Neurologic Manifestations of PTEN Hamartoma Tumor Syndrome Get Their Due in First-Ever Guidelines

PTEN hamartoma tumor syndrome (PHTS) is associated with a predilection for benign overgrowths and increased cancer risk linked to a defect in the PTEN gene. While these are leading characteristics of the autosomal dominant disorder, PHTS also entails diverse neurodevelopmental and neurological challenges.

These neurological and neurodevelopmental manifestations of PHTS are now, for the first time, the focus of management guidelines in the form of recommendations published by the PHTS Consensus Guidelines Working Group in Neurology Genetics (2025;11[5]:e200299), developed after a comprehensive literature review and modified Delphi process.

Among the top recommendations are the need to educate patients and caregivers at the time of PHTS diagnosis about the condition’s potential neurodevelopmental and neuropsychiatric complications; the importance of early screening for mood, sleep and neurodevelopmental challenges; and a need for prompt intervention for any identified issues.

“Clinical management of neurological manifestations of PHTS is exceptionally challenging, as the syndrome is so variable and may be diagnosed at any age,” says lead and corresponding author Andrew Dhawan, MD, PhD, staff neuro-oncologist with Cleveland Clinic’s Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center. “We hope these guidelines — developed with international expertise at the highest levels — can increase recognition that neurological issues are a key component of the syndrome and will help standardize management.”

A multi-year international effort

The PHTS Consensus Guidelines Working Group included a small core of PHTS experts with specialties in genetics, neurology, neuropsychiatry and neurodevelopment. In addition to Dr. Dhawan, other core group members were Cleveland Clinic neuropsychologist Robyn Busch, PhD; Thomas Frazier, PhD, former director of the Cleveland Clinic Center for Autism; and the late Charis Eng, MD, PhD, who, until her death in 2024, was founding director of Cleveland Clinic’s Genomic Medicine Institute and a pioneer in PTEN research who played a lead role in describing PHTS.

Additional experts, including individuals from Canada and Europe, and a patient advocate served on an extended panel that developed consensus across multiple rounds of a modified Delphi approach over a three-year period. The result is a collection of 18 recommendations for surveilling and managing neurodevelopmental features of PHTS and 14 for neurological features, with strength-of-evidence grade and consensus agreement indicated for each.

The prominence of neurological features

Two previous articles from this group described neurological features of PHTS based on a systematic literature review (Neurology. 2024;103[7]:e209844) and a multicenter longitudinal study of young patients with PHTS using healthy siblings as controls (Ann Clin Transl Neurol. 2024;11[5]:1301-1309).

PHTS is strongly associated with autism spectrum disorder (present in approximately 22% of PHTS patients), usually with a different presentation than seen in children without PHTS. Children with PHTS and autism spectrum disorder are more likely to have severe cognitive delays, attention deficits, increased impulsivity, and reduced processing speed and executive functioning.

Other frequently seen neurological challenges are language delays, mood and behavioral issues, sleep problems and attention deficit disorder. “It’s important to assess for these and other intellectual and developmental disabilities thoroughly and early on,” Dr. Dhawan urges. “While care for such problems is not specific to PHTS, early interventions can ultimately make a big difference to a patient’s life.”

Epilepsy may also occur (present in 9% to 17% of PHTS patients). Due to strong evidence, the Delphi panel was in complete agreement that mTOR inhibitors should not be used as first-line therapy for epilepsy and that routine mTOR use should be avoided for psychiatric or cognitive symptoms outside of clinical trials.

The guidelines also do not recommend routine MRI screening, although MRI may be indicated for evaluation of problems such as seizures and headaches. MRI also has an important role in detecting vasculopathies, which Dr. Dhawan emphasizes can occur in this population and should be included in the differential diagnosis for neurological symptoms.

Getting help

“There are many nuances to PHTS, and because the syndrome was only identified relatively recently, it is often not well understood, even by the medical community,” Dr. Dhawan explains. “I hope that doctors in the community learn from these guidelines and that patients feel empowered to share this document with their providers.”

He adds that patients or parents who have unresolved concerns about the condition should visit a large center experienced in PHTS, of which there are only a few in the country. Cleveland Clinic is one of the world’s foremost institutions in PHTS research, having described the syndrome and established best practices.

Further research needed – and underway

Dr. Dhawan says it is unclear why neurological issues are so prominent in this condition that is better known for being a cancer predisposition and overgrowth syndrome. He adds that insight into this question and the development of potential targeted interventions will likely hinge on further basic research into the PTEN pathogenic variants at play.

Cleveland Clinic is currently participating in a multicenter study (NCT02461446) evaluating autism spectrum disorder in patients with PHTS compared with other groups, with the aim of characterizing autism-associated PHTS and identifying neural and molecular biomarkers. The study is currently recruiting children and adults with and without a PTEN pathogenic variant and with and without autism.

Dr. Dhawan notes that guidelines on PHTS will proliferate as more evidence comes in. He is especially interested in various neurological and autonomic manifestations of PHTS as a promising new focus of research.

“We have very fruitful relationships with PTEN Research and the PTEN Foundation, which are instrumental in helping with funding and providing patient access,” he says. “We look forward to more productive research in the years ahead, and we are incredibly grateful for the support of PTEN Research and the Developmental Synaptopathies Consortium in these endeavors.”