Pallister-Hall Syndrome: What You Need To Know About This Genetic Disorder And The Mutations That Cause It

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What Is Pallister-Hall Syndrome?

Pallister-Hall Syndrome (PHS) is a very rare genetic disorder. Those who are inflicted with this condition exhibit abnormal growth and development in various areas of the body. Commonly seen examples of such body aberrations include:

  • The formation of hypothalamic hamartomas, which are benign tumors that can cause life-threatening seizures, behavioral problems, early puberty, and optic nerve problems, among other symptoms
  • Hypopituitarism (a condition in which the pituitary gland underproduces certain hormones)
  • Polydactyly (extra fingers and/or toes)
  • Syndactyly (abnormal “webbing” between, or fusing of, adjacent fingers and/or toes)
  • Short limbs
  • Dysplastic nails (i.e., finger nails and toe nails that are flaky and poorly grown)
  • Airway defects that affect the epiglottis, which is the thin membrane structure located at the back of the tongue and which serves to prevent food and liquids from entering the wind pipe
  • Inperforated anus (obstruction of the anus)
  • Kidney problems

Symptoms range from mild to very severe among PHS patients. Severity of symptoms in a particular individual is largely dependent on the nature of the specific gene mutation that the individual harbors. Specific information regarding what is known about the genetics of PHS is provided in the following section.

What Is Known About The Genetics of Pallister-Hall Syndrome?

Molecular biologists have determined that mutations in a gene that is designated GLI3 are causative of PHS. GLI3 encodes a zinc finger protein that is responsible for regulating the production of other proteins, especially at the time of early (i.e., fetal) development. Unfortunately, PHS is an autosomal dominant disorder, which means that only one mutant copy of GLI3 is needed to effect the manifestation of PHS in an individual.

Most PHS-causing mutations affect the GLI3 gene in a manner that causes a shortened version of its protein to be made. This is problematic because whereas normal versions of the GLI3 protein are able to stimulate and repress the activities of certain growth and development genes at critical stages of fetal development, shortened versions of the GLI3 protein are only able to repress these genes. As a result, certain genes that are required for early growth and development are not stimulated, or at least are not adequately stimulated, at critical times in individuals having a GLI3 gene mutation.

Interestingly, not all of the symptoms listed above are generally thought of as “fetal growth and development” symptoms. For example, the development of hypothalamic hamartomas is not a symptom of this variety. Molecular geneticists are currently working to determine why such symptoms are caused by a gene that is highly involved in early growth and development.

Finally, it is also known that some GLI3 mutations, which are namely certain missense mutations, hardly affect the normal activity of GLI3 or its proteins. Those who have a mutation of this kind usually exhibit no or very mild PHS symptoms.


Genetics Home Reference, National Institutes of Health, Pallister-Hall Syndrome:

J.S. Kuo et al., Pallister-Hall Syndrom__e: Clinical and MR Features, American Journal of Neuroradiology, 20:1839-1841 (1999).

L.G. Biesecker, Pallister-Hall Syndrome, Gene Reviews, Unviveristy of Washington: