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Holoprosencephaly 14(HPE14)

MedGen UID:
1811868
Concept ID:
C5676994
Disease or Syndrome
Synonyms: HOLOPROSENCEPHALY 14; HPE14
 
Gene (location): PLCH1 (3q25.31)
 
Monarch Initiative: MONDO:0030886
OMIM®: 619895

Definition

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). [from OMIM]

Clinical features

From HPO
Double outlet right ventricle
MedGen UID:
41649
Concept ID:
C0013069
Congenital Abnormality
Double outlet right ventricle (DORV) is a type of ventriculoarterial connection in which both great vessels arise entirely or predominantly from the right ventricle.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Aortic valve atresia
MedGen UID:
451016
Concept ID:
C0265843
Congenital Abnormality
A congenital disorder of the aortic valve in which the orifice of the valve fails to develop.
Macrotia
MedGen UID:
488785
Concept ID:
C0152421
Congenital Abnormality
Median longitudinal ear length greater than two standard deviations above the mean and median ear width greater than two standard deviations above the mean (objective); or, apparent increase in length and width of the pinna (subjective).
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
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.
Holoprosencephaly sequence
MedGen UID:
38214
Concept ID:
C0079541
Congenital Abnormality
Nonsyndromic holoprosencephaly is an abnormality of brain development that also affects the head and face. Normally, the brain divides into two halves (hemispheres) during early development. Holoprosencephaly occurs when the brain fails to divide properly into the right and left hemispheres. This condition is called nonsyndromic to distinguish it from other types of holoprosencephaly caused by genetic syndromes, chromosome abnormalities, or substances that cause birth defects (teratogens). The severity of nonsyndromic holoprosencephaly varies widely among affected individuals, even within the same family.\n\nNonsyndromic holoprosencephaly can be grouped into four types according to the degree of brain division. From most to least severe, the types are known as alobar, semi-lobar, lobar, and middle interhemispheric variant (MIHV). In the most severe forms of nonsyndromic holoprosencephaly, the brain does not divide at all. These affected individuals have one central eye (cyclopia) and a tubular nasal structure (proboscis) located above the eye. Most babies with severe nonsyndromic holoprosencephaly die before birth or soon after. In the less severe forms, the brain is partially divided and the eyes are usually set close together (hypotelorism). The life expectancy of these affected individuals varies depending on the severity of symptoms.\n\nPeople with nonsyndromic holoprosencephaly often have a small head (microcephaly), although they can develop a buildup of fluid in the brain (hydrocephalus) that causes increased head size (macrocephaly). Other features may include an opening in the roof of the mouth (cleft palate) with or without a split in the upper lip (cleft lip), one central front tooth instead of two (a single maxillary central incisor), and a flat nasal bridge. The eyeballs may be abnormally small (microphthalmia) or absent (anophthalmia).\n\nSome individuals with nonsyndromic holoprosencephaly have a distinctive pattern of facial features, including a narrowing of the head at the temples, outside corners of the eyes that point upward (upslanting palpebral fissures), large ears, a short nose with upturned nostrils, and a broad and deep space between the nose and mouth (philtrum). In general, the severity of facial features is directly related to the severity of the brain abnormalities. However, individuals with mildly affected facial features can have severe brain abnormalities. Some people do not have apparent structural brain abnormalities but have some of the facial features associated with this condition. These individuals are considered to have a form of the disorder known as microform holoprosencephaly and are typically identified after the birth of a severely affected family member.\n\nMost people with nonsyndromic holoprosencephaly have developmental delay and intellectual disability. Affected individuals also frequently have a malfunctioning pituitary gland, which is a gland located at the base of the brain that produces several hormones. Because pituitary dysfunction leads to the partial or complete absence of these hormones, it can cause a variety of disorders. Most commonly, people with nonsyndromic holoprosencephaly and pituitary dysfunction develop diabetes insipidus, a condition that disrupts the balance between fluid intake and urine excretion. Dysfunction in other parts of the brain can cause seizures, feeding difficulties, and problems regulating body temperature, heart rate, and breathing. The sense of smell may be diminished (hyposmia) or completely absent (anosmia) if the part of the brain that processes smells is underdeveloped or missing.
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Aqueductal stenosis
MedGen UID:
75614
Concept ID:
C0266476
Congenital Abnormality
Stenosis of the cerebral aqueduct (also known as the mesencephalic duct, aqueductus mesencephali, or aqueduct of Sylvius), which connects the third cerebral ventricle in the diencephalon to the fourth ventricle, which is between the pons and cerebellum.
Gray matter heterotopia
MedGen UID:
452349
Concept ID:
C0266491
Finding
Heterotopia or neuronal heterotopia are macroscopic clusters of misplaced neurons (gray matter), most often situated along the ventricular walls or within the subcortical white matter.
Alobar holoprosencephaly
MedGen UID:
140909
Concept ID:
C0431363
Congenital Abnormality
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.
Partial agenesis of the corpus callosum
MedGen UID:
98127
Concept ID:
C0431368
Congenital Abnormality
A partial failure of the development of the corpus callosum.
Absent septum pellucidum
MedGen UID:
96561
Concept ID:
C0431371
Congenital Abnormality
Absence of the septum pellucidum (meaning translucent wall in Latin - SP), also known as the ventricle of Sylvius. The septum pellucidum is a thin, triangular double membrane separating the frontal horns of the right and left lateral ventricles of the brain. It extends between the anterior portion of the corpus callosum, and the body of the fornix and its width varies from 1.5 to 3.0 mm.
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
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.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Subependymal cysts
MedGen UID:
318876
Concept ID:
C1833431
Anatomical Abnormality
Cerebral cysts, usually located in the wall of the caudate nucleus or in the caudothalamic groove. They are found in up to 5.2% of all neonates, using transfontanellar ultrasound in the first days of life.
Interhemispheric cyst
MedGen UID:
339924
Concept ID:
C1853188
Disease or Syndrome
Cystic collection (sac-like, fluid containing pocket of membranous tissue) located in the interhemispheric fissure, with or without communication with the ventricular system.
Posterior fossa cyst
MedGen UID:
341753
Concept ID:
C1857353
Finding
A discrete posterior fossa cerebrospinal fluid (CSF) collection that does not communicate directly with the fourth ventricle.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Partial absence of cerebellar vermis
MedGen UID:
871190
Concept ID:
C4025667
Congenital Abnormality
Congenital absence of a part of the vermis of cerebellum.
Periventricular heterotopia
MedGen UID:
1766888
Concept ID:
C5399973
Disease or Syndrome
A form of gray matter heterotopia were the mislocalized gray matter is typically located periventricularly, also sometimes called subependymal heterotopia. Periventricular means beside the ventricles. This is by far the most common location for heterotopia. Subependymal heterotopia present in a wide array of variations. There can be a small single node or a large number of nodes, can exist on either or both sides of the brain at any point along the higher ventricle margins, can be small or large, single or multiple, and can form a small node or a large wavy or curved mass.
Dandy-Walker syndrome
MedGen UID:
4150
Concept ID:
C0010964
Disease or Syndrome
Dandy-Walker malformation is defined by hypoplasia and upward rotation of the cerebellar vermis and cystic dilation of the fourth ventricle. Affected individuals often have motor deficits such as delayed motor development, hypotonia, and ataxia; about half have mental retardation and some have hydrocephalus. DWM is a heterogeneous disorder. The low empiric recurrence risk of approximately 1 to 2% for nonsyndromic DWM suggests that mendelian inheritance is unlikely (summary by Murray et al., 1985).
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Enlarged cisterna magna
MedGen UID:
344031
Concept ID:
C1853377
Finding
Increase in size of the cisterna magna, one of three principal openings in the subarachnoid space between the arachnoid and pia mater, located between the cerebellum and the dorsal surface of the medulla oblongata.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
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.
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).
Cleft lip
MedGen UID:
1370297
Concept ID:
C4321245
Anatomical Abnormality
A gap in the lip or lips.
Proboscis
MedGen UID:
1684306
Concept ID:
C5194070
Congenital Abnormality
A fleshy, tube-like structure usually located in the midline of the face or just to one side of the midline.
Cyclopia
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).

Professional guidelines

PubMed

Bardi F, Bergman JEH, Siemensma-Mühlenberg N, Elvan-Taşpınar A, de Walle HEK, Bakker MK
Paediatr Perinat Epidemiol 2022 Nov;36(6):804-814. Epub 2022 Jul 12 doi: 10.1111/ppe.12914. PMID: 35821640Free PMC Article
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Prenat Diagn 2020 May;40(6):674-680. Epub 2020 Mar 31 doi: 10.1002/pd.5663. PMID: 32037567
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

Recent clinical studies

Etiology

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Allam KA, Wan DC, Kawamoto HK, Bradley JP, Sedano HO, Saied S
Plast Reconstr Surg 2011 Feb;127(2):812-821. doi: 10.1097/PRS.0b013e318200aa08. PMID: 21285785
Mochida GH, Walsh CA
Curr Opin Neurol 2001 Apr;14(2):151-6. doi: 10.1097/00019052-200104000-00003. PMID: 11262728

Diagnosis

Hu Y, Sun L, Feng L, Wang J, Zhu Y, Wu Q
BMC Pregnancy Childbirth 2023 May 3;23(1):312. doi: 10.1186/s12884-023-05644-z. PMID: 37138220Free PMC Article
Bardi F, Bergman JEH, Siemensma-Mühlenberg N, Elvan-Taşpınar A, de Walle HEK, Bakker MK
Paediatr Perinat Epidemiol 2022 Nov;36(6):804-814. Epub 2022 Jul 12 doi: 10.1111/ppe.12914. PMID: 35821640Free 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
Visvanathan V, Wynne DM
Int J Pediatr Otorhinolaryngol 2012 Jan;76(1):28-30. Epub 2011 Oct 22 doi: 10.1016/j.ijporl.2011.09.016. PMID: 22024577
Allam KA, Wan DC, Kawamoto HK, Bradley JP, Sedano HO, Saied S
Plast Reconstr Surg 2011 Feb;127(2):812-821. doi: 10.1097/PRS.0b013e318200aa08. PMID: 21285785

Therapy

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
Caba L, Rusu C, Butnariu L, Panzaru M, Braha E, Volosciuc M, Popescu R, Gramescu M, Bujoran C, Martiniuc V, Covic M, Gorduza EV
Rev Med Chir Soc Med Nat Iasi 2013 Apr-Jun;117(2):321-7. PMID: 24340511
Anderson JL, Waller DK, Canfield MA, Shaw GM, Watkins ML, Werler MM
Epidemiology 2005 Jan;16(1):87-92. doi: 10.1097/01.ede.0000147122.97061.bb. PMID: 15613950
Farina A, Sekizawa A, Ralston SJ, D'Alton ME, Bianchi DW
Prenat Diagn 1999 Sep;19(9):840-5. PMID: 10521842
Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, Scherer SW, Tsui LC, Muenke M
Nat Genet 1996 Nov;14(3):357-60. doi: 10.1038/ng1196-357. PMID: 8896572

Prognosis

Borkowski-Tillman T, Garcia-Rodriguez R, Viñals F, Branco M, Kradjen-Haratz K, Ben-Sira L, Lerman-Sagie T, Malinger G
Prenat Diagn 2020 May;40(6):674-680. Epub 2020 Mar 31 doi: 10.1002/pd.5663. PMID: 32037567
Yi L, Liu Z, Deng C, Li X, Wang K, Deng K, Mu Y, Zhu J, Li Q, Wang Y, Dai L
PLoS One 2019;14(6):e0217835. Epub 2019 Jun 6 doi: 10.1371/journal.pone.0217835. PMID: 31170204Free PMC Article
Syngelaki A, Guerra L, Ceccacci I, Efeturk T, Nicolaides KH
Ultrasound Obstet Gynecol 2017 Jul;50(1):45-48. Epub 2017 Apr 23 doi: 10.1002/uog.17286. PMID: 27558969
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
Visvanathan V, Wynne DM
Int J Pediatr Otorhinolaryngol 2012 Jan;76(1):28-30. Epub 2011 Oct 22 doi: 10.1016/j.ijporl.2011.09.016. PMID: 22024577

Clinical prediction guides

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Rao AR, Yourshaw M, Christensen B, Nelson SF, Kerner B
Mol Psychiatry 2017 Jul;22(7):1009-1014. Epub 2016 Oct 11 doi: 10.1038/mp.2016.181. PMID: 27725659Free PMC Article
Syngelaki A, Guerra L, Ceccacci I, Efeturk T, Nicolaides KH
Ultrasound Obstet Gynecol 2017 Jul;50(1):45-48. Epub 2017 Apr 23 doi: 10.1002/uog.17286. PMID: 27558969
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
Croen LA, Shaw GM, Lammer EJ
Am J Med Genet 1996 Aug 23;64(3):465-72. doi: 10.1002/(SICI)1096-8628(19960823)64:3<465::AID-AJMG4>3.0.CO;2-O. PMID: 8862623

Recent systematic reviews

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