Clinical Guidance

The mutational spectra of GCPS and GLI3-PHS are mostly distinct . GCPS is caused by pathogenic variants of all types, whereas GLI3-PHS is overwhelmingly caused by truncating variants that generate a frameshift and a truncation. Within the frameshift variant category, a genotype-phenotype correlation has been demonstrated on two levels:

Source: GeneReviews — "GLI3-Related Pallister-Hall Syndrome"

Penetrance

No instances of incomplete penetrance of GLI3-PHS have been published. reported one individual with apparent germline mosaicism without evident clinical features.

Source: GeneReviews — "GLI3-Related Pallister-Hall Syndrome"

Diagnostic Criteria

Consensus clinical diagnostic criteria for GLI3-related Pallister-Hall syndrome (GLI3-PHS) have been published .

Suggestive Findings

GLI3-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-weighted 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.

Source: GeneReviews — "GLI3-Related Pallister-Hall Syndrome"

Differential Diagnosis

Central polydactyly • Oral-facial-digital syndrome type 6 (OMIM 277170), caused by biallelic pathogenic variants in CPLANE1, includes central polydactyly with hypoplasia of the cerebellar vermis. Renal agenesis and dysplasia have been described. • Holzgreve syndrome (OMIM 236110) includes central polydactyly, cleft palate, and heart defect. Postaxial polydactyly. See . Table 4. Disorders Associated with Postaxial Polydactyly in the Differential Diagnosis of GLI3-Related Pallister-Hall Syndrome

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with GLI3-related Pallister-Hall syndrome (GLI3-PHS), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Recommended Evaluations Following Initial Diagnosis in Individuals with GLI3-Related Pallister-Hall Syndrome

Source: GeneReviews — "GLI3-Related Pallister-Hall Syndrome"

Clinical Guidance

Biopsy or resection of hypothalamic hamartoma may result in complications and lifelong need for hormone replacement. Some stimulants (commonly used for attention-deficit/hyperactivity disorder) may exacerbate seizures.

Source: GeneReviews — "GLI3-Related Pallister-Hall Syndrome"

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.

Source: GeneReviews — "GLI3-Related Pallister-Hall Syndrome"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.

Table 7.

Recommended Surveillance for Individuals with GLI3-Related Pallister-Hall Syndrome

System/Concern | Evaluation | Frequency

Endocrine

| • Assess growth.

• Monitor for signs of precocious puberty.

| Annually throughout childhood

Development

| Monitor developmental progress educational needs.

Psychiatric/Behavioral

| Behavioral assessment

Source: GeneReviews — "GLI3-Related Pallister-Hall Syndrome"