Pallister–Hall syndrome (PHS) is a rare autosomal dominant developmental disorder characterised by a broad spectrum of anomalies involving the central nervous system, endocrine organs, limbs, and craniofacial structures. Although its best-known features include hypothalamic hamartoma and polydactyly, the syndrome frequently presents with complex endocrine and developmental manifestations that require coordinated evaluation from multiple specialities. As survival and detection improve, clinicians increasingly encounter children and adults with PHS who require ongoing hormonal monitoring, growth assessment, and surveillance for complications associated with hypothalamic dysfunction. This article provides a comprehensive overview of current knowledge in the endocrine and developmental evaluation of individuals with PHS, highlighting key clinical markers, diagnostic strategies and emerging areas of research.

Overview of Pallister–Hall Syndrome

Pallister–Hall syndrome results from pathogenic variants in the GLI3 gene, a transcription factor central to the Sonic Hedgehog (SHH) signalling pathway.¹ Because SHH signalling orchestrates embryonic patterning of the brain, pituitary, limbs and other organs, disruptions in GLI3 function produce a highly variable phenotype. Although some individuals present with mild abnormalities, others experience severe endocrine dysfunction, respiratory complications, or life-threatening neonatal issues.

Core clinical features may include:

• Hypothalamic hamartoma (present in nearly all molecularly confirmed cases)²
• Polydactyly, typically postaxial or mesoaxial¹
• Bifid epiglottis
• Genitourinary anomalies
• Endocrine deficiencies related to hypothalamic–pituitary dysfunction³
• Developmental delays or cognitive variability

Because the presentation varies widely, comprehensive and repeated evaluation is essential throughout childhood and adolescence.

Endocrine Manifestations in Pallister–Hall Syndrome

Endocrine abnormalities in PHS arise mainly from dysfunction of the hypothalamus and pituitary gland. The hypothalamic hamartoma, a benign congenital mass, can impair hormonal secretion, disrupt regulatory feedback loops and interfere with normal pubertal or metabolic development.

1. Hypothalamic–Pituitary Axis Dysfunction

Hypopituitarism

Several forms of pituitary hormone deficiency have been described in PHS, including:

• Growth hormone deficiency (GHD)
• Central hypothyroidism
• Adrenocorticotropic hormone (ACTH) deficiency
• Gonadotropin deficiency

Growth hormone deficiency is among the most common endocrine abnormalities, potentially leading to short stature, poor weight gain, and reduced bone mineralisation.³ Central hypothyroidism may cause lethargy, developmental regression, and impaired cognitive growth if untreated.⁴

Adrenal insufficiency

Central adrenal insufficiency, resulting from low ACTH output, can be life-threatening in newborns and infants. Symptoms may include vomiting, hypoglycaemia, poor feeding, and circulatory collapse.⁴ Early morning cortisol and ACTH measurements should be repeated across early development, as deficiencies may evolve.

Hyperprolactinaemia

In some cases, disrupted hypothalamic dopaminergic signalling contributes to elevated prolactin levels. Clinical consequences may include delayed puberty or menstrual irregularities.⁵

2. Disorders of Puberty

PHS patients may develop abnormalities in the timing of puberty due to hypothalamic hamartoma and impaired gonadotropin regulation.

Precocious puberty

While PHS-associated hamartomas are typically non-seizure-generating (unlike in isolated hypothalamic hamartoma), precocious puberty has still been reported in a subset of patients.⁶ This may lead to premature fusion of the growth plates, advanced bone age and reduced adult height.

Delayed puberty

More commonly, however, patients may experience delayed or incomplete pubertal progression due to hypogonadotropic hypogonadism.⁵ Monitoring sex hormone levels, growth velocity and secondary sexual characteristics is essential across adolescence.

3. Feeding and Metabolic Issues

Hypothalamic dysfunction may lead to impaired appetite regulation, feeding difficulties during infancy, or later-onset obesity.⁷ A combination of poor neonatal feeding and subsequent metabolic dysregulation contributes to variable growth trajectories. Regular nutritional assessment is therefore vital.

Developmental Considerations in Pallister–Hall Syndrome

Children with PHS may exhibit a wide spectrum of developmental outcomes, ranging from typical cognitive profiles to significant delays. Early detection and intervention are crucial to support functional independence.

1. Neurodevelopmental Profile

Hypothalamic hamartomas can disrupt neural circuits involved in behaviour, memory formation, and emotional regulation. Although PHS-associated hamartomas rarely cause gelastic seizures, unlike hamartomas in non-PHS cases, subtle neurodevelopmental effects are common.⁸

Potential challenges include:

• Mild to moderate developmental delay
• Language acquisition difficulties
• Attention and executive function challenges
• Motor coordination delays

Formal developmental assessments should begin in infancy and continue at intervals throughout early childhood.

2. Behavioural and Emotional Outcomes

Behavioural features may include anxiety, impulsivity, or autistic traits, though severity varies.⁹ Sleep disturbances due to hypothalamic dysregulation may also contribute to behavioural fluctuations.

Multidisciplinary care (including neuropsychology, behavioural therapy, and sleep medicine) improves long-term outcomes.

3. Growth and Physical Development

Because endocrine abnormalities can significantly alter growth patterns, children require serial height, weight, and head circumference monitoring. Bone age assessments help detect early pubertal changes, GHD, or chronic hormonal insufficiency.³

Recommended Evaluation Strategy

1. Endocrine Baseline Assessment

Shortly after diagnosis, clinicians should evaluate the entire hypothalamic–pituitary axis through:

• Serum cortisol and ACTH
• Thyroid-stimulating hormone (TSH) and free T4
• Insulin-like growth factor 1 (IGF-1)
• Luteinising hormone (LH), follicle-stimulating hormone (FSH), oestradiol/testosterone
• Prolactin levels
• Comprehensive metabolic panel

These tests should be repeated periodically because deficiencies may evolve.

2. Neuroimaging

MRI of the brain, with attention to the hypothalamus and pituitary region, is essential to confirm the presence and size of the hamartoma and to monitor for changes over time.¹⁰

3. Developmental Screening

Developmental evaluation should include:

• Early childhood developmental testing
• Speech and language assessment
• Motor function evaluation
• Cognitive and academic screening (school age)
• Behavioural assessments

Early intervention services should begin as soon as deficits are detected.

4. Genetic Testing and Counselling

Molecular confirmation through GLI3 sequencing not only secures the diagnosis but also informs recurrence risk and guides family counselling.¹ Parents benefit from counselling regarding the autosomal dominant inheritance pattern and variable expressivity.

Future Directions in Endocrine and Developmental Research

Emerging research aims to clarify the mechanisms by which GLI3 mutations alter hypothalamic and pituitary development. Current priorities include:

1. Mapping GLI3–SHH downstream targets

Improved understanding of embryologic signalling could enhance genotype–phenotype correlation.¹¹

2. Long-term natural history studies

Because many reported cases historically died in infancy, adult endocrine outcomes are not well documented. Increasing case registries aim to address this gap.¹²

3. Novel hormonal biomarkers

Researchers are investigating new biomarkers for early pituitary dysfunction, potentially enabling earlier detection of evolving deficiencies.¹³

4. Targeted developmental interventions

Advances in early neurodevelopmental therapies may optimise cognitive trajectories for children with PHS.

Summary

Pallister–Hall syndrome presents a unique combination of endocrine and developmental challenges driven largely by GLI3 pathway disruption and hypothalamic malformation. A comprehensive evaluation, beginning at diagnosis and continuing throughout childhood, adolescence, and adulthood, is essential to identify hormonal deficiencies early, support growth and pubertal development and address neurodevelopmental needs. As research continues to clarify the full spectrum of endocrine involvement and associated developmental patterns, coordinated multidisciplinary care will remain the cornerstone of improving outcomes for individuals with PHS.