Elsevier

Bone

Volume 75, June 2015, Pages 229-239
Bone

Original Full Length Article
Hypophosphatasia: Validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients

https://doi.org/10.1016/j.bone.2015.02.022Get rights and content

Highlights

  • Hypophosphatasia (HPP) clinical nosology in children is validated and expanded.

  • Childhood HPP manifests in both a severe and a mild form.

  • TNSALP analysis clarifies dominant versus recessive prevalence of pediatric HPP.

  • TNSALP mutant allele dosage generally explains HPP severity.

  • The new pediatric HPP nosology will support natural history studies in children.

Abstract

Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) within the gene TNSALP that encodes the “tissue-nonspecific” isoenzyme of alkaline phosphatase (TNSALP). In HPP, inorganic pyrophosphate, an inhibitor of mineralization and substrate for TNSALP, accumulates extracellularly often leading to rickets or osteomalacia and tooth loss, and sometimes to craniosynostosis and calcium crystal arthropathies. HPP's remarkably broad-ranging expressivity spans stillbirth from profound skeletal hypomineralization to adult-onset dental problems or arthropathies without bone disease, which is largely explained by autosomal recessive versus autosomal dominant transmission from among several hundred, usually missense, TNSALP mutations. For clinical purposes, this expressivity has been codified according to absence or presence of skeletal disease and then patient age at presentation and diagnosis. Pediatric patients are reported principally with “odonto”, “childhood”, “infantile”, or “perinatal” HPP. However, this nosology has not been tested using a cohort of patients, and the ranges of the clinical and laboratory findings have not been defined and contrasted among these patient groups.

To evaluate the extant nosology for HPP in children, we assessed our 25 years experience with 173 pediatric HPP patients. Data were exclusively from inpatient studies. The childhood form of HPP was further designated “mild” or “severe”. Here, we focused on demographic, clinical, and dual-energy X-ray absorptiometry parameters compared to data from healthy American children.

The 173-patient cohort comprised 64 individuals with odonto HPP, 38 with mild childhood HPP, 58 with severe childhood HPP, and 13 with infantile HPP. None was a survivor of perinatal HPP. TNSALP analysis revealed a mutation(s) in all 105 probands tested. Thirteen mutations were unique. Most patients represented autosomal dominant inheritance of HPP. Mutant allele dosage generally indicated the disorder's severity. Gender discordance was found for severe childhood HPP; 42 boys versus 16 girls (p = 0.006), perhaps reflecting parental concern about stature and strength. Key disease parameters (e.g., height, weight, numbers of teeth lost prematurely, grip strength, spine and hip bone mineral density) were increasingly compromised as HPP was designated more severe. Although data overlapped successively between the four patient groups, body size (height and weight) differed significantly.

Thus, our expanded nosology for HPP in children organizes the disorder's broad-ranging expressivity and should improve understanding of HPP presentation, natural history, complications, and prognosis.

Introduction

Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) within the gene that encodes the “tissue-nonspecific” isoenzyme of alkaline phosphatase (TNSALP) [1]. Its biochemical hallmark, low serum ALP activity (hypophosphatasemia), reflects a generalized deficiency of TNSALP phosphohydrolase activity on cell surfaces, especially in the skeleton, liver, and kidney [2]. Consequently, TNSALP substrates accumulate extracellularly, including inorganic pyrophosphate (PPi) [3], [4], an inhibitor of mineralization [5], [6], and pyridoxal 5/-phosphate [7], one of the major intracellular bioactive forms of vitamin B6 [8]. The excess PPi can lead to rickets or osteomalacia, tooth loss, and calcium crystal arthropathies [1], [9]. When the TNSALP deficiency is profound, vitamin B6-dependent seizures may occur [10]. No approved medical therapy is available for HPP [11].

Following the first report of HPP in 1948 [12], sufficient numbers of affected individuals were described so that the disorder's clinical, radiological, biochemical, and histopathological features are now well documented [1]. Additionally, it is clear that HPP expressivity ranges remarkably, spanning from neonatal death due to profound skeletal hypomineralization [13] to dental or arthritic problems manifesting without bone disease in adult life [9], [14], [15]. We now understand that this expressivity is largely explained by autosomal recessive (AR) versus autosomal dominant (AD) transmission of at least 275 mutations (74% being missense) within TNSALP (ALPL) that encodes TNSALP [16], [17], [18], [19]. AR inheritance usually explains severe HPP, whereas AD or AR inheritance is found in mild HPP [1], [20].

To codify the expressivity of HPP, largely for prognostication and recurrence risk counseling, a clinical nosology has evolved since 1957 [21], [22], [23] consisting of five principal forms. In order of increasing severity, affected individuals are considered to have “odonto”, “adult”, “childhood”, “infantile”, and “perinatal” HPP [1], [2]. These five forms are distinguished first by absence or presence of skeletal disease, and second by patient age at HPP presentation and diagnosis [1], [23].

Odonto HPP refers to dental manifestations alone (see below) occurring in HPP [1], and can manifest at essentially any age. Clinical, radiographic, and biopsy evidence of rickets or osteomalacia is absent [1], [2].

Adult HPP typically presents during middle-age, although some patients recount premature loss of deciduous teeth or rickets during childhood [14], [15], [24], [25], [26], [27]. Then, osteomalacia can cause poorly-healing metatarsal stress fractures and sometimes painful femoral pseudofractures [14], [15], [25], [26]. Loss of adult teeth seems common [14], [15]. Generalized bone pain and further fractures can become debilitating [24].

Childhood HPP is diagnosed after six months-of-age [1], and features rickets [28] and premature painless exfoliation of one or more deciduous teeth with intact roots before age 5 years [29], [30], [31] due to insufficient mineralized cementum anchoring them to the periodontal ligament [1], [2]. The rickets may manifest only radiographically. Craniosynostosis can deform the skull and increase intracranial pressure. When childhood HPP is severe, a muscle weakness of unknown pathogenesis, but mimicking first-generation bisphosphonate (etidronate) toxicity [1], delays walking and other gross motor milestones and features a characteristic waddling gait [32].

Infantile HPP presents before six months-of-age [1], [33], [34], [35], [36]. Affected newborns appear healthy, but soon after often develop poor feeding, inadequate weight gain, hypotonia, wide fontanels, and rachitic deformities [11], [33], [34], [35], [36]. The blocked entry of minerals into the skeleton can lead to hypercalcemia and hypercalciuria and sometimes nephrocalcinosis, nephrolithiasis, and renal compromise [11]. If rapidly progressive skeletal demineralization causes chest deformity, death from pulmonary compromise is likely [11], [12], [33], [34], [35], [36], [37]. Vitamin B6-dependent seizures also predict a fatal outcome [10]. Functional craniosynostosis may occur. For those who survive infancy, there can be premature loss of the primary dentition, persisting rickets and deformity, bony craniosynostosis, and muscle weakness [1], although sometimes considerable improvement occurs [37].

Perinatal HPP is obvious by the end of pregnancy and at birth [13], [38]. Caput membranaceum, wide fontanels, short limbs, chest deformity, and respiratory distress reflect profound skeletal hypomineralization [38]. Survival is very rare. Perinatal HPP must be distinguished from distinctly milder “benign prenatal” HPP featuring skeletal disease detected by ultrasound in utero or at birth that is much less severe and undergoes spontaneous improvement with an outcome ranging from infantile to odonto HPP [23].

However, this nosology for HPP remains untested, and the natural history only for perinatal HPP [13] seems well understood. Also, the degree and range of severity for the various clinical disturbances are not defined for the different forms of HPP. Now, as medical treatment for HPP seems to be emerging [11], [39], a validated nosology will improve understanding of the disorder's presentation, course, complications, and prognosis.

Here, we assessed for children with HPP the extant as well as an expanded clinical nosology by contrasting key demographic, clinical, and bone densitometric findings acquired over 25 years with 173 pediatric patients.

Section snippets

Patients

The study cohort comprised all 173 pediatric patients (probands and affected siblings) with HPP investigated from September 1983 to December 2008 (i.e., 25 years) at the Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children; St. Louis, MO, USA (Research Center). Referral was required before age 18 years, with follow-up possible until age 21 years. All referred children were ambulatory except a two- and a three-year-old who were carried by their parents but later

Referrals

The 173 HPP patients were from the USA (n = 165), Canada (n = 6), Guatemala (n = 1), and England (n = 1), and represented 139 probands/families (Fig. 2). Ages at study ranged from 4 months to 21 years. One patient died — an American girl with infantile HPP complicated by pneumonia at age 9 months.

The referrals from within the USA consisted of 131 probands (165 patients) from 32 States. Twenty-five probands (40 patients) were from Missouri. The 106 American probands who lived outside of Missouri comprised

Discussion

Although the etiology, pathogenesis, and clinical and laboratory features of HPP are now largely understood [1], the prevailing nosology for organizing its remarkably broad-ranging expressivity remains mainly untested. This classification according to presence or absence of skeletal disease and patient age at presentation and diagnosis has nevertheless been used to discuss with HPP families the disorder's inheritance patterns and recurrence risks. Now, availability of TNSALP mutation analysis

Conflicts of interest and funding sources

Dr. Whyte reports consulting fees and research grant support from Enobia Pharma, Montreal, Canada, and Alexion Pharmaceuticals, Cheshire, CT, USA. Dr. Deborah Wenkert received consulting fees from Enobia Pharma, Montreal, Canada, and is now an employee of Amgen Inc., Thousand Oaks, CA, USA, where she has salary, stock, and stock options. All other authors report no conflict of interest. No funding source played a role in the study design; collecting, analyzing, and interpreting the data; or

Acknowledgments

Our report was made possible by the skill and dedication of the nursing, laboratory, dietary, radiology, and rehabilitation therapy services staff at the Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA. TNSALP mutation analysis was assisted by Jonathan Jones, Patrick Finnegan, Sara Banze, Michael Geimer, Xiafang Zhang, Margaret Huskey, and Shenghui Duan. We are grateful to Dr. Thomas Kelly (Hologic Incorporated, Waltham, MA) for

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  • Cited by (0)

    Presented in part at the 36th Annual Meeting of the American Society for Bone and Mineral Research, September 12–15, 2014, Houston, TX, USA [J Bone Miner Res 29 (Suppl 1): S-120, 2014].

    1

    Current address: Amgen, Inc. (Thousand Oaks, CA, USA).

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