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Hyperphosphatasia with intellectual disability syndrome 1(HPMRS1)

MedGen UID:
1647044
Concept ID:
C4551502
Disease or Syndrome
Synonyms: GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 2; HPMRS1; HYPERPHOSPHATASIA WITH IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME 1; MABRY SYNDROME
 
Gene (location): PIGV (1p36.11)
 
Monarch Initiative: MONDO:0009398
OMIM®: 239300

Definition

Hyperphosphatasia with impaired intellectual development syndrome-1 (HPMRS1) is an autosomal recessive disorder characterized by impaired intellectual development, 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). The disorder is caused by a defect in glycosylphosphatidylinositol biosynthesis; see GPIBD1 (610293). Genetic Heterogeneity of Hyperphosphatasia with Impaired Intellectual Development Syndrome See also HPMRS2 (614749), caused by mutation in the PIGO gene (614730) on chromosome 9p13; HPMRS3 (614207), caused by mutation in the PGAP2 gene (615187) on chromosome 11p15; HPMRS4 (615716), caused by mutation in the PGAP3 gene (611801) on chromosome 17q12; HPMRS5 (616025), caused by mutation in the PIGW gene (610275) on chromosome 17q12; and HPMRS6 (616809), caused by mutation in the PIGY gene (610662) on chromosome 4q22. Knaus et al. (2018) provided a review of the main clinical features of the different types of HPMRS, noting that some patients have a distinct pattern of facial anomalies that can be detected by computer-assisted comparison, particularly those with mutations in the PIGV and PGAP3 genes. Individuals with HPMRS have variable increased in alkaline phosphatase (AP) as well as variable decreases in GPI-linked proteins that can be detected by flow cytometry. However, there was no clear correlation between AP levels or GPI-linked protein abnormalities and degree of neurologic involvement, mutation class, or gene involved. Knaus et al. (2018) concluded that a distinction between HPMRS and MCAHS (see, e.g., 614080), which is also caused by mutation in genes involved in GPI biosynthesis, may be artificial and even inaccurate, and that all these disorders should be considered and classified under the more encompassing term of 'GPI biosynthesis defects' (GPIBD). [from OMIM]

Additional description

From MedlinePlus Genetics
Another common feature of Mabry syndrome is shortened bones at the ends of fingers (brachytelephalangy), which can be seen on x-ray imaging. Underdeveloped fingernails (nail hypoplasia) may also occur. Sometimes, individuals with Mabry syndrome have abnormalities of the digestive system, including narrowing or blockage of the anus (anal stenosis or anal atresia) or Hirschsprung disease, a disorder that causes severe constipation or blockage of the intestine. Rarely, affected individuals experience hearing loss.

Hyperphosphatasia begins within the first year of life in people with Mabry syndrome. There are many different types of alkaline phosphatase found in tissues; the type that is increased in Mabry syndrome is called the tissue non-specific type and is found throughout the body. In affected individuals, alkaline phosphatase levels in the blood are usually increased by one to two times the normal amount, but can be up to 20 times higher than normal. The elevated enzyme levels remain relatively stable over a person's lifetime. Hyperphosphatasia appears to cause no negative health effects, but this finding can help health professionals diagnose Mabry syndrome.

The signs and symptoms of Mabry syndrome vary among affected individuals. Those who are least severely affected have only intellectual disability and hyperphosphatasia, without distinctive facial features or the other health problems listed above.

Individuals with Mabry syndrome have distinctive facial features that include wide-set eyes (hypertelorism), long openings of the eyelids (long palpebral fissures), a nose with a broad bridge and a rounded tip, downturned corners of the mouth, and a thin upper lip. These facial features usually become less pronounced over time.

People with Mabry syndrome have intellectual disability that is often moderate to severe. They typically have little to no speech development and are delayed in the development of motor skills (such as sitting, crawling, and walking). Many affected individuals have low muscle tone (hypotonia) and develop recurrent seizures (epilepsy) in early childhood. Seizures are usually the generalized tonic-clonic type, which involve muscle rigidity, convulsions, and loss of consciousness.

Mabry syndrome is a condition characterized by intellectual disability, distinctive facial features, increased levels of an enzyme called alkaline phosphatase in the blood (hyperphosphatasia), and other signs and symptoms.  https://medlineplus.gov/genetics/condition/mabry-syndrome

Clinical features

From HPO
Abnormal renal morphology
MedGen UID:
1633142
Concept ID:
C4551596
Anatomical Abnormality
Any structural anomaly of the kidney.
Tapered finger
MedGen UID:
98098
Concept ID:
C0426886
Finding
The gradual reduction in girth of the finger from proximal to distal.
Short toe
MedGen UID:
322858
Concept ID:
C1836195
Finding
A toe that appears disproportionately short compared to the foot.
Short distal phalanx of finger
MedGen UID:
326590
Concept ID:
C1839829
Finding
Short distance from the end of the finger to the most distal interphalangeal crease or the distal interphalangeal joint flexion point. That is, hypoplasia of one or more of the distal phalanx of finger.
Delayed ossification of carpal bones
MedGen UID:
374771
Concept ID:
C1841684
Finding
Ossification of carpal bones occurs later than age-adjusted norms.
Abnormal heart morphology
MedGen UID:
6748
Concept ID:
C0018798
Congenital Abnormality
Any structural anomaly of the heart.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Anteriorly placed anus
MedGen UID:
333160
Concept ID:
C1838705
Finding
Anterior malposition of the anus.
Abnormal rectum morphology
MedGen UID:
1757949
Concept ID:
C5399764
Anatomical Abnormality
An abnormaltiy of the rectum, the final segment of the large intestine that stores solid waste until it passes through the anus.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Athetosis
MedGen UID:
2115
Concept ID:
C0004158
Disease or Syndrome
A slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Athetosis involves continuous smooth movements that appear random and are not composed of recognizable sub-movements or movement fragments. In contrast to chorea, in athetosis, the same regions of the body are repeatedly involved. Athetosis may worsen with attempts at movement of posture, but athetosis can also occur at rest.
Aganglionic megacolon
MedGen UID:
5559
Concept ID:
C0019569
Disease or Syndrome
The disorder described by Hirschsprung (1888) and known as Hirschsprung disease or aganglionic megacolon is characterized by congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR) when aganglionosis extends proximal to the sigmoid (Amiel et al., 2008). Total colonic aganglionosis and total intestinal HSCR also occur. Genetic Heterogeneity of Hirschsprung Disease Several additional loci for isolated Hirschsprung disease have been mapped. HSCR2 (600155) is associated with variation in the EDNRB gene (131244) on 13q22; HSCR3 (613711) is associated with variation in the GDNF gene (600837) on 5p13; HSCR4 (613712) is associated with variation in the EDN3 gene (131242) on 20q13; HSCR5 (600156) maps to 9q31; HSCR6 (606874) maps to 3p21; HSCR7 (606875) maps to 19q12; HSCR8 (608462) maps to 16q23; and HSCR9 (611644) maps to 4q31-q32. HSCR also occurs as a feature of several syndromes including the Waardenburg-Shah syndrome (277580), Mowat-Wilson syndrome (235730), Goldberg-Shprintzen syndrome (609460), and congenital central hypoventilation syndrome (CCHS; 209880). Whereas mendelian modes of inheritance have been described for syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance. The development of surgical procedures decreased mortality and morbidity, which allowed the emergence of familial cases. HSCR occurs as an isolated trait in 70% of patients, is associated with chromosomal anomaly in 12% of cases, and occurs with additional congenital anomalies in 18% of cases (summary by Amiel et al., 2008).
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Delayed myelination
MedGen UID:
224820
Concept ID:
C1277241
Finding
Delayed myelination.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Finding
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Plagiocephaly
MedGen UID:
1825944
Concept ID:
C2081594
Finding
Asymmetric head shape, which is usually a combination of unilateral occipital flattening with ipsilateral frontal prominence, leading to rhomboid cranial shape.
Elevated circulating alkaline phosphatase concentration
MedGen UID:
727252
Concept ID:
C1314665
Finding
Abnormally increased serum levels of alkaline phosphatase activity.
Cleft upper lip
MedGen UID:
40327
Concept ID:
C0008924
Congenital Abnormality
A gap or groove in the upper lip. This is a congenital defect resulting from nonfusion of tissues of the lip during embryonal development.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Broad nasal tip
MedGen UID:
98424
Concept ID:
C0426429
Finding
Increase in width of the nasal tip.
Tented upper lip vermilion
MedGen UID:
326574
Concept ID:
C1839767
Finding
Triangular appearance of the oral aperture with the apex in the midpoint of the upper vermilion and the lower vermilion forming the base.
Long palpebral fissure
MedGen UID:
340300
Concept ID:
C1849340
Finding
Distance between medial and lateral canthi is more than two standard deviations above the mean for age (objective); or, apparently increased length of the palpebral fissures.
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Midface retrusion
MedGen UID:
339938
Concept ID:
C1853242
Anatomical Abnormality
Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.
Short nose
MedGen UID:
343052
Concept ID:
C1854114
Finding
Distance from nasion to subnasale more than two standard deviations below the mean, or alternatively, an apparently decreased length from the nasal root to the nasal tip.
Short philtrum
MedGen UID:
350006
Concept ID:
C1861324
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD below the mean. Alternatively, an apparently decreased distance between nasal base and midline upper lip vermilion border.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
Downturned corners of mouth
MedGen UID:
356471
Concept ID:
C1866195
Anatomical Abnormality
A morphological abnormality of the mouth in which the angle of the mouth is downturned. The oral commissures are positioned inferior to the midline labial fissure.
Highly arched eyebrow
MedGen UID:
358357
Concept ID:
C1868571
Finding
Increased height of the central portion of the eyebrow, forming a crescent, semicircular, or inverted U shape.
Cleft palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
Small nail
MedGen UID:
537942
Concept ID:
C0263523
Finding
A nail that is diminished in length and width, i.e., underdeveloped nail.
Hyperconvex nail
MedGen UID:
488894
Concept ID:
C0423807
Finding
When viewed on end (with the digit tip pointing toward the examiner's eye) the curve of the nail forms a tighter curve of convexity.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Abnormally large globe
MedGen UID:
344595
Concept ID:
C1855852
Finding
Diffusely large eye (with megalocornea) without glaucoma.

Recent clinical studies

Etiology

Knaus A, Pantel JT, Pendziwiat M, Hajjir N, Zhao M, Hsieh TC, Schubach M, Gurovich Y, Fleischer N, Jäger M, Köhler S, Muhle H, Korff C, Møller RS, Bayat A, Calvas P, Chassaing N, Warren H, Skinner S, Louie R, Evers C, Bohn M, Christen HJ, van den Born M, Obersztyn E, Charzewska A, Endziniene M, Kortüm F, Brown N, Robinson PN, Schelhaas HJ, Weber Y, Helbig I, Mundlos S, Horn D, Krawitz PM
Genome Med 2018 Jan 9;10(1):3. doi: 10.1186/s13073-017-0510-5. PMID: 29310717Free PMC Article
Abdel-Hamid MS, Issa MY, Otaify GA, Abdel-Ghafar SF, Elbendary HM, Zaki MS
Clin Genet 2018 Jan;93(1):84-91. Epub 2017 Aug 4 doi: 10.1111/cge.13033. PMID: 28390064
Horn D, Wieczorek D, Metcalfe K, Barić I, Paležac L, Cuk M, Petković Ramadža D, Krüger U, Demuth S, Heinritz W, Linden T, Koenig J, Robinson PN, Krawitz P
Eur J Hum Genet 2014 Jun;22(6):762-7. Epub 2013 Oct 16 doi: 10.1038/ejhg.2013.241. PMID: 24129430Free PMC Article

Diagnosis

Abi Farraj L, Khatoun WD, Abou Chebel N, Wakim V, Dawali K, Ghassibe-Sabbagh M
Diagn Pathol 2019 Nov 4;14(1):123. doi: 10.1186/s13000-019-0902-5. PMID: 31684969Free PMC Article
Fu L, Liu Y, Chen Y, Yuan Y, Wei W
BMC Pediatr 2019 Feb 27;19(1):68. doi: 10.1186/s12887-019-1440-8. PMID: 30813920Free PMC Article
Xue J, Li H, Zhang Y, Yang Z
Brain Dev 2016 Oct;38(9):807-18. Epub 2016 May 10 doi: 10.1016/j.braindev.2016.04.008. PMID: 27177984
Knaus A, Awaya T, Helbig I, Afawi Z, Pendziwiat M, Abu-Rachma J, Thompson MD, Cole DE, Skinner S, Annese F, Canham N, Schweiger MR, Robinson PN, Mundlos S, Kinoshita T, Munnich A, Murakami Y, Horn D, Krawitz PM
Hum Mutat 2016 Aug;37(8):737-44. Epub 2016 May 19 doi: 10.1002/humu.23006. PMID: 27120253Free PMC Article
Horn D, Wieczorek D, Metcalfe K, Barić I, Paležac L, Cuk M, Petković Ramadža D, Krüger U, Demuth S, Heinritz W, Linden T, Koenig J, Robinson PN, Krawitz P
Eur J Hum Genet 2014 Jun;22(6):762-7. Epub 2013 Oct 16 doi: 10.1038/ejhg.2013.241. PMID: 24129430Free PMC Article

Prognosis

Knaus A, Pantel JT, Pendziwiat M, Hajjir N, Zhao M, Hsieh TC, Schubach M, Gurovich Y, Fleischer N, Jäger M, Köhler S, Muhle H, Korff C, Møller RS, Bayat A, Calvas P, Chassaing N, Warren H, Skinner S, Louie R, Evers C, Bohn M, Christen HJ, van den Born M, Obersztyn E, Charzewska A, Endziniene M, Kortüm F, Brown N, Robinson PN, Schelhaas HJ, Weber Y, Helbig I, Mundlos S, Horn D, Krawitz PM
Genome Med 2018 Jan 9;10(1):3. doi: 10.1186/s13073-017-0510-5. PMID: 29310717Free PMC Article

Clinical prediction guides

Fu L, Liu Y, Chen Y, Yuan Y, Wei W
BMC Pediatr 2019 Feb 27;19(1):68. doi: 10.1186/s12887-019-1440-8. PMID: 30813920Free PMC Article
Knaus A, Pantel JT, Pendziwiat M, Hajjir N, Zhao M, Hsieh TC, Schubach M, Gurovich Y, Fleischer N, Jäger M, Köhler S, Muhle H, Korff C, Møller RS, Bayat A, Calvas P, Chassaing N, Warren H, Skinner S, Louie R, Evers C, Bohn M, Christen HJ, van den Born M, Obersztyn E, Charzewska A, Endziniene M, Kortüm F, Brown N, Robinson PN, Schelhaas HJ, Weber Y, Helbig I, Mundlos S, Horn D, Krawitz PM
Genome Med 2018 Jan 9;10(1):3. doi: 10.1186/s13073-017-0510-5. PMID: 29310717Free PMC Article
Xue J, Li H, Zhang Y, Yang Z
Brain Dev 2016 Oct;38(9):807-18. Epub 2016 May 10 doi: 10.1016/j.braindev.2016.04.008. PMID: 27177984

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