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Disease Profile

Pitt-Hopkins syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Infancy

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ICD-10

Q87.0

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Pitt Hopkins syndrome; Intellectual disability, wide mouth, distinctive facial features, and intermittent hyperventilation followed by apnea

Categories

Congenital and Genetic Diseases; Nervous System Diseases

Summary

Pitt-Hopkins syndrome (PTHS) is a genetic syndrome that causes developmental delays, moderate to severe intellectual disability, behavioral differences, distinctive facial features, and breathing problems such as episodes of rapid breathing (hyperventilation) and breath-holding. Other features may include symptoms of autism spectrum disorder, sleep disturbances, seizures, constipation, nearsightedness, and minor skeletal abnormalities.[1][2]

PTHS is caused by a mutation in the TCF4 gene, or by a loss (deletion) of the part of chromosome 18 that contains the TCF4 gene. Inheritance is autosomal dominant, but PTHS typically is not inherited from a parent, occurring sporadically due to a new mutation in people with no family history of PTHS. The diagnosis may be suspected based on signs and symptoms and can be confirmed with genetic testing.[1]

There is no cure for PTHS, but there are ways to manage or improve many of the signs and symptoms. Management may include early intervention services for infants and young children, an individualized education plan for school-aged children, behavioral therapy, and routine treatment of seizures, nearsightedness, constipation, and skeletal abnormalities.[1]

Symptoms

Pitt-Hopkins syndrome (PTHS) can have a variety of signs and symptoms. Specific symptoms present and their severity can vary from person to person. Early symptoms, which often become apparent in the first year of life, may include very low muscle tone (hypotonia) and significant developmental delays. Some infants have a small head size (microcephaly). Children may learn to walk months or years later than expected, and some children never acquire the skills to walk independently. Speech is significantly delayed, and while some children learn to say a few words, most do not speak. However, some are able to understand and follow simple directions. Intellectual disability generally ranges from moderate to severe.[1][2][3]

Additional signs and symptoms of PTHS may include:[1][2][3][4]

  • Behavioral differences: Symptoms of autism spectrum disorder may be present. Other behavioral characteristics that have been reported include unusual behavior during feeding, aggressive outbursts, anxiety, hand biting and head banging, and other stereotypic hand or head movements. However, many children with PTHS are described as having happy dispositions.
  • Distinctive facial features: These may become more obvious with age and may include deeply-set eyes, a prominent nose, short philtrum, wide mouth, full lower lip, widely-spaced teeth, and/or a prominent chin.
  • Breathing problems: These may include episodes of rapid breathing (episodic hyperventilation) followed by episodes of struggling to breath or not breathing. Episodes of breathing problems may be triggered by anxiety, excitement, or tiredness. Failure to breathe may cause a bluish discoloration of the skin (cyanosis) or fainting.
  • Seizures: These occur in almost half of people with PTHS, and the type and severity varies. Seizures may begin any time during childhood or adolescence.
  • Sleep disturbances: These may include problems falling asleep or staying asleep, and/or night terrors.
  • Eye or vision problems: Nearsightedness (myopia) can be severe and may become apparent before 2 years of age. Other eye abnormalities may include misalignment (strabismus) and astigmatism.
  • Gastrointestinal problems: These may include early feeding issues (which often resolve), constipation (which can be severe), and reflux.
  • Skeletal features: Those that have been reported in people with PTHS include scoliosisflat feet, clubfoot, small hands and feet, broad fingertips or tapered fingers, bent or curved finger (clinodactyly), and overlapping toes.

More detailed information about signs and symptoms that may occur in people with PTHS is available from the National Organization for Rare Disorders (NORD) and GeneReviews.

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormal palate morphology
Abnormality of the palate
Abnormality of the roof of the mouth

[ more ]

0000174
Anteverted nares
Nasal tip, upturned
Upturned nasal tip
Upturned nose
Upturned nostrils

[ more ]

0000463
Aphasia
Difficulty finding words
Losing words
Loss of words

[ more ]

0002381
Astigmatism
Abnormal curving of the cornea or lens of the eye
0000483
Broad fingertip
Broad fingertips
0011300
Coarse facial features
Coarse facial appearance
0000280
Constipation
0002019
Deeply set eye
Deep set eye
Deep-set eyes
Sunken eye

[ more ]

0000490
Dysphasia
0002357
Echolalia
Echoing another person's speech
0010529
Esophagitis
Inflammation of the esophagus
0100633
Failure of eruption of permanent teeth
0006352
Failure to thrive
Faltering weight
Weight faltering

[ more ]

0001508
Feeding difficulties
Feeding problems
Poor feeding

[ more ]

0011968
Finger clinodactyly
0040019
Full cheeks
Apple cheeks
Big cheeks
Increased size of cheeks
Large cheeks

[ more ]

0000293
Gastroesophageal reflux
Acid reflux
Acid reflux disease
Heartburn

[ more ]

0002020
Global developmental delay
0001263
Hiatus hernia
Stomach hernia
0002036
Intellectual disability, moderate
IQ between 34 and 49
0002342
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference

[ more ]

0000252
Misalignment of teeth
Abnormal dental position
Abnormal teeth spacing
Abnormality of alignment of teeth
Abnormality of teeth spacing
Crooked teeth
Malaligned teeth
Malposition of teeth
Malpositioned teeth

[ more ]

0000692
Muscular hypotonia
Low or weak muscle tone
0001252
Mutism
Inability to speak
Muteness

[ more ]

0002300
Myopia
Close sighted
Near sighted
Near sightedness
Nearsightedness

[ more ]

0000545
Narrow forehead
Decreased width of the forehead
0000341
Overhanging nasal tip
Drooping nasal tip
Hooked tip of nose
Low hanging nasal tip
Nasal tip, overhanging

[ more ]

0011833
Pes planus
Flat feet
Flat foot

[ more ]

0001763
Pes valgus
0008081
Prominent nasal bridge
Elevated nasal bridge
High nasal bridge
Prominent bridge of nose
Prominent nasal root
Protruding bridge of nose
Protruding nasal bridge

[ more ]

0000426
Short metatarsal
Short long bone of foot
0010743
Short neck
Decreased length of neck
0000470
Short philtrum
0000322
Single transverse palmar crease
0000954
Small hand
Disproportionately small hands
0200055
Specific learning disability
0001328
Tapered finger
Tapered fingertips
Tapering fingers

[ more ]

0001182
Thick vermilion border
Full lips
Increased volume of lip
Plump lips
Prominent lips
Thick lips

[ more ]

0012471
Thickened helices
0000391
Upslanted palpebral fissure
Upward slanting of the opening between the eyelids
0000582
Wide mouth
Broad mouth
Large mouth

[ more ]

0000154
30%-79% of people have these symptoms
Absent speech
Absent speech development
Lack of language development
Lack of speech
No speech development
No speech or language development
Nonverbal

[ more ]

0001344
Acrocyanosis
Persistent blue color of hands, feet, or parts of face
0001063
Aplasia/Hypoplasia of the corpus callosum
0007370
Gait ataxia
Inability to coordinate movements when walking
0002066
Hyperventilation
Rapid breathing
0002883
Narrow foot
Slender feet

Diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Treatment

    There is no cure for Pitt-Hopkins syndrome (PTHS), but there are ways to manage or improve signs and symptoms. Treatment depends on the specific symptoms and severity in each person and ideally is managed by a team of specialists with knowledge of PTHS. Treatment may involve:[1][3]

    • Early intervention services for infants and young children, which may include occupational, physical, speech and feeding therapies.
    • An individualized education plan (IEP) for preschool and school-aged children.
    • Behavioral therapies children may benefit from treatments for autism spectrum disorder (such as applied behavioral analysis, or ABA) or medications.
    • Consideration of medication for significant breathing problems. Some individuals with PTHS have reported improvement of breathing problems with antiepileptic drugs or acetazolamide.
    • Routine treatment of seizures, nearsightedness, constipation, and orthopedic problems.
    • The use of durable medical equipment (such as wheelchairs, walkers, and adaptive strollers) as needed.

    Children with PTHS should continue to have developmental assessments as their needs change with age. Regular appointments with an ophthalmologist are recommended to monitor and manage vision changes and other eye conditions. Periodic evaluations with a genetics professional are also recommended, as new information about the course of PTHS and treatment options may become available.[1]

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Social Networking Websites

      • RareConnect has an online community for patients and families with this condition so they can connect with others and share their experiences living with a rare disease. The project is a joint collaboration between EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders).

      Organizations Providing General Support

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

          In-Depth Information

          • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
          • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
          • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss Pitt-Hopkins syndrome. Click on the link to view a sample search on this topic.

            References

            1. Sweetser DA, Elsharkawi I, Yonker L, Steeves M, Parkin K, Thibert R. Pitt-Hopkins Syndrome. GeneReviews. April 12, 2018; https://www.ncbi.nlm.nih.gov/books/NBK100240/.
            2. Pitt-Hopkins syndrome. Genetics Home Reference (GHR). February, 2015; https://ghr.nlm.nih.gov/condition/pitt-hopkins-syndrome.
            3. Pitt-Hopkins Syndrome. National Organization for Rare Disorders (NORD). 2018; https://rarediseases.org/rare-diseases/pitt-hopkins-syndrome/.
            4. de Winter CF, Baas M, Bijlsma EK, van Heukelingen J, Routledge S, Hennekam RCM. Phenotype and natural history in 101 individuals with Pitt-Hopkins syndrome through an internet questionnaire system. Orphanet Journal of Rare Diseases. 2016; 11:37:https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0422-2.

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