Information on the following diseases can be found in the Related Disorders section of this report:

• Grieg cephalo-polysyndactyly syndrome
• Isolated postaxial polysyndactyly type A
• Holt-Oram Syndrome
• McKusick-Kaufman syndrome
• Oral-Facial-Digital Syndrome
• Hydrolethalus Syndrome
• Smith-Lemli-Opitz Syndrome

Symptoms and findings in individuals with Pallister Hall syndrome may vary greatly in range and severity from case to case. Whereas some affected individuals may have only a few characteristic abnormalities (e.g., hypothalamic hamartoblastoma, polydactyly), others may have a majority of symptoms and physical features associated with the disorder.

According to reports in the medical literature, one of the most significant features of Pallister-Hall syndrome is the presence of a malformation of the hypothalamus (hypothalamic hamartoblastoma), 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. The malformation of the hypothalamus 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, and more rarely, can cause diabetes or lack of cortisol production. The hypothalamic hamartomablastoma can also cause neurologic complications such as seizures.

Many individuals with Pallister-Hall syndrome 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). Additional characteristic features may include the presence of extra fingers and/or toes (polydactyly); webbing or fusion (syndactyly) of certain fingers and/or toes (digits); and improper development (dysplasia) of the nails. In some cases, the polydactyly associated with Pallister-Hall syndrome may be characterized by the presence of an extra digit between the third and fourth digits (central polydactyly) of the hands and/or feet. In other cases, 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).

Individuals who are severely affected with Pallister Hall syndrome may have an opening between the larynx and the trachea (laryngotracheal cleft) which can be fatal in the newborn period. The other life-threatening complication which occurs rarely is absent adrenal function leading to a lack of cortisol production.

In some infants with Pallister-Hall syndrome, symptoms and findings due to decreased or absent pituitary function (hypopituitarism) may be present at birth. Such abnormalities may include 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). In addition, benign tumor growth (hypothalamic hamartoblastoma) may inhibit the normal flow of cerebrospinal fluid (CSF) in the brain, causing abnormal accumulation of CSF in the skull and increased pressure on brain tissue (hydrocephalus). Hypopituitarism, hydrocephalus, increased cranial pressure, and/or other abnormalities may result in severe, life-threatening complications without prompt, appropriate treatment. (For more information on hydrocephalus, see the Related Disorders section of this report.)

Infants with Pallister-Hall syndrome may also have distinctive abnormalities of the head and facial (craniofacial) area including unusually 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 an unusually small tongue (microglossia); an abnormal 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 abnormal division of the epiglottis (bifid epiglottis), the flap of cartilage in front of the entrance to the larynx.

In some cases, individuals with Pallister-Hall syndrome 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; and/or heart defects that are present at birth (congenital heart defects). In addition, affected males may have an abnormally small penis (micropenis) and/or undescended testes (cryptorchidism).
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Pallister-Hall syndrome has autosomal dominant inheritance with wide variability in expression. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from the affected parent to offspring is 50% with each pregnancy regardless of the sex of the resulting child.

In most cases, individuals with a defective gene for Pallister-Hall syndrome will have symptoms and findings associated with the disorder (high penetrance). However, in such cases, the characteristics that are manifested may vary greatly in range and severity from case to case (variable expressivity). The variability within a particular family appears to be less than the variability in affected members of different families.

A gene responsible for Pallister-Hall syndrome, known as the "GLI3" gene has been located on the short arm (p) of chromosome 7 (7p13). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into many bands that are numbered. For example, "chromosome 7p13" refers to band 13 on the short arm of chromosome 7.

To date, all affected families have unique mutations in the GL13 gene so gene testing is available on a research basis only.
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Pallister-Hall syndrome, an extremely rare disorder that may be apparent at birth (congenital), appears to affect males and females equally. Approximately 100 cases have been reported in the medical literature, including affected individuals from several large families (kindreds) and isolated cases in which a positive family history has not been found. The range and severity of associated symptoms and findings may vary greatly from case to case (variable expressivity). Because Pallister-Hall syndrome 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 disorder is estimated to occur in fewer than 1 in 1,000 individuals in the developed world.

Symptoms of the following disorders can be similar to those of Pallister-Hall syndrome. Comparisons may be useful for a differential diagnosis:

GLI3 morphopathies are a group of related disorders characterized by mutations in the GLI3 gene located on the short arm of chromosome 7. This group of disorders includes Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, postaxial polydactyly type A, and preaxial polydactyly type IV. These disorders occur due to different mutations of the GLI3 gene (allelic disorders) and share some similar characteristics. Despite similarities, these disorders are considered distinct clinical entities.

Greig cephalopolysyndactyly syndrome (GCPS) is a very rare inherited disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the head and facial (craniofacial) area. Characteristic digital features may include extra (supernumerary) fingers and/or toes (polydactyly), webbing and/or fusion of the fingers and/or toes (syndactyly), and/or additional abnormalities. Craniofacial malformations associated with this disorder may include a large and/or unusually shaped skull; a high, prominent forehead (frontal bossing); an abnormally broad nasal bridge; widely spaced eyes (ocular hypertelorism); and/or other physical abnormalities. The range and severity of symptoms may vary greatly from case to case. In most cases, GCPS is inherited as an autosomal dominant trait. For more information on this disorder, choose "Greig Cephalopolysyndactyly syndrome" as your search term in the Rare Disease Database.

Oral-facial-digital syndrome (OFD) is a rare inherited disorder categorized into types I-IV. Symptoms common to all four types of the syndrome include neuromuscular disturbances, overgrowth of the band of tissue under the tongue (frenulum), extra skin folds at the inner corners of the eyes (epicanthus), broad-based nose, malformations of the hands and feet (i.e., webbing between the fingers and/or toes), extra divisions between the bones of the skull, and/or clefts of the tongue, jaw, and/or lip. Other symptoms depend on the form of the syndrome affecting the individual, and may include mental disturbances, extra teeth and/or tooth malformations, and/or eyes that look away from each other (exotropia) or wink involuntarily in an alternating pattern). (For more information on this disorder, choose "Oral- Facial-Digital Syndrome" as your search term in the Rare Disease Database.)

Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by distinctive malformations of the bones of the thumbs and forearms (upper limbs) and/or abnormalities of the heart. The symptoms and physical findings associated with Holt-Oram syndrome may vary greatly from case to case. In many infants with the disorder, the thumbs may be absent or underdeveloped (hypoplastic) or have an extra bone (triphalangy). Affected infants may also have additional upper limb malformations such as underdevelopment (hypoplasia) of or extra bones in the wrists (e.g., scaphoid bone); malformations of certain bones of the hands (metacarpals); and/or underdevelopment of the bones of the forearms (radius and ulna) and/or the bones of the upper arms (humerus). The shoulder blades (scapulae), the collarbones (clavicles), and/or other bones may also be abnormal. (For more information on this disorder, choose "Holt-Oram Syndrome" as your search term in the Rare Disease Database.)

McKusick-Kaufman syndrome is a rare genetic disorder characterized by the presence of a cystic abdominal mass caused by dilation of the vagina and uterus and containing cervical secretions (hydrometrocolpos), abnormalities of the heart and extra well formed digits on the hands and /or feet (postaxial polydactyly).

Hydrolethalus syndrome is a very rare developmental disorder characterized by severe brain and/or spinal (central nervous system) malformations and extra fingers and/or toes. Two great toes on each foot, underdeveloped eyes, a small lower jaw, and/or a poorly formed nose are common. The head may be oversized (macrocephaly) with prominent areas on the forehead (frontal) and at the back of the head (occipital). Lung and heart abnormalities may also occur.

Diagnosis
A diagnosis of Pallister-Hall syndrome is suspected based upon 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 Pallister-Hall syndrome include renal ultrasonography and fiberoptic laryngoscopy.

Treatment
Infants with Pallister-Hall syndrome who have decreased or absent pituitary function (hypopituitarism) must be treated immediately with hormonal replacement therapy (i.e., thyroxine, hydrocortisone, and growth hormone). 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 severe 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 hamartoblastomas. Surgical removal of a hamartoblastoma is not indicated since the tumor is almost always benign. Surgical removal of extra digits is often performed during infancy.

Seizures may be treated with an anticonvulsant medication such as carbamazepine.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

A study sponsored by the National Human Genome Research Institute is being conducted (2005) to increase understanding of the cause(s) and characteristics of Pallister-Hall syndrome and several related syndromes. For information, contact the NIH Patient Recruitment Office listed above.

TEXTBOOKS
Feuillan P, Biesecker LG. Pallister-Hall Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:230-31.

Buyce ML., ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:932-4.

JOURNAL ARTICLES
Johnston JJ, Olivos-Glander I, Killoran C, et al. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. Am J Hum Genet. 2005;76:609-22.

Boudreau EA, Liow K, Frattali CM, et al. Hypothalamic hamartomas and seizures: distinct natural history of isolated and Pallister-Hall syndrome cases. Epilepsia. 2005;46:42-7.

Turner C, Killoran CE, Thomas NS, et al. Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer. Hum Genet. 2003;112:303-09.

Biesecker LG, et al. Pallister-Hall syndrome. J Med Genet. 1996;33;585-89.

Biesecker LG, Abbott M, Allen J, et al. Report from the workshop on Pallister-Hall syndrome and related phenotypes. Am J Med Genet .1996;65:76-81.

Biesecker LG. Coupling genomics and human genetics to delineate basic mechanisms of development. Genetic Med. 2002;4 (6 Suppl) 39S-42S.

Feuillan P, Peters KF, Cutler GB Jr, et al. Evidence for decreased growth hormone in patients with hypothalamic hamartoma due to Pallister-Hall syndrome. J Pediatr Endocrinol Metab. 2001;14:141-49.

Graham JM, et al. A cluster of Pallister-Hall syndrome cases (congenital hypothalamic hamartoblastoma syndrome). Am J Med Genet Suppl. 1996;2;53-63.

Kang S, Allen J, Graham JM Jr, et al. Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome. J Med Genet. 1997;34:441-6.

Kang S, et al. GL13 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nature Genet. 1997;15;266-68.

Killoran CE, Abbott M, McKusick VA, et al. Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis. Clin Genet. 2000;58:28-30.

Kuo JS, Casey SO, Thompson L, et al. Pallister-Hall syndrome: clinical and MR features. AJNR Am J Neuroradiol. 1999;20:1839-41.

Ming JE, Roessler E, Muenke M. Human developmental disorders and the Sonic hedgehog pathway. Mol Med Today. 1998;4:343-39.

Kang S, Graham JM Jr, Abbott M, et al. Autosomal dominant Pallister-Hall syndrome maps to 7p13. Am J Hum Genet. 1996;59(suppl): A17.

FROM THE INTERNET
Biesecker LG, Pallister-Hall syndrome GeneReviews at GeneTests: Medical Genetics Information Resource (database online). 2000. Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org.

Helon GW. Pallister-Hall Foundation (Aust). Pallister-Hall Syndrome (PHS) Patients Reference Guide. 2001-2003.
www.pallisterhall.com

Jones EK. PALLISTER HALL SYNDROME. Contact a Family. Last Updated; October 2001:2pp.
www.cafamily.org.uk/Direct/p07.html