Neurodevelopmental and Neurologic Manifestations of PTEN Hamartoma Tumor Syndrome

Abstract

Background and Objectives

PTEN hamartoma tumor syndrome (PHTS) is an autosomal dominant cancer predisposition and overgrowth syndrome due to pathogenic germline variants in the PTEN gene. PHTS harbors a diverse range of clinical manifestations including an associated neurodevelopmental (ND) and neurologic phenotype, requiring a multidisciplinary approach to care. There are no clinical practice guidelines for the management of ND or neurologic comorbidities. The objective of these clinical guidelines was to use the latest knowledge to generate a resource for providers, researchers, and patients on the best practices in the practical management of neurologic and ND challenges in PHTS.

Methods

The PHTS Consensus Guidelines Working Group was established, comprising a core group of seven experts in the diagnosis and management of PHTS, including genetics, neurology, neuropsychology, and neurodevelopment (including psychiatry and psychology). The Working Group held joint meetings with a Patient Advisory Group (PTEN Foundation), comprising patients with PHTS and their advocates. Informed by a comprehensive literature review, the Working Group met regularly between 2022 and 2024 to produce guideline statements, refined through iterative feedback. A modified Delphi approach was used with an independent extended panel of neurologists, neuropsychologists, and psychiatrists, to establish final consensus guidelines.

Results

The first iteration of the clinical consensus recommendations for the management of ND and neurologic features in patients with PHTS was formed. Guidelines encompass ND challenges, mood disorders, ND screening, neuroimaging abnormalities, neurologic comorbidities, and tumors affecting the CNS.

Discussion

While multiple efforts are ongoing to better characterize the natural history of PHTS, the clinical management of individuals with PHTS is complex and remains challenging because of variable expressivity and age-related specificities. As part of a comprehensive effort to develop consensus management guidelines, which cover all manifestations of PHTS, we present the first iteration of guidelines for the ND and neurologic manifestations of PHTS, aimed at improving care for affected individuals and families.

Introduction

PTEN hamartoma tumor syndrome (PHTS) is an autosomal dominant cancer predisposition and overgrowth syndrome due to pathogenic germline variants in PTEN.^1,2 PHTS is a molecularly defined diagnosis encompassing clinically heterogeneous phenotypes including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome, (PS) and Proteus-like syndrome.³ PTEN is a tumor suppressor gene inhibiting the PI3K/AKT/mTOR pathway and plays an essential role in embryogenesis and development, especially within the nervous system.^4-8 PTEN, along with the signal cascades it regulates, affects brain development during cell proliferation and differentiation, migration, neurite outgrowth, synaptogenesis, and myelination.⁹

Given the myriad roles PTEN plays, individuals with PHTS present in a bimodal age distribution, with a spectrum of findings. Children are most often diagnosed after evaluation for vascular malformations, macrocephaly, or neurodevelopmental (ND) delay.^10-12 Likewise, adults are identified after germline genetic testing because of intestinal polyposis, a family history of cancer, or a PHTS-associated malignancy.

Despite advances in our understanding of the PI3K/AKT/mTOR-opathies (e.g., tuberous sclerosis complex and neurofibromatosis type 1), and the ND/neurologic features of PHTS, there are no guidelines for the management of these comorbidities. PHTS guidelines have been published by the National Comprehensive Cancer Network (NCCN) in the United States and the European Reference Network (ERN) for Genetic Tumor Risk Syndromes, focusing on cancer surveillance, but not neurologic or neuropsychologic symptoms.^13-15 To address this gap, the PHTS Consensus Guidelines Working Group was established, comprising a group of seven experts in PHTS, including genetics, neurology, neuropsychology, psychiatry, and neurodevelopment (core group). The core group held joint meetings with a Patient Advisory Group. A modified Delphi approach with an independent panel of experts was used to validate guideline statements. Our aim was to generate patient/family and provider-centered evidence-based guidelines for the practical management of neurologic/ND challenges in PHTS.

Methods

Guideline Scope

Guideline scope was defined by the core panel to comprehensively summarize the surveillance, screening, management, and evidence for the neurologic/ND features of PHTS. This was generated in conjunction with an expansive literature search recently reported in a corresponding review on the subject.¹⁶ Core group members met and discussed the results of the literature search to define draft statements based on the domains identified by the literature search and their clinical experience.

Literature Search

A comprehensive literature search was performed initially on September 6, 2022. An updated literature search was performed on January 4, 2023, to include articles published after the original search to capture studies not included in the initial search. We used OVID MEDLINE and EMBASE databases of all articles published between 2002 and 2023. Search terms for OVID MEDLINE and EMBASE included the following (alone or in combination with): “PTEN Hamartoma Tumour Syndrome,” “Cowden Syndrome,” “Bannayan-Riley-Ruvalcaba Syndrome,” “Proteus syndrome,” “Proteus-like syndrome,” “Lhermitte Duclos,” “PHTS,” “PTEN or PTEN Phosphohydrolase,” “Nervous System Diseases,” “Mental Disorders,” and “(neur* or psych* or autism or ASD or seiz* or epilep* or “developmental delay” or “ADD” or “ADHD” or “attention deficit*).”

Identified articles were imported into Covidence systematic review software, where studies were deduplicated and screened. Studies reporting on incidence, prevalence, morbidity, or mortality of neurologic and psychiatric manifestations related to PHTS were included. Publications without suitable English translation were excluded. Review articles, editorials, opinion pieces, and meeting abstracts/posters were also excluded. Cumulatively, 1,996 studies were identified across both database searches, with 399 duplicates subsequently removed. After screening, 177 published articles were included for data extraction. Studies were categorized by study type (e.g., case report, case series, and therapeutic trials). Elements extracted from each study included the following: study population, study design, intervention, outcomes measured, and result summary.

Evidence Grading Criteria

The amount of high-level evidence available to inform these guidelines was limited. We used an evidence grading scale to balance the weight of published evidence and expert knowledge, as implemented by Tischkowitz et al.¹³ The scale is as follows: strong evidence: consistent evidence with new evidence unlikely to change recommendation and expert consensus; moderate evidence: inconsistent evidence or significant new evidence expected and expert consensus; and weak evidence: inconsistent evidence and expert consensus. Statements without evidence and limited expert agreement were classified separately as expert opinion statements. All core members agreed on evidence grading for each statement. Any discrepancies were addressed through discussion with all core group members until consensus was reached.

Working Group and Extended Panel Members

The authors formed the PHTS Consensus Guidelines Working Group (core group) with the intention of including a diverse set of clinicians and patients/advocates with experience in the neurologic/ND aspects of PHTS. The core group functioned in parallel and analogously to guideline groups focused on oncology/overgrowth, vascular anomalies, and dermatology. The seven core neurology/neurodevelopment group members (AD, SS, AYH, MU, KLL, TWF, and RMB) were recommended by patient advocates and expert opinion. The group's expertise included clinical psychology (MU, TWF, and RMB), psychiatry (AYH), medical genetics (KLL), neurology/neuro-oncology (AD), pediatric neurology (SS), and neurodevelopment (SS, MU, TWF, and RMB). Likewise, 11 individuals were recommended for the extended panel, residing in the United States (8), Canada (1), Denmark (1), and Germany (1), based on whether they were senior or corresponding authors on articles related to neurologic/ND features of PHTS. Seven individuals, all from the United States, responded to the invitation, with 1 stating that they did not have sufficient clinical experience. The remaining 6 (extended Delphi panel) completed the modified Delphi rounds. Group structure is illustrated in eFigure 1.

Modified Delphi Approach

A two-stage modified Delphi approach was used to achieve consensus among the core group and extended Delphi panel members. Core group members convened regularly from 2022 to 2024 to develop statements. The first stage involved 3 rounds of electronically administered standardized surveys through Microsoft Forms (eAppendix 1) among the core group members until consensus was reached (defined as 100% agreement). Core group members voted whether to keep, remove, or modify each statement, with an optional free-text response supporting their decision or suggesting changes. Anonymized responses were reviewed at a joint meeting with the working group and patients/advocates after each round to amend statements, until 100% agreement was reached among the core group. The second stage of the modified Delphi approach consisted of an independent expert panel (n = 6, extended Delphi panel, listed in Acknowledgments) providing feedback. This extended Delphi panel participated in 2 rounds of standardized surveys until consensus was reached (defined as 80% agreement). The core group and patients/advocates met after every round to amend statements based on anonymized feedback until 100% agreement was reached among the core group.

Results

Neurodevelopmental Features: General

These guidelines apply to individuals with a germline pathogenic variant in PTEN, unless otherwise stated. Recommendations for ND and neurologic (N) care in PHTS are summarized in Tables 1 and 2.

Table 1.

Surveillance and Management Consensus Guidelines for Neurodevelopmental Features in Patients With PHTS (Based on the Second Stage of the Modified Delphi Process)

Statement	Clinical recommendation	Evidence grade and agreement, (%)	Key details
Initial diagnosis and patient education
N1/ND1	Educate patients/caregivers at diagnosis on potential neurodevelopmental/neuropsychiatric complications	Weak (100)	Complications to discuss: autism, mood/behavioral issues, sleep problems, IDD, learning differences, ADHD Less common: Seizures, Lhermitte-Duclos disease, vasculopathy
Routine monitoring and screening
ND3	Routinely measure head circumference (occipitofrontal) up to age 5 y	Weak (83)	At least annually
ND4	Conduct developmental evaluation for young children at diagnosis; monitor ongoing if indicated	Strong (83)	Identify issues and guide accommodations/interventions
ND5	Conduct comprehensive neuropsychological assessment at diagnosis	Strong (83)	Regardless of age, proactively identify issues and guide accommodations/interventions
ND8	Assess fine and gross motor skills via formal neurologic examination at diagnosis (all ages)	Strong (83)	Regardless of age, at least by school age for early diagnoses. Can be part of developmental/neuropsychological assessment
ND9	Assess sensory features	Strong (83)	Regardless of age; at least by school age for early diagnoses
ND10	Offer assessment of psychological and behavioral functioning (all ages)	Strong (83)	At diagnosis, or at least by school age for early diagnoses, as clinically indicated
ND11	Routinely screen for depression and anxiety symptoms	Weak (80)	Start as early as age 6 y (if indicated), at least by age 12 y. Screen at least annually, or more frequently
ND16	Screen for and counsel about potential sleep issues	Expert opinion (67)	Includes insomnia, frequent arousals, RLS, reduced restful sleep, anxiety-related sleep disorders, OSA, and other sleep challenges
Targeted interventions and management
ND2	Avoid routine mTOR inhibitors for neuropsychiatric/neurocognitive symptoms outside of clinical trials	Strong (100)	Use only if deemed clinically appropriate by the treating clinician
ND6	Implement appropriate behavioral interventions for diagnosed ASD or significant autism symptoms	Strong (100)	Focus on improving social interaction, communication, and adaptive functioning
ND7	Promptly conduct hearing and comprehensive speech-language evaluation for expressive/receptive language delays (e.g., nonspeaking and minimally verbal)	Strong (100)	By 3.5 y of age, identify specific issues and guide accommodations/interventions
ND12	Refer individuals with psychological/behavioral difficulties to a licensed professional	Strong (100)	For treatment (behavioral support, psychotherapy, pharmacotherapy) or psychiatric evaluation, as indicated
ND13	Use sleep hygiene and behavioral sleep medicine techniques as first-line treatment for insomnia	Strong (100)
ND14	Evaluate for OSA if headache/excessive daytime sleepiness OR if STOP-BANG criteria met.	Strong (83)	STOP-BANG criteria: ≥2 of snoring, tiredness, observed apnea, high BP. BMI >35, age >50 y, neck circumference >40 cm, male sex. If confirmed, treat with CPAP/other interventions via sleep specialist
ND15	Follow relevant practice guidelines for sleep disorders in PHTS and autism spectrum disorder	Weak (100)
ND17	Minimize sedative/hypnotic medications (e.g., zolpidem) for sleep disturbances	Expert opinion (100)	Lack of scientific evidence for routine use in PHTS
ND18	For established RLS, check serum ferritin levels	Expert opinion (83)	If ferritin <50−75 μg/L, trial oral iron supplementation (2–3 mo) before drug therapy

Abbreviations: ADHD = attention deficit hyperactivity disorder; ASD = autism spectrum disorder; BMI = body mass index; BP = blood pressure; CPAP = continuous positive airway pressure; IDD = intellectual developmental disorder; ND = neurodevelopmental; OSA = obstructive sleep apnea; PHTS = PTEN hamartoma tumor syndrome.

Table 2.

Surveillance and Management Consensus Guidelines for Neurologic Features in Patients With PHTS (Based on the Second Stage of the Modified Delphi Process)

Statement	Clinical recommendation	Evidence grade and agreement, (%)	Key details
Initial diagnosis and patient education
N1/ND1	Educate patients/caregivers at diagnosis on potential neurodevelopmental/neuropsychiatric complications	Weak (100)	Complications to discuss: Autism, mood/behavioral issues, sleep problems, IDD, learning differences, ADHD Less common: seizures, Lhermitte-Duclos disease, vasculopathy
N2	Screen for seizures by history at diagnosis and as symptoms arise	Weak (83)	Look for: focal motor/sensory, convulsions, dyscognitive, developmental/language regression
Routine monitoring and screening
N7	Avoid routine screening neuroimaging of brain/neuroaxis	Expert opinion (83)	Only if neurologic symptoms/signs are present
N12	Perform neurologic examination to assess for intra-axial AVMs	Weak (80)	Focus on motor/sensory findings. If suspected/identified, obtain contrast MRA/MRV, consider conventional angiography, involve multidisciplinary vascular team
N15	Follow established guidelines for ocular pathologies	Weak (100)	Refer to experienced ophthalmology team
N16	Diagnose headaches using ICHD-3 criteria; manage per evidence-based practices	Weak (83)	Standard of care applies. Refer to headache neurology if refractory
Targeted interventions and management
N3	Refer to neurology and work-up for epilepsy if concern for seizures or developmental regression	Strong (83)	Workup: detailed history, examination, EEG. Consider additional EEG/imaging (MRI/MRA) based on results. Rule out epilepsy-associated pathologies (e.g., focal cortical dysplasia, and tumors) on imaging
N4	Select antiepileptic medications based on predominant seizure type	Strong (100)	No first-line mTOR inhibitors. Obtain brain MRI to rule out structural etiologies. Consider neuropsychiatric comorbidities/side effects
N5	Consider MRA/MRV with MRI for focal neurologic findings	Weak (100)	Use hemosiderin-specific sequences (e.g., GRE and SWI) for cavernous malformations
N6	Do not routinely image for typical headaches	Weak (100)	Image for: worrisome focal features (positional, projectile emesis, focal neuro-findings), abnormal examination, change in pattern, ICP signs, OR new-onset headaches in child <5 y
N8	IV contrast (gadolinium) may be used with clinically indicated brain MRI/MRA	Expert opinion (100)	Depends on diagnostic need; helpful for delineating tumors
N9	Evaluate atypical LDD with neuro-oncology/neurology and neurosurgery for biopsy/resection consideration	Moderate (100)	Atypical: noncerebellar location, contrast enhancement, diffusion restriction, rapid growth. Typical LDD (cerebellar, T1-hypo, T2-hyper, “tigroid”): monitor with serial imaging (3–12 mo) if asymptomatic/no CSF obstruction. Surgical evaluation for impending CSF obstruction
N10	Conduct serial neuroimaging and clinical examinations after LDD resection	Weak (100)	Monitor for recurrence; 6–12 mo interval. Target examinations/imaging to lesion site, use specialized MRI protocols
N11	Conduct serial neuroimaging and clinical examinations for identified meningiomas	Moderate (100)	Follow NCCN guidelines (e.g., serial MRI at 3, 6, and 12 mo, then every 6–12 months for 5 y, then every 1–3 y). Involve multidisciplinary team for symptomatic/critical meningiomas
N13	Follow established guidelines for other CNS tumors or ocular pathologies	Weak (100)
N14	Exercise caution with diagnostic/therapeutic radiation exposure	Weak (100)	Balance benefit vs potential secondary malignancy risk (typically 10–20 y later). MRI is not a risk factor

Abbreviations: ADHD = attention deficit hyperactivity disorder; ASD = autism spectrum disorder; AVM = arteriovenous malformation; GRE = gradient recalled echo; ICHD-3 = International Classification of Headache Disorders Version 3; ICP = intracranial pressure; LDD = Lhermitte-Duclos disease; N = neurologic; NCCN = National Comprehensive Cancer Network; PHTS = PTEN hamartoma tumor syndrome; SWI = susceptibility weighted imaging.

Recommendations

N1/ND1

We recommend educating all individuals with PHTS and/or their family/spouse/parents/caregivers of the following potential complications/comorbidities at the time of diagnosis: autism symptoms, mood/behavioral difficulties, sleep problems, intellectual developmental disorders (IDDs), learning differences, ADHD, and, although less frequently observed in the context of PHTS, seizures, Lhermitte-Duclos disease, and vasculopathy. (100% Agreement)

ND2

We do not recommend the routine use of mTOR inhibitors for prophylaxis or treatment of neuropsychiatric or neurocognitive symptoms in individuals with PHTS outside of a clinical trial, unless deemed to be clinically appropriate by the treating clinician. (100% Agreement)

Macrocephaly

Macrocephaly, defined as an occipitofrontal circumference ≥97th percentile or ≥2 SDs over the age/sex-associated population mean,^17,18 is a characteristic feature of PHTS.^19-32 The frequency of macrocephaly in PHTS is estimated to be 81%–100% in children and 61%–79% in adults.^{19,22-24,29,31,32} The nature of this difference in frequency of macrocephaly observed in children and adults with PHTS is unclear but may be due, in part, to the recognition of milder phenotypes later in life.

Recommendations

ND3

We recommend routine head circumference (occipitofrontal circumference) measurements in individuals with PHTS (at least annually in individuals up to age 5 years). (83% Agreement)

While head circumference in PHTS is generally above the population mean, each patient's trajectory should remain consistent over time. Thus, to ensure a consistent growth trajectory, particularly for individuals with developmental delay, measurement to 5 years is recommended. Major deviations should prompt a workup for causes of growth delay (if decreasing) or hydrocephalus (if accelerating). If hydrocephalus is suspected, urgent head imaging (CT brain, head ultrasound [if feasible early in life], or MRI brain) should be performed, in addition to neurosurgical consultation.

IDDs and ASD

Individuals with PHTS present on a spectrum from high functioning to severe neurocognitive impairments.^19,22,24,33 A large series including adults and pediatric patients with PHTS reported frequencies of ND disorders (including ASD, DD, and/or IDD) at 23% and 35%, respectively.^31,34

IDD, characterized by deficits in intellectual/adaptive functioning, is similarly variable in PHTS.^22,35-38 IDD in PHTS is associated with difficulties in working memory, executive functioning, and manual dexterity. Both expressive and receptive language delays have also been noted in PHTS, to a greater degree in those with ASD.^28,36

Neurocognitive and behavioral profiles of PHTS patients with ASD (PTEN-ASD) differ significantly from those of PHTS patients without ASD (PTEN-no ASD).^35-40 Patients with PTEN-ASD have more severe impairments in all domains (e.g., full-scale IQ, attention, impulsivity, reaction time, and processing speed) and motor functioning compared with patients with PTEN-no ASD. Patients with PTEN-ASD may show lower ADOS-2 severity scores, compared with patients with ASD and macrocephaly without PTEN pathogenic variants, but exhibit greater difficulties with sensory functioning (i.e., taste/smell sensitivity, low energy/weak, and under-responsive/seeks sensation).³⁶ In patients with PTEN-no ASD, measures of global cognitive ability do not differ significantly from controls, but these patients may have lower scores in working memory, impulsivity, visuomotor integration, processing speed, and motor coordination.^35,41

Recommendations

ND4

We recommend that young children with PHTS undergo a developmental evaluation at the time of diagnosis with ongoing monitoring, if clinically indicated, to identify any issues and recommend appropriate accommodations/interventions. (83% Agreement)

In PHTS, early intervention plays a crucial role in optimizing cognitive development. The developmental evaluation should include well-validated, standardized measures to screen for ASD, IDD, and global developmental delay to identify appropriate accommodations/interventions as early as possible. It may be reasonable to repeat developmental evaluation annually.

ND5

We recommend that children (as developmentally appropriate) and adults with PHTS undergo a comprehensive neuropsychological assessment at the time of diagnosis, if clinically indicated, to proactively identify any issues and recommend appropriate accommodations/interventions. (83% Agreement)

Neuropsychological assessment should include well-validated, standardized measures to characterize cognitive strengths and weaknesses, evaluate autism symptoms, assess adaptive functions, and estimate (pre)academic function, to identify appropriate accommodations/interventions as early as possible. This evaluation should cover all cognitive domains, with focus on processing speed, attention, working memory, executive functioning, and episodic memory. Of note, while there is overlap between recommendations ND4 and ND5, we note that developmental and neuropsychological assessments play complementary roles in characterizing the neurocognitive and behavioral profiles of individuals with PHTS. Developmental evaluations focus on screening for a diagnosis of ND disorders while neuropsychological assessments provide the quantification of cognitive functions and associated behaviors, regardless of a formal diagnosis.

As clinically indicated, the provider may consider follow-up evaluation to ensure neuropsychological profile stability and to update accommodations/interventions. Symptoms may remain stable over time (for at least 2 years, based on current research⁴²); however, the interval for assessment should be based on symptoms and clinical judgment. Indications for re-assessment may include, but are not limited to, patient/parent/teacher/caregiver concern, academic underachievement, new behavioral problems, regression, major medical/treatment changes, or new seizures. If feasible and not burdensome to the patient/family, consider more regular screening. We recommend the test-retest interval to be at least 12–24 months, unless a shorter interval is indicated. While PHTS patients with ASD display distinct neurocognitive/behavioral profiles compared with PHTS patients without ASD, no management changes are necessary, except for identifying and addressing specific concerns.

ND6

We recommend that all patients with PHTS who have a diagnosis of ASD or significant/impairing autism symptoms engage with appropriate behavioral interventions to improve social interaction, communication skills, and adaptive functioning. (100% Agreement)

ND7

We recommend that individuals with PHTS who demonstrate delays in expressive or receptive language (e.g., nonspeaking and minimally verbal) undergo hearing and comprehensive speech-language evaluation to identify specific language issues and guide appropriate accommodations/interventions. This should ideally be completed as soon as possible when language delays are identified. (100% Agreement)

This should be completed as soon as possible or, for older patients, when language delays are identified. If language delays are identified or suspected, we recommend hearing assessment. Comprehensive speech-language assessment should include standardized language performance measures to identify specific issues and recommend appropriate accommodations/interventions.

ND8

We recommend that all patients with PHTS undergo assessment of motor skills through a formal neurologic examination (fine and gross motor) at the time of diagnosis, as clinically indicated, to identify any issues and recommend appropriate accommodations/interventions. This should be completed regardless of age at diagnosis and at least by school age for those diagnosed early. (83% Agreement)

Motor examination may be part of a developmental/neuropsychological assessment.

ND9

We recommend that all patients with PHTS undergo assessment of sensory features, as clinically indicated, at the time of diagnosis to identify any issues and guide appropriate accommodations/interventions. This should be completed regardless of age at diagnosis and at least by school age for those diagnosed early. (83% Agreement)

Assessment of sensory features involves a clinical interview with the patient and/or caregiver regarding sensory sensitivities and preferences (e.g., to sounds, smells, textures, lights, and movement), clinical observation, and the use of well-validated, standardized sensory processing questionnaires (e.g., Sensory Processing Measure). A neurologist, developmental pediatrician, neuropsychologist, or primary care provider may identify potential concerns and refer as needed to occupational therapy.

Behavioral Difficulties and Mood Disorders

Psychiatric diagnoses, including anxiety, depression, bipolar disorder, ADHD, obsessive-compulsive disorder, and psychosis, have been reported in PHTS at frequencies ranging from 11% to 44%.^22,28,43 It remains unclear whether these are linked to PTEN variants, but the increased frequency may suggest a possible association with PHTS.

Recommendations

ND10

We recommend that all individuals with PHTS are offered assessment of psychological and behavioral functioning. This should be completed regardless of age at diagnosis, as clinically indicated, and at least by school age for those diagnosed early. (83% Agreement)

This assessment should focus on internalizing and externalizing problems, including mood/anxiety disorders, ADHD, and challenging behavior. For children, symptoms should be corroborated with parent/teacher and/or interventionist reports, if available. For adults, self-report and corroboration by family members or friends are adjuncts to the evaluation.

ND11

We recommend that all individuals with PHTS undergo routine inquiry/screening for symptoms of depression and anxiety (as early as 6 years, if clinically indicated, and at least by 12 years) to proactively identify any issues and guide appropriate treatment. Inquiry/screening should be completed at least annually, or more frequently, as clinically indicated. (80% Agreement)

Inquiry/screening should be completed at least annually, or more frequently, as clinically indicated.

ND12

We recommend that all individuals with PHTS who have psychological and/or behavioral difficulties be referred to a licensed mental health professional for appropriate treatment (e.g., behavioral intervention/support, psychotherapy, and pharmacotherapy) and/or to a psychiatric evaluation if clinically indicated. (100% Agreement)

Sleep

The prevalence of sleep problems in patients with PHTS is greater than that in the general population.⁴⁴ There is no evidence to suggest that treatment for sleep disorders should be different from established guidelines in individuals with PHTS. From clinical experience, individuals with PHTS may suffer from restless legs, obstructive sleep apnea, and poor sleep hygiene, all of which should be managed per usual clinical care.

Recommendations

ND13

We recommend optimization of sleep hygiene and behavioral sleep medicine techniques as first-line treatments to improve sleep quality in individuals with PHTS who experience insomnia. (100% Agreement)

ND14

We recommend that all individuals with PHTS who present with headache and excessive daytime sleepiness or who meet STOP-BANG criteria (at least 2 of snoring, daytime somnolence, observed apnea, hypertension, BMI >35, age >50, neck circumference >40 cm, and male sex) be evaluated for obstructive sleep apnea and, if confirmed, treated with CPAP or other appropriate interventions, titrated appropriately in consultation with a sleep specialist. (83% Agreement)

ND15

We recommend that providers follow relevant practice guidelines for treatment of sleep disorders in patients with PHTS and ASD. (100% Agreement)

Otolaryngologist evaluation may be helpful, particularly for adenoid/tonsil evaluation, given that 58% of children with PHTS have been reported to have tonsil issues, of whom 74% required tonsillectomy.⁴⁵

Expert Opinion Statements

ND16

We recommend that all individuals with PHTS undergo screening for and be counseled about the following potential sleep issues: insomnia, frequent arousals, restless leg syndrome, reduced restful sleep, anxiety-related sleep disorders, obstructive sleep apnea, and other sleep challenges. (67% Agreement)

Patients with sleep disturbance should be screened for concomitant mood/psychiatric disorders.

ND17

Considering the lack of scientific evidence supporting their use, we recommend minimizing the use of sedative/hypnotic medications (e.g., zolpidem) in individuals with PHTS who experience sleep disturbances. (100% Agreement, expert opinion because of weak evidence)

ND18

We recommend checking serum ferritin levels in individuals with PHTS with established restless leg syndrome and using oral iron supplementation for a trial period of 2–3 months if ferritin is <50–75ug/L before initiating drug therapy. (83% Agreement, expert opinion because of weak evidence)

Restless leg syndrome diagnosis should be confirmed by a sleep specialist.

Neurologic Features: Epilepsy and EEG Abnormalities

Individuals with PHTS have a predisposition to epilepsy. Epilepsy may be secondary to focal cortical dysplasia,^46-48 polymicrogyria,⁴⁹ or other intracranial lesions (e.g., cavernoma).⁵⁰ A recent series of patients with PHTS estimated epilepsy prevalence between 9% and 17%, compared with a prevalence of roughly 1% in the general population.^{19,29,30,e1,e2}

Recommendations

N2

We recommend that all individuals with PHTS be screened by history for possible seizures at the time of diagnosis and whenever clinically indicated based on symptom presentation. (83% Agreement)

Seizures in PHTS are often associated with focal cortical dysplasia or polymicrogyria and may present with various seizure types. Clinicians should enquire about transient focal motor/sensory symptoms, convulsions, dyscognitive symptoms, and developmental (particularly language) regression.

N3

We recommend referral to neurology and workup for epilepsy when there is clinical concern for seizures or developmental regression in an individual with PHTS. (83% Agreement)

Workup should include detailed history, examination, and EEG. Depending on results, additional EEG (long-term video-EEG monitoring) or imaging (MRI/MRA) may be indicated. No data support the routine use of EEGs in the evaluation of PHTS. Special attention should be given to imaging to rule out epilepsy-associated pathologies (e.g., focal cortical dysplasia, cortical/vascular malformations, and tumors).

N4

We recommend that medications for treatment of epilepsy in individuals with PHTS be selected based on the predominant seizure type. There is no evidence supporting the first-line use of mTOR inhibitors for epilepsy in individuals with PHTS. As part of the evaluation for epilepsy, an MRI of the brain should be obtained to examine for any potential structural etiologies of epilepsy (e.g., cortical malformation). (100% Agreement)

Management of seizures in PHTS is similar to standard practice. Antiseizure medications in PHTS should be chosen accounting for neuropsychiatric comorbidities and potential side effects (e.g., cognition with topiramate and behavior with levetiracetam).

Neuroimaging Abnormalities

Most individuals with PHTS have macrocephaly secondary to megalencephaly, which may be associated with a low-lying cerebellar tonsil (i.e., Chiari 1 malformation or cerebellar tonsillar ectopia).^{23,29,30,35,e2-e5} Chiari 1 malformations in PHTS are reported with a spectrum of presentations, ranging from asymptomatic to symptomatic requiring surgery^49,e6.

Dilated perivascular spaces are the most frequently reported imaging abnormality in PHTS.^{25,27-29,e7,e8} Other abnormalities observed include periventricular white matter abnormalities, arachnoid cysts, and pseudotumor cerebri.²⁸ Of note, based on clinical experience, there is concern that there may be overdiagnosis of incidental MRI findings in PHTS, necessitating clinical judgment before neuroimaging is ordered. In our clinical experience, most patients with PHTS and actionable neuroimaging findings exhibit early neurologic signs or symptoms. This recommendation, however, is based on expert opinion only (N7).

Recommendations

N5

When MRI is clinically indicated in patients with PHTS for focal neurologic findings, magnetic resonance angiography or MR venogram (MRA/MRV) should also be considered, with attention to the region of suspected pathology (i.e., brain vs spinal segment). (100% Agreement)

MRI scans should include hemosiderin-specific sequences (e.g., gradient echo and susceptibility-weighted imaging) to assess for cavernous malformations.

N6

We do not recommend routine neuroimaging for typical headaches in patients with PHTS, unless there are worrisome focal features (e.g., positional headaches, association with projectile emesis, and focal neurologic findings), abnormal physical examination, a change in headache pattern from baseline, or features concerning for increased intracranial pressure. (100% Agreement)

New onset headaches in a young child (age younger than 5 years) with PHTS should warrant an MRI.

Expert Opinion Statements

N7

We do not recommend screening neuroimaging of the brain or neuroaxis in patients with PHTS in the absence of neurologic symptoms and/or signs on clinical examination. (83% Agreement, expert opinion because of weak evidence)

N8

When brain MRI or MRA is clinically indicated in patients with PHTS, IV contrast (e.g., gadolinium) may be given depending on diagnostic considerations and institutional policies and may be helpful for delineating certain pathologies, such as brain tumor. (100% Agreement, expert opinion because of weak evidence)

Lhermitte-Duclos Disease (LDD)

LDD (dysplastic gangliocytoma of the cerebellum) is a rare, slow-growing hamartoma that is pathognomonic of CS, particularly in adults.^e9-e14 It is diagnosed in the second-third decade of life and is typically unilateral.^e12,e15-e17 The prevalence in PHTS is reportedly 5%–10%, higher in women (11%) than in men (4%).^24,31,e18

Recommendations

N9

We recommend evaluation by neuro-oncology/neurology and neurosurgery for patients with PHTS and LDD with atypical features (e.g., location outside the cerebellum, contrast enhancement, diffusion restriction, and rapid growth on serial imaging) for consideration of biopsy or resection. (100% Delphi Agreement)

LDD is characteristically seen on MRI as a cerebellar T1-hypointense, T2-hyperintense mass. The cerebellar cortex may appear striated, resulting in a “tigroid” appearance. Contrast enhancement is minimal, and diffusivity is not restricted. Hydrocephalus or syrinx may arise from LDD due to compression of the fourth ventricle.^e17,e19,e20 Patients with atypical neuroimaging features of LDD should be considered for biopsy or resection to investigate the possibility of disease mimics. Asymptomatic patients without impending obstruction of CSF flow and typical neuroimaging findings of LDD may be monitored by serial neuroimaging. In patients who are not immediate surgical candidates, serial imaging with contrast-enhanced MRI of the brain is indicated, and a 3–12-month interval between images may be reasonable. Patients with impending CSF flow obstruction should undergo surgical evaluation for intracranial pressure management and tissue diagnosis of LDD.

N10

We recommend serial neuroimaging and clinical examinations in patients with PHTS who have undergone surgical resection for treatment of LDD to ensure no clinical or radiographic recurrence. A 6–12-month interval between images and clinical re-examination may be reasonable. (100% Agreement)

Follow-up evaluations should be targeted to the expected deficits based on the lesion site (e.g., if cerebellar, a focused cerebellar examination should be conducted). Imaging with attention to the lesion site should be conducted, with specialized MRI protocols (e.g., thin cuts through the posterior fossa), if necessary. This should be discussed with neuroradiology to ensure that imaging is high quality.

The management of recurrent LDD should be individualized and treatment decisions made with a multidisciplinary team. Treatment options at recurrence include focal radiation or surgical debulking. Optimal radiation dosing has not yet been determined. Surgical management should be considered regarding the likelihood of improving symptoms vs operative risk.

Meningioma

Early evidence suggests an association between meningiomas and PHTS. The reported frequency of meningiomas in PHTS ranges from 3% to 20%.^{35,e5,e13,e21}

Recommendations

N11

We recommend serial neuroimaging and clinical examinations in patients with PHTS who have identified meningiomas to monitor the lesion and any associated symptoms. The NCCN guidelines should be followed (i.e., with increasing intervals between images if there is lesion stability). NCCN guidelines (January 2023 edition) for tumors of the CNS recommend, “serial MRI at 3, 6, and 12 months, then every 6–12 months for 5 years, and then every 1–3 years as clinically indicated” for unresected meningiomas. (100% Agreement)

Multiple meningiomas can be seen in PHTS. If there are symptoms from the meningioma or surrounding edema, or if the meningioma is near critical structures (e.g., brainstem), treatment should be considered and individualized. We recommend a multidisciplinary team involving neurosurgery, neuro-oncology, and radiation oncology to discuss potential treatments. Treatment may involve radiation (e.g., stereotactic radiosurgery), chemotherapy (e.g., everolimus and octreotide), or resection. Of note, the radiographic differential diagnosis for dural-enhancing lesions should include both meningioma and dural metastases. Attention should be given to patients with advanced cancers with increasing dural lesion size or atypical enhancement. In these cases, biopsy or resection for tissue diagnosis should be strongly considered because these may represent dural metastases as opposed to meningioma.

Intra-Axial Arteriovenous Malformations

Patients with PHTS have a predisposition for vascular anomalies that may occur intra-axially or extra-axially with respect to the nervous system.^e14 The prevalence of intra-axial vascular malformations is unknown. Vascular anomalies have been observed in 12% of patients with PHTS, but the proportion that are intra-axial was not reported.³¹ Developmental venous anomalies, typically asymptomatic, are likely the most common intra-axial malformation.^e13 Less common malformations include cavernous malformations,^{20,50,e5,e6,e13} dural arteriovenous fistulas,^e22-e28 and spinal hemangiomas.^e29

Recommendations

N12

We recommend a careful neurologic examination with consideration toward the motor and sensory findings to assess for the possibility of an AVM in patients with PHTS. (80% Agreement)

Evaluation for intra-axial arteriovenous malformations (AVMs) should involve imaging with contrast-enhanced MRA/MRV of the brain/spine, read by an experienced neuroradiologist. Once an AVM is identified, or if suspected and symptomatic, conventional angiography should be considered. Neurosurgery, endovascular neurology, vascular surgery, and vascular medicine should be involved in these cases.

Other Central and Peripheral Nervous System Tumors

There are many reported rare tumors of the central/peripheral nervous system in PHTS. However, it remains unclear whether these are causally related to germline PTEN variants. Observed cases include malignant brain tumors, pineal tumors, and vestibular schwannomas.^e18

Recommendations

N13

We recommend following established guidelines for the treatment and care of patients with PHTS and other nervous system tumors or ocular pathologies not mentioned above. (100% Agreement)

There is currently no evidence to support any alternative to standard of care therapy in PHTS patients with other nervous system tumors or ocular pathologies not mentioned above. Further research is ongoing.

N14

In general, we recommend caution toward excess diagnostic and therapeutic radiation exposure in patients with PHTS because of the potential secondary malignancy risk of meningioma or other radiation-related tumors. However, this must be balanced by the potential for benefit from radiation and the timescale by which these malignancies may occur (typically 10–20 years). (100% Agreement)

The potential for increased incidence of these malignancies in PHTS is theoretical, and further study is needed. There is currently no evidence to suggest that patients with PHTS should receive anything less than standard of care. MRI is not a risk factor.

N15

We recommend following established guidelines for treatment and care of patients with ocular pathologies (e.g., corneal nerve hypertrophy and retinopathy). Evaluation by an experienced ophthalmology team at an academic center is recommended. (100% Agreement)

Owing to the rarity of ocular pathologies, it is not known whether these are related to PHTS or coincidental. Further research is ongoing.

Headache

Migraines are common among adults and older adolescents with PHTS and a major source of disability. However, the overall prevalence of headaches in PHTS remains unknown and potentially confounded by reduced reporting in patients with intellectual disability. Both primary and secondary headache disorders have been reported in PHTS.^46,e30,e31 Obstructive hydrocephalus from fourth ventricular effacement in LDD, syringomyelia^e20, dural arteriovenous fistulas,^{e22,e24,e25,e28} and idiopathic intracranial hypertension^e31 have been reported as causes of secondary headaches in PHTS.

Recommendations

N16

We recommend that providers use International Classification of Headache Disorders Version 3 criteria for the diagnosis of headaches in patients with PHTS and follow evidence-based practices for acute and preventive management. (83% Agreement)

There is currently no evidence to suggest that medical management of primary or secondary headache disorders in individuals with PHTS should differ from standard of care, in the absence of contraindications. Patients with PHTS and headaches may benefit from referral to headache neurology if they are refractory to usual medical management.

Discussion

The management of individuals with PHTS is complex and challenging because of variable expressivity, a dearth of clinical evidence, and age-related specificities. In this review, we generated the first iteration of management guidelines for the ND and neurologic challenges in PHTS aimed at standardizing and improving care for affected individuals. This initial set of consensus guidelines have been developed by a core expert panel and affirmed through a two-stage modified Delphi process (agreement percentages in Table 3). These guidelines build on existing guidelines largely focusing on oncologic surveillance, published by the NCCN and ERN, and thereby expand the opportunity to improve care for patients with PHTS. As with all medical evidence, this is an evolving document and will be periodically reviewed and updated as data emerge.

Table 3.

Results of the Second Stage of Modified Delphi Consensus Survey of the Extended Panel of Experts (n = 6)

Statement number	Percent agreement (%)
ND/N1	100
ND2	100
ND3	83
ND4	83
ND5	83
ND6	100
ND7	100
ND8	83
ND9	83
ND10	83
ND11a	80
ND12	100
ND13	100
ND14	83
ND15	100
ND16b	67
ND17	100
ND18	83
N2	83
N3	83
N4	100
N5	100
N6	100
N7	83
N8	100
N9	100
N10	100
N11	100
N12a	80
N13	100
N14	100
N15	100
N16	83

Note that ≥80% extended panel agreement means passed Delphi review. > 20% extended panel disagreement means failed Delphi review.

^aN11 and N12 had 1 participant “unable to comment.”

^bND16 failed extended panel Delphi review and was approved by the core group as an expert opinion statement.

While multiple efforts are ongoing to better characterize the natural history of PHTS, owing to its rarity, the evidence in these guidelines largely comes from nonrandomized, observational studies with small sample size. Ascertainment bias is likely present in many of these studies. Moreover, a lack of published studies constrained our ability to make recommendations on potentially PHTS-associated conditions based on clinical observations, such as dysautonomia. Finally, the lack of prospective natural history studies constrains our understanding of the trajectory of the ND aspects of PHTS. Natural history and deep neuropsychiatric phenotyping studies in PHTS are under way with the hopes of improving future anticipatory guidance.

These guidelines are also limited by their generalizability. Individuals participating in PHTS natural history studies and early randomized trials^e32,e33 are predominantly of European ancestry with access to academic medical centers, which is not representative of the global PHTS population. In the future, it will be important to study diverse patient cohorts that include those from underserved populations. We further acknowledge that all but 1 of the members of the Working Group are United States–based clinicians and are from a relatively small number of academic centers, also necessitating a diversity of clinical expertise in future guideline iterations.

Of note, only 25% of individuals with PHTS-like phenotypes have pathogenic/likely pathogenic germline PTEN variants.^e34 A subset of individuals with wild-type PTEN and PHTS-like phenotypes carry germline variants in genes that are effectors of the PTEN signaling cascade (e.g., AKT1, PIK3CA, and WWP1).^e35-e37 Further research is needed to determine the relevance of these guidelines to these patients.

These consensus guidelines represent the most up-to-date standard of care for the ND/neurologic features of PHTS. Moving forward, it is essential to engage with the wider PHTS community to ensure guideline dissemination and implementation. Obstacles may limit patient access to the recommended care, and in such circumstances, providers may need to adapt recommendations to ensure the provision of care. Concurrently, it is imperative that providers, patients/advocates, and policymakers collaborate in minimizing barriers to care. These efforts are essential in ensuring that these guidelines are put into practice and all patients with PHTS receive the highest quality care.

Glossary

ADHD

attention deficit hyperactivity disorder

ASD

autism spectrum disorder

AVM

arteriovenous malformation

CS

Cowden syndrome

ERN

European Reference Network

IDD

intellectual developmental disorder

LDD

Lhermitte-Duclos disease

MRV

MR venogram

NCAT

National Center for Advancing Translational Science

NCCN

National Comprehensive Cancer Network

ND

neurodevelopmental

PHTS

PTEN hamartoma tumor syndrome

PS

Proteus syndrome

RDCRN

Rare Diseases Clinical Research Network

Author Contributions

A. Dhawan: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. D. Liu: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. S. Baitamouni: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. K. Anthony: study concept or design; analysis or interpretation of data. S. Srivastava: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. A.Y. Hardan: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. M. Uljarevic: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. K.L. Lachlan: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. T.W. Frazier: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. R.M. Busch: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. C.E. Eng: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data.

Study Funding

This work has been funded, in part, by the PTEN Research Foundation, a charity governed by English law (charity number 117358) to A.D. under grant number CCF-18-001 and CCF-21-001. The funding body did not influence the content of this guideline.

Disclosure

The authors declare no competing interests. Professor Charis Eng is deceased; to the best of the authors' knowledge, there are no competing interests or relevant disclosures. Go to Neurology.org/NG for full disclosures.