Pallister Hall syndrome (PHS)

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Pallister Hall syndrome (PHS)

Written	2007-01	Jennifer J Johnston, Leslie G Biesecker
		National Human Genome Research Institute, 49 Convent Drive, Room 4C72, Bethesda, MD 20892-4472, USA

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Identity

Atlas_Id 10126

Genes implicated in GLI3
Inheritance Autosomal dominant; rare with unknown incidence.

Clinics

Phenotype and clinics Major findings : Hypothalamic hamartoma: a non-enhancing mass in the floor of the third ventricle posterior to the optic chiasm that is isointense to grey matter on T1 and T2 pulse sequences of an MRI, but may have distinct intensity on FLAIR. (Neither cranial CT examination nor cranial ultrasound examination is adequate for diagnosis of hypothalamic hamartoma).
Central polydactyly : The presence of six or more well-formed digits with a 'Y' shaped metacarpal or metatarsal bone.
Postaxial polydactyly : Can be either PAP-A with a well shaped digit on the ulnar or fibular aspect of the limb, or PAP-B with a rudimentary digit or nubin in the same position.
Bifid epiglottis : A midline anterior-posterior cleft of the epiglottis that involves at least two-thirds of the epiglottic leaf. It is a useful feature for clinical diagnosis because it appears to be very rare in syndromes other than PHS and is also rare as an isolated malformation.
Other : Imperforate anus, renal abnormalities including cystic malformations, renal hypoplasia, ectopic ureteral implantation, and pulmonary segmentation anomalies such as bilateral bilobed lungs.

Neoplastic risk No increased risk of cancer has been reported for individuals with PHS. Hypothalamic hamartomas, a benign growth, are found in a majority of patients.

Treatment Treatment of individuals with PHS depends on their individual manifestations. Management of epiglottic abnormalities depends on the type of abnormality and extent of respiratory compromise. Seizures are treated symptomatically. Treatment for endocrine abnormalities, especially for cortisol deficiency, is urgent. Repair of polydactyly can be undertaken on an elective basis and anal atresia or stenosis treated in the standard manner. Hypothalamic hamartomas should not be removed or biopsied because of the risk of surgical complications and need for hormone supplements during the individual's remaining life.

Prognosis The prognosis for an individual with PHS and no known family history of PHS is based on the malformations present in the individual. Literature surveys are not useful for this purpose because reported cases tend to show bias of ascertainment to more severe involvement. Although PHS has been categorized as a member of the CAVE (cerebro-acro-visceral early lethality) group of disorders, few affected individuals have an early lethality phenotype. This early lethality is most likely attributable to panhypopituitarism that is caused by pituitary or hypothalamic dysplasia or severe airway malformations such as laryngotracheal clefts. In addition, imperforate anus can cause serious complications if not recognized promptly. Thus, in the absence of life-threatening malformations, the prognosis should be assumed to be excellent for individuals with the nonfamilial occurrence of PHS. For individuals with a family history of affected family members, the prognosis is based on the degree of severity present in the family. Several large families have been reported as having a mild form of PHS with excellent general health and normal longevity.

Genes involved and Proteins

Gene Name GLI3

Location 7p14

DNA/RNA
Description GLI3 has 15 exons, 14 of which are coding exons, and extends over approximately 300 kb of genomic DNA.

Protein
Description 1580 amino acids; GLI3 contains a C2H2 zinc finger and six additional domains conserved between GLI family members.

Function GLI3 functions as both an activator and repressor of transcription, playing a central role in the Sonic Hedgehog pathway. In the presence of Sonic Hedgehog GLI3 enters the nucleus and activates transcription of downstream genes. In the absence of Sonic Hedgehog full length GLI3 is retained in the cytoplasm where it is cleaved into a repressor form. The repressor form is free to move into the nucleus and downregulate transcription.

Homology GLI family of transcription factors, C2H2 zinc finger domain.

Mutations

Germinal Over 36 mutations have been identified in individuals with PHS. All mutations identified to date predict a truncated protein.
Mutations that cause PHS are thought to result in the production of a constituitive repressor protein. The majority of truncating mutations in the middle third of the protein cause PHS. These mutations retain the C2H2 zinc finger but are missing the last third of the protein.

Bibliography

Hypothalamic hamartomas and seizures: distinct natural history of isolated and Pallister-Hall syndrome cases.

Boudreau EA, Liow K, Frattali CM, Wiggs E, Turner JT, Feuillan P, Sato S, Patsalides A, Patronas N, Biesecker LG, Theodore WH

Epilepsia. 2005 ; 46 (1) : 42-47.

PMID 15660767

Long-term treatment with growth hormone improves final height in a patient with Pallister-Hall syndrome.

Galasso C, Scirè G, Fabbri F, Spadoni GL, Killoran CE, Biesecker LG, Boscherini B

American journal of medical genetics. 2001 ; 99 (2) : 128-131.

PMID 11241471

Hirschprung's disease and imperforate anus in Pallister-Hall syndrome: a new association.

Haynes JH, Bagwell CE

Journal of pediatric surgery. 2003 ; 38 (9) : 1411-1412.

PMID 14523835

Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.

Johnston JJ, Olivos-Glander I, Killoran C, Elson E, Turner JT, Peters KF, Abbott MH, Aughton DJ, Aylsworth AS, Bamshad MJ, Booth C, Curry CJ, David A, Dinulos MB, Flannery DB, Fox MA, Graham JM, Grange DK, Guttmacher AE, Hannibal MC, Henn W, Hennekam RC, Holmes LB, Hoyme HE, Leppig KA, Lin AE, Macleod P, Manchester DK, Marcelis C, Mazzanti L, McCann E, McDonald MT, Mendelsohn NJ, Moeschler JB, Moghaddam B, Neri G, Newbury-Ecob R, Pagon RA, Phillips JA, Sadler LS, Stoler JM, Tilstra D, Walsh Vockley CM, Zackai EH, Zadeh TM, Brueton L, Black GC, Biesecker LG

American journal of human genetics. 2005 ; 76 (4) : 609-622.

PMID 15739154

Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome.

Kang S, Allen J, Graham JM Jr, Grebe T, Clericuzio C, Patronas N, Ondrey F, Green E, Schäffer A, Abbott M, Biesecker LG

Journal of medical genetics. 1997 ; 34 (6) : 441-446.

PMID 9192261

GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome.

Kang S, Graham JM Jr, Olney AH, Biesecker LG

Nature genetics. 1997 ; 15 (3) : 266-268.

PMID 9054938

Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis.

Killoran CE, Abbott M, McKusick VA, Biesecker LG

Clinical genetics. 2000 ; 58 (1) : 28-30.

PMID 10945658

Epilepsy and hypothalamic hamartoma: look at the hand Pallister-Hall syndrome.

Kremer S, Minotti L, Thiriaux A, Grand S, Satre V, Le Bas JF, Kahane P

Epileptic disorders : international epilepsy journal with videotape. 2003 ; 5 (1) : 27-30.

PMID 12773293

Polysyndactyly and asymptomatic hypothalamic hamartoma in mother and son: a variant of Pallister-Hall syndrome.

Löw M, Moringlane JR, Reif J, Barbier D, Beige G, Kolles H, Kujat C, Zang KD, Henn W

Clinical genetics. 1995 ; 48 (4) : 209-212.

PMID 8591673

Genitourinary malformations as a feature of the Pallister-Hall syndrome.

McCann E, Fryer AE, Craigie R, Baillie C, Ba'ath ME, Selby A, Biesecker LG

Clinical dysmorphology. 2006 ; 15 (2) : 75-79.

PMID 16531732

Gonadal mosaicism in severe Pallister-Hall syndrome.

Ng D, Johnston JJ, Turner JT, Boudreau EA, Wiggs EA, Theodore WH, Biesecker LG

American journal of medical genetics. Part A. 2004 ; 124 (3) : 296-302.

PMID 14708104

Asymptomatic laryngeal malformations are common in patients with Pallister-Hall syndrome.

Ondrey F, Griffith A, Van Waes C, Rudy S, Peters K, McCullagh L, Biesecker LG

American journal of medical genetics. 2000 ; 94 (1) : 64-67.

PMID 10982485

GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity.

Ruppert JM, Vogelstein B, Arheden K, Kinzler KW

Molecular and cellular biology. 1990 ; 10 (10) : 5408-5415.

PMID 2118997

Stringent delineation of Pallister-Hall syndrome in two long surviving patients: importance of radiological anomalies of the hands.

Verloes A, David A, Ngô L, Bottani A

Journal of medical genetics. 1995 ; 32 (8) : 605-611.

PMID 7473651

Citation

This paper should be referenced as such :

Biesecker, LG ; Johnston, JJ

Pallister Hall syndrome (PHS)

Atlas Genet Cytogenet Oncol Haematol. 2007;11(2):145-147.

Free journal version : [ pdf ] [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/PallisterHallID10126.html

External links

OMIM 146510

Orphanet Pallister-Hall syndrome

MeSH D054975

MedGen D054975

UMLS C0265220

ICD-10 D33.0

Other database Pallister Syndrome - GeneClinics

REVIEW articles automatic search in PubMed

Last year articles automatic search in PubMed

Home Genes Leukemias Solid Tumors Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

Atlas_Id	10126
Genes implicated in	GLI3
Inheritance	Autosomal dominant; rare with unknown incidence.

Phenotype and clinics	Major findings : Hypothalamic hamartoma: a non-enhancing mass in the floor of the third ventricle posterior to the optic chiasm that is isointense to grey matter on T1 and T2 pulse sequences of an MRI, but may have distinct intensity on FLAIR. (Neither cranial CT examination nor cranial ultrasound examination is adequate for diagnosis of hypothalamic hamartoma). Central polydactyly : The presence of six or more well-formed digits with a 'Y' shaped metacarpal or metatarsal bone. Postaxial polydactyly : Can be either PAP-A with a well shaped digit on the ulnar or fibular aspect of the limb, or PAP-B with a rudimentary digit or nubin in the same position. Bifid epiglottis : A midline anterior-posterior cleft of the epiglottis that involves at least two-thirds of the epiglottic leaf. It is a useful feature for clinical diagnosis because it appears to be very rare in syndromes other than PHS and is also rare as an isolated malformation. Other : Imperforate anus, renal abnormalities including cystic malformations, renal hypoplasia, ectopic ureteral implantation, and pulmonary segmentation anomalies such as bilateral bilobed lungs.


Neoplastic risk	No increased risk of cancer has been reported for individuals with PHS. Hypothalamic hamartomas, a benign growth, are found in a majority of patients.
Treatment	Treatment of individuals with PHS depends on their individual manifestations. Management of epiglottic abnormalities depends on the type of abnormality and extent of respiratory compromise. Seizures are treated symptomatically. Treatment for endocrine abnormalities, especially for cortisol deficiency, is urgent. Repair of polydactyly can be undertaken on an elective basis and anal atresia or stenosis treated in the standard manner. Hypothalamic hamartomas should not be removed or biopsied because of the risk of surgical complications and need for hormone supplements during the individual's remaining life.
Prognosis	The prognosis for an individual with PHS and no known family history of PHS is based on the malformations present in the individual. Literature surveys are not useful for this purpose because reported cases tend to show bias of ascertainment to more severe involvement. Although PHS has been categorized as a member of the CAVE (cerebro-acro-visceral early lethality) group of disorders, few affected individuals have an early lethality phenotype. This early lethality is most likely attributable to panhypopituitarism that is caused by pituitary or hypothalamic dysplasia or severe airway malformations such as laryngotracheal clefts. In addition, imperforate anus can cause serious complications if not recognized promptly. Thus, in the absence of life-threatening malformations, the prognosis should be assumed to be excellent for individuals with the nonfamilial occurrence of PHS. For individuals with a family history of affected family members, the prognosis is based on the degree of severity present in the family. Several large families have been reported as having a mild form of PHS with excellent general health and normal longevity.

DNA/RNA
Description	GLI3 has 15 exons, 14 of which are coding exons, and extends over approximately 300 kb of genomic DNA.

Protein
Description	1580 amino acids; GLI3 contains a C2H2 zinc finger and six additional domains conserved between GLI family members.
Function	GLI3 functions as both an activator and repressor of transcription, playing a central role in the Sonic Hedgehog pathway. In the presence of Sonic Hedgehog GLI3 enters the nucleus and activates transcription of downstream genes. In the absence of Sonic Hedgehog full length GLI3 is retained in the cytoplasm where it is cleaved into a repressor form. The repressor form is free to move into the nucleus and downregulate transcription.
Homology	GLI family of transcription factors, C2H2 zinc finger domain.

Mutations


Germinal	Over 36 mutations have been identified in individuals with PHS. All mutations identified to date predict a truncated protein. Mutations that cause PHS are thought to result in the production of a constituitive repressor protein. The majority of truncating mutations in the middle third of the protein cause PHS. These mutations retain the C2H2 zinc finger but are missing the last third of the protein.

OMIM	146510
Orphanet	Pallister-Hall syndrome
MeSH	D054975
MedGen	D054975
UMLS	C0265220
ICD-10	D33.0
Other database	Pallister Syndrome - GeneClinics

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed