Clinical Diagnosis

Major findings are the following:

• 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 (i.e., insertional or mesoaxial) polydactyly, the presence of six or more well-formed digits with a 'Y'-shaped metacarpal or metatarsal bone

• Postaxial polydactyly (PAP) types A and B. PAP-A is the presence of a well-formed digit on the ulnar or fibular aspect of the limb. PAP-B is the presence of a rudimentary digit or nubbin in the same location. Postaxial polydactyly is probably more common than central polydactyly; however, the nonspecificity of postaxial polydactyly and the high frequency of postaxial polydactyly type B in persons of central African descent require caution in its use as a diagnostic feature.

• 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, genitourinary anomalies including hydrometrocolpos, pulmonary segmentation anomalies including bilateral bilobed lungs, and non-polydactyly skeletal anomalies including short limbs

The diagnosis is established in the following individuals:

• A proband if central polydactyly and hypothalamic hamartoma are present

• The first-degree relative of a proband if hypothalamic hamartoma or central or postaxial polydactyly are present (Postaxial polydactyly type B can be used as a diagnostic criterion for first-degree relatives only in persons who are not of central African descent.)

Individuals with postaxial (but not central) polydactyly and a hypothalamic hamartoma or central polydactyly without hypothalamic hamartoma or hypothalamic hamartoma and other non-polydactyly malformations should be considered for GLI3 sequencing.

Note: The phenotyping issues for persons with atypical phenotypes and GLI3 mutations are complex and beyond the scope of this review.

Molecular Genetic Testing

Gene. GLI3 is the only gene known to be associated with Pallister-Hall syndrome.

Clinical testing

• Targeted mutation analysis. Testing for the GLI3 mutations c.2009delG (p.Gly670GlufsX21) and c.2020delG (p.Glu674SerfsX17) is available on a clinical basis. The utility of testing for these two mutations is unknown (see Table 3; pdf).

• Sequence analysis. Sequence analysis of GLI3 is available clinically. Unpublished data suggest that approximately 95% of typically affected individuals have mutations in the coding region of GLI3.

Table 1. Summary of Molecular Genetic Testing Used in Pallister-Hall Syndrome

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Gene	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method	Test Availability
GLI3	Targeted mutation analysis	c.2009delG c.2020delG 1, 2	Unknown	Clinical
	Sequence analysis	GLI3 mutations	~95%

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The utility of testing for these two mutations is unknown.

2. See Table 3 (pdf).

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirmation of the diagnosis in a proband. Molecular genetic testing is used when the clinical findings are ambiguous or mild.

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Other phenotypes associated with mutations in GLI3:

• Greig cephalopolysyndactyly syndrome (GCPS) includes polydactyly that is commonly preaxial and may also be postaxial. The polydactyly is commonly associated with cutaneous syndactyly. GCPS has craniofacial features that include ocular hypertelorism, broad forehead, and macrocephaly. Central polydactyly and osseous syndactyly of the metacarpals are not part of GCPS. Most individuals with GCPS have mutations that cause haploinsufficiency of GLI3, although a few individuals with a point mutation have been described. However, it has not been demonstrated that these point mutations have stable mRNA or protein. If the stability of these molecules were reduced, the point mutations would result in functional haploinsufficiency. At least one individual with preaxial polydactyly type IV (PPDIV) has been reported to have a GLI3 mutation [Radhakrishna et al 1999], a finding consistent with clinical suspicion that PPDIV is a mild form of GCPS, in which the limb findings occur without the craniofacial features. However, the craniofacial findings are subtle and there is controversy regarding the distinction of nonsyndromic PPDIV from mild GCPS [Biesecker 2006].

• Isolated postaxial polydactyly type A (PAP-A). Mutations in GLI3 have been identified in individuals with PAP-A [Radhakrishna et al 1999]. However, the PAP-A phenotype has also been shown to result from mutations in other genes.

• Isolated preaxial polydactyly type IV (PPDIV) comprises preaxial polydactyly of the hands and/or feet in the absence of other malformations. The severity of the PPDIV is highly variable [Everman 2006]. Because macrocephaly occurs in the general population and is common in GCPS, the presence of macrocephaly in a person with apparently isolated PPDIV is difficult to interpret.

Natural History

Pallister-Hall syndrome (PHS) displays a wide range of severity. The literature frequently reflects the assumption that PHS is severe and Greig cephalopolysyndactyly syndrome is mild. This is clearly incorrect, as a minority of individuals with PHS show multiple severe anomalies and most individuals with PHS are mildly affected with polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma. Without careful clinical evaluation, these individuals may be incorrectly diagnosed with PAP-A.

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 the purpose of establishing the prognosis because reported cases tend to show bias of ascertainment to more severe involvement. Although PHS has been categorized as a member of the CAVE (cerebroacrovisceral 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.

Hypothalamic hamartoma. Hypothalamic hamartoma is a malformation, not a tumor. Hypothalamic hamartomas grow at the rate of, or slower than, the surrounding brain tissue. Hypothalamic hamartomas may be large (up to 4 cm in greatest dimension); little correlation exists between the size of the hypothalamic hamartoma and presence or severity of symptoms. Individuals with hypothalamic hamartomas may have neurologic symptoms, although most are asymptomatic. Removal of the hypothalamic hamartoma is not indicated and often results in iatrogenic pituitary insufficiency.

Neurologic findings. The best-described neurologic complication of hypothalamic hamartoma is gelastic epilepsy, a partial complex seizure manifest by clonic movements of the chest and diaphragm that simulate laughing. Other types of seizures may be caused by hypothalamic hamartoma. Seizures associated with hypothalamic hamartoma in individuals with PHS are generally milder and are responsive to treatment, in contrast to individuals with nonsyndromic hypothalamic hamartoma who often have refractory seizures [Boudreau et al 2005]. No individual with PHS has been shown to have visual field loss even with a hypothalamic hamartoma near the optic chiasm.

Psychiatric and neuropsychological findings. Some individuals with PHS have behavioral manifestations including a few with severe intellectual disability and behavioral disturbances [Ng et al 2004]. A larger study of behavioral manifestations of this disorder was inconclusive, reflecting the difficulty of assessing mild behavioral phenotypes in rare disorders [Azzam et al 2005].

Endocrine manifestations. The endocrine manifestations of a hypothalamic hamartoma range from isolated growth hormone deficiency or isolated precocious puberty to panhypopituitarism, which can be life threatening. Cortisol deficiency can occur in nonfamilial cases, but appears to be rare in familial cases.

Epiglottic abnormalities. Bifid epiglottis is nearly always asymptomatic; however, the more severe clefts of the larynx reported in individuals with PHS can cause severe airway symptoms. Posterior laryngeal clefts can be fatal.

Genotype-Phenotype Correlations

Genotype-phenotype correlations of GLI3 mutations

• GCPS is caused by the following:

  • Actual or functional haploinsufficiency for GLI3

  • Truncating mutations within and 5' of the zinc finger domains and in the 3'-most third of the gene

• PHS is generally caused by truncating mutations in the middle third of the gene [Johnston et al 2005].

Penetrance

No instances of incomplete penetrance of PHS have been published.

Ng et al [2004] reported one individual with apparent germline mosaicism without evident clinical features.

Anticipation

Anticipation is not seen in PHS.

Nomenclature

Other descriptors used include the following:

• Hypothalamic hamartoblastoma syndrome. This is incorrect as "blastoma" refers to tissues in which the neural elements of hamartomas are immature, and it is also incorrect as it does not reflect the syndromic nature of the phenotype and may be confused with isolated hamartomas.

• CAVE complex (cerebroacrovisceral early lethality). This designation is inappropriate as most individuals are mildly affected and do not manifest early lethality.

• Hall-Pallister syndrome
  
  Note: The abbreviation "HPS" is used for the Hermansky-Pudlak syndrome.

Prevalence

PHS is rare. The prevalence is unknown. Approximately 100 cases are known to the author [Biesecker, personal observation]. It is suspected that many individuals with postaxial polydactyly and asymptomatic hypothalamic hamartoma or bifid epiglottis may be misdiagnosed as having nonsyndromic PAP-A.

PHS is pan ethnic.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Pallister-Hall syndrome (PHS), the following evaluations are recommended:

• Assessment for cortisol deficiency. This must be performed urgently in individuals who have no family history of PHS and in individuals who have family members with PHS and cortisol deficiency. Of note, adrenal crisis can be lethal in infants who have not undergone proper evaluation and treatment for adrenal insufficiency.

• Consultation by an endocrinologist, including evaluation of growth hormone secretion, FSH and LH secretion, and serum concentration of thyroid hormone in early infancy after evaluation for and treatment of ACTH deficiency

• Cranial MRI to establish the location and extent of hamartoma

• Neurologic examination to exclude signs of intracranial hypertension, which is not typical of hypothalamic hamartomas

• Limb radiographs to distinguish postaxial polydactyly from central polydactyly

• Renal ultrasonography to look for renal anomalies

• Visualization of the epiglottis by laryngoscopy. Urgent evaluation by an otolaryngologist for laryngotracheal cleft when signs or symptoms of aspiration are present. Elective evaluation by an otolaryngologist in asymptomatic individuals for the purpose of establishing the diagnosis or establishing the extent of anomalies.

• Surgical consultation for imperforate anus or anal stenosis if present

• Developmental assessment

Treatment of Manifestations

Endocrine abnormalities are treated as in the general population, with treatment for cortisol deficiency being the most urgent.

Anal atresia or stenosis should be treated in standard fashion.

Management of epiglottic abnormalities depends on the type of abnormality and extent of respiratory compromise and is the same as in the general population. Bifid epiglottis is commonly asymptomatic and most do not require treatment, unless accompanied by clear evidence of obstruction or associated with other anomalies, such as tracheal stenosis.

Seizures are treated symptomatically. Seizures associated with PHS are commonly responsive to antiepileptic drugs (AEDs), whereas seizures associated with nonsyndromic hypothalamic hamartomas are more commonly refractory to AEDs.

Repair of polydactyly should be undertaken on an elective basis.

If developmental delays are detected, intervention and/or special education are indicated.

Prevention of Secondary Complications

Only under the most unusual circumstances should a hypothalamic hamartoma be removed or even biopsied because the complications of surgery and the need for lifelong hormone supplements postoperatively generally outweigh the benefits.

Use of stimulants for attention deficit disorder should be considered carefully in persons with a CNS lesion that predisposes to seizures (e.g., hypothalamic hamartoma).

Surveillance

During childhood

• Annual medical evaluations to assess growth and monitor for signs of precocious puberty

• Annual screening for developmental delay or learning disorders

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Pallister-Hall syndrome (PHS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with PHS have an affected parent and some have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo gene mutations is unknown, as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient.

• Because all affected parents to date have had polydactyly, the parents of a proband with no known family history of PHS should be examined for evidence of extra digits.

Sibs of a proband

• The risk to the sibs of a proband depends on the status of the parents of the proband.

• If a parent is affected, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low, but greater than that of the general population because of the possibility of germline mosaicism. One instance of parental mosaicism has been reported [Ng et al 2004].
  
  Note: The description of a single case of mosaicism for a rare disorder does not allow an estimation of the frequency of this event for genetic recurrence risk estimates, but it must be considered as a possibility.

Offspring of a proband

• Every child of an individual with PHS has a 50% chance of inheriting the mutation.

• Because intrafamilial variability appears to be low, affected offspring would be expected to have clinical findings similar to those of the parent.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is found to be affected or to have a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination. In fetuses at 50% risk, prenatal ultrasound examination may detect polydactyly. However, a normal ultrasound examination does not eliminate the possibility of PHS in the fetus.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Literature Cited

1. Azzam A, Lerner DM, Peters KF, Wiggs E, Rosenstein DL, Biesecker LG. Psychiatric and neuropsychological characterization of Pallister-Hall syndrome. Clin Genet. 2005;67:87–92. [PubMed: 15617553]
2. Biesecker LG. What you can learn from one gene: GLI3. J Med Genet. 2006;43:465–9. [PMC free article: PMC2564530] [PubMed: 16740916]
3. Boudreau EA, Liow K, Frattali CM, Wiggs E, Turner JT, Feuillan P, Sato S, Patsalides A, Patronas N, Biesecker LG, Theodore WH. Hypothalamic hamartomas and seizures: distinct natural history of isolated and Pallister-Hall syndrome cases. Epilepsia. 2005;46:42–7. [PubMed: 15660767]
4. Everman D (2006) The polydactylies. In: Stevenson RE, Hall JG (eds) Human Malformations and Related Anomalies. Oxford University Press, pp 937-53.
5. 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. 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. [PMC free article: PMC1199298] [PubMed: 15739154]
6. Ng D, Johnston JJ, Turner JT, Boudreau EA, Wiggs EA, Theodore WH, Biesecker LG. Gonadal mosaicism in severe Pallister-Hall syndrome. Am J Med Genet. 2004;124A:296–302. [PubMed: 14708104]
7. Radhakrishna U, Bornholdt D, Scott HS, Patel UC, Rossier C, Engel H, Bottani A, Chandal D, Blouin JL, Solanki JV, Grzeschik KH, Antonarakis SE. The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type- A/B; No phenotype prediction from the position of GLI3 mutations. Am J Hum Genet. 1999;65:645–55. [PMC free article: PMC1377970] [PubMed: 10441570]
8. Stevens CA, Ledbetter JC. Significance of bifid epiglottis. Am J Med Genet A. 2005;134:447–9. [PubMed: 15782417]

Suggested Reading

1. Biesecker LG, Abbott M, Allen J, Clericuzio C, Feuillan P, Graham JM, Hall J, Kang S, Olney AH, Lefton D, Neri G, Peters K, Verloes A. Report from the workshop on Pallister-Hall syndrome and related phenotypes. Am J Med Genet. 1996;65:76–81. [PubMed: 8914745]
2. Johnston JJ, Biesecker LG (2007) Pallister Hall Syndrome (PHS). Atlas of Genetics and Cytogenetics Oncology and Haematology. atlasgeneticsoncology.org .
3. Vortkamp A, Gessler M, Grzeschik KH. GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature. 1991;352:539–40. [PubMed: 1650914]

Author Notes

Author's Web page

The author is a board-certified clinical geneticist and pediatrician. He performs clinical and molecular research on PHS and related disorders at the NIH.

Revision History

• 15 June 2010 (cd) Revision: deletion/duplication analysis no longer available clinically

• 3 February 2009 (cd) Revision: deletion/duplication analysis available clinically

• 18 March 2008 (me) Comprehensive update posted to live Web site

• 2 June 2006 (cd) Revision: prenatal diagnosis clinically available

• 6 June 2005 (me) Comprehensive update posted to live Web site

• 1 May 2003 (me) Comprehensive update posted to live Web site

• 25 May 2000 (me) Review posted to live Web site

• 20 January 2000 (lb) Original submission