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Alobar holoprosencephaly

MedGen UID:
140909
Concept ID:
C0431363
Congenital Abnormality
Synonyms: Alobar Holoprosencephalies; Alobar Holoprosencephaly; Holoprosencephalies, Alobar; Holoprosencephaly, Alobar; Holoprosencephaly, Familial Alobar
SNOMED CT: Alobar holoprosencephaly (253137003)
Modes of inheritance:
Non-Mendelian inheritance
MedGen UID:
109109
Concept ID:
C0600599
Genetic Function
Source: Orphanet
A mode of inheritance that depends on genetic determinants in more than one gene.
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
HPO: HP:0006988
Monarch Initiative: MONDO:0019757
OMIM®: 236100
Orphanet: ORPHA93925

Definition

A type of holoprosencephaly characterized by the presence of a single ventricle and no separation of the cerebral hemisphere. The single midline ventricle is often greatly enlarged. [from HPO]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAlobar holoprosencephaly
Follow this link to review classifications for Alobar holoprosencephaly in Orphanet.

Conditions with this feature

Holoprosencephaly 1
MedGen UID:
78617
Concept ID:
C0266667
Congenital Abnormality
Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain and occurs after failed or abbreviated midline cleavage of the developing brain during the third and fourth weeks of gestation. HPE occurs in up to 1 in 250 gestations, but only 1 in 8,000 live births (Lacbawan et al., 2009). Classically, 3 degrees of severity defined by the extent of brain malformation have been described. In the most severe form, 'alobar HPE,' there is a single ventricle and no interhemispheric fissure. The olfactory bulbs and tracts and the corpus callosum are typically absent. In 'semilobar HPE,' the most common type of HPE in neonates who survive, there is partial cortical separation with rudimentary cerebral hemispheres and a single ventricle. In 'lobar HPE,' the ventricles are separated, but there is incomplete frontal cortical separation (Corsello et al., 1990). An additional milder form, called 'middle interhemispheric variant' (MIHV) has also been delineated, in which the posterior frontal and parietal lobes are incompletely separated and the corpus callosum may be hypoplastic (Lacbawan et al., 2009). Finally, microforms of HPE include a single maxillary median incisor or hypotelorism without the typical brain malformations (summary by Mercier et al., 2011). Cohen (2001) discussed problems in the definition of holoprosencephaly, which can be viewed from 2 different perspectives: anatomic (fixed) and genetic (broad). When the main interest is description, the anatomic perspective is appropriate. In genetic perspective, a fixed definition of holoprosencephaly is not appropriate because the same mutational cause may result in either holoprosencephaly or some microform of holoprosencephaly. Cohen (2001) concluded that both fixed and broad definitions are equally valid and depend on context. Munke (1989) provided an extensive review of the etiology and pathogenesis of holoprosencephaly, emphasizing heterogeneity. See also schizencephaly (269160), which may be part of the phenotypic spectrum of HPE. Genetic Heterogeneity of Holoprosencephaly Several loci for holoprosencephaly have been mapped to specific chromosomal sites and the molecular defects in some cases of HPE have been identified. Holoprosencephaly-1 (HPE1) maps to chromosome 21q22. See also HPE2 (157170), caused by mutation in the SIX3 gene (603714) on 2p21; HPE3 (142945), caused by mutation in the SHH gene (600725) on 7q36; HPE4 (142946), caused by mutation in the TGIF gene (602630) on 18p11; HPE5 (609637), caused by mutation in the ZIC2 gene (603073) on 13q32; HPE6 (605934), mapped to 2q37; HPE7 (610828), caused by mutation in the PTCH1 gene (601309) on 9q22; HPE8 (609408), mapped to 14q13; HPE9 (610829), caused by mutation in the GLI2 gene (165230) on 2q14; HPE10 (612530), mapped to 1q41-q42; HPE11 (614226), caused by mutation in the CDON gene (608707) on 11q24; HPE12 (618500), caused by mutation in the CNOT1 gene (604917) on 16q21; HPE13 (301043), caused by mutation in the STAG2 gene (300826) on Xq25; and HPE14 (619895), caused by mutation in the PLCH1 gene (612835) on 3q25. Wallis and Muenke (2000) gave an overview of mutations in holoprosencephaly. They indicated that at least 12 different loci had been associated with HPE. Mutations in genes involved in the multiprotein cohesin complex, including STAG2, have been shown to be involved in midline brain defects such as HPE. Mutations in some of those genes cause Cornelia de Lange syndrome (CDLS; see 122470), and some patients with severe forms of CDLS may have midline brain defects. See, for example, CDLS2 (300590), CDLS3 (610759), and CDLS4 (614701).
Kabuki syndrome
MedGen UID:
162897
Concept ID:
C0796004
Congenital Abnormality
Kabuki syndrome (KS) is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities (including isolated premature thelarche in females), feeding problems, and hearing loss.
Holoprosencephaly 2
MedGen UID:
322517
Concept ID:
C1834877
Disease or Syndrome
A rare disorder characterized by the partial separation of the cerebral hemispheres. It is associated with mutations in the SIX3 gene.
Holoprosencephaly 9
MedGen UID:
324369
Concept ID:
C1835819
Disease or Syndrome
Holoprosencephaly-9 refers to a disorder characterized by a wide phenotypic spectrum of brain developmental defects, with or without overt forebrain cleavage abnormalities. It usually includes midline craniofacial anomalies involving the first branchial arch and/or orbits, pituitary hypoplasia with panhypopituitarism, and postaxial polydactyly. The disorder shows incomplete penetrance and variable expressivity (summary by Roessler et al., 2003 and Bertolacini et al., 2012). For general phenotypic information and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100).
Holoprosencephaly 7
MedGen UID:
372134
Concept ID:
C1835820
Disease or Syndrome
Holoprosencephaly (HPE) is the most commonly occurring congenital structural forebrain anomaly in humans. HPE is associated with mental retardation and craniofacial malformations. Considerable heterogeneity in the genetic causes of HPE has been demonstrated (Ming et al., 2002). For general phenotypic information and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100).
Hartsfield-Bixler-Demyer syndrome
MedGen UID:
335111
Concept ID:
C1845146
Congenital Abnormality
FGFR1-related Hartsfield syndrome comprises two core features: holoprosencephaly (HPE) spectrum disorder and ectrodactyly spectrum disorder. HPE spectrum disorder, resulting from failed or incomplete forebrain division early in gestation, includes alobar, semilobar, or lobar HPE. Other observed midline brain malformations include corpus callosum agenesis, absent septum pellucidum, absent olfactory bulbs and tracts, and vermian hypoplasia. Other findings associated with the HPE spectrum such as craniofacial dysmorphism, neurologic issues (developmental delay, spasticity, seizures, hypothalamic dysfunction), feeding problems, and endocrine issues (hypogonadotropic hypogonadism and central insipidus diabetes) are common. Ectrodactyly spectrum disorders are unilateral or bilateral malformations of the hands and/or feet characterized by a median cleft of hand or foot due to absence of the longitudinal central rays (also called split-hand/foot malformation). The number of digits on the right and left can vary. Polydactyly and syndactyly can also be seen.
Holoprosencephaly 5
MedGen UID:
355304
Concept ID:
C1864827
Disease or Syndrome
Holoprosencephaly associated with mutations in the ZIC2 gene.
Chromosome 3q13.31 deletion syndrome
MedGen UID:
815820
Concept ID:
C3809490
Disease or Syndrome
The chromosome 3q13.31 deletion syndrome is characterized by marked developmental delay, characteristic facies with a short philtrum and protruding lips, and abnormal male genitalia (Molin et al., 2012). Patients with Primrose syndrome (PRIMS; 259050) exhibit features overlapping those of the chromosome 3q13.31 deletion syndrome but also have ossified ear cartilage, severe muscle wasting, and abnormalities of glucose metabolism resulting in insulin-resistant diabetes mellitus in adulthood. Primrose syndrome is caused by mutation in the ZBTB20 gene (606025) on chromosome 3q13.
Holoprosencephaly 13, X-linked
MedGen UID:
1714826
Concept ID:
C5393308
Disease or Syndrome
X-linked holoprosencephaly-13 (HPE13) is a neurologic disorder characterized by midline developmental defects that mainly affect the brain and craniofacial structure. The severity and manifestations are variable: some patients may have full alobar HPE with cyclopia, whereas others have semilobar HPE or septooptic dysplasia. Dysmorphic features include microcephaly, hypotelorism, low-set ears, micrognathia, and cleft lip/palate. Patients with a more severe phenotype may die in the newborn period, whereas those with a less severe phenotype show global developmental delay. Additional variable features include congenital heart defects and vertebral anomalies. Phenotypic variability may be related to the type of mutation, X-inactivation status, and possible incomplete penetrance. The STAG2 protein is part of the multiprotein cohesin complex involved in chromatid cohesion during DNA replication and transcriptional regulation; HPE13 can thus be classified as a 'cohesinopathy' (summary by Kruszka et al., 2019). For a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100).
Holoprosencephaly 14
MedGen UID:
1811868
Concept ID:
C5676994
Disease or Syndrome
Holoprosencephaly-14 (HPE14) is an autosomal recessive condition characterized by severe developmental delay secondary to brain malformations within the holoprosencephaly spectrum (Drissi et al., 2022). For general phenotypic information and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100).

Professional guidelines

PubMed

De Catte L, De Keersmaeker B, Claus F
Paediatr Drugs 2012 Jun 1;14(3):143-55. doi: 10.2165/11597030-000000000-00000. PMID: 22242843
Hahn JS, Plawner LL
Pediatr Neurol 2004 Aug;31(2):79-88. doi: 10.1016/j.pediatrneurol.2004.03.006. PMID: 15301825
Lai TH, Chang CH, Yu CH, Kuo PL, Chang FM
Prenat Diagn 2000 May;20(5):400-3. doi: 10.1002/(sici)1097-0223(200005)20:5<400::aid-pd839>3.0.co;2-l. PMID: 10820408

Recent clinical studies

Etiology

Boakye-Yiadom AP, Nguah SB, Mahama H, Plange-Rhule G
Ghana Med J 2022 Sep;56(3):231-235. doi: 10.4314/gmj.v56i3.14. PMID: 37449001Free PMC Article
Elfarawi H, Tolusso L, McGowan ML, Cortezzo D, Vawter-Lee M
Prenat Diagn 2022 May;42(5):617-627. Epub 2022 Mar 10 doi: 10.1002/pd.6130. PMID: 35253927
Syngelaki A, Cimpoca B, Litwinska E, Akolekar R, Nicolaides KH
Ultrasound Obstet Gynecol 2020 Apr;55(4):474-481. Epub 2020 Mar 6 doi: 10.1002/uog.21938. PMID: 31788879
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
Shah K, Nayak SS, Shukla A, Girisha KM
Congenit Anom (Kyoto) 2016 May;56(3):119-26. doi: 10.1111/cga.12149. PMID: 26663027

Diagnosis

Montaguti E, Cariello L, Brunelli E, Youssef A, Livi A, Salsi G, Pilu G
J Matern Fetal Neonatal Med 2022 Dec;35(25):9717-9723. Epub 2022 Mar 10 doi: 10.1080/14767058.2022.2050900. PMID: 35272544
Elfarawi H, Tolusso L, McGowan ML, Cortezzo D, Vawter-Lee M
Prenat Diagn 2022 May;42(5):617-627. Epub 2022 Mar 10 doi: 10.1002/pd.6130. PMID: 35253927
Volpe N, Dall'Asta A, Di Pasquo E, Frusca T, Ghi T
Ultrasound Obstet Gynecol 2021 Feb;57(2):204-214. doi: 10.1002/uog.23149. PMID: 33049801
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
Ionescu CA, Calin D, Navolan D, Matei A, Dimitriu M, Herghelegiu C, Ples L
Medicine (Baltimore) 2018 Jul;97(29):e11521. doi: 10.1097/MD.0000000000011521. PMID: 30024536Free PMC Article

Therapy

Nagane M, Tsuchida T, Takemura N, Hayakawa I
Surg Neurol 1993 Oct;40(4):314-9. doi: 10.1016/0090-3019(93)90143-o. PMID: 8211642
Ronen GM, Andrews WL
Am J Med Genet 1991 Aug 1;40(2):151-4. doi: 10.1002/ajmg.1320400206. PMID: 1897567

Prognosis

Elfarawi H, Tolusso L, McGowan ML, Cortezzo D, Vawter-Lee M
Prenat Diagn 2022 May;42(5):617-627. Epub 2022 Mar 10 doi: 10.1002/pd.6130. PMID: 35253927
Syngelaki A, Cimpoca B, Litwinska E, Akolekar R, Nicolaides KH
Ultrasound Obstet Gynecol 2020 Apr;55(4):474-481. Epub 2020 Mar 6 doi: 10.1002/uog.21938. PMID: 31788879
Pavone P, Praticò AD, Vitaliti G, Ruggieri M, Rizzo R, Parano E, Pavone L, Pero G, Falsaperla R
Ital J Pediatr 2014 Oct 18;40:79. doi: 10.1186/s13052-014-0079-1. PMID: 25326191Free PMC Article
De Catte L, De Keersmaeker B, Claus F
Paediatr Drugs 2012 Jun 1;14(3):143-55. doi: 10.2165/11597030-000000000-00000. PMID: 22242843
Barr M Jr, Cohen MM Jr
Am J Med Genet 1999 Jun 25;89(2):116-20. PMID: 10559767

Clinical prediction guides

Syngelaki A, Cimpoca B, Litwinska E, Akolekar R, Nicolaides KH
Ultrasound Obstet Gynecol 2020 Apr;55(4):474-481. Epub 2020 Mar 6 doi: 10.1002/uog.21938. PMID: 31788879
Ionescu CA, Calin D, Navolan D, Matei A, Dimitriu M, Herghelegiu C, Ples L
Medicine (Baltimore) 2018 Jul;97(29):e11521. doi: 10.1097/MD.0000000000011521. PMID: 30024536Free PMC Article
Syngelaki A, Chelemen T, Dagklis T, Allan L, Nicolaides KH
Prenat Diagn 2011 Jan;31(1):90-102. doi: 10.1002/pd.2642. PMID: 21210483
Hayashi M, Araki S, Kumada S, Itoh M, Morimatsu Y, Matsuyama H
Acta Neuropathol 2004 Mar;107(3):190-6. Epub 2003 Dec 18 doi: 10.1007/s00401-003-0784-0. PMID: 14685895
Chen CP, Chern SR, Wang W, Lee CC, Chen WL, Chen LF, Chang TY, Tzen CY
Prenat Diagn 2001 May;21(5):346-50. doi: 10.1002/pd.63. PMID: 11360273

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