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Heterotopia, periventricular, X-linked dominant(PVNH1)

MedGen UID:
376309
Concept ID:
C1848213
Disease or Syndrome
Synonyms: Heterotopia familial nodular; HETEROTOPIA, PERIVENTRICULAR, 1; Nodular heterotopia bilateral periventricular; PERIVENTRICULAR NODULAR HETEROTOPIA 1; PERIVENTRICULAR NODULAR HETEROTOPIA 4; PVNH1; X-linked periventricular heterotopia
SNOMED CT: X-linked periventricular heterotopia (448227009)
 
Gene (location): FLNA (Xq28)
 
Monarch Initiative: MONDO:0010233
OMIM®: 300049

Disease characteristics

Excerpted from the GeneReview: FLNA Deficiency
FLNA deficiency is associated with a phenotypic spectrum that includes FLNA-related periventricular nodular heterotopia (Huttenlocher syndrome), congenital heart disease (patent ductus arteriosus, atrial and ventricular septal defects), valvular dystrophy, dilatation and rupture of the thoracic aortic, pulmonary disease (pulmonary hypertension, alveolar hypoplasia, emphysema, asthma, chronic bronchitis), gastrointestinal dysmotility and obstruction, joint hypermobility, and macrothrombocytopenia. [from GeneReviews]
Authors:
Ming Hui Chen  |  Christopher A Walsh   view full author information

Additional description

From OMIM
Periventricular nodular heterotopia is a disorder of neuronal migration in which neurons fail to migrate appropriately from the ventricular zone to the cortex during development, resulting in the formation of nodular brain tissue lining the ventricles. Most affected individuals with the X-linked form are female, while hemizygous males tend to die in utero. Affected females usually present with epilepsy, but have normal intelligence. Additional features include defects of the cardiovascular system, such as patent ductus arteriosus, bicuspid aortic valve, and dilation of the sinuses of Valsalva or the thoracic aorta (summary by Fox et al., 1998). Several patients with PVNH and mutations in the FLNA gene have been reported with a spectrum of connective tissue abnormalities characterized by combinations of vascular, cardiac, cutaneous, and joint-related symptoms (summary by Reinstein et al., 2013). Genetic Heterogeneity of Periventricular Nodular Heterotopia Periventricular nodular heterotopia is a genetically heterogeneous condition: see also PVNH2 (608097), caused by mutation in the ARFGEF2 gene (605371) on chromosome 20q13; PVNH3 (608098), associated with anomalies of 5p; PVNH5 (612881), associated with deletions of chromosome 5q; PVNH6 (615544), caused by mutation in the ERMARD gene (615532) on chromosome 6q27; PVNH7 (617201), caused by mutation in the NEDD4L gene (606384) on chromosome 18q21; PVNH8 (618185), caused by mutation in the ARF1 gene (103180) on chromosome 1q42; and PVNH9 (618918), caused by mutation in the MAP1B gene (157129) on chromosome 5q13. The form of PVNH that was previously designated the Ehlers-Danlos variant (PVNH4) is now considered to be the same as X-linked PVNH1.  http://www.omim.org/entry/300049

Clinical features

From HPO
Syndactyly
MedGen UID:
52619
Concept ID:
C0039075
Congenital Abnormality
Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are referred to as "bony" syndactyly if the fusion occurs in a radio-ulnar axis. Fusions of bones of the fingers or toes in a proximo-distal axis are referred to as "symphalangism".
Short finger
MedGen UID:
334977
Concept ID:
C1844548
Anatomical Abnormality
Abnormally short finger associated with developmental hypoplasia.
Clinodactyly
MedGen UID:
1644094
Concept ID:
C4551485
Congenital Abnormality
An angulation of a digit at an interphalangeal joint in the plane of the palm (finger) or sole (toe).
Patent ductus arteriosus
MedGen UID:
4415
Concept ID:
C0013274
Congenital Abnormality
In utero, the ductus arteriosus (DA) serves to divert ventricular output away from the lungs and toward the placenta by connecting the main pulmonary artery to the descending aorta. A patent ductus arteriosus (PDA) in the first 3 days of life is a physiologic shunt in healthy term and preterm newborn infants, and normally is substantially closed within about 24 hours after bith and completely closed after about three weeks. Failure of physiologcal closure is referred to a persistent or patent ductus arteriosus (PDA). Depending on the degree of left-to-right shunting, PDA can have clinical consequences.
Stroke disorder
MedGen UID:
52522
Concept ID:
C0038454
Disease or Syndrome
Sudden impairment of blood flow to a part of the brain due to occlusion or rupture of an artery to the brain.
Bicuspid aortic valve
MedGen UID:
57436
Concept ID:
C0149630
Congenital Abnormality
Aortic valve disease-2 (AOVD2) is characterized by bicuspid aortic valve (BAV) and dilation of the ascending aorta. Calcification of the valve and the aorta has been observed, and some patients exhibit coarctation of the aorta (Tan et al., 2012; Luyckx et al., 2019; Park et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of aortic valve disease, see AOVD1 (109730).
Cerebral hemorrhage
MedGen UID:
423648
Concept ID:
C2937358
Pathologic Function
Hemorrhage into the parenchyma of the brain.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
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.
Cerebellar hypoplasia
MedGen UID:
120578
Concept ID:
C0266470
Congenital Abnormality
Cerebellar hypoplasia is a descriptive term implying a cerebellum with a reduced volume, but a normal shape and is stable over time.
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.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Abnormality of neuronal migration
MedGen UID:
324748
Concept ID:
C1837249
Congenital Abnormality
An abnormality resulting from an anomaly of neuronal migration, i.e., of the process by which neurons travel from their origin to their final position in the brain.
Thin corpus callosum
MedGen UID:
1785336
Concept ID:
C5441562
Anatomical Abnormality
An abnormally thin corpus callous, due to atrophy, hypoplasia or agenesis. This term is intended to be used in situations where it is not known if thinning of the corpus callosum (for instance, as visualized by magnetic resonance tomography) is due to abnormal development (e.g. a leukodystrophy) or atrophy following normal development (e.g. neurodegeneration).
Abnormality of the coagulation cascade
MedGen UID:
604
Concept ID:
C0005779
Disease or Syndrome
An abnormality of the coagulation cascade, which is comprised of the contact activation pathway (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway) as well as cofactors and regulators.
Bone marrow maturation arrest
MedGen UID:
549798
Concept ID:
C0302173
Cell or Molecular Dysfunction
Interruption of the procecss of diffferentiation of hematopoietic cells in the bone marrow, manifested by an increased proportion of immature cells in the bone marrow.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.

Professional guidelines

PubMed

Guerrini R, Carrozzo R
Seizure 2002 Apr;11 Suppl A:532-43; quiz 544-7. PMID: 12185771
Guerrini R, Carrozzo R
Seizure 2001 Oct;10(7):532-43; quiz 544-7. doi: 10.1053/seiz.2001.0650. PMID: 11749114

Recent clinical studies

Etiology

Lange M, Kasper B, Bohring A, Rutsch F, Kluger G, Hoffjan S, Spranger S, Behnecke A, Ferbert A, Hahn A, Oehl-Jaschkowitz B, Graul-Neumann L, Diepold K, Schreyer I, Bernhard MK, Mueller F, Siebers-Renelt U, Beleza-Meireles A, Uyanik G, Janssens S, Boltshauser E, Winkler J, Schuierer G, Hehr U
Orphanet J Rare Dis 2015 Oct 15;10:134. doi: 10.1186/s13023-015-0331-9. PMID: 26471271Free PMC Article
Kasper BS, Kurzbuch K, Chang BS, Pauli E, Hamer HM, Winkler J, Hehr U
Am J Med Genet A 2013 Jun;161A(6):1323-8. Epub 2013 May 1 doi: 10.1002/ajmg.a.35917. PMID: 23636902
Guerrini R, Marini C
Exp Brain Res 2006 Aug;173(2):322-33. Epub 2006 May 25 doi: 10.1007/s00221-006-0501-z. PMID: 16724181
Guerrini R, Carrozzo R
Seizure 2002 Apr;11 Suppl A:532-43; quiz 544-7. PMID: 12185771
Poussaint TY, Fox JW, Dobyns WB, Radtke R, Scheffer IE, Berkovic SF, Barnes PD, Huttenlocher PR, Walsh CA
Pediatr Radiol 2000 Nov;30(11):748-55. doi: 10.1007/s002470000312. PMID: 11100490

Diagnosis

Berrou E, Adam F, Lebret M, Planche V, Fergelot P, Issertial O, Coupry I, Bordet JC, Nurden P, Bonneau D, Colin E, Goizet C, Rosa JP, Bryckaert M
Arterioscler Thromb Vasc Biol 2017 Jun;37(6):1087-1097. Epub 2017 Apr 20 doi: 10.1161/ATVBAHA.117.309337. PMID: 28428218
Lange M, Kasper B, Bohring A, Rutsch F, Kluger G, Hoffjan S, Spranger S, Behnecke A, Ferbert A, Hahn A, Oehl-Jaschkowitz B, Graul-Neumann L, Diepold K, Schreyer I, Bernhard MK, Mueller F, Siebers-Renelt U, Beleza-Meireles A, Uyanik G, Janssens S, Boltshauser E, Winkler J, Schuierer G, Hehr U
Orphanet J Rare Dis 2015 Oct 15;10:134. doi: 10.1186/s13023-015-0331-9. PMID: 26471271Free PMC Article
Lu J, Sheen V
Epilepsy Behav 2005 Sep;7(2):143-9. doi: 10.1016/j.yebeh.2005.05.001. PMID: 15996530
Guerrini R, Carrozzo R
Seizure 2001 Oct;10(7):532-43; quiz 544-7. doi: 10.1053/seiz.2001.0650. PMID: 11749114
Huttenlocher PR, Taravath S, Mojtahedi S
Neurology 1994 Jan;44(1):51-5. doi: 10.1212/wnl.44.1.51. PMID: 8290091

Therapy

Sheen VL, Basel-Vanagaite L, Goodman JR, Scheffer IE, Bodell A, Ganesh VS, Ravenscroft R, Hill RS, Cherry TJ, Shugart YY, Barkovich J, Straussberg R, Walsh CA
Brain Dev 2004 Aug;26(5):326-34. doi: 10.1016/j.braindev.2003.09.004. PMID: 15165674

Prognosis

Oda H, Sato T, Kunishima S, Nakagawa K, Izawa K, Hiejima E, Kawai T, Yasumi T, Doi H, Katamura K, Numabe H, Okamoto S, Nakase H, Hijikata A, Ohara O, Suzuki H, Morisaki H, Morisaki T, Nunoi H, Hattori S, Nishikomori R, Heike T
Eur J Hum Genet 2016 Mar;24(3):408-14. Epub 2015 Jun 10 doi: 10.1038/ejhg.2015.119. PMID: 26059841Free PMC Article
LaPointe MM, Spriggs EL, Mhanni AA
BMC Neurol 2014 Jun 7;14:125. doi: 10.1186/1471-2377-14-125. PMID: 24906659Free PMC Article
Reinstein E, Chang BS, Robertson SP, Rimoin DL, Katzir T
Am J Med Genet A 2012 Aug;158A(8):1897-901. Epub 2012 Jun 27 doi: 10.1002/ajmg.a.35455. PMID: 22740120
Moro F, Carrozzo R, Veggiotti P, Tortorella G, Toniolo D, Volzone A, Guerrini R
Neurology 2002 Mar 26;58(6):916-21. doi: 10.1212/wnl.58.6.916. PMID: 11914408

Clinical prediction guides

Oda H, Sato T, Kunishima S, Nakagawa K, Izawa K, Hiejima E, Kawai T, Yasumi T, Doi H, Katamura K, Numabe H, Okamoto S, Nakase H, Hijikata A, Ohara O, Suzuki H, Morisaki H, Morisaki T, Nunoi H, Hattori S, Nishikomori R, Heike T
Eur J Hum Genet 2016 Mar;24(3):408-14. Epub 2015 Jun 10 doi: 10.1038/ejhg.2015.119. PMID: 26059841Free PMC Article
LaPointe MM, Spriggs EL, Mhanni AA
BMC Neurol 2014 Jun 7;14:125. doi: 10.1186/1471-2377-14-125. PMID: 24906659Free PMC Article
Kasper BS, Kurzbuch K, Chang BS, Pauli E, Hamer HM, Winkler J, Hehr U
Am J Med Genet A 2013 Jun;161A(6):1323-8. Epub 2013 May 1 doi: 10.1002/ajmg.a.35917. PMID: 23636902
Guerrini R, Carrozzo R
Seizure 2002 Apr;11 Suppl A:532-43; quiz 544-7. PMID: 12185771
Guerrini R, Carrozzo R
Seizure 2001 Oct;10(7):532-43; quiz 544-7. doi: 10.1053/seiz.2001.0650. PMID: 11749114

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