Pallister-Hall syndrome 1

Genetic testing can be offered for other family members if a GLI3 gene mutation is found in an affected person. Testing can be offered to other people depending on who is diagnosed first. An example is the following:

Some people with Pallister-Hall syndrome have a split (cleft) in the flap of tissue that usually covers the airway when swallowing. This is called a bifid epiglottis. Some people have more severe clefts of the voice box. Some clefts of the voice box can cause airway problems and even death.

About 95% of people with Pallister-Hall syndrome have a GLI3 gene mutation.

A gene change that is brand new and not inherited from a parent is called a de novo gene mutation. About 25% of people with Pallister-Hall syndrome have a de novo GLI3 mutation.

There can be neurological differences in people with Pallister-Hall syndrome. There can be a hypothalamic hamartoma in the brain. This is a malformation, not a tumor. This is a mass in the floor of the third ventricle of the brain. Sometimes a hypothalamic hamartoma can cause seizures.

There can be kidney differences in Pallister-Hall syndrome. There may be cysts. The kidneys may be underdeveloped or malformed. There may be a missing kidney. Someone may have an ectopic ureter (the ureter ends at a different site rather than the bladder).

The usual abbreviation for Pallister-Hall syndrome is PHS.

The prognosis for Pallister-Hall syndrome is variable. The prognosis depends on certain factors.

Few people experience death early on. In these cases, death is likely due to:

When someone has polydactyly, they have extra fingers and/or toes. There are certain types of polydactyly that are typically seen in Pallister-Hall syndrome. These include:

Pallister-Hall syndrome is an inherited condition that can affect different parts of the body. Some features include extra fingers and/or toes (polydactyly), fusion of fingers and/or toes (syndactyly), abnormal nails, an abnormal growth in the brain called a hypothalamic hamartoma, a division of the flap of tissue that covers the windpipe when swallowing (bifid epiglottis), an anus that is missing or blocked (imperforate anus), and kidney abnormalities. The abnormal growth in the brain can sometimes cause seizures and hormone abnormalities. Not everyone with this condition is affected the same way.

Everyone has two copies of the GLI3 gene. The official name of this gene is “GLI family zinc finger 3.” This gene is located on chromosome 7. We get one GLI3 gene from our mother and one GLI3 gene from our father. Having a specific harmful change (mutation) in one copy of the GLI3 gene causes Pallister-Hall syndrome.

There can be endocrine (hormone) differences in people with Pallister-Hall syndrome. These are due to a hypothalamic hamartoma (malformation in the brain). Some people only have growth deficiency. Some people only have early puberty. Some people have poor or absent production of some pituitary hormones (panhypopituitarism). Some people have life-threatening cortisol deficiency.

A “variant” is a change in a gene. We do not know if the change causes a particular condition. So, if a person inherits a variant in the GLI3 gene, it is unknown if that variant causes Pallister-Hall syndrome. These are often called variants of uncertain significance (VUS). Sometimes the interpretation of variants change as more people are tested and more data is available.

Genotype-phenotype correlation means that a specific change in a gene causes specific medical concerns or a specific condition. There is genotype-phenotype correlation for GLI3 gene mutations and Pallister-Hall syndrome.

People with a hypothalamic hamartoma (a malformation in the brain) can have a specific type of seizure disorder called gelastic epilepsy. They can also have hormone (endocrine) differences. Gelastic epilepsy involves jerking (clonic) movements of the chest and diaphragm that stimulate laughing. Most seizures associated with a hypothalamic hamartoma in Pallister-Hall syndrome are milder and respond to treatment. Most people with Pallister-Hall syndrome who have a hypothalamic hamartoma do not have seizures. Endocrine differences can include growth deficiency, early puberty, poor or absent production of some pituitary hormones (panhypopituitarism), and sometimes life-threatening cortisol deficiency.

People with Pallister-Hall syndrome should have certain evaluations and see some medical specialists. These include:

There is treatment for Pallister-Hall syndrome.

Each state has a newborn screen that includes certain genetic conditions. Pallister-Hall syndrome is not included in any newborn screens in the United States. If there is a family history of Pallister-Hall syndrome or if Pallister-Hall syndrome is suspected at birth, genetic testing can be done using cord blood or another blood sample.

As of January 25, 2016, there is only one gene, GLI3, known to be associated with Pallister-Hall syndrome. Genetic testing involves looking at this gene for changes. There are two ways to look at this gene. One is called sequencing. The other is called deletion/duplication testing.
Imagine that the GLI3 gene is a long sentence that gives instructions to the body. Sequencing looks for spelling errors in this sentence. Deletion/duplication testing looks for extra or missing words in this sentence. Spelling errors and extra/missing words can make the sentence no longer make sense. Therefore, it cannot give correct instructions for the body to grow and develop. This causes Pallister-Hall syndrome.

Some labs in the United States do both sequencing and deletion/duplication testing of the GLI3 gene. Some labs in the United States just offer sequencing or deletion/duplication testing of the GLI3 gene. Reportedly, no GLI3 gene mutations associated with Pallister-Hall syndrome have been detected by deletion/duplication analysis.
Some labs may prefer that a specific region of the GLI3 gene be tested first. This is because this region is known to have mutations. Some labs have genetic testing panels. These panels include testing of the GLI3 gene plus other genes.

Some families know the specific GLI3 gene mutation in their family. In those cases, labs can look specifically for that mutation in family members. This test is called site-specific mutation analysis.

As of June 3, 2016, there is no clinical research listed for Pallister-Hall syndrome. There was recently clinical research performed for Pallister-Hall syndrome. This study ended in January 2016. Information for this clinical research is the following:

Name of the Study: Phenotype and Etiology of Pallister-Hall Syndrome
Purpose: “We aim to delineate the range of severity, natural history, molecular etiology, and pathophysiology of Pallister-Hall syndrome (PHS), Greig cephalopolysyndactyly syndrome (GCPS), McKusick-Kaufman syndrome (MKS), Bardet-Biedl syndrome (BBS), Oro-facial digital syndromes (OFDs), and other overlapping phenotypes. These disorders comprise a syndrome community of overlapping manifestations and we hypothesize that this is a reflection of a common mechanistic pathway. This hypothesis will be addressed by a combined clinical-molecular approach where we bring up to 50-100 patients with each disorder to the NIH clinical center for a comprehensive clinical evaluation with follow-up at a frequency appropriate to the disorder. Specimens will be collected and evaluated in the laboratory by linkage analysis, physical mapping, candidate gene characterization, mutation screening, and cell biologic studies of normal mutant proteins.”

Please refer to this study by its ClinicalTrials.gov identifier: NCT00001404

If someone with Pallister-Hall syndrome has seizures, they should avoid certain stimulants. Specifically, they should avoid stimulants used for attention deficit and hyperactivity disorders. These could make the seizure activity worse.

In some cases, polydactyly (extra fingers and/or toes) can be seen on prenatal ultrasound if a baby has Pallister-Hall syndrome. Not all babies with Pallister-Hall syndrome have findings on prenatal ultrasound.

There is no cure for Pallister-Hall syndrome. Treatment is limited to surgical intervention and management/surveillance of medical concerns.

People with Pallister-Hall syndrome are affected differently. It can be difficult to predict what medical concerns a person will have. Some people are more mildly affected and some people are more severely affected. If there is a family history of Pallister-Hall syndrome, the affected individuals usually have similar clinical features.

Removing a hypothalamic hamartoma (a malformation in the brain) in someone with Pallister-Hall syndrome is not indicated. There can be serious complications from this surgery. There would also be a need for lifelong hormone supplements. The benefits of removing the tumor do not justify these risks.

For some babies, Pallister-Hall syndrome can be life-threatening if their pituitary function is decreased or absent. Signs of this can include low blood sugar levels, abnormal electrolyte levels, and high levels of acid in the blood (metabolic acidosis). A primary care provider should be aware of this and assess for this as soon as possible. A primary care provider should especially be concerned if there is no family history of Pallister-Hall syndrome, or if there are affected family members who have cortisol deficiency.

The primary care provider should watch for swallowing difficulties and clefts that can be life-threatening. The primary care provider should regularly check growth and look for signs of early puberty. They should make referrals to see specialists (endocrinologist, neurologist, nephrologist, otolaryngologist, and surgeon). The primary care provider should screen for developmental delay and learning disabilities, and refer to a developmental specialist if needed.

If a person is affected with Pallister-Hall syndrome and has a known GLI3 gene mutation, there is a 50% chance that each of his/her children will be affected. People with Pallister-Hall syndrome in the same family usually have similar clinical features.

If a mother or father is affected with Pallister-Hall syndrome and has a known GLI3 gene mutation, genetic testing can be done during a pregnancy. Testing involves looking for the specific GLI3 gene mutation found in the mother or father. However, clinical features cannot be predicted before birth.

Chorionic villus sampling (CVS) and amniocentesis are procedures that collect samples for testing. Because CVS and amniocentesis are invasive, there is a small risk for miscarriage.
CVS removes a piece of the placenta to send to a laboratory for genetic testing. CVS can be done around 10-12 weeks of gestation.
Amniocentesis removes a sample of amniotic fluid to send to a laboratory for genetic testing. Amniocentesis can be done starting at 15 weeks of gestation.

If you are interested in prenatal testing, you can speak with a genetic counselor in your area. To find a genetic counselor near you, use the "Find a Genetic Counselor" tool on the National Society of Genetic Counselors’ website.

Parents who have a child with Pallister-Hall syndrome but do not have a GLI3 mutation could have germline/gonadal mosaicism. In these cases, some of the egg cells from the mother or some of the sperm cells from the father have the GLI3 gene mutation. This cannot be found through a blood test.

It is also possible that a parent could have mosaic Pallister-Hall syndrome, or only have a GLI3 mutation in some of their body cells (other than the egg or sperm cells). There is one report of a parent with this type of mosaicism. Because of this, parents of a child with Pallister-Hall syndrome without a family history of the condition should be checked for extra fingers or toes. If there is no evidence of extra fingers or toes in a parent, the risk of mosaicism is likely very low.

As of January 25, 2016, about nine different laboratories in the United States perform genetic testing for Pallister-Hall syndrome. Genetic testing is typically ordered by a geneticist and genetic counselor. Two websites that list the different labs are the following:

Pallister-Hall syndrome is inherited in a dominant pattern. Everyone has two copies of their GLI3 gene. One copy comes from your mother and one copy comes from your father. When a person has a change (mutation) in one copy of their GLI3 gene, they have a genetic diagnosis of Pallister-Hall syndrome.

Genetic testing for Pallister-Hall syndrome is typically ordered by a geneticist and genetic counselor. A clinic appointment includes a review of the patient’s medical history and family history, a physical examination, discussion of testing, and consent for genetic testing if the patient is interested. Sometimes this happens in one clinic visit, and sometimes this happens over a few clinic visits.
In terms of insurance, sometimes the clinic checks with your insurance. Sometimes it is your responsibility to call your insurance. If a patient wants genetic testing, a blood sample and signed paperwork is sent to a laboratory. Results are then sent back to the geneticist and genetic counselor. They will then contact the patient/guardian with the results.
To find a genetic counselor near you, use the "Find a Genetic Counselor" tool on the National Society of Genetic Counselors’ website.

The GLI3 gene instructs the body to make a certain protein/building block. This GLI3 protein helps turn other genes on and off. It regulates how genes are expressed. This protein plays an important role in the shaping of many organs and tissues before birth.
When the GLI3 protein is made incorrectly, it can only turn genes off. This can affect the development of different organs and tissues. It is unknown exactly how this causes certain features of Pallister-Hall syndrome, like polydactyly (extra fingers and/or toes) and hypothalamic hamartoma.

Clinical research can be found on the following:

Pallister-Hall syndrome is rare. It is unknown how common this condition actually is. More than 100 people with Pallister-Hall syndrome have been reported. Pallister-Hall syndrome is likely under-diagnosed or misdiagnosed as some other condition.

Genetic testing for Pallister-Hall syndrome typically involves using a blood sample. Some laboratories accept saliva samples. It is best to call the lab to see if they accept a saliva sample. Biopsy (muscle or skin cells) is typically not done for Pallister-Hall syndrome genetic testing.

People with Pallister-Hall syndrome can have intellectual disability and/or behavioral disturbances. Developmental and behavioral concerns are not hallmarks of Pallister-Hall syndrome. However, developmental assessments should be performed yearly.

Certain types of GLI3 gene mutations cause Greig cephalopolysyndactyly syndrome (GCPS), oral-facial-digital syndrome (OFD), and isolated polydactyly that is not associated with a genetic syndrome.

Mostly everyone with a GLI3 gene mutation associated with Pallister-Hall syndrome has features of the condition. This is called complete penetrance. There have not been any reports of someone with a GLI3 mutation who does not have clinical features (this would be called non-penetrant or incomplete penetrance).

A technology called preimplantation genetic diagnosis (PGD) can be used if a GLI3 gene mutation is known in the family. Embryos are made in a laboratory using the mother’s egg cells and father’s sperm cells. Genetic testing is then done to see if the GLI3 gene mutation is present. The embryos that do not have the GLI3 gene mutation can then be implanted in the mother.

If someone is interested in pursuing PGD for Pallister-Hall syndrome, they can speak with a genetic counselor who specializes in preimplantation genetic diagnosis and/or assisted reproductive technology. To find a genetic counselor near you, use the "Find a Genetic Counselor" tool on the National Society of Genetic Counselors’ website.

There are published management and surveillance guidelines for Pallister-Hall syndrome. These are published on the website GeneReviews.org. The exact website for Pallister-Hall syndrome is http://www.ncbi.nlm.nih.gov/books/NBK1465/ .

There are other names for Pallister-Hall syndrome. They include the following:

There are other less common medical concerns in people with Pallister-Hall syndrome. These include:

There are support groups for Pallister-Hall syndrome. Some are specific for Pallister-Hall syndrome, and some are for certain features of this condition. They include the following:

Hope for Hypothalamic Hamartomas
P. O. Box 721
Waddell, AZ 85355
Email: [email protected]
Website: http://hopeforhh.org/

Hydrocephalus Association
4340 East West Highway Ste 950
Bethesda, MD 20814 USA
Phone: (301) 202-3811
Toll-free: (888) 598-3789
Email: [email protected]
Website: http://www.hydroassoc.org

Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Phone: (301) 251-4925
Toll-free: (888) 205-2311
Website: http://rarediseases.info.nih.gov/GARD/

Hydrocephalus Support Group, Inc.
1933 Mistflower Glen Ct.
Chesterfield, MO 63005-4236 USA
Phone: (636) 532-8228
Email: [email protected]

Facebook Pallister-Hall Syndrome/PHS/Support Hub
https://www.facebook.com/Pallister.Hall.Syndrome

American Epilepsy Society (AES)
https://www.aesnet.org/

Epilepsy Foundation
8301 Professional Place East
Suite 200
Landover MD 20785-7223
Phone: 800-332-1000 (toll-free)
Email: [email protected]
http://www.epilepsy.com/

Women with Pallister-Hall syndrome who have gelastic epilepsy and/or hypopituitarism should follow the pregnancy guidelines for those medical concerns. They may want to speak to a maternal fetal medicine doctor who specializes in high-risk pregnancies. Pregnancy management for these medical concerns is included in the articles cited below.

There are other genetic conditions that are similar to Pallister-Hall syndrome.

Genetic conditions caused by mutations in the GLI3 gene that are similar to Pallister-Hall syndrome include: