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Holoprosencephaly 4(HPE4)

MedGen UID:
374488
•Concept ID:
C1840528
•
Disease or Syndrome
Synonym: HPE4
 
Gene (location): TGIF1 (18p11.31)
 
Monarch Initiative: MONDO:0007734
OMIM®: 142946

Definition

A rare disorder caused by mutations in the TGIF gene mapped to chromosome 18p11.3. It is characterized by semilobar holoprosencephaly, hypotelorism, and ptosis. [from NCI]

Clinical features

From HPO
Semilobar holoprosencephaly
MedGen UID:
199694
•Concept ID:
C0751617
•
Congenital Abnormality
A type of holoprosencephaly in which the left and right frontal and parietal lobes are fused and the interhemispheric fissure is only present posteriorly.
See: Feature record | Search on this feature
Absent nasal septal cartilage
MedGen UID:
867277
•Concept ID:
C4021638
•
Anatomical Abnormality
Lack of the cartilage of the nasal septum.
See: Feature record | Search on this feature
Depressed nasal bridge
MedGen UID:
373112
•Concept ID:
C1836542
•
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
See: Feature record | Search on this feature
Median cleft upper lip
MedGen UID:
342454
•Concept ID:
C1850256
•
Congenital Abnormality
A type of cleft lip presenting as a midline (median) gap in the upper lip.
See: Feature record | Search on this feature
Median cleft palate
MedGen UID:
340670
•Concept ID:
C1850968
•
Congenital Abnormality
Cleft palate of the midline of the palate.
See: Feature record | Search on this feature
Depressed nasal tip
MedGen UID:
347214
•Concept ID:
C1859717
•
Finding
Decreased distance from the nasal tip to the nasal base.
See: Feature record | Search on this feature
Ptosis
MedGen UID:
2287
•Concept ID:
C0005745
•
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
See: Feature record | Search on this feature
Hypotelorism
MedGen UID:
96107
•Concept ID:
C0424711
•
Finding
Interpupillary distance less than 2 SD below the mean (alternatively, the appearance of an decreased interpupillary distance or closely spaced eyes).
See: Feature record | Search on this feature
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Professional guidelines

PubMed

Pituitary stalk interruption syndrome: cause, clinical manifestations, diagnosis, and management.
Voutetakis A, Sertedaki A, Dacou-Voutetakis C
Curr Opin Pediatr 2016 Aug;28(4):545-50. doi: 10.1097/MOP.0000000000000378. PMID: 27386973
Etiopathogenetic advances and management of holoprosencephaly: from bench to bedside.
Bellone S, De Rienzo F, Prodam F, Savastio S, Busti A, Genoni G, Aimaretti G, Bona G
Panminerva Med 2010 Dec;52(4):345-54. PMID: 21183895
A new view of the neonatal brain: clinical utility of supplemental neurologic US imaging windows.
Di Salvo DN
Radiographics 2001 Jul-Aug;21(4):943-55. doi: 10.1148/radiographics.21.4.g01jl14943. PMID: 11452069

Recent clinical studies

Etiology

The rare malformation holoprosencephaly: pathogenesis, association with pregestational diabetes and the possible link with food pollutants.
Taruscio D, Mantovani A
Ann Ist Super Sanita 2023 Oct-Dec;59(4):295-303. doi: 10.4415/ANN_23_04_09. PMID: 38088397
Rhomboencephalosynapsis: Review of the Literature.
Fouda MA, Kim TY, Cohen AR
World Neurosurg 2022 Mar;159:48-53. Epub 2021 Dec 22 doi: 10.1016/j.wneu.2021.12.062. PMID: 34954057
Diagnosis of fetal non-chromosomal abnormalities on routine ultrasound examination at 11-13 weeks' gestation.
Syngelaki A, Hammami A, Bower S, Zidere V, Akolekar R, Nicolaides KH
Ultrasound Obstet Gynecol 2019 Oct;54(4):468-476. doi: 10.1002/uog.20844. PMID: 31408229
Monosomy 18p.
Turleau C
Orphanet J Rare Dis 2008 Feb 19;3:4. doi: 10.1186/1750-1172-3-4. PMID: 18284672Free PMC Article
Genetics of septo-optic dysplasia.
Kelberman D, Dattani MT
Pituitary 2007;10(4):393-407. doi: 10.1007/s11102-007-0055-5. PMID: 17587179

Diagnosis

Rhomboencephalosynapsis: Review of the Literature.
Fouda MA, Kim TY, Cohen AR
World Neurosurg 2022 Mar;159:48-53. Epub 2021 Dec 22 doi: 10.1016/j.wneu.2021.12.062. PMID: 34954057
Diagnosis of fetal non-chromosomal abnormalities on routine ultrasound examination at 11-13 weeks' gestation.
Syngelaki A, Hammami A, Bower S, Zidere V, Akolekar R, Nicolaides KH
Ultrasound Obstet Gynecol 2019 Oct;54(4):468-476. doi: 10.1002/uog.20844. PMID: 31408229
Triploidy: Variation of Phenotype.
Toufaily MH, Roberts DJ, Westgate MN, Holmes LB
Am J Clin Pathol 2016 Jan;145(1):86-95. doi: 10.1093/ajcp/aqv012. PMID: 26712875
The cavum septi pellucidi: why is it important?
Winter TC, Kennedy AM, Byrne J, Woodward PJ
J Ultrasound Med 2010 Mar;29(3):427-44. doi: 10.7863/jum.2010.29.3.427. PMID: 20194938
Disorders of prosencephalic development.
Volpe P, Campobasso G, De Robertis V, Rembouskos G
Prenat Diagn 2009 Apr;29(4):340-54. doi: 10.1002/pd.2208. PMID: 19184971

Therapy

Survival of children with rare structural congenital anomalies: a multi-registry cohort study.
Coi A, Santoro M, Pierini A, Rankin J, Glinianaia SV, Tan J, Reid AK, Garne E, Loane M, Given J, Ballardini E, Cavero-Carbonell C, de Walle HEK, Gatt M, García-Villodre L, Gissler M, Jordan S, Kiuru-Kuhlefelt S, Kjaer Urhoj S, Klungsøyr K, Lelong N, Lutke LR, Neville AJ, Rahshenas M, Scanlon I, Wellesley D, Morris JK
Orphanet J Rare Dis 2022 Mar 29;17(1):142. doi: 10.1186/s13023-022-02292-y. PMID: 35351164Free PMC Article
Central nervous system pathology in the amniotic rupture sequence.
Shannon P
Clin Neuropathol 2020 Nov/Dec;39(6):288-299. doi: 10.5414/NP301266. PMID: 32589127
Human germline hedgehog pathway mutations predispose to fatty liver.
Guillen-Sacoto MJ, Martinez AF, Abe Y, Kruszka P, Weiss K, Everson JL, Bataller R, Kleiner DE, Ward JM, Sulik KK, Lipinski RJ, Solomon BD, Muenke M
J Hepatol 2017 Oct;67(4):809-817. Epub 2017 Jun 21 doi: 10.1016/j.jhep.2017.06.008. PMID: 28645738Free PMC Article
Teratogenesis of holoprosencephaly.
Cohen MM Jr, Shiota K
Am J Med Genet 2002 Apr 15;109(1):1-15. doi: 10.1002/ajmg.10258. PMID: 11932986
Animal models for human craniofacial malformations.
Johnston MC, Bronsky PT
J Craniofac Genet Dev Biol 1991 Oct-Dec;11(4):277-91. PMID: 1812129

Prognosis

Etiopathogenetic advances and management of holoprosencephaly: from bench to bedside.
Bellone S, De Rienzo F, Prodam F, Savastio S, Busti A, Genoni G, Aimaretti G, Bona G
Panminerva Med 2010 Dec;52(4):345-54. PMID: 21183895
Disorders of prosencephalic development.
Volpe P, Campobasso G, De Robertis V, Rembouskos G
Prenat Diagn 2009 Apr;29(4):340-54. doi: 10.1002/pd.2208. PMID: 19184971
Monosomy 18p.
Turleau C
Orphanet J Rare Dis 2008 Feb 19;3:4. doi: 10.1186/1750-1172-3-4. PMID: 18284672Free PMC Article
Holoprosencephaly: genetic, neuroradiological, and clinical advances.
Hahn JS, Pinter JD
Semin Pediatr Neurol 2002 Dec;9(4):309-19. doi: 10.1053/spen.2002.32507. PMID: 12523555
Electroencephalography in congenital malformations of the central nervous system.
Campos P, Cruz G, Lizarraga R, Bancalari E, Guillen D, Castañeda C
Arq Neuropsiquiatr 1994 Dec;52(4):515-22. doi: 10.1590/s0004-282x1994000400010. PMID: 7611945

Clinical prediction guides

Routine first-trimester ultrasound screening using a standardized anatomical protocol.
Liao Y, Wen H, Ouyang S, Yuan Y, Bi J, Guan Y, Fu Q, Yang X, Guo W, Huang Y, Zeng Q, Qin Y, Xiang H, Li S
Am J Obstet Gynecol 2021 Apr;224(4):396.e1-396.e15. Epub 2020 Oct 27 doi: 10.1016/j.ajog.2020.10.037. PMID: 33127430
Comorbidity of congenital heart defects and holoprosencephaly is likely genetically driven and gene-specific.
Tekendo-Ngongang C, Owosela B, Muenke M, Kruszka P
Am J Med Genet C Semin Med Genet 2020 Mar;184(1):154-158. Epub 2020 Feb 5 doi: 10.1002/ajmg.c.31770. PMID: 32022405
Embryonic holoprosencephaly: pathology and phenotypic variability.
Yamada S
Congenit Anom (Kyoto) 2006 Dec;46(4):164-71. doi: 10.1111/j.1741-4520.2006.00123.x. PMID: 17096815
Development of the facial midline.
Carstens MH
J Craniofac Surg 2002 Jan;13(1):129-87; discussion 188-90. doi: 10.1097/00001665-200201000-00032. PMID: 11887012
Myelomeningocele before birth.
Osaka K, Tanimura T, Hirayama A, Matsumoto S
J Neurosurg 1978 Nov;49(5):711-24. doi: 10.3171/jns.1978.49.5.0711. PMID: 712393

Recent systematic reviews

Risks of specific congenital anomalies in offspring of women with diabetes: A systematic review and meta-analysis of population-based studies including over 80 million births.
Zhang TN, Huang XM, Zhao XY, Wang W, Wen R, Gao SY
PLoS Med 2022 Feb;19(2):e1003900. Epub 2022 Feb 1 doi: 10.1371/journal.pmed.1003900. PMID: 35104296Free PMC Article
Hydranencephaly complicated by central diabetes insipidus: report of two cases and systematic review of literature.
Omar AT 2nd, Khu KJO
Childs Nerv Syst 2019 Jul;35(7):1165-1171. Epub 2019 Mar 30 doi: 10.1007/s00381-019-04137-9. PMID: 30929071

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