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Archives de pédiatrie
Volume 24, n° 5S2
pages 580-584 (mai 2017)
Doi : 10.1016/S0929-693X(18)30020-4
Hypophosphatasia: oral cavity and dental disorders
Hypophosphatasie : atteintes buccale et dentaire
 

A. Bloch-Zupan 1, 2, 3, 4, , F. Vaysse 5, 6, 7
1 Faculté de chirurgie dentaire et institut d’études avancées (USIAS, Institute of Advanced Studies), Université de Strasbourg, 8, rue Sainte-Elisabeth, 67000 Strasbourg, France 
2 Pôle de médecine et chirurgie bucco-dentaires, centre de référence des manifestations odontologiques des maladies rares, O Rares, FMTS, filière Tête-Cou-Dents, hôpitaux universitaires de Strasbourg, 1, place de l’Hôpital, 67000 Strasbourg, France 
3 Centre européen de recherche en biologie et en médecine (CERBM), institut de génétique et de biologie moléculaire et cellulaire (IGBMC), université de Strasbourg, CNRS UMR 7104, INSERM U964, 1, rue Laurent-Fries, 67404 Illkirch, France 
4 Eastman Dental Institute, UCL, 256, Gray’s Inn Rd, London WC1X 8LD, United Kingdom 
5 Service d’odontologie, centre hospitalier universitaire de Toulouse, France 
6 Faculté de chirurgie dentaire, Université de Toulouse, France 
7 Laboratoire d’anthropologie moléculaire et imagerie de synthèse, CNRS-UPS-UMR 5288 

*Corresponding author.
Summary

Dental anomalies exist in every subtype of hypophosphatasia (HPP), from the most severe to the most moderate, called odontohypophosphatasia. The forms are defined by the age at onset of the initial symptoms. These anomalies affect all dental mineralized tissues from enamel, dentin and cementum to alveolar bone in a gradient proportional to the severity of the disease. Early loss of the deciduous teeth, before 3 years of age, and then possibly of the permanent teeth, is due to an abnormality of the cementum, the tissue attaching the teeth to alveolar bone, and is the most frequent abnormality. Tooth loss is a very important diagnostic sign and needs to be recognized. Patients with HPP need specialized oral and dental care in coordination with the reference and expert centers. The oral and dental signs and their treatment remain poorly known. The recording of the abnormalities and their treatment in a registry is indispensable in order to enhance patient management and oral and dental health.

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Résumé

Les anomalies dentaires sont présentes dans toutes les formes de l’hypophosphatasie (HPP), de la plus sévère à la plus modérée dite « odontohypophosphatasie ». Elles sont définies par l’âge d’apparition des premiers symptômes. Ces anomalies touchent tous les tissus minéralisés de la dent, à savoir : l’émail, la dentine, le cément et l’os alvéolaire selon un gradient proportionnel à la sévérité de la maladie. La perte précoce de dents temporaires avant l’âge de 3 ans, puis éventuellement de dents permanentes, liée à une anomalie du cément, tissu permettant l’attachement de la dent à l’os alvéolaire, est l’anomalie la plus fréquente. Cette perte des dents est un signe diagnostique très important à reconnaître. Les patients atteints d’HPP nécessitent une prise en charge bucco-dentaire adaptée en coordination avec les centres de référence et de compétence. Ces signes bucco-dentaires et leur prise en charge sont encore mal connus ; le recensement de ces anomalies et leur traitement dans un registre sont indispensables à une amélioration de la prise en charge et de la santé bucco-dentaire des patients.

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Introduction

HPP is a genetic disease due to a deficiency in Tissue-Nonspecific Alkaline Phosphatase (TNSALP), an enzyme coded for by the gene Alkaline Phosphatase, Liver/Bone/Kidney (ALPL ), which is important for the mineralization of the skeleton and hard tissues of the teeth and periodontium, namely the enamel, dentin, cementum and alveolar bone [1]. The disease has a wide range of clinical presentations, from the most severe, perinatal, resulting in death in utero to the most moderate, known as odontological HPP. The latter presents as dental abnormalities without any other clinical manifestations. The oral/dental features consist in the early and spontaneous loss of the lacteal teeth before age 3 years and, possibly, loss of the permanent teeth. These orodental signs have long been known [2, 3] and were reported when the disease was first described [4]. Early deciduous tooth loss may be the first sign of the disease, emerging as of age 6 months and before age 3 years. All the forms of HPP include dental development abnormalities in the clinical picture [5, 6, 7, 8]. The various dental tissues referred to in this article are defined and their locations shown in Figure 1.



Figure 1


Figure 1. 

Dental tissues.

The teeth consist of four tissues which are distinct but have strong functional or biological links. Dentin, a tissue like bone, accounts for the majority of the organ. The coronal dentin is covered by enamel and the radicular dentin by a very thin layer of cementum. The dental pulp retains its odontogenesis properties throughout its life. The teeth are connected to alveolar bone by the alveolodental (or periodontal) ligament.

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Literature review

The oral cavity and, in particular, diet play an important role in HPP. Feeding and weight gain difficulties during childhood are frequently mentioned by patients and their parents (38% of patients and 81% of those in whom the disease is expressed before age 1 year) [9]. Alkaline phosphatase is involved in dental development and the mineralization of the enamel, dentin, cementum and alveolar bone [10, 11, 12]. Animal models have been used to simulate the dental abnormalities encountered in human HPP [13, 14]. The proposed treatments, enzyme replacement [15, 16, 17] or gene therapy [18], alleviate the orodental manifestations in those models.

Etiology

The accumulation of inorganic pyrophosphate, the substrate of alkaline phosphatase, in the extracellular matrix, underlies the disorders of mineralization of hard dental tissues and, in particular, premature tooth loss [19] due to defective development of the noncellular cementum [20].

Clinical aspects

The orodental manifestations affect all the mineralized tissues and appear proportional to the severity of the alkaline phosphatase deficiency.

The cementum, the tissue that anchors a tooth to alveolar bone via the periodontal ligament, seems particularly vulnerable to the accumulation of inorganic pyrophosphate, a substrate not degraded by the defective enzyme and a potent inhibitor of mineralization [21]. Thus, defective cementum underlies the early tooth loss observed in all forms of HPP [22, 23]. Early tooth loss is considered as a significant diagnostic sign of the disease, particularly for moderate forms diagnosed during childhood [8]. The teeth become loose and gradually fall out with an intact root in the absence of any infectious or inflammatory context. The dental abnormalities of HPP are listed in Table 1 and illustrated in Figure 2 [6]. The deciduous dentition seems to be more strongly affected than the permanent teeth [24, 25]. Thus, premature loss of the deciduous teeth is not always followed by loss of the permanent teeth. Some patients with adult onset HPP report a history of tooth loss in infancy [26]. It is thus of great importance to question patients about early loss of the lacteal teeth and to determine whether there is a family history of tooth loss. Feeding difficulties and high caries activity evidenced by the presence of numerous caries or dental restorations should also be noted.



Figure 2


Figure 2. 

Panoramic X rays.

2A) Child, aged 6 years, with odontohypophosphatasia, which resulted in the gradual loss of the mandibular deciduous incisors, with the first tooth lost at about 30 months. To be noted: marked alveolysis of the maxillary deciduous incisors, which were loose. There was a familial history of early tooth loss on the maternal side (mother and grandmother). The child’s dentition was deciduous. No other dental abnormality was observed. Genetic diagnostics confirmed the presence of an heterozygous mutation c.3o1T>G (p.Y1o1D ) of the ALPL gene, a severe mutation with a probable negative dominant effect.

2B) Child with a severe perinatal form of hypophosphatasia. Early tooth loss affected almost all of the deciduous teeth. The child’s dentition was mixed. The deciduous molars (54, 85 crowned, 75) persisted on the arch. The enamel was malformed. The permanent molars presented with taurodontism including elongation of the crown and of the the pulp chamber along the axis of the tooth, and within the apical branching of the roots.

Zoom

Risks and complications

HPP is a disease that may be difficult to diagnose. It is very important to take the oral signs into account and in the event of early deciduous or permanent tooth loss, to prescribe blood alkaline phosphatase measurement and, depending on the results, to request molecular diagnosis and refer the patient to a rare disease reference and expert center [27].

The complications of HPP are related to the difficulty of treating tooth loss and instituting appropriate prosthetic rehabilitation as of early childhood (3 years). It is important to realize that the dental abnormalities, particularly those related to dentin formation and tooth loss, may be progressive. Adult patients complain of pain and difficulties adapting to and using partial or complete dentures [28].

Management

Irrespective of the form or degree of severity, HPP is associated with early orodental lesions. The lesions are the consequence of an abnormal structure of the alveolar bone and/or of the tooth and may give rise to root and bone resorption, ankylosis, severe caries of the deciduous teeth, and, above all, premature deciduous and permanent tooth loss [29]. It is, however, to be noted that the lesions are not constant and sometimes have no patent clinical impact [30]. While published data on management are rare, management involves appropriate prevention and dental rehabilitation. The management of oral health in HPP patients should be instated as soon as the diagnosis is made, and during the rest of the patient’s lifetime.

Promoting patient and professional awareness

While caries and, above all, early alveolysis seem ineluctable, usual preventive measures may retard the disease progression, particularly in adults. Prevention involves rigorous orodental hygiene oriented toward periodontal prevention with regular use of a supple toothbrush and fluoride toothpaste. Ancillaries such as interdental brushes, dental sprays and flossing are also of value. It is also appropriate to minimize the usual cofactors of periodontal disease such as smoking and dental extraction.

Periodontal management

In addition to the deciduous dentition, the mandibular incisors are almost always the first teeth affected. Periodontal cleaning may be done at early stages of the disease, but is only intended to remove the local determinants of alveolysis (dental plaque, tartar). Alvelolysis of the permanent dentition is generally more gradual and local treatment may slow the progression.

Caries management

Early clinical and radiological screening is very important to prevent tooth loss and retention of dental plaque; noteworthy, the bacterial biofilm gives rise to caries and periodontal disease.

Orthodontic management

Due to premature exfoliations, children with HPP may have important needs for orthodontic treatment. Once again, the literature does not enable any conclusion as to the safety of such treatments. The situation is to be evaluated on the individual basis depending on the benefit / risk ratio, including close periodontal monitoring.

Rehabilitation

Early multidisciplinary management and esthetic and functional rehabilitation of the oral cavity are essential components in preserving the teeth of HPP patients. Rehabilitation employs conventional techniques but uses them in an unusual context, which may complicate implementation outside of the expert centers / networks of reference. In the context of deciduous and mixed dentition, pediatric crowns and adjunctive prostheses are to be preferred. Adult dental rehabilitation has been poorly reported so far. In two published clinical cases a conventional prosthesis was used [31, 32]. A fixed prosthesis is to be preferred in view of its comfort and superior periodontal tolerability. Particular attention is to be paid to the prosthetic embrasures to enable enhanced periodontal cleaning. Management by dental implants is described in a single patient. This HPP patient experienced one implant rejection, yet still benefited from six implants after 13 and 7 years of follow-up [33]. While cementum malformation doubtless has no impact on implant durability, it is difficult to about the role of the bone deficit in implant success.

Conclusion

The literature is scarce on the orodental treatment of patients with HPP. Collection of data in a registry would therefore be of value in order to better understand the disease and thus facilitate diagnosis and improve patient care. A registry has been set up thanks to a cooperative initiative by the rare diseases networks TETECOU (rare malformations of the head, neck and teeth, Tête-Cou-Dents – www.tetecou.fr) and OSCAR (rare diseases of bone, calcium and cartilage – www.filiere-oscar.fr) and their associated reference centers. The participation of healthcare professionals and patients (who have given their informed consent) is necessary for the success of the initiative. For the features related to the oral cavity, we record clinical data (dedicated registry and form D[4]/phenodent/hypophosphatasie at www.phenodent.org) together with intra-oral photographs and panoramic X rays. The patients and their families are invited, if they so wish, to attend an assessment consultation at an reference center expert in oral health and rare diseases.

The patient association Hypophosphatasie Europe (wp.hypophosphatasie.com) is actively supporting the initiative.


Acknowledgments

We would like to express our gratitude to the patients and their families, to the Patients’ Group Chairperson, Mr. Steve Ursprung, and to the members of the association Hypophosphatasie Europe for their support. We would also like to thank Ms Heidy Bloch for her assistance in preparing Figure 1. This work was conducted in the context of the programs Offensive Sciences INTERREG IV, A27: ‘Orodental manifestations of rare diseases’ and RARENET INTERREG V No. 1.7, co-financed by the European Regional Development Fund (ERDF) of the European Union.

Statement of interests

A. Bloch-Zupan has received remuneration from the Alexion company for expert review missions. F. Vaysse has no conflicts of interest to report.

References

Mornet E., Hofmann C., Bloch-Zupan A., Girschick H., Le Merrer M. Clinical utility gene card for: hypophosphatasia – update 2013 Eur J Hum Genet 2014 ; 22
Bruckner R.J., Rickles N.H., Porter D.R. Hypophosphatasia with premature shedding of teeth and aplasia of cementum Oral Surg Oral Med Oral Pathol 1962 ;  15 : 1351-1369 [cross-ref]
Sobel E.H., Clark L.C., Fox R.P., Robinow M. Rickets, deficiency of alkaline phosphatase activity and premature loss of teeth in childhood Pediatrics 1953 ;  11 (4) : 309-322
Rathbun J.C. Hypophosphatasia; a new developmental anomaly Am J Dis Child 1948 ;  75 (6) : 822-831 [cross-ref]
Foster B.L., Ramnitz M.S., Gafni R.I., Burke A.B., Boyce A.M., Lee J.S., and al. Rare Bone Diseases and Their Dental, Oral, and Craniofacial Manifestations J Dent Res 2014 ;  93 : 7S-19S
Bloch-Zupan A. Hypophosphatasia: diagnosis and clinical signs – a dental surgeon perspective Int J Paediatr Dent 2016 ;  26 : 426-438 [cross-ref]
Foster B.L., Nagatomo K.J., Tso H.W., Tran A.B., Nociti F.H., Narisawa S., and al. Tooth root dentin mineralization defects in a mouse model of hypophosphatasia J Bone Miner Res 2013 ;  28 : 271-282 [cross-ref]
Reibel A., Maniere M.C., Clauss F., Droz D., Alembik Y., Mornet E., and al. Orodental phenotype and genotype findings in all subtypes of hypophosphatasia Orphanet J Rare Dis 2009 ;  4 : 6 [cross-ref]
Skinar AM, Smith J, Landy.H. Burden of illness in children and adults with hypophosphatasia Survey results presented at the American College of Medical Genetics Annual Clinical Genetics Meeting. ACMG, Albuquerque 2010:Abstract 255.
Hotton D., Mauro N., Lezot F., Forest N., Berdal A. Differential expression and activity of tissue-nonspecific alkaline phosphatase (TNAP) in rat odontogenic cells in vivo J Histochem Cytochem 1999 ;  47 : 1541-1552 [cross-ref]
Berdal A., Lezot F., Nefussi J.R., Sautier J.M. Mineralized dental tissues: a unique example of skeletal biodiversity derived from cephalic neural crest Morphologie 2000 ;  84 : 5-10
Lezot F., Descroix V., Hotton D., Mauro N., Kato S., Berdal A. Vitamin D and tissue non-specific alkaline phosphatase in dental cells Eur J Oral Sci 2006 ;  114 : 178-182discussion 201-2, 381.  [cross-ref]
Foster BL, Kuss P, Yadav MC, Kolli TN, Narisawa S, Lukashova L, et al. Conditional Alpl Ablation Phenocopies Dental Defects of Hypophosphatasia. J Dent Res 2016. pii: 0022034516663633 [Epub ahead of print].
Foster B.L., Sheen C.R., Hatch N.E., Liu J., Cory E., Narisawa S., and al. Periodontal Defects in the A116T Knock-in Murine Model of Odontohypophosphatasia J Dent Res 2015 ;  94 : 706-714 [cross-ref]
Yadav M.C., de Oliveira R.C., Foster B.L., Fong H., Cory E., Narisawa S., and al. Enzyme replacement prevents enamel defects in hypophosphatasia mice J Bone Miner Res 2012 ;  27 : 1722-1734 [cross-ref]
Rodrigues T.L., Foster B.L., Silverio K.G., Martins L., Casati M.Z., Sallum E.A., and al. Correction of hypophosphatasia-associated mineralization deficiencies in vitro by phosphate/pyrophosphate modulation in periodontal ligament cells J Periodontol 2012 ;  83 : 653-663 [cross-ref]
McKee M.D., Nakano Y., Masica D.L., Gray J.J., Lemire I., Heft R., and al. Enzyme replacement therapy prevents dental defects in a model of hypophosphatasia J Dent Res 2011 ;  90 : 470-476 [cross-ref]
Okawa R, Iijima O, Kishino M, kawa H, Toyosawa S, Sugano-Tajima H, et al. Gene therapy improves dental manifestations in hypophosphatasia model mice. J Periodontal Res 2016.
Whyte M.P. Hypophosphatasia – aetiology, nosology, pathogenesis, diagnosis and treatment Nat Rev Endocrinol 2016 ;  12 : 233-246 [cross-ref]
Lundgren T., Westphal O., Bolme P., Modéer T., Norén J.G. Retrospective study of children with hypophosphatasia with reference to dental changes Scand J Dent Res 1991 ;  99 : 357-364 [cross-ref]
Foster B.L., Nagatomo K.J., Nociti F.H., Fong H., Dunn D., Tran A.B., and al. Central role of pyrophosphate in acellular cementum formation PLoS One 2012 ;  7 (6) : e38393
Whyte M.P., Wenkert D., Zhang F. Hypophosphatasia: Natural history study of 101 affected children investigated at one research center Bone 2016 ;  93 : 125-138 [cross-ref]
Whyte M.P., Zhang F., Wenkert D., McAlister W.H., Mack K.E., Benigno M.C., and al. Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients Bone 2015 ;  75 : 229-239 [cross-ref]
el-Labban N.G., Lee K.W., Rule D. Permanent teeth in hypophosphatasia: light and electron microscopic study J Oral Pathol Med 1991 ;  20 : 352-360 [cross-ref]
Lepe X., Rothwell B.R., Banich S., Page R.C. Absence of adult dental anomalies in familial hypophosphatasia J J Periodontal Res 1997 ;  32 : 375-380 [cross-ref]
Riemsma R, Büyükkaramikli N, Corro Ramos I, et al. Asfotase alfa for treating paediatric-onset hypophosphatasia. Kleijnen Systematic Reviews Ltd in collaboration with Erasmus University Rotterdam and Maastricht University 2015;1-219.
Mornet E, Baujat G, Bloch-Zupan A, et al. Hypophosphatasie, arbres décisionnels Association des praticiens de génétique moléculaire, ANPGM 2015 ; mise à jour : 106.
Administration TTG. AusPAR attachment 2. Extract from the clinical evaluation report for asfotase alfa (rch). 2015;1-115.
Atar M., Korperich E.J. Systemic disorders and their influence on the development of dental hard tissues: a literature review J Dent 2010 ;  38 : 296-306 [cross-ref]
Vaysse F., Bah A., Kemoun P., Cousty S. The biology of dental development Arch Pediatr 2015 ;  22 : 149-150 [inter-ref]
Bagis B., Baltacioglu E., Aydogan E., Tamam E. Prosthetic rehabilitation of hypophosphatasia: a case report Cases J 2008 ;  2 : 7626
Grewal P.S., Gupta K.P. Prosthetic rehabilitation of a young patient with Hypophosphatasia – A review and case report Contemp Clin Dent 2012 ;  3 : 74-77
Lynch C.D., Ziada H.M., Buckley L.A., Sullivan V.R., Aherne T., Aherne S. Prosthodontic rehabilitation of hypophosphatasia using dental implants: a review of the literature and two case reports J Oral Rehabil 2009 ;  36 : 462-468 [cross-ref]



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