December 09, 2022
Years published: 1994, 1998, 2003, 2005, 2013, 2016, 2019, 2022
NORD gratefully acknowledges Daniel Balcarcel, NORD Editorial Intern from the University of Notre Dame, and Leslie G. Biesecker, MD, Director, Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, for assistance in the preparation of this report.
Pallister-Hall syndrome (PHS) is an extremely rare genetic disorder that is typically apparent at birth. The symptoms and findings associated with the disorder may vary greatly in range and severity from patient to patient. However, in most individuals with PHS the abnormalities may include the presence of extra fingers and/or toes; an abnormal division of the epiglottis (bifid epiglottis); a malformation of the hypothalamus (hypothalamic hamartoma), a portion of the brain that coordinates the function of the pituitary gland and has several other functions; decreased pituitary function; and/or a condition in which a thin covering blocks the anal opening or the passage that normally connects the anus and the lowest part of the large intestine (rectum) fails to develop (imperforate anus). Additional symptoms and findings may include characteristic malformations of the head and facial area and/or other abnormalities, including genito-urinary malformations. PHS is inherited in an autosomal dominant pattern and is caused by pathogenic variants (gene changes) in the GLI3 gene.
Pallister-Hall syndrome is named for Judith Hall and Philip Pallister who described the condition in 1980.
Symptoms and findings in individuals with PHS may vary greatly in range and severity from patient to patient. Whereas some affected individuals may have only a few characteristic abnormalities, others may have most symptoms and physical features associated with the disorder.
The most common characteristic features of PHS include the presence of extra fingers and/or toes (polydactyly); fusion (osseous syndactyly) of certain fingers and/or toes (digits); and improper development (dysplasia) of the nails. In some affected persons, the polydactyly associated with PHS may be characterized by the presence of an extra digit between the third and fourth digits (mesoaxial polydactyly) of the hands and/or feet. Affected individuals may have an extra (supernumerary) digit on the “pinky” (ulnar) side of the hand or the outer (fibular) aspect of the foot (postaxial polydactyly). Many individuals with PHS may also have a condition in which a thin covering blocks the anal opening or the passage that normally connects the anus and the lowest part of the large intestine (rectum) fails to develop (imperforate anus). A few affected individuals also have genito-urinary malformations including hypospadias, bifid or hypoplastic scrotum, hydrometrocolpos and vaginal atresia.
According to reports in the medical literature, one of the most significant features of PHS is the presence of a malformation of the hypothalamus (hypothalamic hamartoma), a portion of the brain that coordinates the function of the pituitary gland and that regulates many additional bodily functions. The pituitary gland is the hormone-producing gland at the base of the brain. This is a malformation (and is not a tumor) of the hypothalamus and may cause abnormalities in pituitary function in those who are severely affected. Impaired pituitary function can cause an abnormally small penis (micropenis), low functioning of the thyroid (hypothyroidism), growth hormone deficiency, precious puberty, or more rarely, can cause diabetes or lack of cortisol production. Seizures are also commonly associated with a hypothalamic hamartoma.
In some infants affected by severe hypothalamic hamartoma, decreased or absent pituitary function (hypopituitarism) may be present at birth. This may lead to low blood sugar (hypoglycemia), abnormal electrolyte levels, and unusually high acid levels in blood and body tissue (metabolic acidosis). Affected individuals may also experience lethargy and an abnormal yellowish discoloration of the skin, mucous membranes, and whites of the eyes (jaundice). Hypopituitarism may result in severe, life-threatening complications without prompt, appropriate treatment. (For more information on hypopituitarism, see the Related Disorders section of this report.)
Infants with PHS may also have distinctive features of the head and facial (craniofacial) area including small ears that are rotated toward the back of the head; a short nose with upturned nostrils (anteverted nares) and a broad or flat nasal bridge; and/or an unusually long vertical groove in the middle of the upper lip (philtrum). Affected individuals may also have a small tongue (microglossia); a cleft or fissure in the larynx, the organ in the throat that is involved in voice production and that prevents food from entering the airway during swallowing; and division of the epiglottis (bifid epiglottis), the flap of cartilage in front of the entrance to the larynx.
Some individuals with PHS may have additional abnormalities. These may include the presence of certain teeth at birth (natal teeth), abnormal folds of movement-limiting mucous membrane tissue in the cheek area of the mouth (buccal frenula), abnormally short arms and/or legs (limbs), and/or dislocated hips. In some affected individuals, additional abnormalities may include abnormal development of the lobes of the lungs, absence (agenesis) and/or improper development (dysplasia) of the kidneys, heart defects that are present at birth (congenital heart defects), hypospadias, bifid or hypoplastic scrotum, hydrometrocolpos, and vaginal atresia.
Although most individuals with PHS do not have life-threatening malformations, some affected individuals have an early lethality variant of the disorder. This early lethality is most likely attributable to adrenocortical hormone deficiency caused by the hypothalamic hamartoma or severe airway malformations such as laryngotracheal clefts.
PHS is typically inherited in an autosomal dominant pattern with wide variability in expression and is caused by pathogenic variants in the GLI3 gene, termed GLI3-related PHS. In affected families, most individuals with the familial GLI3 gene variant will have symptoms and findings associated with the disorder (high penetrance). However, in such instances, the characteristics may vary in range and severity from patient to patient. The variability within a particular family appears to be less than the variability in affected members of different families. GLI3 is the associated gene in 95% of affected individuals with PHS. A few patients have been found to have two variants in the SMO gene, termed SMO-related PHS. This rare form of PHS is inherited in an autosomal recessive pattern.
Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In a number of patients with GLI3-related PHS, the GLI3 variant is not inherited from either parent and is instead caused by a new mutation. In general, these patients are more likely to be severely affected than is a child born to an affected parent.
SMO-related PHS is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
PHS is an extremely rare disorder that is typically apparent at birth (congenital), appears to affect males and females equally. Approximately 100 patients have been reported in the medical literature, including affected individuals from several large families (kindreds) and single occurrences in which a positive family history has not been found. The range and severity of associated symptoms and findings may vary greatly from one affected individual to the next (variable expressivity). Because PHS is extremely variable and therefore may be under- or misdiagnosed, it may be difficult to determine the true frequency of the disorder in the general population.
The diagnosis of PHS is made based on a thorough clinical evaluation, a detailed family history and a variety of specialized tests such as magnetic resonance imaging (MRI) used to detect the presence and dimensions of a hamartoma. Additional tests that may aid in the diagnosis and evaluating the severity of PHS include renal ultrasonography and fiberoptic laryngoscopy. Molecular genetic testing for variants in the GLI3 gene can confirm the diagnosis and may be especially important in helping to diagnose individuals with more mild presentations of the disorder. If the testing for GLI3 variants is negative, testing for SMO variants should be considered.
Clinical Testing and Work-Up
The following evaluations may be done to determine the severity of disease in an individual diagnosed with PHS. Assessment for cortisol deficiency, consultation by an endocrinologist, cranial MRI to establish the location and extent of hamartoma, neurologic examination, limb X-rays, kidney ultrasound, laryngoscopy to view the epiglottis, surgical consultation if imperforate anus or anal stenosis is present and a developmental assessment.
Infants with PHS who have decreased, or absent pituitary function (hypopituitarism) must be treated immediately with hormonal replacement therapy (i.e., thyroxine, and hydrocortisone). Treatment of hypopituitarism usually resolves the associated symptoms (hypoglycemia, abnormal electrolyte levels, and/or metabolic acidosis). Close monitoring and prompt treatment is imperative to prevent life-threatening complications.
Periodic examinations with specialized equipment to monitor the hypothalamic malformation associated with this disorder are essential. An MRI test is often required since computerized tomography (CT scan) may not always detect hypothalamic hamartomas. Surgical removal of a hamartoma is generally not indicated since it is a malformation and is not a tumor. Surgical removal of extra digits is often performed during infancy but is increasingly being done later in life due to concerns about potential cognitive effects of general anesthesia in young children.
Seizures may be treated with an anticonvulsant medication such as carbamazepine.
Genetic counseling is recommended for affected individuals and their family members.
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