Hyperphosphatasia with mental retardation syndrome 1 (HPMRS1)

(OMIM phenotype number #239300)

Hyperphosphatasia with mental retardation syndrome (HPMRS), also called "Mabry syndrome", is a rare autosomal recessive form of intellectual disability, with facial dysmorphism, seizures, brachytelephalangy, and consistently elevated serum alkaline phosphatase (ALP).
HPMRS type 1 is caused by homozygous or compound heterozygous mutation in the PIGV gene, which is a member of the glycosylphosphatidylinositol (GPI) anchor synthesis pathway. PIGV mutations leads to a defect in GPI anchor synthesis with a consequent reduction in the level of GPI-anchored substrates such as ALP localized at the cell surface. PIGV mutations have been reported in eight families affected by HPMRS1 so far.

Gene

PIGV gene, 1p36.11 (OMIM gene/locus number #610274)

Phenotype

Mental retardation, various neurologic abnormalities such as seizures and hypotonia, facial dysmorphism, variable degrees of hypoplastic terminal phalanges (brachytelephalangy). Midface hypoplasia, prognathism, hypertelorism, long palpebral fissures, arched eyebrows, broad nasal bridge and tip, cleft palate (rare), short philtrum, downturned corners of the mouth, tented mouth, ventral septal defect (rare), feeding problems necessitating tube feeding (in some patients), anteriorly displaced anus (in some patients), anovestibular fistula (in some patients), anorectal anomalies (in some patients), plagiocephaly, tapered fingers, hypoplastic toes (in some patients), bilateral adducted forefoot (rare), hypoplastic nails (in some patients), curved nails (in some patients), severe athetoid and dystonic hand movements (in some patients), moderate cortical atrophy (in some patients), delayed myelinization (in some patients), speech delay (in some patients), and no speech development (in most patients).

Main biochemical alterations:

High ALP, high Pi, normal Ca, markedly high ALP, high acid phosphatase, high uric acid.

Images

Fig. 1) Hand anomalies of patients with PIGV mutations. (a) Brachytelephalangy with missing and hypoplastic nails of fingers. (b) Hand radiograph showing hypoplastic distal phalanges. (c) Broad hallux and hypoplastic toenails. Reproduced by permission from Macmillan Publishers Ltd: Eur J Hum Genet 22(6):762-7, copyright 2014.

d e f

Fig. 2) (d, e, f) The distinct pattern of facial anomalies present in a patient with PIGV mutation consisted of wide-set eyes, often with a large appearance, a short nose with a broad nasal bridge and tip, and a tented upper lip.

Reproduced by permission from Macmillan Publishers Ltd: Eur J Hum Genet 22(6):762-7, copyright 2014


References

  1. Horn D, Wieczorek D, Metcalfe K et al. Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome. Eur J Hum Genet. 2014 Jun;22(6):762-7.
  2. Horn D, Krawitz P, Mannhardt A, et al. Hyperphosphatasia-mental retardation syndrome due to PIGV mutations: expanded clinical spectrum. Am J Med Genet A. 2011 Aug;155A(8):1917-22.
  3. Krawitz PM, Schweiger MR, Rödelsperger C, et al. Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome. Nat Genet. 2010 Oct;42(10):827-9.
  4. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  5. http://www.omim.org