ALPL – Odontohypophosphatasia

Odontohypophosphatasia is a mild form of hypophosphatasia characterized by premature exfoliation of primary teeth and low serum tissue-nonspecific alkaline phosphatase (Gene Symbol; Disease Name). Two unrelated pediatric probands have been described with oral-only manifestations and pathogenic ALPL variants. In one, a 2-year-old girl with deciduous tooth mobility and low ALP (253 U/L) harbored a de novo heterozygous missense mutation and responded partially to asfotase alfa enzyme replacement therapy(PMID:32694888). In another, a 4-year-old boy with premature primary tooth loss was compound heterozygous for c.346G>A (p.Ala116Thr) and c.1563C>G (p.Ser521Arg), with asymptomatic heterozygous carrier status in one sibling(PMID:37408354).

The inheritance pattern is primarily autosomal recessive, although heterozygous variants may manifest a dominant effect in some pedigrees. Segregation analysis in one family showed at least 3 additional affected relatives with low ALP and fracture history. The variant spectrum in odonto-HPP includes missense changes; c.346G>A (p.Ala116Thr) is recurrent in dominant pedigrees. Functional data specific to odonto-HPP are limited, but asfotase alfa therapy prevented tooth mobility when started early([PMID:32694888]).

Clinical Validity

ClinGen Classification: Limited
Rationale: Two unrelated probands with odonto-HPP carrying ALPL variants, segregation in one family([PMID:32694888], [PMID:37408354]).

Genetic Evidence

Tier: Limited
Rationale: Identification of 3 pathogenic ALPL variants in 2 probands; compound heterozygosity in one and a de novo heterozygote in another, with segregation in a single pedigree([PMID:32694888], [PMID:37408354]).

Functional Evidence

Tier: Limited
Rationale: Efficacy of recombinant alkaline phosphatase (asfotase alfa) in preventing deciduous tooth exfoliation in odonto-HPP when administered early([PMID:32694888]).

Key Take-home: ALPL sequencing should be considered in children with isolated premature loss of primary teeth, as early enzyme replacement can mitigate dental complications.

References

• Clinical Pediatric Endocrinology • 2020 • Odontohypophosphatasia treated with asfotase alfa enzyme replacement therapy in a toddler: a case report. PMID:32694888
• Journal of Clinical Pediatric Dentistry • 2023 • Odontohypophosphatasia caused by a novel combination of two heterozygous variants: a case report. PMID:37408354

Evidence Based Scoring (AI generated)