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Holoprosencephaly 11(HPE11)

MedGen UID:
481845
Concept ID:
C3280215
Disease or Syndrome
Synonym: HPE11
 
Gene (location): CDON (11q24.2)
 
Monarch Initiative: MONDO:0013642
OMIM®: 614226

Definition

Any holoprosencephaly in which the cause of the disease is a mutation in the CDON gene. [from MONDO]

Clinical features

From HPO
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.
Corpus callosum, agenesis of
MedGen UID:
104498
Concept ID:
C0175754
Congenital Abnormality
The corpus callosum is the largest fiber tract in the central nervous system and the major interhemispheric fiber bundle in the brain. Formation of the corpus callosum begins as early as 6 weeks' gestation, with the first fibers crossing the midline at 11 to 12 weeks' gestation, and completion of the basic shape by age 18 to 20 weeks (Schell-Apacik et al., 2008). Agenesis of the corpus callosum (ACC) is one of the most frequent malformations in brain with a reported incidence ranging between 0.5 and 70 in 10,000 births. ACC is a clinically and genetically heterogeneous condition, which can be observed either as an isolated condition or as a manifestation in the context of a congenital syndrome (see MOLECULAR GENETICS and Dobyns, 1996). Also see mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600). Schell-Apacik et al. (2008) noted that there is confusion in the literature regarding radiologic terminology concerning partial absence of the corpus callosum, where various designations have been used, including hypogenesis, hypoplasia, partial agenesis, or dysgenesis.
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.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Polysplenia
MedGen UID:
383959
Concept ID:
C1856659
Congenital Abnormality
Polysplenia is a congenital disease manifested by multiple small accessory spleens.
Thick eyebrow
MedGen UID:
377914
Concept ID:
C1853487
Finding
Increased density/number and/or increased diameter of eyebrow hairs.
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.
Synophrys
MedGen UID:
98132
Concept ID:
C0431447
Congenital Abnormality
Meeting of the medial eyebrows in the midline.
Proptosis
MedGen UID:
41917
Concept ID:
C0015300
Disease or Syndrome
An eye that is protruding anterior to the plane of the face to a greater extent than is typical.
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

Qi Q, Jiang Y, Zhou X, Lü Y, Xiao R, Bai J, Lou H, Sun W, Lian Y, Hao N, Li M, Chang J
Ultrasound Obstet Gynecol 2024 May;63(5):664-671. Epub 2024 Apr 15 doi: 10.1002/uog.27517. PMID: 37842862
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
Raam MS, Solomon BD, Muenke M
Indian Pediatr 2011 Jun;48(6):457-66. doi: 10.1007/s13312-011-0078-x. PMID: 21743112Free PMC Article

Recent clinical studies

Etiology

Addissie YA, Kruszka P, Troia A, Wong ZC, Everson JL, Kozel BA, Lipinski RJ, Malecki KMC, Muenke M
Environ Health 2020 Jun 8;19(1):65. doi: 10.1186/s12940-020-00611-z. PMID: 32513280Free PMC Article
Heinke D, Nestoridi E, Hernandez-Diaz S, Williams PL, Rich-Edwards JW, Lin AE, Van Bennekom CM, Mitchell AA, Nembhard WN, Fretts RC, Roberts DJ, Duke CW, Carmichael SL, Yazdy MM; National Birth Defects Prevention Study
Obstet Gynecol 2020 Jan;135(1):133-140. doi: 10.1097/AOG.0000000000003614. PMID: 31809437Free PMC Article
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
Raam MS, Solomon BD, Muenke M
Indian Pediatr 2011 Jun;48(6):457-66. doi: 10.1007/s13312-011-0078-x. PMID: 21743112Free PMC Article
Alatzoglou KS, Dattani MT
Early Hum Dev 2009 Nov;85(11):705-12. Epub 2009 Sep 16 doi: 10.1016/j.earlhumdev.2009.08.057. PMID: 19762173

Diagnosis

Qi Q, Jiang Y, Zhou X, Lü Y, Xiao R, Bai J, Lou H, Sun W, Lian Y, Hao N, Li M, Chang J
Ultrasound Obstet Gynecol 2024 May;63(5):664-671. Epub 2024 Apr 15 doi: 10.1002/uog.27517. PMID: 37842862
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
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
Raam MS, Solomon BD, Muenke M
Indian Pediatr 2011 Jun;48(6):457-66. doi: 10.1007/s13312-011-0078-x. PMID: 21743112Free PMC Article
Kagan KO, Staboulidou I, Syngelaki A, Cruz J, Nicolaides KH
Ultrasound Obstet Gynecol 2010 Jul;36(1):10-4. doi: 10.1002/uog.7646. PMID: 20564304

Therapy

Addissie YA, Kruszka P, Troia A, Wong ZC, Everson JL, Kozel BA, Lipinski RJ, Malecki KMC, Muenke M
Environ Health 2020 Jun 8;19(1):65. doi: 10.1186/s12940-020-00611-z. PMID: 32513280Free PMC Article
Howley MM, Fisher SC, Van Zutphen AR, Waller DK, Carmichael SL, Browne ML; National Birth Defects Prevention Study
Birth Defects Res 2017 Nov 1;109(18):1471-1481. Epub 2017 Jul 31 doi: 10.1002/bdr2.1095. PMID: 28758357Free 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
Graham JM Jr, Shaw GM
Birth Defects Res A Clin Mol Teratol 2005 Nov;73(11):865-7. doi: 10.1002/bdra.20193. PMID: 16265646
Johnston MC, Bronsky PT
J Craniofac Genet Dev Biol 1991 Oct-Dec;11(4):277-91. PMID: 1812129

Prognosis

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, 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
Raam MS, Solomon BD, Muenke M
Indian Pediatr 2011 Jun;48(6):457-66. doi: 10.1007/s13312-011-0078-x. PMID: 21743112Free PMC Article
Yang MT, Lee WT, Peng SS, Lin HC, Tseng CL, Liang JS, Wang PJ, Shen YZ
Epileptic Disord 2004 Sep;6(3):173-80. PMID: 15504716
DeMyer W
Birth Defects Orig Artic Ser 1975;11(7):155-81. PMID: 764897

Clinical prediction guides

Brauner R, Bignon-Topalovic J, Bashamboo A, McElreavey K
PLoS One 2023;18(12):e0292664. Epub 2023 Dec 14 doi: 10.1371/journal.pone.0292664. PMID: 38096238Free PMC Article
Addissie YA, Kruszka P, Troia A, Wong ZC, Everson JL, Kozel BA, Lipinski RJ, Malecki KMC, Muenke M
Environ Health 2020 Jun 8;19(1):65. doi: 10.1186/s12940-020-00611-z. PMID: 32513280Free PMC Article
Heinke D, Nestoridi E, Hernandez-Diaz S, Williams PL, Rich-Edwards JW, Lin AE, Van Bennekom CM, Mitchell AA, Nembhard WN, Fretts RC, Roberts DJ, Duke CW, Carmichael SL, Yazdy MM; National Birth Defects Prevention Study
Obstet Gynecol 2020 Jan;135(1):133-140. doi: 10.1097/AOG.0000000000003614. PMID: 31809437Free 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
DeMyer W
Birth Defects Orig Artic Ser 1975;11(7):155-81. PMID: 764897

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