Genetic mutations: Pallister-Hall syndrome (PHS) is caused by mutations or defects in the GLI3 gene. This gene provides instructions for making the GLI3 protein (also known as zinc finger protein GLI3). This protein plays a role in regulating gene expression, meaning that it helps determine whether certain genes are turned on or off in certain cells so that they either produce the protein they should or not. Gene expression affects the development of many organs before birth. When the GLI3 protein is functioning normally, it can regulate its own gene, so it will either stop producing the protein or make more, depending on the body's needs. When a mutated GLI3 gene causes an abnormally short GLI3 protein to be made, the protein can only turn certain genes off. It is not yet clear how this mutation directly causes the symptoms associated with PHS.
Autosomal dominant inheritance: PHS is inherited or passed down among families as an autosomal dominant trait. Individuals receive two copies of most genes, one from the mother and one from the father. For a dominant disorder to occur, only one defective copy of the GLI3 gene is necessary. If one parent has the disorder, there is a 50% chance that his or her child will have the disorder. If both parents have the disorder, there is a 75% chance that their child will have the disorder.
Random occurrence: Some cases of PHS occur in individuals with no family history of the condition. This may be the result of a spontaneous genetic mutation in the egg, sperm cells, or developing embryo.
General: Diagnosis of Pallister-Hall syndrome (PHS) is based on a complete family history, physical exam, and the clinical findings of hypothalamic hamartoma, the formation of abnormal growths in the hypothalamus, a region of the brain that controls the function of the pituitary gland. The pituitary gland secretes hormones involved in regulating homeostasis (the body's normal environment). Other classic symptoms of PHS include central and postaxial polydactyly, in which individuals have extra fingers or toes that may be fused together; bifid epiglottis, which is a split in the small piece of skin that controls the flow of air through the trachea (airway) into the lungs and the passage of food or liquid into the esophagus; an imperforate anus, in which there is a piece of skin that covers the anal opening; and kidney abnormalities.
Cognitive function: Some individuals with PHS may have intellectual disabilities. Even though intellectual disability is an irreversible condition, early diagnosis and prompt treatment has been shown to help improve long-term prognosis. Doctors diagnose intellectual disability after a medical history, physical examination, and intelligence quotient (IQ) test. If a patient does not show signs of adaptive behavior and scores well below average on the IQ test, then a positive diagnosis is made. To measure the patient's adaptive behavior, professionals will compare the patient's abilities against those of children of his or her age. Many skills, including daily living skills (e.g., getting dressed, eating, and using the toilet), communication skills, and social skills are important to adaptive behavior.
Imaging studies: Imaging studies that may be helpful in the diagnosis of PHS include magnetic resonance imaging (MRI), which uses magnets to create an image of internal organs; computed tomography (CT), which scans images of an organ so it can be viewed at different levels; ultrasound, another imaging technology that uses sound waves to visualize organs inside the body; and X-ray, which uses radiation to view structures within the body, most typically to view abnormalities in the bones or lungs. Some researchers suggest that MRI of the brain is the best method for identifying the presence of hypothalamic hamartoma, a growth in the hypothalamus characteristic of PHS.
The blood urea nitrogen (BUN) test assesses kidney function by measuring levels of nitrogen in urea, a byproduct of protein formed in the liver, then filtered from the blood and excreted into the urine by the kidneys. High BUN levels can indicate kidney dysfunction, but because blood urea nitrogen is also affected by protein intake and liver function, the test is usually done in conjunction with a blood creatinine test, a more specific indicator of kidney function. A blood creatinine test measures blood levels of creatinine, a byproduct of muscle energy metabolism that, like urea, is filtered from the blood by the kidneys and excreted into the urine. Production of creatinine depends on an individual's muscle mass, which usually fluctuates very little. With normal kidney function, then, the amount of creatinine in the blood remains relatively constant and normal. For this reason, and because creatinine is affected very little by liver function, an elevated blood creatinine level is a more sensitive indication of impaired kidney function than the BUN test.
Genetic testing: If PHS is suspected, a deoxyribonucleic acid (DNA) test may be performed to confirm a diagnosis. A sample of the patient's blood is taken and analyzed in a laboratory for defects in the GLI3 gene. If this defect is detected, a positive diagnosis is made.
Prenatal DNA testing: If there is a family history of PHS, prenatal testing may be performed to determine whether the fetus has the disorder. Amniocentesis and chorionic villus sampling (CVS) can diagnose PHS. However, because there are serious risks associated with these tests, patients should discuss the potential health benefits and risks with a medical professional.
During amniocentesis, a long, thin needle is inserted through the abdominal wall and into the uterus, and a small amount of amniotic fluid is removed from the sac surrounding the fetus. Cells in the fluid are then analyzed for normal and abnormal chromosomes. This test is performed after 15 weeks of pregnancy. The risk of miscarriage is about one in 200-400 patients. Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.
During chorionic villus sampling (CVS), a small piece of tissue (chorionic villi) is removed from the placenta between the ninth and 14th weeks of pregnancy. CVS may be performed through the cervix or through the abdomen. The cells in the tissue sample are then analyzed for the mutation in the GLI3 gene. Miscarriage occurs in about 0.5-1% of women who undergo this procedure.
signs and symptoms
General: Signs and symptoms of Pallister-Hall syndrome (PHS) are progressive, may be apparent at birth, and can range from mild to severe. However, many people with this condition do not develop severe complications.
Airway: A common feature of PHS is a bifid epiglottis, a split in the small piece of skin that controls the flow of air through the trachea (airway) into the lungs and the passage of food or liquid into the esophagus. Although many patients with this feature remain asymptomatic throughout their lives, individuals with extensive bifurcation typically present as infants with a history of feeding and breathing difficulties. These individuals experience an obstruction of the airway from a collapse of the folds in the skin of the epiglottis.
Anus: In some people with PHS, there is a piece of skin that covers the anal opening. When this occurs, an individual is unable to eliminate feces (solid waste), which can cause serious complications if not recognized and treated.
Behavioral problems: Some people with Pallister-Hall syndrome (PHS) may have behavioral problems or intellectual disability.
Brain: A distinctive feature of PHS is the formation of abnormal growths in the brain. These growths, known as hypothalamic hamartomas, occur in the part of the brain that controls the function of the pituitary gland, which secretes hormones involved in regulating homeostasis (the body's normal environment). Hypothalamic hamartomas often do not tend to cause any medical complications. In some cases, however, they may lead to seizure or hormonal abnormalities, particularly in endocrine hormones such as gonadotrophin-releasing hormone (GnRH) and corticotrophin-releasing hormone (CRH), among others. These hormones are responsible for stimulating or inhibiting the release of other hormones from the pituitary gland. The pituitary gland regulates a variety of functions, including the production of milk in the mammary glands and the stimulation of growth. Hormonal abnormalities in any of these pathways may, for example, stunt growth or prevent milk production. Infants with severe forms of PHS may die shortly after birth because of such hormonal problems. The size of the hamartoma does not seem to be related to the severity of symptoms.
Hands and feet: Most people with PHS have extra fingers or toes, a condition called polydactyly. In some cases, the skin between the fingers and toes is fused (called syndactyly). Extra digits may share skin, bones, nerves, blood vessels, or nails. Depending on how the hand or foot is fused, function of the hand or foot may be decreased.
Kidneys: Some people with PHS have kidney problems, including the formation of cysts, which are closed, sac-like structures that are not a normal part of the tissue and can be filled with a gaseous, liquid, or semisolid substance. Most cysts that form in this way are benign, meaning that they are not cancerous.
Other: Other symptoms of PHS may include structural abnormalities of the head and skull, poorly developed or underdeveloped fingernails and toenails, lung abnormalities, and problems with the genitals and urinary system, including hydrometrocolpos, which is a collection of watery fluid in the uterus and vagina.
Epiglottis problems: Most people with Pallister Hall syndrome (PHS) who have a split epiglottis have no symptoms. The epiglottis is the small piece of skin that controls the flow of air through the trachea (airway) into the lungs and the passage of food or liquid into the esophagus. In some cases, however, the split epiglottis may cause severe airway problems that result in difficulty eating or breathing.
Hormonal problems: Hormonal problems that may occur in people with PHS include a deficiency of growth hormone, which may prevent the individual from reaching full height. Individuals with PHS who develop hormonal problems may experience puberty earlier than normal; they may be deficient in the stress hormone cortisol, which increases blood pressure and blood sugar to prepare the body to act in a stressful situation; and they may develop a condition called panhypopituitarism, which is a decreased secretion of the majority of pituitary hormones.
Neurological problems: Hypothalamic hamartomas, abnormal growths in a region of the brain known as the hypothalamus, which controls the function of the pituitary gland, are seen in people with PHS. The pituitary gland secretes hormones involved in regulating homeostasis (the body's normal environment). These growths may cause seizure disorders, including gelastic epilepsy, which is characterized by movements of the chest and diaphragm that can look like laughter.
Pallister-Hall syndrome (PHS) is inherited, or passed down among family members. Therefore, the only known risk factor is a family history of the disorder. PHS is extremely rare, with about 100 known cases worldwide. The exact prevalence of the syndrome is unknown. PHS does not appear to affect any one sex or ethnicity more than any other.
PHS is inherited as an autosomal dominant trait. Individuals inherit two copies of most genes, one from the mother and one from the father. To inherit an autosomal dominant trait, only one defective copy of the causative gene must be inherited. Occasionally, PHS occurs in individuals with no family history of the disorder. This may be the result of a spontaneous genetic mutation in the egg, sperm cell, or developing embryo. Individuals who acquire PHS as the result of a spontaneous mutation may pass on the mutation to their children. The proportions of those who inherit PHS and those who acquire the syndrome as the result of a spontaneous mutation are not known.