HPMRS1 is an autosomal recessive disorder characterized by mental retardation, various neurologic abnormalities such as seizures and hypotonia, and hyperphosphatasia. Other features include facial dysmorphism and variable degrees of brachytelephalangy (summary by Krawitz et al., 2010).
... HPMRS1 is an autosomal recessive disorder characterized by mental retardation, various neurologic abnormalities such as seizures and hypotonia, and hyperphosphatasia. Other features include facial dysmorphism and variable degrees of brachytelephalangy (summary by Krawitz et al., 2010). - Genetic Heterogeneity of Hyperphosphatasia with Mental Retardation Syndrome See also HPMRS2 (614749), caused by mutation in the PIGO gene (614730) on chromosome 9p13, and HPMRS3 (614207), caused by mutation in the PGAP2 gene (615187) on chromosome 11p15.
Mabry et al. (1970) reported 3 sibs and a first cousin with severe mental retardation, seizures, various neurologic abnormalities, and greatly elevated alkaline phosphatase. Both pairs of parents were consanguineous. The alkaline phosphatase present in excess seemed to ... Mabry et al. (1970) reported 3 sibs and a first cousin with severe mental retardation, seizures, various neurologic abnormalities, and greatly elevated alkaline phosphatase. Both pairs of parents were consanguineous. The alkaline phosphatase present in excess seemed to be of hepatic origin. Kruse et al. (1988) reported that over a 10-year period they had observed 9 children (6 females) from 6 families who had unexplained persistent hyperphosphatasia and mental retardation. Six of the patients had moderately delayed motor and speech development and 3 of these patients had seizures. The other 3 patients, including male identical twins, had severe primary delayed development and generalized muscular hypotonia since early infancy, with decreased tendon jerk. They also had severe seizures that were resistant to anticonvulsant drugs. One of the twins died at age 1.9 years of an unknown cause; autopsy revealed no evidence of macroscopic or microscopic brain lesions. Even at the age of 8 and 4 years, respectively, the other 2 patients were unable to sit, speak, or make emotional contact. Marcelis et al. (2007) reported 2 sisters, born to consanguineous Moroccan parents, with a syndrome of mental retardation, epilepsy, anteriorly displaced anus, hypoplastic terminal phalanges, hypoplastic nails, hypotonia, delayed myelinization in the brain, arched eyebrows, hypertelorism, and downturned corners of the mouth. The elder sister also had anovestibular fistula, and her nail hypoplasia was associated with hypoplasia of the distal phalanx of the fifth finger. The younger sister also had clefting of the hard and soft palates, and a small ventricular septal defect. Both sisters had elevated levels of alkaline phosphatase. Marcelis et al. (2007) noted similarities to Coffin-Siris syndrome (135900) but considered the disorder in the sibs to be distinct because neither sib had the coarse face and sparse scalp hair characteristic of Coffin-Siris syndrome. Horn et al. (2010) reported 3 sibs, a 4-year-old girl and dizygotic twin brothers, with a syndrome consisting of severe mental retardation, considerably elevated levels of alkaline phosphatase, hypoplastic terminal phalanges, and distinct facial features. Shortness of the distal phalanges was demonstrated both clinically and radiologically in all. The girl had Hirschsprung disease, both boys had hearing impairment, and 1 boy had macrocephaly and cleft lip/palate. Horn et al. (2010) suggested that their patients and those reported by Marcelis et al. (2007) and Rabe et al. (1991) had the same syndrome originally described by Mabry et al. (1970). Rabe et al. (1991) had suggested the diagnosis of Coffin-Siris syndrome in 2 sisters with hyperphosphatasia, severe mental retardation, brachytelephalangy, and facial features characterized by hypertelorism, long palpebral fissures, broad nasal bridge or tip, and a tented mouth. Horn et al. (2010) stated that all 7 patients had hyperphosphatasia, severe psychomotor retardation, the same facial gestalt, and brachytelephalangy. Five patients learned to walk, 2 were still not walking at 2 years and 9 years, and none had developed speech. Five patients had documented hypotonia and 3 of the 5 had seizures. Four patients had anorectal anomalies. Thompson et al. (2010) reported 5 patients, 2 sibs, 1 child of consanguineous patients, and 2 sporadic patients, with hyperphosphatasia, mental retardation, and seizures; one of the patients had previously been reported by Thompson et al. (2006). All had similar facial dysmorphism characterized by hypertelorism, broad nasal bridge, and a tented mouth. All had some degree of brachytelephalangy, but the phalangeal shortening varied in position and degree. In all there was a persistent elevation of alkaline phosphatase activity with no evidence of active bone or liver disease. The degree of hyperphosphatasia varied considerably between patients (1.3 to 20 times the upper age-adjusted reference limit), but was relatively constant over time. All 5 patients were products of a normal pregnancy and birth history. None of the patients had growth delay, 2 had macrocephaly, 2 had normocephaly, and 1 had microcephaly. All had moderate to severe psychomotor retardation, hypotonia in the first year of life, and seizures with age of onset ranging from less than 1 month to 7 years. Of 2 patients tested, seizures were pyridoxine-responsive in one but not in the other. One patient had autistic behavior. Thompson et al. (2010) commented that at least 1 member of the family reported by Mabry et al. (1970) was found to have intracellular inclusions on biopsy of some but not all tissues; inclusions were found in a rectal biopsy, tooth, and liver. Thompson et al. (2010) found similar inclusions in only some tissues of 3 of their patients; patients 1 and 5 had inclusions in fibroblasts, and patient 2 had inclusions in osteoblasts and fibroblasts. The intracellular storage material was not identified. Thompson et al. (2010) stated that hyperphosphatasia and the presence of intracellular inclusions distinguish this disorder and suggested the designation Mabry syndrome. Krawitz et al. (2010) reported a family in which 3 sibs, including a pair of dizygotic twin boys, had the hyperphosphatasia mental retardation syndrome. They were born of nonconsanguineous German parents. All had severe global developmental delay without any speech development, and characteristic facies, including hypertelorism, large appearing eyes, short nose with broad nasal bridge and tip, and thin upper lip with downturned corners of the mouth. Several distal phalanges, particularly digits II and V, were shortened. One patient had seizures. Alkaline phosphatase was persistently elevated in all 3 patients. Horn et al. (2011) reported 2 unrelated patients with hyperphosphatasia mental retardation syndrome confirmed by genetic analysis. One was of German and Dutch/Polish origin and the other was of Polish origin. Both patients had developmental delay, brachytelephalangy, hyperphosphatasia, and a facial gestalt, including hypertelorism, long palpebral fissures, broad nasal bridge and tip, and tented mouth. One patient had a more severe phenotype with hypotonia, seizures, lack of speech, inability to walk, hearing impairment, Hirschsprung disease, and cleft palate. The other patient had anal atresia and a small atrial septal defect.
Using whole-exome capture and sequencing in combination with a Hidden Markov Model algorithm to detect regions of the genome that are identical by descent, Krawitz et al. (2010) identified a homozygous mutation in the PIGV gene (A341E; 610274.0001) ... Using whole-exome capture and sequencing in combination with a Hidden Markov Model algorithm to detect regions of the genome that are identical by descent, Krawitz et al. (2010) identified a homozygous mutation in the PIGV gene (A341E; 610274.0001) in 3 German sibs with the hyperphosphatasia mental retardation syndrome. Further study of this gene identified homozygous or compound heterozygous mutations (610274.0001-610274.0004) in affected individuals from 3 additional families, including those reported by Rabe et al. (1991) and Marcelis et al. (2007), as well as in 1 patient reported by Thompson et al. (2010).