Hyperphosphatasia with mental retardation syndrome type 4 In two siblings-expanding the phenotypic and mutational spectrum

Eur J Med Genet. 2019 Jun;62(6):103535. doi: 10.1016/j.ejmg.2018.09.002. Epub 2018 Sep 11.


Hyperphosphatasia with mental retardation syndrome (HPMRS) (OMIM # 239300), is an autosomal recessive disease with phenotypic variability, ranging from mild nonsyndromic intellectual disability to syndromic form with severe intellectual disability, seizures, elevated alkaline phosphatase, brachytelephalangy and facial dysmorphism, Six subgroups of HPMRS were defined in which pathogenic mutations affect genes involved in either synthesis or remodeling of the anchor proteins. Among these, PGAP3 mutations are associated with HPMRS type 4. We report two siblings with a novel homozygous variant in PGAP3 expanding both the phenotypic findings and the mutational spectrum of HPMRS type 4. Developmental delay, hypotonia, facial dysmorphism were the consistent findings with HPMRS in our patients. Large anterior fontanel size, gum hypertrophy, pes equinovarus, concentric ventricle hypertrophy, frontoparietal atrophy and dysphagia were the findings of our patients that have been reported for the first time in this syndrome. Although there is an extensive list of differential diagnoses in patients with developmental delay and hypotonia, the recognizable pattern of facial features, parental consanguinity and mild to moderate serum ALP elevation should be sufficiently suggestive of HPMRS type 4.

Keywords: Alkaline phosphatase; Exome sequencing; Hyperphosphatasia with mental retardation; Intellectual disability; PGAP3.

Publication types

  • Case Reports

MeSH terms

  • Abnormalities, Multiple / blood
  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Alkaline Phosphatase / blood
  • Carboxylic Ester Hydrolases
  • Diagnosis, Differential
  • Female
  • Humans
  • Infant
  • Intellectual Disability / blood
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Male
  • Mutation*
  • Phenotype*
  • Phosphorus Metabolism Disorders / blood
  • Phosphorus Metabolism Disorders / genetics*
  • Phosphorus Metabolism Disorders / pathology
  • Receptors, Cell Surface / genetics*
  • Siblings


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

Supplementary concepts

  • Hyperphosphatasia with Mental Retardation