Clinical, genetic, and molecular characterization of hyperphosphatasia with mental retardation: a case report and literature review

Diagn Pathol. 2019 Nov 4;14(1):123. doi: 10.1186/s13000-019-0902-5.


Background: Hyperphosphatasia with mental retardation syndrome (HPMRS) is a recessive disorder characterized by high blood levels of alkaline phosphatase together with typical dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and developmental delay. Genes involved in the glycosylphosphatidylinositol pathway and known to be mutated in HPMRS have never been characterized in the Lebanese population.

Case presentation: Herein, we describe a pair of monozygotic twins presenting with severe intellectual disability, distinct facial dysmorphism, developmental delay, and increased alkaline phosphatase level. Two individuals underwent whole exome sequencing followed by Sanger sequencing to confirm the co-segregation of the mutation in the consanguineous family. A biallelic loss of function mutation in PGAP3 was detected. Both patients were homozygous for the c.203delC (p.C68LfsX88) mutation and the parents were carriers confirming the founder effect of the mutation. High ALP serum levels confirmed the molecular diagnosis.

Conclusion: Our findings have illustrated the genomic profile of PGAP3-related HPMRS which is essential for targeted molecular and genetic testing. Moreover, we found previously unreported clinical findings such as hypodontia and skin hyperpigmentation. These features, together with the novel mutation expand the phenotypic and genotypic spectrum of this rare recessive disorder.

Keywords: Cleft palate; HPMRS; Lebanese population; PGAP3; Syndromic.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics*
  • Carboxylic Ester Hydrolases / genetics*
  • Humans
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Mutation / genetics*
  • Pedigree
  • Phenotype
  • Phosphorus Metabolism Disorders / diagnosis
  • Phosphorus Metabolism Disorders / genetics*
  • Receptors, Cell Surface / genetics*


  • Receptors, Cell Surface
  • Carboxylic Ester Hydrolases
  • PGAP3 protein, human

Supplementary concepts

  • Hyperphosphatasia with Mental Retardation