Childhood hypophosphatasia and the premature loss of teeth: A clinical and laboratory study of seven cases

doi:10.1016/0030-4220(73)90028-5

Oral Surgery, Oral Medicine, Oral Pathology

Volume 35, Issue 5, May 1973, Pages 631-640

Oral Surgery, Oral M...

https://doi.org/10.1016/0030-4220(73)90028-5 Get rights and content

Abstract

Hypophosphatasia, an inheritable metabolic disease, causes a premature loss of deciduous teeth. Because of the early dental exfoliation, the dentist is often consulted first. The diagnosis can be established by certain clinical features, x-ray findings, and chemical abnormalities. The childhood form of the disease is self-limiting and does not require treatment.

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Cited by (60)

Dental manifestation and management of hypophosphatasia
2022, Japanese Dental Science Review
Citation Excerpt :
It has been speculated that the reason why primary anterior teeth rather than posterior teeth tend to be lost is because they have a single, short root, erupt earlier, and are more susceptible to lateral forces than posterior teeth [22]. Early exfoliation of primary teeth is caused by poor mineralization of cementum due to low ALP activity (Fig. 3) [22,25,27,53–56]. Cementum of the teeth and alveolar bone are connected via the periodontal ligament [58].
Hypophosphatasia is an inherited metabolic disorder characterized by defective mineralization of bones and teeth with a wide variety of manifestations, ranging from stillbirth to dental symptoms alone. Recently, the prognosis of severe hypophosphatasia patients has been greatly improved by the introduction of enzyme replacement therapy. The typical dental manifestation is early exfoliation of primary teeth due to disturbed cementum formation, so dentures are recommended to ensure that important oral functions are acquired. Some studies have shown that enzyme replacement therapy improves dental mineralization, resulting in the stabilization of periodontal tissues and better growth of tooth roots. A nationwide Japanese survey revealed the common genetic and dental manifestations of patients with mild hypophosphatasia, which markedly differ from those of the severe forms. There may be many undiagnosed mild patients, so dentists should contribute to the early diagnosis by screening possible cases based on the typical finding of early exfoliation of primary teeth. Early diagnosis is important for patients to receive early intervention in both medical and dental fields. The establishment of fundamental dental therapy to solve the dental problems is still underway and is eagerly anticipated.
Rickets and osteomalacia
2018, Encyclopedia of Endocrine Diseases
Defective mineralization of the skeleton results in rickets (affecting growth plates) and osteomalacia (affecting established bone). Effective mineralization requires adequate supply of minerals (calcium and phosphate), the hormone calcitriol which controls intestinal mineral absorption (calcitriol synthesized from vitamin D), and enzymes that aid mineralization (alkaline phosphatase). A lack in any of the above can lead to rickets and osteomalacia. The underlying pathology in all forms of rickets is low phosphorus availability to hypertrophic growth plate chondrocytes and osteoblasts irrespective of the cause (calcipaenia, phosphopaenia and hypophosphatasia).
The most frequent and preventable calcipaenic cause of rickets/osteomalcia worldwide is “nutritional” resulting from deficient dietary calcium and/or deficient sunshine exposure leading to vitamin D deficiency. Calcipaenia affects a substantial proportion of mankind and serious pediatric manifestations only represent the tip of an iceberg, revealing widespread deficiency. Genetic conditions affecting calcitriol synthesis and action are rare and serve as fascinating examples to understand mineralization and bone physiology. The differential diagnosis of phosphopaenia and hypophosphatasaemia has advanced rapidly over the last 15 years. This has led to novel drug developments for X-linked hypophosphataemic rickets (XLH) and life-threatening hypophosphatasia (HPP). The rare bone diseases discussed here require management by bone specialists in tertiary centers.
Hypophosphatasia-associated deficiencies in mineralization and gene expression in cultured dental pulp cells obtained from human teeth
2012, Journal of Endodontics
Citation Excerpt :
In HPP, mutations in ALPL reduce TNAP function, resulting in skeletal mineralization defects including rickets and osteomalacia (3, 4). Dental case reports indicate defective cementum (5, 7, 18, 19), whereas dentin has been described as normal or variably affected (8–11). Here we began to bridge the gap between case reports on dentin pathology and a molecular understanding of how odontoblasts are affected by HPP.
Mutations in the gene ALPL in hypophosphatasia (HPP) reduce the function of tissue nonspecific alkaline phosphatase, and the resulting increase in pyrophosphate (PP_i) contributes to bone and tooth mineralization defects by inhibiting physiologic calcium-phosphate (P_i) precipitation. Although periodontal phenotypes are well documented, pulp/dentin abnormalities have been suggested in the clinical literature although reports are variable and underlying mechanisms remains unclear. In vitro analyses were used to identify mechanisms involved in HPP-associated pulp/dentin phenotypes.
Primary pulp cells cultured from HPP subjects were established to assay alkaline phosphatase (ALP) activity, mineralization, and gene expression compared with cells from healthy controls. Exogenous P_i was provided to the correct P_i/PP_i ratio in cell culture.
HPP cells exhibited significantly reduced ALP activity (by 50%) and mineral nodule formation (by 60%) compared with the controls. The expression of PP_i regulatory genes was altered in HPP pulp cells, including reduction in the progressive ankylosis gene (ANKH) and increased ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). Odontoblast marker gene expression was disrupted in HPP cells, including reduced osteopontin (OPN), dentin matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP), and matrix extracellular phosphoprotein (MEPE). The addition of P_i provided a corrective measure for mineralization and partially rescued the expression of some genes although cells retained altered messenger RNA levels for PP_i-associated genes.
These studies suggest that under HPP conditions pulp cells have the compromised ability to mineralize and feature a disrupted odontoblast profile, providing a first step toward understanding the molecular mechanisms for dentin phenotypes observed in HPP.
Hypophosphatasia
2012, Pediatric Bone
Hypophosphatasia is the rare, heritable form of rickets or osteomalacia that features low serum alkaline phosphatase (ALP) activity (hypophosphatasemia). Hypophosphatasemia in HPP is explained by a generalized reduction of activity of the “tissue-non-specific” isoenzyme of ALP (TNSALP) caused by loss-of-function mutation(s) within the TNSALP gene. The tissue-specific ALP isoenzyme genes are intact. In HPP, extracellular accumulation of the TNSALP substrate inorganic pyrophosphate (PPi), an inhibitor of mineralization, explains the skeletal disease. Characterization of this inborn error-of-metabolism verified a role for ALP in bone formation. The discoveries of elevated endogenous levels of three phospho compounds in HPP clarified the metabolic basis for this inborn-error-of-metabolism and the physiological role of TNSALP. HPP occurs worldwide. It is especially prevalent for inbred Mennonite families in Manitoba, Canada, where approximately 1 in 2500 newborns manifests severe disease, and approximately 1 in 25 individuals is a carrier. The prognosis for the various forms of HPP typically reflects the severity of the skeletal disease that corresponds with the age at presentation.
Hypophosphatasia
2011, Pediatric Bone: Biology and Diseases
Hypophosphatasia is the rare, heritable form of rickets or osteomalacia that features low serum alkaline phosphatase (ALP) activity (hypophosphatasemia). Hypophosphatasemia in HPP is explained by a generalized reduction of activity of the “tissue-non-specific” isoenzyme of ALP (TNSALP) caused by loss-of-function mutation(s) within the TNSALP gene. The tissue-specific ALP isoenzyme genes are intact. In HPP, extracellular accumulation of the TNSALP substrate inorganic pyrophosphate (PPi), an inhibitor of mineralization, explains the skeletal disease. Characterization of this inborn error-of-metabolism verified a role for ALP in bone formation. The discoveries of elevated endogenous levels of three phospho compounds in HPP clarified the metabolic basis for this inborn-error-of-metabolism and the physiological role of TNSALP. HPP occurs worldwide. It is especially prevalent for inbred Mennonite families in Manitoba, Canada, where approximately 1 in 2500 newborns manifests severe disease, and approximately 1 in 25 individuals is a carrier. The prognosis for the various forms of HPP typically reflects the severity of the skeletal disease that corresponds with the age at presentation.
Systemic disorders and their influence on the development of dental hard tissues: A literature review
2010, Journal of Dentistry
This report highlights the influence of a number of disorders with systemic physiological effects that impact on the development of dental hard tissues. It focuses in particular, on the pathological effects of systemic conditions with less well recognised, but no less important, impacts on dental development. Such conditions, include cystic fibrosis, HIV/AIDS, leukaemia, Alstrom syndrome, hypophosphatasia, Prader-Willi syndrome, Tricho-dento-osseous syndrome, tuberous sclerosis, familial steroid dehydrogenase deficiency and epidermolysis bullosa. These, along with developmental and environmental causes of enamel and dentine defects, are discussed and the possible aetiology of such effects are proposed. Furthermore, the dental management and long-term dental care of these patients is outlined.
MEDLINE/PubMed.
Enamel and dentine defects can present with a wide spectrum of clinical features and may be caused by a variety of factors occurring throughout tooth development from before birth to adulthood. These may include host traits, genetic factors, immunological responses to cariogenic bacteria, saliva composition, environmental and behavioural factors and systemic diseases. These diseases and their spectrum of clinical manifestations on the organs affected (including the dentition) require an increased knowledge by dental practitioners of the disease processes, aetiology, relevant treatment strategies and prognosis, and must encompass more than simply the management of the dental requirements of the patient. It is important that the impact of the disease and its treatment, particularly in respect of immunosuppression where dental interventions may become life-threatening, is also taken into consideration.

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^∗: Assistant Professor of Oral Biology and Oral Diagnosis, School of Dentistry.

^∗∗: Associate Professor of Oral Biology and Pathology, School of Dentistry.

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Childhood hypophosphatasia and the premature loss of teeth: A clinical and laboratory study of seven cases

Abstract

Lancet

Am. J. Med

Oral Surg

Lancet

Lancet

Hypophosphatasia

Am. J. Dis. Child

Hypophosphatasia

Am. J. Roentgenol

Hypophosphatasia in the Adult

Am. J. Med

Hypophosphatasia in the Adult

Clin. Orthop