Case report: hypophosphatemic rickets and aggressive periodontitis: a review of the role of dentine matrix protein 1 in the pathogenesis.
Abstract: BACKGROUND: The association between hypophosphatemic rickets (HR) and excessive periodontal breakdown was reported in mice models of HR. In humans, this is the first report of a possible association between HR and periodontal breakdown. CASE REPORT: The following presents a report of a case of a 15 year-old child diagnosed with HR at age 9 years, with atypical premature spontaneous loss of teeth due to periodontal defects in the absence of dental abscesses, dental caries, or trauma. The case is discussed in the context of relevant literature; the possible role of dentine matrix protein 1 in the aetiology of such periodontal defects in patients with HR is also discussed. CONCLUSION: Spontaneous loss of teeth in the absence of abscess formation is not one of the reported features of HR, however, this report may alert clinicians of the possibility of such association especially in the autosomal recessive type. Further case reports and more elaborate genetic and molecular testing is needed to verify this especially in late diagnosis cases.

Key words: hypophosphatemia, rickets, dentine matrix protein, periodontitis
Article Type: Case study
Subject: Hypophosphatemia (Diagnosis)
Hypophosphatemia (Care and treatment)
Hypophosphatemia (Case studies)
Periodontitis (Diagnosis)
Periodontitis (Care and treatment)
Periodontitis (Case studies)
Authors: Al-Jundi, S.H.
Hammad, M.M.
Dabous, I.
Pub Date: 02/01/2011
Publication: Name: European Archives of Paediatric Dentistry Publisher: European Academy of Paediatric Dentistry Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2011 European Academy of Paediatric Dentistry ISSN: 1818-6300
Issue: Date: Feb, 2011 Source Volume: 12 Source Issue: 1
Geographic: Geographic Scope: Jordan Geographic Code: 7JORD Jordan
Accession Number: 277106727
Full Text: Background

Hypophosphatemic rickets (HR) is a rare genetic disorder, which is characterised by diminished phosphate reabsorption in renal tubules leading to chronic hyperphosphaturia and hypophosphatemia, which are associated with normal or low levels of 1,25(OH)2 Vitamin D3. This phosphorus-wasting disturbance affects bone metabolism, causing rickets in paediatric patients and osteomalacia in adults [Rowe, 2000].

According to the genetic mode of inheritance and laboratory findings, HR was classified into four distinct forms with different modes of inheritance, one of these forms was recently described as autosomal recessive hypophosphatemia, and was found to be caused by mutations in Dentine Matrix Protein-1 (DMP1)[Feng et al., 2006; Lorenz-Depiereux et al., 2006]. This protein is highly expressed in osteocytes in bone as well as in teeth and in hypertrophic chondrocytes in cartilage [Feng et al., 2003].

One study using DMP1-null mice, (a mouse model of HR), demonstrated an early-onset periodontal defect in these mice with porous alveolar bone, and defective cementum, consequently, there was significant interproximal alveolar bone loss, combined with detachment between the periodontal ligament (PDL) and cementum in these mice. Ye et al. [2008] concluded that without proper phosphate treatment and dental care, hypophosphatemic individuals might be predisposed to bacterial infection and PDL breakdown.

We report a case of a child diagnosed with HR who showed excessive periodontal breakdown, which may indicate a possible association with mutation of DMP1.

Case report

A 15 year-old male patient diagnosed with HR was referred to the dental teaching centre in Jordan University of Science and Technology (JUST) due to spontaneous loss of his maxillary and mandibular permanent incisors. The child was brought by his mother who stated that he was a member of a family of 11 children (8 girls and 3 boys) and that he had a sister (18 years-old) who was also diagnosed with HR and who had already lost all of her permanent teeth spontaneously. The mother denied the presence of rickets or early tooth loss in any of the parents' respective families; she also stated that she and her husband were distant cousins. The child was diagnosed with HR at age 9 years of age, and had since been treated with oral phosphate supplements at a dose of 50 mg/ kg/day, and bio-activated vitamin D 40 ng/kg/day.

Clinical examination. The child exhibited typical general appearance of HR with short stature at a height of 149 cm, which is below the 5th percentile for height in Jordanian boys, bowing of the lower extremities, and abnormal gait, his facial appearance indicated a prognathic mandible (Fig 1a).

An intraoral examination revealed a permanent dentition with loss of teeth 14, 12, 21, 22, 25, 32, 31, 42, 41. Both child and mother stated that these teeth had been lost spontaneously after becoming excessively mobile. The intraoral examination also revealed poor oral hygiene, gingival inflammation, carious teeth (36,46), and class III canine and molar relationship (Fig 1b). The boy's mother also stated that her child's primary teeth were also prematurely lost.

The dental record of the child had an orthopantomogram (Fig 2a) made a year previously, which revealed that teeth 14, 12, 21, 22 had not been lost then, however they showed excessive periodontal defects with widened periodontal ligament space, loss of crestal bone height and no caries.

Periodontal examination. Periodontal parameters are shown in Table 1. On presentation 13/16 teeth were mobile, ranging between Miller's scores 1 and 2. Many teeth presented with increased probing pocket depth (PD). A few teeth showed excessive attachment loss.

Radiographic examination. Full mouth periapical radiographs and right and left bitewings were obtained to assess bone level and supporting structures (Fig 2b). The radiographs indicated general reduced trabeculation and reduced radioopacity of lamina dura characteristic of rickets. Most teeth show minimal to moderate crestal bone loss. The lamina dura was diminished, and even lost completely in some areas with widening of the periodontal ligament space (Fig 2a). Teeth 36 and 46 showed extensive loss of alveolar bone and abscess formation.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Laboratory tests. Examination of the patient's medical record revealed that his laboratory findings, upon diagnosis, were elevated serum alkaline phosphatase, hypophosphatemia, and border line serum calcium level diagnostic of HR. White blood cell, red blood cell, and differential counts were normal, so was the haemoglobin level.

Treatment

The patient was referred to the periodontal department at JUST for treatment. Initially scaling, polishing, and a maintenance oral health program were performed, chlorhexidine gel 0.2% was prescribed, and extraction of teeth 36, 46 was carried out.

Follow-up

Two months later the patient was reviewed clinically, his oral hygiene had improved, however no change was seen on the periodontal condition. A removable prosthesis was made and fitted for the child to replace his missing teeth. Unfortunately, the patient failed to attend for the three months follow-up.

At the time of the 6 months review a telephone call with his mother revealed that the boy had undergone osteotomy surgery for his lower limbs to correct the bowing, and that he had been unable to attend for dental follow-up. The patient was rescheduled after healing of his surgery.

Discussion

Hypophosphatemia is defined as a serum phosphate level less than 2.5 mg/dL (0. 8mmol/L). Hypophosphatemia is caused by inadequate intake, decreased intestinal absorption (malabsorption, phosphate binding antacids, and vitamin D deficiency), 4,6 excessive urinary excretion (hyperparathyroidism, vitamin D deficiency, oncogenic osteomalacia, and familial hypophosphatemic rickets) [Assadi, 2010]. HR is the most common inherited form of rickets and is characterized by short stature, bone pain, radiographic evidence of rickets, renal phosphate wasting, and inappropriately low levels of serum concentration of 1,25-dihydroxyvitamin D [Assadi, 2010].

HR, sometimes referred to as hypophosphatemia, is diagnosed on the basis of the clinical picture, laboratory finding and radiographic alterations. In this disease patients will develop symptoms related to growth retardation (unproportional growth stature) and rachitic skeletal deformities mainly in upper and lower limbs [Farach-Carson and Nemere, 2003]. These deformities are more prominent in areas that grow rapidly, specifically at the age of increasing activity in that part of the body. Therefore, the position and severity of the deformity varies according to a patient's age and level of activities. These deformities include smooth bowing, gait disturbance, knock knees, metaphyseal widening, frontal bossing, and horizontal depression along the lower border of the chest. In addition insufficient weight gain, recurrent bone fractures, bone pain and tenderness, alteration in the shape of the head by the thickness of central parts of parietal and frontal bone, alpaca can be seen in patients with this disease [Whyte and Thakke, 2005].

It is worth mentioning that HR must be differentiated from hypophosphatasia; in the latter premature loss of teeth due to defects in cementum is a characteristic feature of the disease in which serum alkaline phosphatase activity is diminished together with elevated levels of phosphoethanolamine in the urine [Armitage, 1999].

HR is now recognised to occur in four forms. The most common form is inherited in an X-linked dominant manner (XLH), associated with mutations in the PHEX gene (Phosphate regulating gene with Homologies to Endopeptidases on the X-chromosome) [Feng, 2006; Lorenz-Depiereux et al., 2006]. The second is an autosomal dominant form (ADHR); it is associated with mutation in the gene of Fibroblast Growth Factor 23 (FGF-23). The last form, which was recently described, is autosomal recessive HR with two different genes that are involved in two different diseases. The first disease is hypophosphatemia that is caused by mutations in Dentine Matrix Protein-1 (DMP1) [Feng, 2006; Lorenz-Depiereux et al., 2006]. The second is Hereditary HR with Hypercalciuria (HHRH); caused by mutation in the gene SLC34C3 encoding the renal sodium-phosphate co-transporter NaPi-IIc. Patients with the first three conditions have hypophosphatemia and normal or low level of Vitamin D. Patients with the last condition have appropriate or increased concentration of 1,25[(OH).sub.2]D, and hypercalciuria [Negri, 2007], (Table 2).

Recently a study described a family with HR where mutations were predicted to abolish ENPP1 activity and are associated with inappropriately high FGF23 plasma levels. The authors suggested that ENPP1 is the fourth gene that, if mutated, causes hypophosphatemic rickets due to elevated FGF23 levels [Lorenz-Depiereux et al., 2010].

The Dentine Matrix Protein 1 (DMP1) and ricketsDMP1 is one of the bone-tooth mineral matrix phospho-glycoproteins [Rowe et al., 2000], it belongs to a group of non-collagenous protein termed the SIBLING (Small Integrin-Binding LIgand, N-linked Glycoprotein) family. These polyanionic SIBLING proteins are believed to play key biological roles in the mineralisation of bone and dentine [Qin et al., 2004]. The processing of DMP1 is crucial in osteogenesis and dentinogenesis, and a failure in this processing would cause defective mineralisation in bone and dentine, as observed in X-linked hypophosphatemic rickets. Functional studies have demonstrated that DMP1 is essential in the maturation of odontoblasts and osteoblasts, as well as in mineralisation via local and systemic mechanisms [Feng et al., 2003]. Studies on DMP1 null mice suggest that DMP1 may also be an important factor in the regulation of the osteocyte response to load, ablation of DMP1 may lead to pathological response to physiological mechanical loading, such as mastication leading to greater bone loss. This, combined with the lack of support by the defective alveolar bone and cementum due to the absence of DMP1, may exacerbate bony defects [Ye et al., 2008]. The above might explain the mechanism of the periodontal defects seen in our patient, and may alert clinicians working with hypophosphatemic patient of the possibility of occurrence of such defects.

Aggressive periodontitis is a well-known entity that affects a small percentage of otherwise healthy children. However, when aggressive periodontits is detected in a child, it is recommended to consult with a paediatrician to rule out systemic disease. Many systemic diseases are associated with advanced alveolar bone loss that may lead to premature loss of teeth, such as hypophosphatesia, Papillon-Lefevre syndrome, histiocytosis X, agranulocytosis, leukocyte adherence deficiency, neutropenias, leukemias, diabetes mellitus, scleroderma, fibrous dysplasia, acrodynia, and Chediak-Higashi syndrome [Armitage, 1999].

While the periodontal findings in our patient may be coincidental, the atypical presentation as well as the possible association with DMP1 in the aetiology of HR raises concerns, and may alert clinicians and researchers in this field to be aware of the possibility of such associations.

The boy described herein is the first case report in the literature of a patient with HR and aggressive periodontitis. One study in China [Ji-mei et al., 2007] has reported a three-year-old child with HR, excessive mobility of many primary teeth and spontaneous loss of maxillary primary central incisors with no evidence of caries, trauma or abscesses. However those authors did not elaborate on the possible cause of early tooth loss in that child. Goodman et al. [1998] described dental problems in 17 HR patients and mentioned that one of the children in her sample was a 4 year old child presenting with mobile primary teeth for which they did not give an explanation.

The child in the present case report was diagnosed late (at age 9 years); his medical record revealed that phosphate therapy was started only 4 years previously. The delay in treatment may have caused some periodontal defects as seen in the mouse models of HR [Ye et al., 2008], this coupled with poor oral hygiene may account for the clinical picture described in this child. The periodontal findings in this case are unique, teeth were lost due to excessive mobility mimicking aggressive periodontitis, however, periodontal and radiographic examination revealed that both attachment levels and crestal bone heights are not those characteristic of aggressive periodontitis where severe bone and attachment loss are the most common features. This leads to the assumption that tooth loss in this case occurred due to a defect in alveolar bone and cementum leading to detachment between PDL and cementum with bacteria playing a secondary role here as was described in DMP1 null mice [Ye et al., 2008].

The bone loss and furcation involvement associated with teeth 36 and 46 are most likely due to caries and endodontic European Archives of Paediatric Dentistry 12 (Issue 1). 2011 involvements. The presence of probing depth in areas where there was no attachment loss is due to false pocketing resulting from gingival inflammation.

Genetic testing was not carried out for this child due to institutional limitations in the availability of the primer for this kind of test at the time of making the report. Nevertheless, the clinical presentation suggests a possible association with loss of DMP1, and therefore may indicate that the child has the recently identified autosomal recessive type of HR.

Reports on dental manifestations of HR in the literature suggest that the mechanism of spontaneous dental abscesses often related to this disease is due to ingress of bacteria through the defective globular dentine after loss of enamel through attrition [Seow and Latham, 1986], however Goodman et al. [1998] could not explain the route of ingress of bacteria in many of the abscessed permanent teeth in their sample]. Accordingly, we propose another possible route for bacterial ingress into the furcation and periapical areas that is through the periodontal defects, however further studies are needed to validate this assumption.

Conclusion

Spontaneous loss of teeth in the absence of abscess formation is not one of the reported features of HR, however, this report may alert clinicians of the possibility of such association especially in the autosomal recessive type. Further case reports and more elaborate genetic and molecular testing is needed to verify this especially in late diagnosis cases.

Acknowledgements

The authors would like to acknowledge Dr. Yasmine El-Naimi for her help in examination of the case.

References

Armitage GC. Development of a Classification System for Periodontal Diseases and Conditions. Ann Periodontol 1999; 4 : 1-6.

Assadi F. Hypophosphatemia An Evidence-based Problem-Solving Approach to Clinical Cases. Iranian Journal of Kidney Diseases 2010; 4:

Farach-Carson MC, Nemere I. Membrane receptors for vitamin D steroid hormones: potential new drug targets. Curr Drug Targets 2003; 4: 67-76.

Feng JQ, Huang H, Lu Y, et al. The Dentin matrix protein 1 (Dmp1) is specifically expressed in mineralized, but not soft, tissues during development. J Dent Res 2003; 82: 776-780.

Feng JQ, Ward LM, Liu S, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 2006; 38: 1310-1315.

Goodman JR, Gelbier MJ, Bennett JH, Winter GB. Dental problems associated with hypophosphataemic vitamin D resistant rickets. Int J Pediatr Dent 1998; 8: 19-28.

Ji-mei SU, Yun LI, Xiao-wei YE, Zhi-fang WU. Oral findings of hypophosphatemic vitamin D-resistant rickets: report of two cases Chin Med J 2007; 120: 1468-1470

Lorenz-Depiereux B, Bastepe M, Benet-Pages A, et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of Phosphate homeostasis. Nat Genet 2006; 38: 1248-1250.

Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom T. Loss-of Function ENPP1 Mutations Cause Both Generalized Arterial Calcification of Infancy and Autosomal-Recessive Hypophosphatemic Rickets. Am J Hum Genet. 2010 February 12; 86(2): 267-272

Negri AL. Hereditary hypophosphatemias: New genes in the bone-kidney axis. Journal Asian Pacific Society of Nephrology. 2007; 12: 317-320.

Qin C, Baba O, Butler WT. Post-translational modifications of sibling proteins and their roles in osteogenesis and dentinogenesis. Crit Rev Oral Biol Med. 2004; 15:126-36

Rowe OS. The molecular background to hypophosphatemic rickets. Arch Dis Child 2000; 83:192-4.

Rowe OS, de Zoysa PA, Dong R, et al. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. Genomics. 2000; 67: 54-68.

Seow WK, Latham SC. The spectrum of dental manifestations in vitamin Dresistant rickets: implications for management. Pediatr Dent 1986; 8: 245-50.

Whyte MP, Thakke RV. Rickets and osteomalacia . The Medicine Publishing Company Ltd 2005; 33:70-74.

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S.H. Al-Jundi *, M.M. Hammad *, I. Dabous **

* Dept. Preventive Dentistry, Jordan University of Science and Technology, Irbid, ** Private specialist practice, Amman, Jordan.

Postal address: Dr S.H.S. Al-Jundi. PO Box 810053, Irbid 22110, Jordan.

Email: aljundisuhad@yahoo.com
Table 1. Periodontal chart recording of patient with hypophosatemic
rickets.

Mailla      Mobility         X     0     2     0     X     1     X

            Clinical         X     0     0     0     X     5     X
            attachment
            loss

            Buccal PD        X     2     4     4     X     2     X

            Tooth           18    17    16    15    14    13    12
            number

            Ligual PD        X     2     3     4     X     2     X

Mandible    Mobility         X     0     1     2     1     3     X

            Clinical         X     0     0     0     0     0     X
            attachment
            loss

            Buccal PD        X     2     3     3     3     2     X

            Tooth           48    47    46    45    44    43    42
            number

            Ligual PD        X     2     2     2     2     2     X

Mailla      Mobility         1     X     X     1     1     X     2

            Clinical         1     X     X     2     2     X     1
            attachment
            loss

            Buccal PD        2     X     X     2     2     X     2

            Tooth           11    21    22    23    24    25    26
            number

            Ligual PD        2     X     X     2     2     X     3

Mandible    Mobility         X     X     X     1     1     2     0

            Clinical         X     X     X     1     1     0     0
            attachment
            loss

            Buccal PD        X     X     X     2     2     3     5

            Tooth           41    31    32    33    34    35    36
            number

            Ligual PD        X     X     X     2     2     2     3

Mailla      Mobility         0     X

            Clinical         0     X
            attachment
            loss

            Buccal PD        4     X

            Tooth           27    28
            number

            Ligual PD        2     X

Mandible    Mobility         0     X

            Clinical         0     X
            attachment
            loss

            Buccal PD        3     X

            Tooth           37    38
            number

            Ligual PD        3     X

Mobility: According to Miller; Clinical attachment loss in mm;
PD: Probing depth in mm

Table 2. Characteristics of hypophosphatemic syndromes
as reported in the literature.

                        XLH                     ADHR

Prevalence              1 in 20,000             Rare
                        individuals

Serum phosphorous       Low                     Low

Serum calcium           Normal                  Normal

1,25[(OH).sub.2]D3      Normal/low              Normal/low

PTH                     Normal/high             Normal

TmP/GFR                 Decreased               Decreased

Urine calcium           Normal                  Normal

Dental defect           Dentine defects,        Dental abscesses
                        dental abscesses

Muscle weakness         Minimal                 Present

Inheritance             X-linked dominant       Autosomal dominant

Penetrance              Complete with           Incomplete, delayed
                        variable expression.    onset reversion.

Chromosome              Xp22.1                  12p13

Gene                    PHEX                    FGF23

                        ARHR                    HHRH

Prevalence              Rare                    Rare, 1 large
                                                kindred, 4 small
                                                kindreds, several
                                                sporadic cases

Serum phosphorous       Low                     Low

Serum calcium           Normal                  Normal/high

1,25[(OH).sub.2] D3     Normal/low              High

PTH                     Normal                  Suppressed

TmP/GFR                 Decreased               Decreased

Urine calcium           Normal                  Elevated

Dental defect           Not reported            None

Muscle weakness         Not reported            Present

Inheritance             Autosomal recessive     Autosomal recessive

Penetrance              Variable                Variable

Chromosome              Unknown                 Unknown

Gene                    DMP1                    SLC34C3
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