Hypophosphatasia

Hypophosphatasia is a highly variable genetic condition that features anomalies in the bone and/or tooth mineralisation, caused by a deficiency of tissue-nonspecific alkaline phosphatase. Presentations range from severe bone mineralisation anomalies that result in stillbirth to pathological fractures in adulthood.

Clinical features vary widely but may include:

• features of infantile rickets (such as growth failure, bowed legs, hypotonia, blue sclerae, flail chest, craniosynostosis and thickened ankles, knees and/or wrists);
• fractures, which in neonatal cases can be mistaken for osteogenesis imperfecta, making it key to test alkaline phosphatase (ALP) levels;
• dental caries;
• bone pain;
• early loss of deciduous (primary or ‘baby’) teeth – the dental root often remains attached to the lost tooth; and
• seizures that are responsive to pyridoxine (vitamin B6).

Atypical laboratory findings may include:

• hypercalciuria;
• reduced serum unfractionated alkaline phosphatase (ALP) activity – serial measurements may be necessary (whereas in rickets the ALP is often elevated);
• elevated plasma pyridoxine (vitamin B6);
• elevated serum pyridoxal 5′-phosphate (PLP);
• elevated urine inorganic pyrophosphate (PPi); and
• plasma calcium and phosphate levels that are normal or elevated (whereas in X-linked hypophosphatemia the plasma phosphate levels are low).

Radiographic features may include:

• prenatally recognised bowing of the long bones, with osteochondral spurs and under-mineralised bones;
• signs of infantile rickets (such as under-mineralised bones, flared metaphyses, bowing of the long bones, widened sutures and craniosynostosis);
• metaphyseal focal bony anomalies that resemble ‘tongues’;
• bone mineralisation anomalies, with or without teeth mineralisation; and
• pathological fractures.

Hypophosphatasia has a spectrum with seven recognised clinical forms. The list below outlines these clinical forms, which are typically based on the age of diagnosis and the severity of presentation, and each of their distinguishing features.

• Perinatal (severe): pulmonary insufficiency and hypercalcaemia.
• Perinatal (benign): manifests prenatally – and can be mistaken for a more severe or even lethal form – but slowly resolves into one of the milder clinical forms.
• Infantile: onset up to six months of age and has clinical features of rickets with elevated serum alkaline phosphatase (ALP).
• Severe childhood (juvenile): variable presentation, progresses to rickets.
• Mild childhood: increased chance of fractures, premature loss of primary teeth (roots remain intact) and low bone mineral density for age.
• Adult: stress fractures and pseudofractures of lower extremities in middle age, may have early loss of adult teeth and may have had transient rickets in childhood.
• Odontohypophosphatasia: premature exfoliation of primary teeth, severe dental caries and no wider skeletal features.

Clinical, laboratory and radiographic features may indicate the diagnosis of hypophosphatasia, but there are currently no consensus clinical diagnostic criteria.

Hypophosphatasia is caused by pathogenic variants in the ALPL gene, which encodes alkaline phosphatase, a tissue-specific isoenzyme present in the liver, kidney and bone. Pathogenic variants are typically distributed throughout the gene with the majority (over 70%) being missense. Deletions, frameshifts, splice variants and small insertions/deletions (indels) are also reported.

There is no well-established genotype-phenotype relationship, and a combination of different variants with, for example, compound heterozygous inheritance, can lead to highly variable clinical expression.

For information about testing, please see Presentation: Child with suspected hypophosphatasia.

Hypophosphatasia can be an autosomal dominant  or an autosomal recessive condition.

Perinatal and infantile hypophosphatasia more typically show autosomal recessive inheritance. If both parents are carriers, there is a 25% chance of each child being affected, although they may have a variable presentation.

Adult onset and/or milder forms of hypophosphatasia may be dominant or recessive. In dominant forms, reduced penetrance may occur, contributing to greater interfamilial variation. Where a parent is affected, there is a 50% chance of each child inheriting the pathogenic variant, although expression and penetrance can vary.

Accurate genomic counselling relies on the identification of the causative pathogenic variant(s) in the family. Referral to clinical genetics is suggested.

Management of children with hypophosphatasia is complex and should be delivered via a multidisciplinary team, with monitoring of skeletal features, dentition and calcium homeostasis. Depending on the severity of the condition, different interventions may be useful. Children with severe forms of the condition can be referred for recombinant enzyme therapy.

For clinicians

• GeneReviews: Hypophosphatasia
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• Skeletal Dysplasia Management Consortium: Best practice guidelines
• Skeletal Dysplasia Group (promotes teaching and research)
• US National Library of Medicine: ClinicalTrials.gov database

References:

• Firth HV, Hurst JA. ‘Oxford Desk References: Clinical Genetics and Genomics, second edition’. Oxford University Press 2017: pages 158–159. DOI: 10.1093/med/9780199557509.001.0001

For patients

• Soft Bones UK