Analysis of prevalence and degree of macrocephaly in patients with germline PTEN mutations and of brain weight in Pten knock-in murine model

Abstract

PTEN Hamartoma Tumour Syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and other conditions resulting from germline mutation of the PTEN tumour suppressor gene. Although macrocephaly, presumably due to megencephaly, is found in both CS and BRRS, the prevalence and degree have not been formally assessed in PHTS. We evaluated head size in a prospective nested series of 181 patients found to have pathogenic germline PTEN mutations. Clinical data including occipital-frontal circumference (OFC) measurement were requested for all participants. Macrocephaly was present in 94% of 161 evaluable PHTS individuals. In patients r18 years, mean OFC was +4.89 standard deviations (SD) above the population mean with no difference between genders (P¼0.7). Among patients 418 years, average OFC was 60.0 cm in females and 62.8 cm in males (Po0.0001). To systematically determine whether macrocephaly was due to megencephaly, we examined Pten M3M4 missense mutant mice generated and maintained on mixed backgrounds. Mice were killed at various ages, brains were dissected out and weighed. Average brain weight for Pten M3M4 homozygous mice (N¼15) was 1.02 g compared with 0.57 g for heterozygous mice (N¼29) and 0.49 g for wild-type littermates (N¼24) (Po0.0001). Macrocephaly, secondary to megencephaly, is an important component of PHTS and more prevalent than previously appreciated. Patients with PHTS have increased risks for breast and thyroid cancers, and early diagnosis is key to initiating timely screening to reduce patient morbidity and mortality. Clinicians should consider germline PTEN testing at an early point in the diagnostic work-up for patients with extreme macrocephaly.

Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly

“…This finding corroborates a recent study that examined the prevalence and degree of macrocephaly in PTEN mutation-positive individuals and reported the prevalence and mean OFC (Z18 years) to be 94% and þ 4.89 SDs above the mean, respectively. 19 Biochemical analyses of urine and blood from individuals in our study did not reveal amino acid or organic acid alterations that could be associated with a specific subgroup, such as ASD and macrocephaly or an ASD and germline PTEN mutations. The elevations in plasma succinate that we had previously observed among PTEN and SDH mutation-positive individuals meeting criteria for Cowden Syndrome were not observed among our cohort of PTEN mutation-positive individuals with ASD and macrocephaly.…”

“…11 Germline PTEN mutations are positively associated with the occurrence and degree of macrocephaly both in humans and in Pten knock-in mice. 19 Germline PTEN mutations molecularly define PTEN hamartoma tumor syndrome (PHTS), a cancer predisposition syndrome, and are associated with an elevated risk of female breast, epithelial thyroid, renal, and endometrial cancers. 20 PHTS is a molecular-based umbrella term that encompasses PTEN mutation-positive individuals that may be affected with clinically distinct syndromes, chief of which are CS and BRRS.…”

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

“…For example, of the 6 PTEN mutationpositive patients reported in the study by Varga et al [18] their OFCs ranged from 2.9 to 5.8 SDs above the mean. A 2011 study by our group at the Cleveland Clinic [25] examined OFCs in a cohort of 181 PTEN mutation-positive individuals, finding their average head size to be +3.5 SDs from average in adults and +5 SDs in the pediatric subset. While subgroup analyses were only performed for age, sex, and mutation type (missense, truncating, or whole-gene deletions), individuals could be enrolled in the study for PTEN mutation testing if they met 1 of several criteria, including the relaxed definition of Cowden syndrome or the presence of autism plus macrocephaly [25].…”

“…A 2011 study by our group at the Cleveland Clinic [25] examined OFCs in a cohort of 181 PTEN mutation-positive individuals, finding their average head size to be +3.5 SDs from average in adults and +5 SDs in the pediatric subset. While subgroup analyses were only performed for age, sex, and mutation type (missense, truncating, or whole-gene deletions), individuals could be enrolled in the study for PTEN mutation testing if they met 1 of several criteria, including the relaxed definition of Cowden syndrome or the presence of autism plus macrocephaly [25]. The degree of macrocephaly was above that reported in many other genetic syndromes, which may allow for a shorter differential diagnosis and more costefficient efforts to identify a causative mutation in children with extreme macrocephaly and ASD.…”

PTEN hamartoma tumor syndromes in childhood: Description of two cases and a proposal for follow‐up protocol

“…In contrast with CS, there are no agreed international criteria for the diagnosis of BRRS. However, after the discovery of the PTEN gene, it became apparent that PTEN mutation testing might facilitate early diagnosis in childhood Mester et al, 2011]. Recently a prospective multicenter study defined clinical criteria useful to decide which pediatric (<18 years) patients to test for PTEN (Table III) [Tan et al, 2011].…”