Multigenerational case examples of hypophosphatasia: Challenges in genetic counseling and disease management

Abstract

Hypophosphatasia (HPP) is an inherited metabolic condition caused by pathogenic mutations in the ALPL gene. This leads to deficiency of tissue non-specific alkaline phosphatase (TNSALP), resulting in decreased mineralization of the bones and/or teeth and multi-systemic complications. Inheritance may be autosomal dominant or recessive, and the phenotypic spectrum, including age of onset, varies widely. We present four families demonstrating both modes of inheritance of HPP and phenotypic variability and discuss the resultant challenges in disease management, genetic counseling, and risk assessment. Failure to consider different modes of inheritance in a family with HPP may lead to an inaccurate risk assessment upon which medical and reproductive decisions may be made. We highlight the essential role of high-quality genetic counseling and meaningful biochemical and molecular testing strategies in the evaluation and management of families with HPP.

Keywords: ALPL gene; Alkaline phosphatase; Dominant inheritance; Family history; Genetic counseling; Hypophosphatasia; Recessive inheritance.

Fig. 1

Family #1 pedigree demonstrating AD inheritance in generations I and II and AR inheritance in generation III.

Fig. 2

Family #2 pedigree demonstrating suspected AD inheritance in generations II and III and AR inheritance in generation IV.

Fig. 3

Family #3 Pedigree demonstrating suspected AD inheritance in generation II and AR inheritance in generation III.

Fig. 4

Family #4 pedigree demonstrating AR inheritance in generations II and III with variable expressivity among affected individuals with the same genotype.