Author, year of publication, country of study | Reference Number | Recruitment procedure | Sample size (n) | Comparison Group (no PTEN mutation) | Sex | Age | Assessment tools/methods | Specific details of ASD definition/assessment (for papers used in meta-analysis) | Findings | Quality score |
---|---|---|---|---|---|---|---|---|---|---|
*Balci et al. (2018), Canada | [39] | Patients seen in the Genetics clinic at the Children’s Hospital of Eastern Ontario with PTEN mutations and white matter lesions. No information on referral | 11 | N/A | 10 (M) | 4–45 years | Search of medical records | Diagnosis of ASD stated as present or not (no further detail) | Normal development in six participants. Further characteristics: adult onset movement disorder (n = 1), bipolar disorder (n = 1), memory problems (n = 2), GAD (n = 2), OCD (n = 1), self-harm (n = 1), pica (n = 1), low processing speed (n = 1), speech or language delays (n = 3), ADHD (n = 2), motor delay (n = 3), psychotic episode (n = 1) and ASD (n = 1) | 0.5 |
*Busa et al. (2015), France | [40] | Children found to carry a PTEN germline mutation between 1 January 2009 to 1 January 2014 with no family history of CS. Identified due to a variety of problems such as lipomas, macrocephaly, facial arteriovenous malformation | 7 | N/A | 3 (M) | Search of clinical data | Diagnosis of ASD stated as present or not (no further detail) | Motor delay (n = 3), speech delay (n = 4) and ASD reported in one participant | 0.5 | |
Busch et al. (2013), USA | [41] | Recruited from an ongoing prospective observational study of PHTS in Cleveland, Ohio between July 2007 and July 2012 and complete 4 h of assessment. Invited if they had undergone mutation analysis or had phenotypic features consistent with CS or BRRS | 25 (PTEN = 23, CS = 1, BRRS = 1) | N/A (normative data used in analysis) | 7 (M) | 5–60 years | Wechsler Adult Intelligence Scale – Third Edition, Wechsler Intelligence Scale for Children – Fourth Edition, or Wechsler Preschool and Primary Scale of Intelligence, WMS-III=Wechsler Memory Scale – Third Edition, Children’s Memory Scale, Trail Making Test, Boston Naming Test, Semantic Fluency, COWA, Wisconsin Card Sorting, Ruff Figural Fluency Test Judgement of Line Orientation, AVLT, Finger Tapping Test and Grooved Pegboard | N/A | Means scores for those with PHTS were significantly lower than controls in motor (fine motor dexterity, large effect), executive functioning (verbal fluency and novel problem solving, medium effect) and memory (immediate and delayed recall, small effect) domains. Global impairments in 12% IQ Range = 80–135, Mean = 107 | 0.67 |
Busch et al. (2019), USA | [42] | Recruited from four large tertiary medical centres as part of an ongoing, multicentre prospective study designed to examine the natural history of ASD and germline heterozygous PTEN mutations. All screened by a clinical psychologist to determine if DSM-5 criteria for ASD. No information on referral | PTEN-ASD n = 36 and PTEN-no ASD n = 23 | Macrocephaly-autism n = 25 | 64 (M) | 3–21 years | Age appropriate measures of: Global cognitive ability, attention/impulsivity, working memory, processing speed, language, visuo-spatial skills (if severely impaired, inferred from guardians). Guardians completed a number of standardised questionnaires | N/A | PTEN-no ASD not significantly different from control norms on global cognitive measures. Impaired motor and sensory functioning. PTEN-ASD poorer performance than no-ASD in every domain (d = 0.41–2.21). Greater behavioural and sensory dysfunction. Severely impaired in verbal and non-verbal IQ, attention, motor and sensory. Moderate impaired on working memory, processing speed, language, visual-spatial and problem behaviour PTEN-ASD and macro-ASD scored similarly in both repetitive behaviour and social responsiveness but lower severity on ADOS-2 which may reflect passivity of PTEN-ASD rather than reduced severity. | 0.83 |
*Ciaccio et al. (2019), Italy | [43] | Participants are paediatric patients seen and diagnosed with PTEN mutations in two hospitals in Milan between 2006 and 2017 | 16 | N/A | 14 (M) | 2 years 5 months–12 years 2 months | Unknown | ASD was assessed in the research centres or in territorial neuropsychiatric using standardised scales (no further detail) | Developmental delay or intellectual disability in 56% of participants. ASD in 25% and normal development in 2 participants | 0.58 |
Frazier et al. (2015), USA | [44] | Unknown | PTEN-ASD n = 17 | Macrocephaly-ASD n = 16, ASD without macrocephaly n = 38, healthy controls n = 14 | 67 (M) PTEN: 13 (M) | 11.4–14 years (means) | ADI-R, clinical observations, Autism Diagnostic Observation Schedule, Social Responsiveness Scale, Mullen Scales of Early Learning or the Wechsler Abbreviated Scale of Intelligence, Conners’ Continuous Performance Test and Wide Range Assessment of Memory and Learning | N/A | Reduced FSIQ, verbal IQ, non-verbal IQ, in PTEN-ASD group compared to other ASD groups and healthy controls (smallest Wald Χ2 (3) = 16.86, p < .001). Processing speed, working memory, auditory immediate memory and adaptive function (most notably community living) was also reduced in the PTEN-ASD group compared to the macrocephaly-ASD group (Cohen’s d = 1.15, 1.07, 0.96, 0.94) | 0.67 |
*Hansen-Kiss et al. (2017), USA | [45] | Retrospective chart review in a paediatric population.“Problem List” on electronic medical records (EPIC) searched for: PTEN mutation, PTEN hamartoma tumour syndrome, CS and/or BRRS. “Laboratory Testing” section was queried for positive/pathogenic results on PTEN gene characterisation gene sequencing | 47 | N/A | 29 (M) | 1–26 years | Search of medical records which, for some participants, reported on results from a number of measures including; Leiter-R Full Scale, Stanford Binet Full Scale, WISC-IV, WPPSI-III, Autism Spectrum Rating Scale, Autism Diagnostic Observation Schedule, Childhood Autism Rating Scale, Autism Diagnostic Interview, Mullen Early Learning Composite, Vineland-II Adaptive Behaviour Composite | ASD diagnosis in medical notes. Where known, the measure used was reported in Supplementary material | ASD: n = 25 (53%), ID: n = 15 (IQ < 80, average = 65), 18 more had diagnosis of ID or developmental delay with no scores. IQ range: 39–124, ASD and ID (n = 10), 16 participants (34%) had additional behavioural/ psychological diagnoses, including: learning disabilities, social communication disorder, disruptive behaviour disorder, ADHD, depression, bipolar disorder, OCD, ODD and/or aggression | 0.5 |
Lachlan et al. (2009), UK | [9] | Individuals with known PTEN mutations were recruited through UK clinical genetics services | 42 | N/A | 26 (M) | 4–75 years | Search of molecular and histological reports and clinical details | N/A | Motor delays and learning difficulties. 12% (2/17) of non-probands had learning difficulties | 0.58 |
*Lynch et al. (2009), Ireland | [46] | Review of genetic and neurology records between 2004 and 2007 for PTEN mutation. No referral information available | 6 | N/A | 5 (M) | 2 years 7 months–8 years at diagnosis | Unknown | ASD diagnosis in medical notes (no further detail) | Learning difficulties (n = 1), autistic features (n = 2), motor delay (n = 5), Asperger Syndrome (n = 1), language delay (n = 1) and speech delay (n = 2) | 0.5 |
*Smpokou et al. (2014), USA | [47] | Electronic records of all patients seen at Boston Children’s hospital between 1996 and 2011 were searched for “PTEN”, “Bannayan-Riley-Ruvalcaba”, and “Cowden”. No referral information available | 34 | N/A | 23 (M) | 2–26 at last clinical evaluation | Developmental evaluation by a developmental paediatrician or clinical psychologist. Documentation of attainment of developmental milestones by either a clinical geneticist or a paediatric neurologist and records review | ASD classification based on clinical/researcher developmental appraisal | Developmental or intellectual disability, language delay, motor delay and ASD. | 0.58 |
*Vanderver et al. (2014), International | [48] | Patients referred for unclassified white matter disorders who had clinical features of BRRS and abnormal PTEN sequencing or identified based on macrocephaly and/or developmental abnormalities with brain MRI and tested positive for PTEN mutation. In almost all cases, referrals were due to concerns related to macrocephaly and developmental delay | 23 | N/A | 13 (M) | Newborn–5 years | MRI and review of clinical history | ASD diagnosis noted in clinical history (no further detail) | Developmental delay (n = 23), autistic features (n = 2), ASD (n = 5), motor delay (n = 4) | 0.58 |
Yehia et al. (2019), International | [49] | Medical records of patients diagnosed with CS, CS-like and BRRS | 511 (309 with confirmed PTEN) | N/A | 161 (M) | 1–89 years (mean = 45 years) | Review of medical records | N/A | ASD (n = 45), global developmental delay (n = 64), “mental retardation” (n = 12), learning disability (n = 10). | 0.50 |
*Yehia et al. (2020), International | [50] | Participants were recruited from community and academic medical centres internationally between Sept 2005 and Jan 2018. Inclusion criteria included meeting relaxed Cowden syndrome diagnosis, macrocephaly plus a neurodevelopmental disorder and/or penile freckling or a known PTEN mutation. Checklist completed and blood specimen drawn along with medical records review | 481 | N/A | 213 (M) | Mean = 33.2 SD = 21.6 years | Review of medical records | ASD diagnosis in medical records (no further detail) | ASD or developmental delay (n = 110), no evidence of ASD or DD (n = 194) | 0.58 |