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Clinical Utility Gene Card For: Hypophosphatasia – Update 2013

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Clinical Utility Gene Card For: Hypophosphatasia – Update 2013 European Journal of Human Genetics (2014) 22, doi:10.1038/ejhg.2013.177 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg CLINICAL UTILITY GENE CARD UPDATE Clinical utility gene card for: Hypophosphatasia – update 2013 Etienne Mornet*,1,2, Christine Hofmann3,Agne`s Bloch-Zupan4,5,6, Hermann Girschick7 and Martine Le Merrer8 European Journal of Human Genetics (2014) 22, doi:10.1038/ejhg.2013.177; published online 7 August 2013 Update to: European Journal of Human Genetics (2010) 19, doi:10.1038/ejhg.2010.170; published online 27 October 2010 1. DISEASE CHARACTERISTICS large deletions by quantitative multiplex PCR of short fragments,9 but 1.1 Name of the disease (synonyms) this does not significantly increase the detection rate because large Hypophosphatasia (HP), HPP, rathbun disease and phosphoethanola- deletions seem rare in the ALPL gene. For prenatal diagnosis, a set of minuria. linked microsatellites sequences strongly linked to the ALPL gene may be used for indirect diagnosis and/or excluding maternal cell 1.2 OMIM# of the disease contamination. 146300, 241500 and 241510 1.7 Analytical validation 1.3 Name of the analysed genes or DNA/chromosome segments The existence of mutations is confirmed by testing the parental Alkaline phosphatase (AP) liver type (ALPL), 1p36.1-p34. DNA or, when the parental DNA is not available, by sequencing Used other names: TNAP and tissue nonspecific AP. a second and independant PCR product. Newly discovered missense mutations may be tested in vitro by site-directed mutagenesis for enzymatic activity, protein stability, cell localisation 1.4 OMIM# of the gene(s) and so on, clarifying their disease-causing role and estimating their 171760. degree of severity.1 1.5 Mutational spectrum Over 250 different disease-causing mutations have been reported in 1.8 Estimated frequency of the disease (incidence at birth (‘birth the ALPL gene mutations. prevalence’) or population prevalence) 10 Database http://www.sesep.uvsq.fr/03_hypo_mutations.php. The According to a report from 1957 in Toronto, Canada, the distribution is as follows: 75.5% missense mutations; 10.5% small incidence of severe cases of HP (perinatal and infantile forms) is deletions; 6% splicing mutations; 4% nonsense mutations; 2% small 1 in 100 000. On the basis of molecular diagnosis in France and insertions; and 1% or less: complex insertion/deletions, large deletions Europe, the incidence of severe forms has been estimated at and mutations in the regulatory sequence. The large proportion of 1/300 000, a lower value that may reflect a founder effect 11 missense mutations with various effects on the enzymatic activity of previously observed in the region of Toronto. Study of the AP, based upon in vitro studies, has been correlated with the high prevalence of mild forms (prenatal benign, childhood, adult and clinical variability.1 A number of missense mutations exhibit a odontoHP) has not been reported yet, but it is expected higher dominant-negative effect2–5 explaining dominant inheritance of because of low selective pressure and because heterozygotes for mild forms of the disease.6–8 some mutations may express the disease. 1.6 Analytical methods 1.9 If applicable, prevalence in the ethnic group of investigated The main strategy for mutation screening consists in sequencing person of genomic exonic DNA, including flanking intronic sequences. Greenberg et al.12 suggested that the disease prevalence in Canadian This allows the detection of approximately 95% of mutations in Mennonites could be up to 1 in 2500. HP seems very rare in patients with HP. The analysis may be completed by screening for populations of black ancestry.13 1Unite´ de Pathologie Cellulaire et Ge´ ne´tique UPRES-EA2493, Faculte´ de Me´decine Paris Ile de France Ouest PRES Universud Paris, University of Versailles Saint Quentin en Yvelines, Versailles, France; 2Unite´ de Ge´ne´tique Constitutionnelle, Centre Hospitalier de Versailles, Paris, France; 3Funktionsbereich Pa¨diatrische Rheumatologie, Immunologie und Osteologie, Kinderklinik und Poliklinik Universita¨tWu¨ rzburg, Wu¨ rzburg, Germany; 4Faculty of Dentistry, University of Strasbourg, Strasbourg, France; 5Reference Centre for Orodental Manifestations of Rare Diseases, Poˆ le de Me´decine et Chirurgie Bucco-Dentaires, Hoˆpitaux Universitaires de Strasbourg, Strasbourg, France; 6Institute of Genetics and Molecular and Cellular Biology (IGBMC), Inserm U964, CNRS-UdS UMR7104, Illkirch, France; 7Vivantes Klinikum im Friedrichshain, Department of Pediatrics, Clinic for Pediatric and Adolescent Medicine, Berlin, Germany and 8U781 et De´partement de Ge´ne´tique, Centre de Re´fe´rence des Maladies Osseuses Constitutionnelles, Hopital Necker–Enfant Malades, Paris, France *Correspondence: Dr E Mornet, Unite´ de Ge´ne´tique Constitutionnelle, Centre Hospitalier de Versailles, 2 rue Jean-Louis Forain, Le Chesnay 78150, France. Tel: þ 33 1 39 63 80 13; Fax: þ 33 1 39 63 80 12; E-mail: [email protected] Clinical Utility Gene Card Update e2 1.10 Diagnostic setting 3. CLINICAL UTILITY 3.1 (Differential) diagnostics: The tested person is clinically affected (To be answered if in 1.10 ‘A’ was marked) Yes No (1) Diagnosis: based on clinical courses and severity, HP has A. (Differential) diagnostics 2 & been divided into six major subtypes with different prognoses. B. Predictive Testing 2 & The perinatal form is the most severe one. It results in stillbirth or C. Risk assessment in relatives 2 & death a few days after birth due to hypoplastic lungs, difficulty to treat D. Prenatal 2 & seizures, extensive hypomineralisation, deformities of bone and disturbances of the Ca/P metabolism. In the prenatal benign form, despite prenatal findings on fetal ultrasound, there is a spontaneous Comment: improvement of skeletal defects. The patients manifest limb short- Not applicable. ening and bowing and often dimples overlaying the long bones anomalies, and ultrasounds reveal progressive improvement of the 2. TEST CHARACTERISTICS skeletal anomalies and mineralisation during the third trimester of the pregnancy and after birth.14–16 Clinical signs of the infantile form appear during the first 6 months of life including rickets, premature Genotype or disease A: True positives C: False negative craniosynostosis, irritability, seizures and nephrocalcinosis due to B: False positives D: True negative hypercalciuria. Later, premature loss of deciduous teeth is common. Present Absent Death within the first year of life is common, but the precise risk is not understood. The childhood form in most cases presents after the Test first 6 months of life and is characterised by rickets causing a short Positive A B Sensitivity: A/(A þ C) stature, delayed walking and a waddling gait due to bone deformities Specificity: D/(D þ B) and pain of the lower extremities. Later, premature loss of teeth often Negative C D Positive predictive value: A/(A þ B) Negative predictive value: D/(C þ D) leads to diagnosis. It occurs before 5 years of age, and teeth are generally lost with intact root. Adult HP presents with osteomalacia, chondrocalcinosis, osteoarthropathy and stress fractures during middle age in patients who often had a history of mild rickets in 2.1 Analytical sensitivity childhood. Many patients present loss of permanent teeth. (proportion of positive tests if the genotype is present) Odontohypophosphatasia is characterised by premature exfoliation Nearly 95%. of primary and/or permanent teeth and/or severe dental caries, not associated with abnormalities of the skeletal system. However, 2.2 Analytical specificity it should be noticed that the disease spectrum is a continuum, and (proportion of negative tests if the genotype is not present) that these six clinical subtypes can overlap significantly; for example, Nearly 100%. patients with adult HP often had musculoskeletal symptoms already in childhood. The infantile and the childhood form might be difficult 2.3 Clinical sensitivity to distinguish, because early symptoms might be present in the first (proportion of positive tests if the disease is present) months of life in both subtypes. In addition, dental abnormalities are The clinical sensitivity can be dependent on variable factors such as frequent in other forms of HP. According to the severity of the age or family history. In such cases, a general statement should be disorder, some dental defects were infrequent, whereas other are given, even if a quantification can only be made case by case. always present.17 They consist of abnormal tooth shape (small Nearly 95%. bulbous crown, cervical constrictions and enlarged pulp spaces), abnormal tooth structure (enamel, dentin and cementum formation), 2.4 Clinical specificity tooth colour, dental anomalies of tooth eruption/exfoliation with (proportion of negative tests if the disease is not present) premature loss of predominantly the primary and also the permanent The clinical specificity can be dependent on variable factors such as dentition. Delayed eruption of teeth and primary teeth impaction age or family history. In such cases, a general statement should be (ankylosis) are also recorded. given, even if a quantification can only be made case by case. (2) Differential diagnosis: The differential diagnosis of HP depends Nearly 100%. on the age at which the diagnosis is considered. In utero: osteogenesis imperfecta (OI) type II, campomelic dyspla- 2.5 Positive clinical predictive value sia and chondrodysplasias with bone mineralisation defect (life-time risk to develop the disease if the test is positive) At birth: outwardly difficult to distinguish, radiographs readily 100% in recessive inheritance. distinguish OI (type II) campomelic dysplasia and chondrodysplasias Up to 30–40% in mild forms with dominant inheritance, depend- with bone mineralisation defect, from HP. ing on the mutation. Infancy and childhood: inborn errors of energy metabolism, organic acidemia, primary and secondary rickets, neglect and non- 2.6 Negative clinical predictive value accidental trauma. (probability not to developing the disease if the test is negative) Assume an increased risk based on family history for a non-affected Nutritional and/or vitamin D deficiency, vitamin D resistance or person.
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