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Holoprosencephaly 2(HPE2)

MedGen UID:
322517
Concept ID:
C1834877
Disease or Syndrome
Synonyms: Holoprosencephaly; HPE2
Modes of inheritance:
Heterogeneous
MedGen UID:
67020
Concept ID:
C0242960
Organism Attribute
Source: HPO
The production of the same or similar phenotypes (observed biochemical, physiological, and morphological characteristics of a person determined by his/her genotype) by different genetic mechanisms. There are two types: (1) allelic heterogeneity - when different alleles at a locus can produce variable expression of a condition; and (2) locus heterogeneity - the term used to describe disease in which mutations at different loci can produce the same disease phenotype.
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: HPO
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
Sporadic
MedGen UID:
342827
Concept ID:
C1853237
Finding
Source: HPO
Cases of the disease in question occur without a previous family history, i.e., as isolated cases without being transmitted from a parent and without other siblings being affected.
Sporadic (HPO)
 
Gene (location): SIX3 (2p21)
OMIM®: 157170

Disease characteristics

Excerpted from the GeneReview: Holoprosencephaly Overview
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having “microform” HPE. [from GeneReviews]
Authors:
Benjamin D Solomon  |  Andrea Gropman  |  Maximilian Muenke   view full author information

Additional description

From GHR
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.Nonsyndromic 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.People 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).Some 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.Most 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.  http://ghr.nlm.nih.gov/condition/nonsyndromic-holoprosencephaly

Clinical features

BLOOD GROUP--DIEGO SYSTEM
MedGen UID:
8349
Concept ID:
C0011848
Disease or Syndrome
Diabetes insipidus (DI) causes frequent urination. You become extremely thirsty, so you drink. Then you urinate. This cycle can keep you from sleeping or even make you wet the bed. Your body produces lots of urine that is almost all water. DI is different from diabetes mellitus (DM), which involves insulin problems and high blood sugar. The symptoms can be similar. However, DI is related to how your kidneys handle fluids. It's much less common than DM. Urine and blood tests can show which one you have. Usually, DI is caused by a problem with your pituitary gland or your kidneys. Treatment depends on the cause of the problem. Medicines can often help. NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Small adrenal gland
MedGen UID:
83342
Concept ID:
C0342491
Finding
Developmental hypoplasia of the adrenal glands.
Anterior pituitary agenesis
MedGen UID:
866893
Concept ID:
C4021249
Finding
Absence of the pituitary gland resulting from a developmental defect.
Microphthalmos
MedGen UID:
10033
Concept ID:
C0026010
Congenital Abnormality
Microphthalmia is an eye abnormality that arises before birth. In this condition, one or both eyeballs are abnormally small. In some affected individuals, the eyeball may appear to be completely missing; however, even in these cases some remaining eye tissue is generally present. Such severe microphthalmia should be distinguished from another condition called anophthalmia, in which no eyeball forms at all. However, the terms anophthalmia and severe microphthalmia are often used interchangeably. Microphthalmia may or may not result in significant vision loss.People with microphthalmia may also have a condition called coloboma. Colobomas are missing pieces of tissue in structures that form the eye. They may appear as notches or gaps in the colored part of the eye called the iris; the retina, which is the specialized light-sensitive tissue that lines the back of the eye; the blood vessel layer under the retina called the choroid; or in the optic nerves, which carry information from the eyes to the brain. Colobomas may be present in one or both eyes and, depending on their size and location, can affect a person's vision.People with microphthalmia may also have other eye abnormalities, including clouding of the lens of the eye (cataract) and a narrowed opening of the eye (narrowed palpebral fissure). Additionally, affected individuals may have an abnormality called microcornea, in which the clear front covering of the eye (cornea) is small and abnormally curved.Between one-third and one-half of affected individuals have microphthalmia as part of a syndrome that affects other organs and tissues in the body. These forms of the condition are described as syndromic. When microphthalmia occurs by itself, it is described as nonsyndromic or isolated.
Cyclopia
MedGen UID:
78617
Concept ID:
C0266667
Congenital Abnormality
Cyclopia is a congenital abnormality in which there is only one eye. That eye is centrally placed in the area normally occupied by the root of the nose.
Hypotelorism
MedGen UID:
96107
Concept ID:
C0424711
Congenital Abnormality
Interpupillary distance less than 2 SD below the mean (alternatively, the appearance of an decreased interpupillary distance or closely spaced eyes).
Seizure Disorders
MedGen UID:
4506
Concept ID:
C0014544
Disease or Syndrome
Epilepsy is a brain disorder that causes people to have recurring seizures. The seizures happen when clusters of nerve cells, or neurons, in the brain send out the wrong signals. People may have strange sensations and emotions or behave strangely. They may have violent muscle spasms or lose consciousness. Epilepsy has many possible causes, including illness, brain injury, and abnormal brain development. In many cases, the cause is unknown. Doctors use brain scans and other tests to diagnose epilepsy. It is important to start treatment right away. There is no cure for epilepsy, but medicines can control seizures for most people. When medicines are not working well, surgery or implanted devices such as vagus nerve stimulators may help. Special diets can help some children with epilepsy. NIH: National Institute of Neurological Disorders and Stroke.
Intellectual functioning disability
MedGen UID:
7544
Concept ID:
C0025362
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Microcephalus
MedGen UID:
44422
Concept ID:
C0025958
Congenital Abnormality
Occipito-frontal (head) circumference (OFC) less than -3 standard deviations compared to appropriate, age matched, normal standards (Ross JJ, Frias JL 1977, PMID:9683597). Alternatively, decreased size of the cranium.
Holoprosencephaly sequence
MedGen UID:
38214
Concept ID:
C0079541
Congenital Abnormality
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having “microform” HPE.
Corpus callosum agenesis
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). 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.
Congenital cerebellar hypoplasia
MedGen UID:
120578
Concept ID:
C0266470
Congenital Abnormality
Underdevelopment of the cerebellum.
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.
Anterior pituitary agenesis
MedGen UID:
866893
Concept ID:
C4021249
Finding
Absence of the pituitary gland resulting from a developmental defect.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Constipation means that a person has three or fewer bowel movements in a week. The stool can be hard and dry. Sometimes it is painful to pass. At one time or another, almost everyone gets constipated. In most cases, it lasts a short time and is not serious. . There are many things you can do to prevent constipation. They include - Eating more fruits, vegetables and grains, which are high in fiber. - Drinking plenty of water and other liquids. - Getting enough exercise. - Taking time to have a bowel movement when you need to. - Using laxatives only if your doctor says you should. - Asking your doctor if medicines you take may cause constipation. . It's not important that you have a bowel movement every day. If your bowel habits change, however, check with your doctor. . NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A diminution of the skeletal muscle tone marked by a diminished resistance to passive stretching.
Microcephalus
MedGen UID:
44422
Concept ID:
C0025958
Congenital Abnormality
Occipito-frontal (head) circumference (OFC) less than -3 standard deviations compared to appropriate, age matched, normal standards (Ross JJ, Frias JL 1977, PMID:9683597). Alternatively, decreased size of the cranium.
Scoliosis
MedGen UID:
195976
Concept ID:
C0700208
Finding
The presence of an abnormal lateral curvature of the spine.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Anatomical Abnormality
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Absent nasal septal cartilage
MedGen UID:
867277
Concept ID:
C4021638
Anatomical Abnormality
Lack of the cartilage of the nasal septum.
Microcephalus
MedGen UID:
44422
Concept ID:
C0025958
Congenital Abnormality
Occipito-frontal (head) circumference (OFC) less than -3 standard deviations compared to appropriate, age matched, normal standards (Ross JJ, Frias JL 1977, PMID:9683597). Alternatively, decreased size of the cranium.
Microphthalmos
MedGen UID:
10033
Concept ID:
C0026010
Congenital Abnormality
Microphthalmia is an eye abnormality that arises before birth. In this condition, one or both eyeballs are abnormally small. In some affected individuals, the eyeball may appear to be completely missing; however, even in these cases some remaining eye tissue is generally present. Such severe microphthalmia should be distinguished from another condition called anophthalmia, in which no eyeball forms at all. However, the terms anophthalmia and severe microphthalmia are often used interchangeably. Microphthalmia may or may not result in significant vision loss.People with microphthalmia may also have a condition called coloboma. Colobomas are missing pieces of tissue in structures that form the eye. They may appear as notches or gaps in the colored part of the eye called the iris; the retina, which is the specialized light-sensitive tissue that lines the back of the eye; the blood vessel layer under the retina called the choroid; or in the optic nerves, which carry information from the eyes to the brain. Colobomas may be present in one or both eyes and, depending on their size and location, can affect a person's vision.People with microphthalmia may also have other eye abnormalities, including clouding of the lens of the eye (cataract) and a narrowed opening of the eye (narrowed palpebral fissure). Additionally, affected individuals may have an abnormality called microcornea, in which the clear front covering of the eye (cornea) is small and abnormally curved.Between one-third and one-half of affected individuals have microphthalmia as part of a syndrome that affects other organs and tissues in the body. These forms of the condition are described as syndromic. When microphthalmia occurs by itself, it is described as nonsyndromic or isolated.
Congenital absence of nose
MedGen UID:
120555
Concept ID:
C0265740
Congenital Abnormality
Complete absence of all nasal structures.
Cleft uvula
MedGen UID:
75600
Concept ID:
C0266122
Congenital Abnormality
Uvula separated into two parts most easily seen at the tip.
Cyclopia
MedGen UID:
78617
Concept ID:
C0266667
Congenital Abnormality
Cyclopia is a congenital abnormality in which there is only one eye. That eye is centrally placed in the area normally occupied by the root of the nose.
Hypotelorism
MedGen UID:
96107
Concept ID:
C0424711
Congenital Abnormality
Interpupillary distance less than 2 SD below the mean (alternatively, the appearance of an decreased interpupillary distance or closely spaced eyes).
Submucous cleft hard palate
MedGen UID:
98472
Concept ID:
C0432103
Congenital Abnormality
Hard-palate submucous clefts are characterized by bony defects in the midline of the bony palate that are covered by the mucous membrane of the roof of the mouth. It may be possible to detect a submucous cleft hard palate upon palpation as a notch in the bony palate.
Single upper central incisor
MedGen UID:
326686
Concept ID:
C1840235
Disease or Syndrome
The presence of a single, median maxillary incisor, affecting both the primary maxillary incisor and the permanent maxillary incisor.
Midface retrusion
MedGen UID:
339938
Concept ID:
C1853242
Finding
Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Anatomical Abnormality
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Median cleft lip and palate
MedGen UID:
413888
Concept ID:
C2750604
Finding
Cleft lip or palate affecting the midline region of the palate.
Absent nasal septal cartilage
MedGen UID:
867277
Concept ID:
C4021638
Anatomical Abnormality
Lack of the cartilage of the nasal septum.

Recent clinical studies

Etiology

Hayashi Y, Suzumori N, Sugiura T, Sugiura-Ogasawara M
Congenit Anom (Kyoto) 2015 Aug;55(3):161-3. doi: 10.1111/cga.12103. PMID: 25620469
Khalil A, Papageorghiou A, Bhide A, Akolekar R, Thilaganathan B
Prenat Diagn 2014 Feb;34(2):134-8. Epub 2013 Nov 29 doi: 10.1002/pd.4269. [Epub ahead of print] PMID: 24293286
Tatsi C, Sertedaki A, Voutetakis A, Valavani E, Magiakou MA, Kanaka-Gantenbein C, Chrousos GP, Dacou-Voutetakis C
J Clin Endocrinol Metab 2013 Apr;98(4):E779-84. Epub 2013 Mar 8 doi: 10.1210/jc.2012-3982. [Epub ahead of print] PMID: 23476075
Vaz SS, Chodirker B, Prasad C, Seabrook JA, Chudley AE, Prasad AN
Am J Med Genet A 2012 Apr;158A(4):751-8. Epub 2012 Mar 14 doi: 10.1002/ajmg.a.35240. [Epub ahead of print] PMID: 22419615
Chen CP, Kuo YK, Su YN, Chern SR, Tsai FJ, Wu PC, Chen YT, Town DD, Wang W
Taiwan J Obstet Gynecol 2011 Jun;50(2):182-7. doi: 10.1016/j.tjog.2011.04.001. PMID: 21791305

Diagnosis

Genç M, Genç B, Solak A, Alkiliç L, Uyar M
Ital J Anat Embryol 2015;120(2):83-8. PMID: 27086438
Akamatsu T, Hanai U, Nakajima S, Kobayashi M, Miyasaka M, Matsuda S, Ikegami M
Tokai J Exp Clin Med 2015 Jun 20;40(2):58-62. PMID: 26150185
Mouden C, de Tayrac M, Dubourg C, Rose S, Carré W, Hamdi-Rozé H, Babron MC, Akloul L, Héron-Longe B, Odent S, Dupé V, Giet R, David V
PLoS One 2015;10(2):e0117418. Epub 2015 Feb 6 doi: 10.1371/journal.pone.0117418. PMID: 25658757Free PMC Article
Hayashi Y, Suzumori N, Sugiura T, Sugiura-Ogasawara M
Congenit Anom (Kyoto) 2015 Aug;55(3):161-3. doi: 10.1111/cga.12103. PMID: 25620469
Khalil A, Papageorghiou A, Bhide A, Akolekar R, Thilaganathan B
Prenat Diagn 2014 Feb;34(2):134-8. Epub 2013 Nov 29 doi: 10.1002/pd.4269. [Epub ahead of print] PMID: 24293286

Therapy

Lee W, Bae JS
Blood Coagul Fibrinolysis 2015 Sep;26(6):628-34. doi: 10.1097/MBC.0000000000000320. PMID: 26126169
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
Seidahmed MZ, Shaheed MM, Abdulbasit OB, Al Dohami H, Babiker M, Abdullah MA, Abomelha AM
Birth Defects Res A Clin Mol Teratol 2006 Feb;76(2):138-42. doi: 10.1002/bdra.20199. PMID: 16470853
Cohen MM Jr, Shiota K
Am J Med Genet 2002 Apr 15;109(1):1-15. PMID: 11932986
Ronen GM, Andrews WL
Am J Med Genet 1991 Aug 1;40(2):151-4. doi: 10.1002/ajmg.1320400206. PMID: 1897567

Prognosis

Hayashi Y, Suzumori N, Sugiura T, Sugiura-Ogasawara M
Congenit Anom (Kyoto) 2015 Aug;55(3):161-3. doi: 10.1111/cga.12103. PMID: 25620469
Gorovoy IR, Layer N, de Alba Campomanes AG
J Pediatr Ophthalmol Strabismus 2014 Mar 4;51 Online:e16-8. doi: 10.3928/01913913-20140225-03. PMID: 25314309
França MM, Jorge AA, Carvalho LR, Costalonga EF, Otto AP, Correa FA, Mendonca BB, Arnhold IJ
Clin Endocrinol (Oxf) 2013 Apr;78(4):551-7. doi: 10.1111/cen.12044. PMID: 22967285
Coletă E, Siminel M, Gheonea M
Rom J Morphol Embryol 2011;52(2):725-8. PMID: 21655669
Ribeiro LA, Bertolacini CD, Quiezi RG, Richieri-Costa A
Clin Dysmorphol 2011 Jul;20(3):160-2. doi: 10.1097/MCD.0b013e32834116ae. PMID: 21368660

Clinical prediction guides

Savastano CP, Bernardi P, Seuánez HN, Moreira MÂ, Orioli IM
Birth Defects Res A Clin Mol Teratol 2014 Apr;100(4):300-6. Epub 2014 Feb 12 doi: 10.1002/bdra.23216. [Epub ahead of print] PMID: 24677696
Tatsi C, Sertedaki A, Voutetakis A, Valavani E, Magiakou MA, Kanaka-Gantenbein C, Chrousos GP, Dacou-Voutetakis C
J Clin Endocrinol Metab 2013 Apr;98(4):E779-84. Epub 2013 Mar 8 doi: 10.1210/jc.2012-3982. [Epub ahead of print] PMID: 23476075
França MM, Jorge AA, Carvalho LR, Costalonga EF, Otto AP, Correa FA, Mendonca BB, Arnhold IJ
Clin Endocrinol (Oxf) 2013 Apr;78(4):551-7. doi: 10.1111/cen.12044. PMID: 22967285
Kevelam SH, van Harssel JJ, van der Zwaag B, Smeets HJ, Paulussen AD, Lichtenbelt KD
Am J Med Genet A 2012 Jan;158A(1):166-73. Epub 2011 Nov 21 doi: 10.1002/ajmg.a.34350. [Epub ahead of print] PMID: 22106008
Ribeiro LA, Bertolacini CD, Quiezi RG, Richieri-Costa A
Clin Dysmorphol 2011 Jul;20(3):160-2. doi: 10.1097/MCD.0b013e32834116ae. PMID: 21368660

Recent systematic reviews

Alp MY, Çebi AH, Seyhan S, Cansu A, Aydin H, Ikbal M
Genet Couns 2016;27(1):43-9. PMID: 27192891
Sebold C, Soileau B, Heard P, Carter E, O'Donnell L, Hale DE, Cody JD
Am J Med Genet A 2015 Feb;167A(2):313-23. Epub 2015 Jan 14 doi: 10.1002/ajmg.a.36880. [Epub ahead of print] PMID: 25586871
Cordero DR, Bendavid C, Shanske AL, Haddad BR, Muenke M
Eur J Med Genet 2008 Mar-Apr;51(2):106-12. Epub 2007 Sep 15 doi: 10.1016/j.ejmg.2007.08.004. [Epub ahead of print] PMID: 18178536Free PMC Article
Chen CP, Chern SR, Lin CC, Wang TH, Li YC, Hsieh LJ, Lee CC, Hua HM, Wang W
Prenat Diagn 2006 Apr;26(4):313-20. doi: 10.1002/pd.1399. PMID: 16506269
Walsh LE, Vance GH, Weaver DD
Am J Med Genet 2001 Jan 15;98(2):137-44. PMID: 11223849

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