Pallister-Hall Syndrome

Clinical characteristics.

Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.

Diagnosis/testing.

The diagnosis of Pallister-Hall syndrome can be established in a proband with both hypothalamic hamartoma and mesoaxial polydactyly. Identification of a heterozygous pathogenic variant in GLI3 confirms the diagnosis.

Management.

Treatment of manifestations: Urgent treatment for endocrine abnormalities, especially cortisol deficiency; management of epiglottic abnormalities depending on the abnormality and the extent of respiratory compromise. Bifid epiglottis, the most common abnormality, typically does not need treatment. Standard treatment of anal atresia or stenosis; symptomatic treatment of seizures; elective repair of polydactyly; developmental intervention or special education for developmental delays.

Prevention of secondary complications: Biopsy or resection of hypothalamic hamartoma may result in complications and lifelong need for hormone replacement; seizures may begin or worsen with use of stimulants for attention deficit disorder.

Surveillance: During childhood, annual developmental assessment and annual medical evaluation to assess growth and monitor for signs of precocious puberty.

Genetic counseling.

Pallister-Hall syndrome is inherited in an autosomal dominant manner. Individuals with PHS may have an affected parent or may have the disorder as the result of a de novo pathogenic variant. About 25% of individuals have a de novo pathogenic variant. Persons with a de novo pathogenic variant are generally more severely affected than those with a family history of PHS. The risk to offspring of an affected individual is 50%. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known. The reliability of ultrasound examination for prenatal diagnosis is unknown.

Suggestive Findings

Pallister-Hall syndrome (PHS) should be suspected in individuals with the following features:

• Hypothalamic hamartoma, a non-enhancing mass in the floor of the third ventricle posterior to the optic chiasm that is isointense to gray matter on T₁ and T₂ pulse sequences of an MRI, but may have distinct intensity on FLAIR
  Note: Neither cranial CT examination nor cranial ultrasound examination is adequate for diagnosis of hypothalamic hamartoma.
• Mesoaxial (i.e., insertional or central) polydactyly, the presence of six or more well-formed digits with a Y-shaped metacarpal or metatarsal
• 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 mesoaxial 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

Establishing the Diagnosis

The clinical diagnosis of PHS is established in a proband with BOTH hypothalamic hamartoma and mesoaxial polydactyly.

Identification of a heterozygous pathogenic variant in GLI3 by molecular genetic testing confirms the diagnosis of PHS (see Table 1).

The clinical diagnosis of sub-PHS is established in a proband with:

• One of the following:
  • Mesoaxial polydactyly
  • Hypothalamic hamartoma
  • Oligodactyly
  • Postaxial polydactyly; AND
• One of the following:
  • Bifid epiglottis
  • Imperforate anus
  • Small nails
  • Hypopituitarism
  • Growth hormone deficiency
  • Genital hypoplasia

Identification of a heterozygous pathogenic variant in GLI3 by molecular genetic testing confirms the diagnosis of sub-PHS (see Table 1).

Note: Several individuals with nonsyndromic hypothalamic hamartomas and somatic mosaicism for GLI3 pathogenic variants in the hamartoma have been reported [Wallace et al 2008]. While these individuals do not meet the clinical diagnostic criteria for PHS sensu stricto, they may be considered to have a partial form of PHS and consideration should be given to evaluating such individuals for other manifestations of the disorder.

Clinical Description

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 postaxial polydactyly type A (PAP-A).

Hypothalamic hamartoma. Hypothalamic hamartoma is a malformation, not a tumor. Hypothalamic hamartomas grow at the rate of – or more slowly than – the surrounding brain tissue. Hypothalamic hamartomas may be large (≤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 or other complications.

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

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.

Polydactyly. Postaxial polydactyly may be more common than mesoaxial polydactyly in individuals with PHS. Postaxial polydactyly (PAP) type A is the presence of a well-formed digit on the ulnar or fibular aspect of the limb. PAP type B is the presence of a rudimentary digit or nubbin in the same location. Mesoaxial (i.e., insertional or central) polydactyly is the presence of six or more well-formed digits with a Y-shaped metacarpal or metatarsal.

Note: The nonspecificity of postaxial polydactyly and the high frequency of PAP type B in persons of central African descent require caution in its use as a diagnostic feature.

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.

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].

Genitourinary anomalies. Renal abnormalities include cystic malformations, renal hypoplasia, and ectopic ureteral implantation; genitourinary anomalies include hydrometrocolpos. The pathogenetic mechanism of the genitourinary anomalies has been delineated [Blake et al 2016].

Other findings include imperforate anus, pulmonary segmentation anomalies including bilateral bilobed lungs, and non-polydactyly skeletal anomalies including short limbs.

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 persons 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 pan hypopituitarism 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 good 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.

Genotype-Phenotype Correlations

See Figure 1. The mutational spectra of GCPS and PHS are mostly distinct. GCPS is caused by pathogenic variants of all types, whereas PHS is only caused by truncating variants and one splice variant that generates a frameshift and a truncation. Within the frameshift variant category, a genotype-phenotype correlation has been demonstrated on two levels:

Figure 1.

The mutational spectra of PHS and GCPS are mostly distinct.

• Class of variant. Pathogenic variants of all classes can cause Greig cephalopolysyndactyly syndrome (GCPS), whereas the majority of pathogenic variants that cause the allelic disorder PHS are frameshift variants. Haploinsufficiency for GLI3 causes GCPS, whereas truncating variants 3' of the zinc finger domain of GLI3 generally cause PHS [Kang et al 1997] (Figure 1A).
• Variant position. Among all frameshift variants in GLI3, variants in the first third of the gene are only known to cause GCPS (Figure 1B). Frameshift variants in the middle third of the gene cause PHS and (uncommonly) GCPS. Frameshift variants in the final third of the gene cause GCPS. There is no apparent correlation of the variant position within each of the three regions and the severity of the corresponding phenotypes.

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.

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 is also incorrect as it does not reflect the syndromic nature of the phenotype and may be confused with isolated hamartomas.
• CAVE (cerebroacrovisceral early lethality) complex. 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. More than 100 affected persons are known to the author [Biesecker, personal observation] and a number of additional individuals have been reported (see, e.g., Démurger et al [2015]). 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 and needs in an individual diagnosed with Pallister-Hall syndrome (PHS), the following evaluations are recommended if they have not already been completed:

• 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
• 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
• Limb radiographs to distinguish postaxial polydactyly from central polydactyly
• Evaluation by a hand surgeon to assess the timing and surgical approach to correct the polydactyly. Note that the surgical correction of mesoaxial polydactyly is typically more complex than for postaxial polydactyly and should be undertaken by an expert surgeon.
• Renal ultrasonography to evaluate for renal anomalies
• Surgical consultation for imperforate anus or anal stenosis if present
• Developmental assessment
• Consultation with a clinical geneticist and/or genetic counselor

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.

Occupational therapy for manual dexterity of the hands may be necessary as some individuals with mesoaxial polydactyly have digital malalignment.

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

Agents/Circumstances to Avoid

As noted in Prevention of Secondary Complications, some stimulants (commonly used for attention deficit and hyperactivity disorders) may exacerbate seizures.

Evaluation of Relatives at Risk

It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

• If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
• If the pathogenic variant in the family is not known, clinical examination for polydactyly, laryngoscopy for bifid epiglottis, or MRI for hypothalamic hamartoma can be used to clarify the genetic status of at-risk relatives.
• The first-degree relative of a proband is considered affected if hypothalamic hamartoma or central or postaxial polydactyly are present in the relative. (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.)

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

Pregnancy Management

Pregnancy management of a woman affected with PHS should be attuned to guidelines for the specific manifestations of the disorder. For example, the management of pregnant women with gelastic epilepsy who need to take anticonvulsants is challenging. As there are no guidelines specific to PHS, the author recommends following general guidelines for anticonvulsants in pregnancy [Borthen & Gilhus 2012].

In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of antiepileptic medication during pregnancy reduces this risk. However, exposure to antiepileptic medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from antiepileptic medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of antiepileptic medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

The management of fertility and pregnancy (which is uncommon in individuals with hypopituitarism) in individuals with hypopituitarism caused by PHS is similarly challenging and again, it is recommended that general guidelines be followed [Kübler et al 2009].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.