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Pitt-Hopkins syndrome(PTHS)

MedGen UID:
370910
Concept ID:
C1970431
Disease or Syndrome
Synonyms: ENCEPHALOPATHY, SEVERE EPILEPTIC, WITH AUTONOMIC DYSFUNCTION; MENTAL RETARDATION, SYNDROMAL, WITH INTERMITTENT HYPERVENTILATION; Mental retardation, wide mouth, distinctive facial features, and intermittent hyperventilation followed by apnea; PTHS
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
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).
 
Gene: TCF4
Cytogenetic location: 18q21.2
OMIM: 610954

Disease characteristics

Excerpted from the GeneReview: Pitt-Hopkins Syndrome
Pitt-Hopkins syndrome (PTHS) is characterized by distinctive facial features which become more apparent with age (100%), developmental delay/intellectual disability (100%), and episodic hyperventilation and/or breath-holding while awake (55%-60%). Global developmental delays are significant and intellectual disability is moderate to severe: mean age of walking is four to six years; most affected individuals are nonverbal. Other common findings are behavioral issues, hand stereotypic movements, seizures (40%-50%), constipation, and severe myopia. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Description  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Holly H Ardinger  |  Holly I Welsh  |  Carol J Saunders   view full author information

Additional descriptions

From OMIM
The Pitt-Hopkins syndrome is characterized by mental retardation, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea (Zweier et al., 2007). See also Pitt-Hopkins-like syndrome-1 (610042), caused by mutation in the CNTNAP2 gene (604569) on chromosome 7q35, and Pitt-Hopkins-like syndrome-2 (600565), caused by mutation in the NRXN1 gene (600565) on chromosome 2p16.3.  http://www.omim.org/entry/610954
From GHR
Pitt-Hopkins syndrome is a condition characterized by intellectual disability and developmental delay which range from moderate to severe, breathing problems, recurrent seizures (epilepsy), and distinctive facial features. People with Pitt-Hopkins syndrome have severe intellectual disability and developmental delay. Most affected individuals do not learn to walk unassisted. People with this condition typically do not develop speech; some may learn to say a few words. Breathing problems in individuals with Pitt-Hopkins syndrome are characterized by episodes of rapid breathing (hyperventilation) followed by periods in which breathing slows or stops (apnea). These episodes can cause a lack of oxygen in the blood, leading to a bluish appearance of the skin or lips (cyanosis). In some cases, the lack of oxygen can cause loss of consciousness. Some older individuals with Pitt-Hopkins syndrome develop widened and rounded tips of the fingers and toes (clubbing) because of recurrent episodes of decreased oxygen in the blood. The breathing problems occur only when the person is awake and typically first appear within the first decade of life; they can begin as early as infancy. Episodes of hyperventilation and apnea can be triggered by emotions such as excitement or anxiety or by extreme tiredness (fatigue). Epilepsy occurs in most people with Pitt-Hopkins syndrome and usually begins during childhood, although it can be present from birth. Individuals with Pitt-Hopkins syndrome have distinctive facial features that include thin eyebrows, sunken eyes, a prominent nose with a high nasal bridge, a pronounced double curve of the upper lip (Cupid's bow), a wide mouth with full lips, and widely spaced teeth. The ears are usually thick and cup-shaped. Children with Pitt-Hopkins syndrome typically have a happy, excitable demeanor with frequent smiling, laughter, and hand-flapping movements. However, they can also experience anxiety and behavioral problems. Other features of Pitt-Hopkins syndrome may include constipation and other gastrointestinal problems, small hands and feet, a single crease across the palms of the hands, flat feet (pes planus), an unusually small head (microcephaly), nearsightedness (myopia), eyes that do not look in the same direction (strabismus), short stature, and minor brain abnormalities. Males with Pitt-Hopkins syndrome may have an unusually small penis or undescended testes (cryptorchidism).  http://ghr.nlm.nih.gov/condition/pitt-hopkins-syndrome

Clinical features

Cryptorchidism
MedGen UID:
504309
Concept ID:
CN000029
Finding
Absence of one or both testes from the scrotum owing to failure of the testis or testes to descend through the inguinal canal to the testis.
Micropenis
MedGen UID:
504321
Concept ID:
CN000054
Finding
Abnormally small `penis` (FMA:9707). At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Wide mouth
MedGen UID:
504368
Concept ID:
CN000150
Finding
Distance between the oral commissures more than 2 SD above the mean. Alternatively, an apparently increased width of the oral aperture (subjective).
Abnormality of the teeth
MedGen UID:
424982
Concept ID:
CN000160
Finding
Any abnormality of the `teeth` (FMA:12516).
Abnormality of the palate
MedGen UID:
427798
Concept ID:
CN000169
Finding
Any abnormality of the `palate` (FMA:54549), i.e., of roof of the mouth).
Thick lower lip vermilion
MedGen UID:
504381
Concept ID:
CN000174
Finding
Increased thickness of the lower lip, leading to a prominent appearance of the lower lip. The height of the vermilion of the lower lip in the midline is more than 2 SD above the mean. Alternatively, an apparently increased height of the vermilion of the lower lip in the frontal view (subjective).
Wide nasal bridge
MedGen UID:
504442
Concept ID:
CN000404
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Deeply set eye
MedGen UID:
504464
Concept ID:
CN000458
Finding
An `eye` (FMA:54448) that is more deeply recessed into the plane of the face than is typical.
Upslanted palpebral fissure
MedGen UID:
504509
Concept ID:
CN000546
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.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
Misalignment of the visual axes of the eyes. In comitant strabismus the degree of ocular misalignment does not vary with the direction of gaze. In noncomitant strabismus the degree of misalignment varies depending on direction of gaze or which eye is fixating on the target. (Miller, Walsh & Hoyt's Clinical Neuro-Ophthalmology, 4th ed, p641)
Astigmatism
MedGen UID:
504459
Concept ID:
CN000451
Finding
Astigmatism describes a refractive error characterized by a difference in the horizontal and vertical curvature of the cornea.
Deeply set eye
MedGen UID:
504464
Concept ID:
CN000458
Finding
An `eye` (FMA:54448) that is more deeply recessed into the plane of the face than is typical.
Myopia
MedGen UID:
504487
Concept ID:
CN000511
Finding
An abnormality of refraction characterized by the ability to see objects nearby clearly, while objects in the distance appear blurry.
Cupped ear
MedGen UID:
504426
Concept ID:
CN000353
Finding
Laterally protruding ear that lacks antihelical folding (including absence of inferior and superior crura).
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
IQ 20-34.
Aggressive behavior
MedGen UID:
504570
Concept ID:
CN000675
Finding
Aggressive behavior can denote verbal aggression, physical aggression against objects, physical aggression against people, and may also include aggression towards oneself.
Motor delay
MedGen UID:
504779
Concept ID:
CN001164
Finding
A type of `Developmental delay` (HP:0001263) characterized by a delay in acquiring motor skills.
Gait ataxia
MedGen UID:
505076
Concept ID:
CN001868
Finding
A type of `ataxia` (HP:0001251) characterized by the impairment of the ability to coordinate the movements required for normal walking.
Clubbing
MedGen UID:
504760
Concept ID:
CN001124
Finding
Broadening of the soft tissues (non-edematous swelling of soft tissues) of the digital tips in all dimensions associated with an increased longitudinal and lateral curvature of the nails.
Pes planus
MedGen UID:
427894
Concept ID:
CN001603
Finding
A foot where the `plantar arch` (FMA:43942) is in contact with the ground or floor when the individual is standing; or, in a patient lying supine, a foot where the arch is in contact with the surface of a flat board pressed against the sole of the foot by the examiner with a pressure similar to that expected from weight bearing; or, the height of the arch is reduced.
Gastroesophageal reflux
MedGen UID:
505057
Concept ID:
CN001828
Finding
A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Pathologic Function
A disorder characterized by cessation of breathing.
Hyperventilation
MedGen UID:
9377
Concept ID:
C0020578
Finding
A pulmonary ventilation rate faster than is metabolically necessary for the exchange of gases. It is the result of an increased frequency of breathing, an increased tidal volume, or a combination of both. It causes an excess intake of oxygen and the blowing off of carbon dioxide.
Muscular hypotonia
MedGen UID:
504768
Concept ID:
CN001147
Finding
Muscular hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength. Hypotonia is characterized by a diminished resistance to passive stretching.

Recent clinical studies

Etiology

Sweatt JD
Exp Mol Med 2013 May 3;45:e21. doi: 10.1038/emm.2013.32. PMID: 23640545Free PMC Article
Navarrete K, Pedroso I, De Jong S, Stefansson H, Steinberg S, Stefansson K, Ophoff RA, Schalkwyk LC, Collier DA
Am J Med Genet B Neuropsychiatr Genet 2013 Jan;162B(1):1-16. Epub 2012 Nov 5 doi: 10.1002/ajmg.b.32109. [Epub ahead of print] PMID: 23129290
Van Balkom ID, Vuijk PJ, Franssens M, Hoek HW, Hennekam RC
Dev Med Child Neurol 2012 Oct;54(10):925-31. Epub 2012 Jun 19 doi: 10.1111/j.1469-8749.2012.04339.x. [Epub ahead of print] PMID: 22712893
Gregor A, Albrecht B, Bader I, Bijlsma EK, Ekici AB, Engels H, Hackmann K, Horn D, Hoyer J, Klapecki J, Kohlhase J, Maystadt I, Nagl S, Prott E, Tinschert S, Ullmann R, Wohlleber E, Woods G, Reis A, Rauch A, Zweier C
BMC Med Genet 2011 Aug 9;12:106. doi: 10.1186/1471-2350-12-106. [Epub ahead of print] PMID: 21827697Free PMC Article
Blake DJ, Forrest M, Chapman RM, Tinsley CL, O'Donovan MC, Owen MJ
Schizophr Bull 2010 May;36(3):443-7. Epub 2010 Apr 26 doi: 10.1093/schbul/sbq035. [Epub ahead of print] PMID: 20421335Free PMC Article

Diagnosis

Sweatt JD
Exp Mol Med 2013 May 3;45:e21. doi: 10.1038/emm.2013.32. PMID: 23640545Free PMC Article
Kousoulidou L, Tanteles G, Moutafi M, Sismani C, Patsalis PC, Anastasiadou V
Eur J Med Genet 2013 Jun;56(6):314-8. Epub 2013 Mar 23 doi: 10.1016/j.ejmg.2013.03.005. [Epub ahead of print] PMID: 23528641
Inati A, Abbas HA, Korjian S, Daaboul Y, Harajeily M, Saab R
J Child Neurol 2013 Dec;28(12):1698-701. Epub 2012 Dec 17 doi: 10.1177/0883073812468054. [Epub ahead of print] PMID: 23248353
Steinbusch CV, van Roozendaal KE, Tserpelis D, Smeets EE, Kranenburg-de Koning TJ, de Waal KH, Zweier C, Rauch A, Hennekam RC, Blok MJ, Schrander-Stumpel CT
Clin Genet 2013 Jan;83(1):73-7. Epub 2012 Mar 15 doi: 10.1111/j.1399-0004.2012.01857.x. [Epub ahead of print] PMID: 22335494
Ghosh PS, Friedman NR, Ghosh D
J Child Neurol 2012 Dec;27(12):1602-6. Epub 2012 Feb 28 doi: 10.1177/0883073812437242. [Epub ahead of print] PMID: 22378661

Therapy

Cantarín-Extremera V, González-Gutiérrez-Solana L, Ramírez-Orellana M, López-Marín L, Duat-Rodríguez A, Ruíz-Falcó-Rojas ML
Pediatr Neurol 2012 Nov;47(5):373-4. doi: 10.1016/j.pediatrneurol.2012.08.006. PMID: 23044022
Verhulst SL, De Dooy J, Ramet J, Bockaert N, Van Coster R, Ceulemans B, De Backer W
Am J Med Genet A 2012 Apr;158A(4):932-4. Epub 2012 Mar 9 doi: 10.1002/ajmg.a.35247. [Epub ahead of print] PMID: 22407847
Maini I, Cantalupo G, Turco EC, De Paolis F, Magnani C, Parrino L, Terzano MG, Pisani F
J Child Neurol 2012 Dec;27(12):1585-8. Epub 2012 Feb 28 doi: 10.1177/0883073811435917. [Epub ahead of print] PMID: 22378662

Prognosis

Rossi M, Labalme A, Cordier MP, Till M, Blanchard G, Dubois R, Guibaud L, Heissat S, Javouhey E, Lachaux A, Mure PY, Ville D, Edery P, Sanlaville D
Am J Med Genet A 2012 Dec;158A(12):3174-81. Epub 2012 Nov 19 doi: 10.1002/ajmg.a.35588. [Epub ahead of print] PMID: 23165966
Van Balkom ID, Vuijk PJ, Franssens M, Hoek HW, Hennekam RC
Dev Med Child Neurol 2012 Oct;54(10):925-31. Epub 2012 Jun 19 doi: 10.1111/j.1469-8749.2012.04339.x. [Epub ahead of print] PMID: 22712893
Hasi M, Soileau B, Sebold C, Hill A, Hale DE, O'Donnell L, Cody JD
Hum Genet 2011 Dec;130(6):777-87. Epub 2011 Jun 14 doi: 10.1007/s00439-011-1020-y. [Epub ahead of print] PMID: 21671075Free PMC Article

Clinical prediction guides

Marangi G, Ricciardi S, Orteschi D, Tenconi R, Monica MD, Scarano G, Battaglia D, Lettori D, Vasco G, Zollino M
Am J Med Genet A 2012 Jul;158A(7):1604-11. Epub 2012 Jun 7 doi: 10.1002/ajmg.a.35419. [Epub ahead of print] PMID: 22678594
Whalen S, Héron D, Gaillon T, Moldovan O, Rossi M, Devillard F, Giuliano F, Soares G, Mathieu-Dramard M, Afenjar A, Charles P, Mignot C, Burglen L, Van Maldergem L, Piard J, Aftimos S, Mancini G, Dias P, Philip N, Goldenberg A, Le Merrer M, Rio M, Josifova D, Van Hagen JM, Lacombe D, Edery P, Dupuis-Girod S, Putoux A, Sanlaville D, Fischer R, Drévillon L, Briand-Suleau A, Metay C, Goossens M, Amiel J, Jacquette A, Giurgea I
Hum Mutat 2012 Jan;33(1):64-72. Epub 2011 Nov 23 doi: 10.1002/humu.21639. [Epub ahead of print] PMID: 22045651
Lehalle D, Williams C, Siu VM, Clayton-Smith J
Am J Med Genet A 2011 Jul;155A(7):1685-9. Epub 2011 Jun 10 doi: 10.1002/ajmg.a.34055. [Epub ahead of print] PMID: 21671383
Stavropoulos DJ, MacGregor DL, Yoon G
Eur J Med Genet 2010 Nov-Dec;53(6):396-9. Epub 2010 Sep 21 doi: 10.1016/j.ejmg.2010.08.005. [Epub ahead of print] PMID: 20813211
Giurgea I, Missirian C, Cacciagli P, Whalen S, Fredriksen T, Gaillon T, Rankin J, Mathieu-Dramard M, Morin G, Martin-Coignard D, Dubourg C, Chabrol B, Arfi J, Giuliano F, Claude Lambert J, Philip N, Sarda P, Villard L, Goossens M, Moncla A
Hum Mutat 2008 Nov;29(11):E242-51. doi: 10.1002/humu.20859. PMID: 18781613

Recent systematic reviews

Navarrete K, Pedroso I, De Jong S, Stefansson H, Steinberg S, Stefansson K, Ophoff RA, Schalkwyk LC, Collier DA
Am J Med Genet B Neuropsychiatr Genet 2013 Jan;162B(1):1-16. Epub 2012 Nov 5 doi: 10.1002/ajmg.b.32109. [Epub ahead of print] PMID: 23129290
Rossi M, Labalme A, Cordier MP, Till M, Blanchard G, Dubois R, Guibaud L, Heissat S, Javouhey E, Lachaux A, Mure PY, Ville D, Edery P, Sanlaville D
Am J Med Genet A 2012 Dec;158A(12):3174-81. Epub 2012 Nov 19 doi: 10.1002/ajmg.a.35588. [Epub ahead of print] PMID: 23165966

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