Pallister-Hall syndrome (PHS) is a rare genetic disease characterized by a wide range of anomalies ranging from polydactyly to hypothalamic hamartoma. PHS is inherited in an autosomal dominant pattern and the mutation that causes it is found in the GLI3 gene. PHS is also known for its wide range of symptoms as each manifestation of the condition is different. This variability can be traced back to the mutation that ultimately causes PHS as evidence indicates that the variability of the severity of symptoms within an affected family is less than the variability across different families. This indicates that the mutations in each inheritance are slightly different. In fact, 5% of individuals with PHS don't even have an identifiable gene mutation, suggesting that the impact of the mutation is variable. In many patients, the mutation on the GLI3 gene is not inherited but rather is a de novo mutation or a random new or not inherited mutation. These cases are often more severe than patients born from an affected parent. The GLI3 gene is a dual function gene as it acts as both a transcriptional activator and a repressor of the Shh pathway (also known as the sonic hedgehog pathway, no joke). Essentially, this means that the activator protein formed by GLI3, GLI3A, binds to DNA and stimulates the transcription or copying of nearby genes, while the C-terminally truncated form or the repressor protein, GLI4R, acts as a repressor to the Shh pathway (the Shh pathway happens to be the most studied ligand-based pathway, just in case you were interested in doing more research into it). The Shh pathway or sonic hedgehog pathway plays an essential role during vertebrate embryonic development. Specifically, the pathway is involved in cellular specialization. As a result of the mutation in patients with PHS, the ability of the GLI3A and GLI3R proteins to repress and activate, respectfully, may be weakened or even lost. It is thought that the severity of symptoms is dependent on the mutation’s impact on the tertiary structure of the protein. In terms of the spectrum of symptoms, PHS can cause polydactyly or the presence of extra fingers or toes, syndactyly or the presence of extra skin in between fingers and toes, hypothalamic hamartoma or an abnormal non-cancerous growth on the hypothalamus which can directly impact the pituitary gland, bifid epiglottis or the malformation of the airway, abnormalities in the kidneys, heart defects, small genitalia, cleft palate, imperforate anus or the absence of an opening to the anus, a bifid or split uvula, and developmental and behavioral abnormalities.
Although there are additional symptoms that can stem from the listed symptoms (ex: hormonal abnormalities from a malformed hypothalamus), there are so many that it does not fall within the scope of this article, if you are interested in learning more about these additional symptoms check out the links at the end of the article. The diagnostic requirement for patients with at least one family member with PHS is the simultaneous presence of hypothalamic hamartoma which needs to be confirmed via MRI and mesoaxial polydactyly. The other conditions that are often involved in the differential diagnosis for PHS include Oral Facial Digital syndrome (type 6), Holzgreve-Wagner-Rehder syndrome, McKusick-Kaufman syndrome, Holt-Oram syndrome, Bardet-Biedl syndrome, Smith-Lemli-Opitz syndrome, craniopharyngioma, Greig cephalopolysyndactyly syndrome, Ellis Van Creveld syndrome, and congenital hypothalamic hamartoma syndrome. Treatment for the condition is symptomatic meaning that it is focused on managing and correcting symptoms. After diagnosis, often the first step is to do a full endocrinological workup to ensure that any hormonal imbalances or inconsistencies are corrected as soon as possible. Additionally, with such a large variety of symptoms present, surgical intervention also might be necessary. PHS appears to affect both males and females equally which makes sense because of its autosomal inheritance. There have been approximately 100 reported cases of PHS in the medical literature.
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