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Holoprosencephaly 5(HPE5)

MedGen UID:
355304
Concept ID:
C1864827
Disease or Syndrome
Synonym: HPE5
 
Gene (location): ZIC2 (13q32.3)
 
Monarch Initiative: MONDO:0012322
OMIM®: 609637

Definition

Holoprosencephaly associated with mutations in the ZIC2 gene. [from NCI]

Clinical features

From HPO
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).
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.
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.
Lobar holoprosencephaly
MedGen UID:
96559
Concept ID:
C0431362
Congenital Abnormality
A type of holoprosencephaly in which most of the right and left cerebral hemispheres and lateral ventricles are separated but the most rostral aspect of the telencephalon, the frontal lobes, are fused, especially ventrally.
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.
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.
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.
Lateral ventricle dilatation
MedGen UID:
383904
Concept ID:
C1856409
Pathologic Function
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.
Syntelencephaly
MedGen UID:
1708682
Concept ID:
C5396362
Congenital Abnormality
Syntelencephaly is a rare malformation that consists of an abnormal midline connection of the cerebral hemispheres in the posterior frontal and parietal regions, with interhemispheric separation of the basal forebrain, anterior frontal lobes, and occipital regions.
Trigonocephaly
MedGen UID:
82713
Concept ID:
C0265535
Congenital Abnormality
Wedge-shaped, or triangular head, with the apex of the triangle at the midline of the forehead and the base of the triangle at the occiput.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
High forehead
MedGen UID:
65991
Concept ID:
C0239676
Finding
An abnormally increased height of the forehead.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
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.
Abnormal facial shape
MedGen UID:
98409
Concept ID:
C0424503
Finding
An abnormal morphology (form) of the face or its components.
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.
Narrow forehead
MedGen UID:
326956
Concept ID:
C1839758
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations below the mean (objective); or apparently narrow intertemporal region (subjective).
Deep philtrum
MedGen UID:
374311
Concept ID:
C1839797
Finding
Accentuated, prominent philtral ridges giving rise to an exaggerated groove in the midline between the nasal base and upper vermillion border.
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).
Broad forehead
MedGen UID:
338610
Concept ID:
C1849089
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations above the mean (objective); or apparently increased distance between the two sides of the forehead.
Sloping forehead
MedGen UID:
346640
Concept ID:
C1857679
Finding
Inclination of the anterior surface of the forehead from the vertical more than two standard deviations above the mean (objective); or apparently excessive posterior sloping of the forehead in a lateral view.
Orofacial cleft
MedGen UID:
472000
Concept ID:
C3266076
Congenital Abnormality
The presence of a cleft (gap, opening, or groove) in the oral cavity, including cleft of the upper lip and/or cleft of the palate. Cleft of the upper lip is visible as a groove or fissure in the lip, most frequently due to a congenital failure of the maxillary and median nasal processes to fuse. Cleft palate is characterized by a grooved depression or fissure in the roof of the mouth, most often resulting from a congenital failure of the palate to fuse properly. Clefts of the lip and palate can occur individually or together. It is preferable to code each defect separately.
Synophrys
MedGen UID:
98132
Concept ID:
C0431447
Congenital Abnormality
Meeting of the medial eyebrows in the midline.
Central diabetes insipidus
MedGen UID:
146919
Concept ID:
C0687720
Disease or Syndrome
Neurohypophyseal diabetes insipidus is a disorder of water balance. The body normally balances fluid intake with the excretion of fluid in urine. However, people with neurohypophyseal diabetes insipidus produce too much urine (polyuria), which causes them to be excessively thirsty (polydipsia). Affected people need to urinate frequently, which can disrupt daily activities and sleep.\n\nPeople with neurohypophyseal diabetes insipidus can quickly become dehydrated if they do not drink enough water. Dehydration can lead to constipation and dry skin. If the disorder is not treated, more serious complications of dehydration can occur. These include confusion, low blood pressure, seizures, and coma.\n\nNeurohypophyseal diabetes insipidus can be either acquired or familial. The acquired form is brought on by injuries, tumors, and other factors, and can occur at any time during life. The familial form is caused by genetic mutations; its signs and symptoms usually become apparent in childhood and worsen over time.\n\nNeurohypophyseal diabetes insipidus should not be confused with diabetes mellitus, which is much more common. Diabetes mellitus is characterized by high blood sugar (glucose) levels resulting from a shortage of the hormone insulin or an insensitivity to this hormone. Although neurohypophyseal diabetes insipidus and diabetes mellitus have some features in common, they are separate disorders with different causes.
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).
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).

Professional guidelines

PubMed

Tavano I, De Keersmaecker B, Aertsen M, De Catte L
J Matern Fetal Neonatal Med 2022 Dec;35(25):4976-4984. Epub 2021 Jan 17 doi: 10.1080/14767058.2021.1873942. PMID: 33455493
Kousa YA, du Plessis AJ, Vezina G
Am J Med Genet C Semin Med Genet 2018 Jun;178(2):206-213. Epub 2018 May 17 doi: 10.1002/ajmg.c.31618. PMID: 29770996
Lacbawan F, Solomon BD, Roessler E, El-Jaick K, Domené S, Vélez JI, Zhou N, Hadley D, Balog JZ, Long R, Fryer A, Smith W, Omar S, McLean SD, Clarkson K, Lichty A, Clegg NJ, Delgado MR, Levey E, Stashinko E, Potocki L, Vanallen MI, Clayton-Smith J, Donnai D, Bianchi DW, Juliusson PB, Njølstad PR, Brunner HG, Carey JC, Hehr U, Müsebeck J, Wieacker PF, Postra A, Hennekam RC, van den Boogaard MJ, van Haeringen A, Paulussen A, Herbergs J, Schrander-Stumpel CT, Janecke AR, Chitayat D, Hahn J, McDonald-McGinn DM, Zackai EH, Dobyns WB, Muenke M
J Med Genet 2009 Jun;46(6):389-98. Epub 2009 Apr 2 doi: 10.1136/jmg.2008.063818. PMID: 19346217Free PMC Article

Recent clinical studies

Etiology

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
Jacobs E, Whitehead MT
Pediatr Radiol 2023 Jan;53(1):121-130. Epub 2022 Jul 22 doi: 10.1007/s00247-022-05439-y. PMID: 35867110
Tinker SC, Gilboa SM, Moore CA, Waller DK, Simeone RM, Kim SY, Jamieson DJ, Botto LD, Reefhuis J; National Birth Defects Prevention Study
Am J Obstet Gynecol 2020 Feb;222(2):176.e1-176.e11. Epub 2019 Aug 24 doi: 10.1016/j.ajog.2019.08.028. PMID: 31454511Free PMC Article
Kaliaperumal C, Ndoro S, Mandiwanza T, Reidy F, McAuliffe F, Caird J, Crimmins D
Childs Nerv Syst 2016 May;32(5):801-9. Epub 2016 Jan 15 doi: 10.1007/s00381-016-3015-4. PMID: 26767839
Castillo M, Mukherji SK
Curr Probl Diagn Radiol 1995 Sep-Oct;25(5):169-88. PMID: 8889386

Diagnosis

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
Tavano I, De Keersmaecker B, Aertsen M, De Catte L
J Matern Fetal Neonatal Med 2022 Dec;35(25):4976-4984. Epub 2021 Jan 17 doi: 10.1080/14767058.2021.1873942. PMID: 33455493
Kousa YA, du Plessis AJ, Vezina G
Am J Med Genet C Semin Med Genet 2018 Jun;178(2):206-213. Epub 2018 May 17 doi: 10.1002/ajmg.c.31618. PMID: 29770996
Kaliaperumal C, Ndoro S, Mandiwanza T, Reidy F, McAuliffe F, Caird J, Crimmins D
Childs Nerv Syst 2016 May;32(5):801-9. Epub 2016 Jan 15 doi: 10.1007/s00381-016-3015-4. PMID: 26767839
Pooh RK
Semin Fetal Neonatal Med 2012 Oct;17(5):261-8. Epub 2012 Jul 15 doi: 10.1016/j.siny.2012.05.008. PMID: 22800609

Therapy

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
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
Nasser H, Vera L, Elmaleh-Bergès M, Steindl K, Letard P, Teissier N, Ernault A, Guimiot F, Afenjar A, Moutard ML, Héron D, Alembik Y, Momtchilova M, Milani P, Kubis N, Pouvreau N, Zollino M, Guilmin Crepon S, Kaguelidou F, Gressens P, Verloes A, Rauch A, El Ghouzzi V, Drunat S, Passemard S
J Med Genet 2020 Jun;57(6):389-399. Epub 2020 Feb 3 doi: 10.1136/jmedgenet-2019-106474. PMID: 32015000
Sarnat HB, Flores-Sarnat L
Clin Neuropathol 2013 Jul-Aug;32(4):255-68. doi: 10.5414/NP300588. PMID: 23380462
Cohen MM Jr, Shiota K
Am J Med Genet 2002 Apr 15;109(1):1-15. doi: 10.1002/ajmg.10258. PMID: 11932986

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
Gregory LC, Dattani MT
J Clin Endocrinol Metab 2020 Jun 1;105(6) doi: 10.1210/clinem/dgz184. PMID: 31702014
de Boutray M, Beziat JL, Yachouh J, Bigorre M, Gleizal A, Captier G
J Craniomaxillofac Surg 2016 Jun;44(6):664-71. Epub 2016 Mar 2 doi: 10.1016/j.jcms.2016.02.012. PMID: 27075944
Kaliaperumal C, Ndoro S, Mandiwanza T, Reidy F, McAuliffe F, Caird J, Crimmins D
Childs Nerv Syst 2016 May;32(5):801-9. Epub 2016 Jan 15 doi: 10.1007/s00381-016-3015-4. PMID: 26767839
Peebles DM
Prenat Diagn 1998 May;18(5):477-80. PMID: 9621381

Clinical prediction guides

Tinker SC, Gilboa SM, Moore CA, Waller DK, Simeone RM, Kim SY, Jamieson DJ, Botto LD, Reefhuis J; National Birth Defects Prevention Study
Am J Obstet Gynecol 2020 Feb;222(2):176.e1-176.e11. Epub 2019 Aug 24 doi: 10.1016/j.ajog.2019.08.028. PMID: 31454511Free PMC Article
Asadollahi R, Strauss JE, Zenker M, Beuing O, Edvardson S, Elpeleg O, Strom TM, Joset P, Niedrist D, Otte C, Oneda B, Boonsawat P, Azzarello-Burri S, Bartholdi D, Papik M, Zweier M, Haas C, Ekici AB, Baumer A, Boltshauser E, Steindl K, Nothnagel M, Schinzel A, Stoeckli ET, Rauch A
Eur J Hum Genet 2018 Feb;26(2):197-209. Epub 2018 Jan 10 doi: 10.1038/s41431-017-0019-9. PMID: 29321670Free PMC Article
Pooh RK
Semin Fetal Neonatal Med 2012 Oct;17(5):261-8. Epub 2012 Jul 15 doi: 10.1016/j.siny.2012.05.008. PMID: 22800609
Orioli IM, Castilla EE
Am J Med Genet C Semin Med Genet 2010 Feb 15;154C(1):13-21. doi: 10.1002/ajmg.c.30233. PMID: 20104599
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

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
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
de Boutray M, Beziat JL, Yachouh J, Bigorre M, Gleizal A, Captier G
J Craniomaxillofac Surg 2016 Jun;44(6):664-71. Epub 2016 Mar 2 doi: 10.1016/j.jcms.2016.02.012. PMID: 27075944

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