric Genetics Unit, Department of Pediatrics, Faculty of Medicine, Acibadem University, Istanbul, Turkey 2Professor Emeritus of Radiological Sciences and Pediatrics, UCLA School of Medicine, Los Angeles, California, Clinical Professor, Stanford University, Stanford CA, USA 3International Skeletal Dysplasia Registry, Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA In tro duc ti on Skeletal dysplasias are disorders associated with a generalized abnormality in the skeleton. Although individually rare, the overall birth incidence is estimated to be 1/5000 live births (1). Today, there are more than 450 well-characterized skeletal dysplasias classified primarily on the basis of clinical, radiographic, and molecular criteria (2). Half a century ago, in the 1960s, individuals with disproportionate short stature were diagnosed either as achondroplasia (short-limbed dwarfism) or Morquio syndrome (short-trunked dwarfism). In time, delineation of numerous entities not fitting these two “disorders” led ABS TRACT experts to come up with a systematic approach. The There are more than 450 well-characterized skeletal dysplasias “International Nomenclature of Constitutional Diseases of classified primarily on the basis of clinical, radiographic, and molecular Bone” group, since its first publication in 1970, has criteria. In the latest 2010 revision of the Nosology and Classification of Genetic Skeletal Disorders, an increase from 372 to 456 disorders had intermittently classified these disorders (1970-1977-1983- occurred in the four years since the classification was last revisited in 1992-2001-2005-2009) (3).
    [Show full text]
  • Blueprint Genetics Skeletal Dysplasias Core Panel
    Skeletal Dysplasias Core Panel Test code: MA3501 Is a 113 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of a skeletal dysplasia. The genes on this panel are included in the Comprehensive Skeletal Dysplasias and Disorders Panel and in the Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel. About Skeletal Dysplasias Core The Skeletal Dysplasias Core Panel is designed to detect mutations responsible for various skeletal dysplasias. Some of the resulting skeletal dysplasias are severe and potentially lethal (such as thanatophoric dysplasia, different types of achondrogenesis and osteogenesis imperfecta type II). Other non-lethal skeletal dysplasias result in disproportionate short stature. Achondroplasia is the most common cause of disproportionate short stature worldwide. It is characterized by rhizomelic shortening of the limbs, exaggerated lumbar lordosis, brachydactyly, and macrocephaly with frontal bossing and midface hypoplasia. Type II collagen defects (mutations in COL2A1 genes) have been identified in a spectrum of disorders ranging from perinatally lethal conditions to those with only mild arthropathy. As many different skeletal dysplasias have similar clinical and radiological findings, multigene panel testing allows for efficient diagnostic testing. Identification of causative mutation(s) establishes the inheritance mode in the family and enables genetic counselling. In addition, identifying the causative mutation(s) provides essential information
    [Show full text]