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Multiple congenital anomalies-hypotonia-seizures syndrome

MedGen UID:
1683744
•Concept ID:
C5191419
•
Disease or Syndrome
Synonyms: Congenital disorder of glycosylation due to PIGN (phosphatidylinositol glycan anchor biosynthesis class N) deficiency; Multiple congenital anomalies, hypotonia, seizures syndrome; multiple congenital anomalies-hypotonia-seizures syndrome; PIGN-CDG - phosphatidylinositol glycan anchor biosynthesis class N congenital disorder of glycosylation
SNOMED CT: Congenital disorder of glycosylation due to PIGN (phosphatidylinositol glycan anchor biosynthesis class N) deficiency (785303004); PIGN-CDG - phosphatidylinositol glycan anchor biosynthesis class N congenital disorder of glycosylation (785303004); Multiple congenital anomalies, hypotonia, seizures syndrome (785303004)
 
Related genes: PIGT, PIGN, PIGQ, PIGA
 
Monarch Initiative: MONDO:0100247
OMIM® Phenotypic series: PS614080

Definition

A rare genetic multiple congenital anomalies/dysmorphic syndrome with characteristics of severe global developmental delay, hypotonia, and early-onset seizures, associated with multiple congenital anomalies, such as cardiac (for example patent foramen ovale, atrial septal defect, patent ductus arteriosus), genitourinary (such as hydrocele, renal collecting system dilatation, hydroureter, hydronephrosis, hypertrophic trabecular urinary bladder) and gastrointestinal (including anal stenosis, imperforate anus, ano-vestibular fistula) abnormalities, as well as facial dysmorphism which includes coarse facies, a prominent occiput, bitemporal narrowing, epicanthal folds, hypertelorism, nystagmus/strabismus/wandering eyes, low-set, large ears with auricle abnormalities, depressed nasal bridge, upturned nose, long philtrum, large open mouth with thin lips, high-arched palate, and micro/retrognathia. Caused by homozygous mutation in the PIGN gene on chromosome 18q21. [from SNOMEDCT_US]

Professional guidelines

PubMed

Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.
Loong L, Tardivo A, Knaus A, Hashim M, Pagnamenta AT, Alt K, Böhrer-Rabel H, Caro-Llopis A, Cole T, Distelmaier F, Edery P, Ferreira CR, Jezela-Stanek A, Kerr B, Kluger G, Krawitz PM, Kuhn M, Lemke JR, Lesca G, Lynch SA, Martinez F, Maxton C, Mierzewska H, Monfort S, Nicolai J, Orellana C, Pal DK, Płoski R, Quarrell OW, Rosello M, Rydzanicz M, Sabir A, Śmigiel R, Stegmann APA, Stewart H, Stumpel C, Szczepanik E, Tzschach A, Wolfe L, Taylor JC, Murakami Y, Kinoshita T, Bayat A, Kini U
Genet Med 2023 Jan;25(1):37-48. Epub 2022 Nov 2 doi: 10.1016/j.gim.2022.09.007. PMID: 36322149
Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy.
Fleming L, Lemmon M, Beck N, Johnson M, Mu W, Murdock D, Bodurtha J, Hoover-Fong J, Cohn R, Bosemani T, Barañano K, Hamosh A
Am J Med Genet A 2016 Jan;170A(1):77-86. Epub 2015 Sep 23 doi: 10.1002/ajmg.a.37369. PMID: 26394714Free PMC Article

Recent clinical studies

Etiology

Asfotase alfa improved skeletal mineralization and fracture healing in a child with MCAHS.
Kang M, Wu M, Crane JL
Bone 2023 Jul;172:116778. Epub 2023 Apr 21 doi: 10.1016/j.bone.2023.116778. PMID: 37088336Free PMC Article
Rare multiple congenital anomalies-hypotonia-seizures syndrome type 1 (MCAHS1) - the clinical and molecular summary.
Bukowska-Olech E, Glista F, Dinwiddie A, Pepler A, Jamsheer A
Eur J Med Genet 2023 Jan;66(1):104668. Epub 2022 Nov 13 doi: 10.1016/j.ejmg.2022.104668. PMID: 36384198
Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.
Loong L, Tardivo A, Knaus A, Hashim M, Pagnamenta AT, Alt K, Böhrer-Rabel H, Caro-Llopis A, Cole T, Distelmaier F, Edery P, Ferreira CR, Jezela-Stanek A, Kerr B, Kluger G, Krawitz PM, Kuhn M, Lemke JR, Lesca G, Lynch SA, Martinez F, Maxton C, Mierzewska H, Monfort S, Nicolai J, Orellana C, Pal DK, Płoski R, Quarrell OW, Rosello M, Rydzanicz M, Sabir A, Śmigiel R, Stegmann APA, Stewart H, Stumpel C, Szczepanik E, Tzschach A, Wolfe L, Taylor JC, Murakami Y, Kinoshita T, Bayat A, Kini U
Genet Med 2023 Jan;25(1):37-48. Epub 2022 Nov 2 doi: 10.1016/j.gim.2022.09.007. PMID: 36322149
Analyzing clinical and genetic characteristics of a cohort with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS).
Jiao X, Xue J, Gong P, Bao X, Wu Y, Zhang Y, Jiang Y, Yang Z
Orphanet J Rare Dis 2020 Mar 27;15(1):78. doi: 10.1186/s13023-020-01365-0. PMID: 32220244Free PMC Article
A homozygous PIGN missense mutation in Soft-Coated Wheaten Terriers with a canine paroxysmal dyskinesia.
Kolicheski AL, Johnson GS, Mhlanga-Mutangadura T, Taylor JF, Schnabel RD, Kinoshita T, Murakami Y, O'Brien DP
Neurogenetics 2017 Jan;18(1):39-47. Epub 2016 Nov 28 doi: 10.1007/s10048-016-0502-4. PMID: 27891564Free PMC Article

Diagnosis

Rare multiple congenital anomalies-hypotonia-seizures syndrome type 1 (MCAHS1) - the clinical and molecular summary.
Bukowska-Olech E, Glista F, Dinwiddie A, Pepler A, Jamsheer A
Eur J Med Genet 2023 Jan;66(1):104668. Epub 2022 Nov 13 doi: 10.1016/j.ejmg.2022.104668. PMID: 36384198
Damaging novel mutations in PIGN cause developmental epileptic-dyskinetic encephalopathy: a case report.
Tian M, Chen J, Li J, Pan H, Lei W, Shu X
BMC Pediatr 2022 Apr 25;22(1):222. doi: 10.1186/s12887-022-03246-w. PMID: 35468813Free PMC Article
A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia-seizures syndrome 2 (MCAHS2) family pedigree via whole-exome sequencing.
Yang J, Wang Q, Zhuo Q, Tian H, Li W, Luo F, Zhang J, Bi D, Peng J, Zhou D, Xin H
Mol Genet Genomic Med 2018 Sep;6(5):739-748. Epub 2018 Jul 4 doi: 10.1002/mgg3.428. PMID: 29974678Free PMC Article
The phenotype of multiple congenital anomalies-hypotonia-seizures syndrome 1: report and review.
Couser NL, Masood MM, Strande NT, Foreman AK, Crooks K, Weck KE, Lu M, Wilhelmsen KC, Roche M, Evans JP, Berg JS, Powell CM
Am J Med Genet A 2015 Sep;167A(9):2176-81. Epub 2015 Apr 29 doi: 10.1002/ajmg.a.37129. PMID: 25920937Free PMC Article
Paroxysmal nocturnal hemoglobinuria.
Brodsky RA
Blood 2014 Oct 30;124(18):2804-11. Epub 2014 Sep 18 doi: 10.1182/blood-2014-02-522128. PMID: 25237200Free PMC Article

Therapy

Asfotase alfa improved skeletal mineralization and fracture healing in a child with MCAHS.
Kang M, Wu M, Crane JL
Bone 2023 Jul;172:116778. Epub 2023 Apr 21 doi: 10.1016/j.bone.2023.116778. PMID: 37088336Free PMC Article

Prognosis

Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.
Loong L, Tardivo A, Knaus A, Hashim M, Pagnamenta AT, Alt K, Böhrer-Rabel H, Caro-Llopis A, Cole T, Distelmaier F, Edery P, Ferreira CR, Jezela-Stanek A, Kerr B, Kluger G, Krawitz PM, Kuhn M, Lemke JR, Lesca G, Lynch SA, Martinez F, Maxton C, Mierzewska H, Monfort S, Nicolai J, Orellana C, Pal DK, Płoski R, Quarrell OW, Rosello M, Rydzanicz M, Sabir A, Śmigiel R, Stegmann APA, Stewart H, Stumpel C, Szczepanik E, Tzschach A, Wolfe L, Taylor JC, Murakami Y, Kinoshita T, Bayat A, Kini U
Genet Med 2023 Jan;25(1):37-48. Epub 2022 Nov 2 doi: 10.1016/j.gim.2022.09.007. PMID: 36322149
PIGN-Related Disease in Two Lithuanian Families: A Report of Two Novel Pathogenic Variants, Molecular and Clinical Characterisation.
Siavrienė E, Maldžienė Ž, Mikštienė V, Petraitytė G, Rančelis T, Dapkūnas J, Burnytė B, Benušienė E, Sasnauskienė A, Grikinienė J, Griškevičiūtė E, Utkus A, Preikšaitienė E
Medicina (Kaunas) 2022 Oct 26;58(11) doi: 10.3390/medicina58111526. PMID: 36363484Free PMC Article
A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia-seizures syndrome 2 (MCAHS2) family pedigree via whole-exome sequencing.
Yang J, Wang Q, Zhuo Q, Tian H, Li W, Luo F, Zhang J, Bi D, Peng J, Zhou D, Xin H
Mol Genet Genomic Med 2018 Sep;6(5):739-748. Epub 2018 Jul 4 doi: 10.1002/mgg3.428. PMID: 29974678Free PMC Article
A homozygous PIGN missense mutation in Soft-Coated Wheaten Terriers with a canine paroxysmal dyskinesia.
Kolicheski AL, Johnson GS, Mhlanga-Mutangadura T, Taylor JF, Schnabel RD, Kinoshita T, Murakami Y, O'Brien DP
Neurogenetics 2017 Jan;18(1):39-47. Epub 2016 Nov 28 doi: 10.1007/s10048-016-0502-4. PMID: 27891564Free PMC Article
Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy.
Fleming L, Lemmon M, Beck N, Johnson M, Mu W, Murdock D, Bodurtha J, Hoover-Fong J, Cohn R, Bosemani T, Barañano K, Hamosh A
Am J Med Genet A 2016 Jan;170A(1):77-86. Epub 2015 Sep 23 doi: 10.1002/ajmg.a.37369. PMID: 26394714Free PMC Article

Clinical prediction guides

Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.
Loong L, Tardivo A, Knaus A, Hashim M, Pagnamenta AT, Alt K, Böhrer-Rabel H, Caro-Llopis A, Cole T, Distelmaier F, Edery P, Ferreira CR, Jezela-Stanek A, Kerr B, Kluger G, Krawitz PM, Kuhn M, Lemke JR, Lesca G, Lynch SA, Martinez F, Maxton C, Mierzewska H, Monfort S, Nicolai J, Orellana C, Pal DK, Płoski R, Quarrell OW, Rosello M, Rydzanicz M, Sabir A, Śmigiel R, Stegmann APA, Stewart H, Stumpel C, Szczepanik E, Tzschach A, Wolfe L, Taylor JC, Murakami Y, Kinoshita T, Bayat A, Kini U
Genet Med 2023 Jan;25(1):37-48. Epub 2022 Nov 2 doi: 10.1016/j.gim.2022.09.007. PMID: 36322149
PIGN-Related Disease in Two Lithuanian Families: A Report of Two Novel Pathogenic Variants, Molecular and Clinical Characterisation.
Siavrienė E, Maldžienė Ž, Mikštienė V, Petraitytė G, Rančelis T, Dapkūnas J, Burnytė B, Benušienė E, Sasnauskienė A, Grikinienė J, Griškevičiūtė E, Utkus A, Preikšaitienė E
Medicina (Kaunas) 2022 Oct 26;58(11) doi: 10.3390/medicina58111526. PMID: 36363484Free PMC Article
Damaging novel mutations in PIGN cause developmental epileptic-dyskinetic encephalopathy: a case report.
Tian M, Chen J, Li J, Pan H, Lei W, Shu X
BMC Pediatr 2022 Apr 25;22(1):222. doi: 10.1186/s12887-022-03246-w. PMID: 35468813Free PMC Article
A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia-seizures syndrome 2 (MCAHS2) family pedigree via whole-exome sequencing.
Yang J, Wang Q, Zhuo Q, Tian H, Li W, Luo F, Zhang J, Bi D, Peng J, Zhou D, Xin H
Mol Genet Genomic Med 2018 Sep;6(5):739-748. Epub 2018 Jul 4 doi: 10.1002/mgg3.428. PMID: 29974678Free PMC Article
Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN.
Maydan G, Noyman I, Har-Zahav A, Neriah ZB, Pasmanik-Chor M, Yeheskel A, Albin-Kaplanski A, Maya I, Magal N, Birk E, Simon AJ, Halevy A, Rechavi G, Shohat M, Straussberg R, Basel-Vanagaite L
J Med Genet 2011 Jun;48(6):383-9. Epub 2011 Apr 14 doi: 10.1136/jmg.2010.087114. PMID: 21493957

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