Hyperphosphatasia with mental retardation syndrome-2 is an autosomal recessive disorder characterized by moderately to severely delayed psychomotor development, facial dysmorphism, brachytelephalangy, and increased serum alkaline phosphatase (hyperphosphatasia). Some patients may have additional features, such as cardiac septal defects ... Hyperphosphatasia with mental retardation syndrome-2 is an autosomal recessive disorder characterized by moderately to severely delayed psychomotor development, facial dysmorphism, brachytelephalangy, and increased serum alkaline phosphatase (hyperphosphatasia). Some patients may have additional features, such as cardiac septal defects or seizures (summary by Krawitz et al., 2012).
Krawitz et al. (2012) reported 2 sisters, born of unrelated British parents, and an unrelated girl with hyperphosphatasia with mental retardation. All 3 patients had normal birth parameters, but were born with anal stenosis or anal atresia with ... Krawitz et al. (2012) reported 2 sisters, born of unrelated British parents, and an unrelated girl with hyperphosphatasia with mental retardation. All 3 patients had normal birth parameters, but were born with anal stenosis or anal atresia with perineal fistula. One of the sisters had vesicoureteral reflux. The unrelated girl also had atrial septal defect, peripheral pulmonary stenosis, left coronal synostosis causing plagiocephaly, enlarged ventricles, and microcephaly (-5 SD). Two of the patients showed poor growth. Psychomotor development was moderately to severely retarded and all showed hypotonia. The unrelated girl died at age 22 months of severe generalized seizures. Common facial features in these patients included wide-set eyes with long palpebral fissures, short nose with broad nasal bridge and tip, and a tented mouth. Fingers showed nail hypoplasia, especially of the second, fourth, and fifth digits, and absent nails of the fifth digits. The halluces were broad, but the toes showed small nails or aplasia of nails, especially of the fourth and fifths digits, all findings consistent with brachytelephalangy. Serum alkaline phosphatase (ALP) activity was persistently elevated.
By exome sequencing of 2 sisters with HPMRS, Krawitz et al. (2012) identified compound heterozygosity for 2 mutations in the PIGO gene (614730.0001 and 614730.0002). Sequencing of this gene in 11 additional patients with a similar disorder identified ... By exome sequencing of 2 sisters with HPMRS, Krawitz et al. (2012) identified compound heterozygosity for 2 mutations in the PIGO gene (614730.0001 and 614730.0002). Sequencing of this gene in 11 additional patients with a similar disorder identified 1 patient who was compound heterozygous for 2 mutations (614730.0001 and 614730.0003). In vitro functional expression studies showed that the mutant proteins either lacked or had decreased functional activity. PIGO-deficient CHO cell lines had decreased cell surface placental ALP activity and increased secretion of ALP, which was rescued by transfection with wildtype PIGO. The findings indicated that hyperphosphatasia in the patients with mutations was a result of release of ALP into the serum due to a defect in glycosylphosphatidylinositol (GPI) anchoring to the cell membrane.