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 ≤ 18 years, mean OFC was +4.89 standard deviations (SD) above the population mean with no difference between genders (P = 0.7). Among patients >18 years, average OFC was 60.0 cm in females and 62.8 cm in males (P < 0.0001). 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 (N = 15) was 1.02 g compared with 0.57 g for heterozygous mice (N = 29) and 0.49 g for wild-type littermates (N = 24) (P < 0.0001). 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.

Figure 1

Adult PHTS patients' OFCs plotted against height for (a) female and (b) male patients, with trendline demonstrating positive correlation between OFC and height. Diamonds represent individual patient measures.

Figure 2

Measured OFC in PTEN mutation-positive patients aged 18 and under plotted on the Nellhaus curves for (a) females and (b) males. Solid line=50^th centile; dashed line=+/− 2 SD; dotted line=+5 SD; x=individual patient measures.

Figure 3

Brain weight from mice with wild-type Pten, or homozygous and heterozygous missense mutations in Pten. (a) Wild-type (left), heterozygote (center), and homozygous mutant (right) littermate female mice at 5 weeks of age, demonstrating obvious macrocephaly in the homozygote. (b) A representative image of wild-type (left), heterozygous (center), and homozygous mutant (right) brains from littermate mice at 2 months of age. (c) Brain weight increases with dose of mutant Pten, potentially interacting with sex (males – grey, females – white). (d) Brain weight with age in Pten^M3M4/M3M4 (circles), Pten^WT/M3M4 (diamonds), and Pten^WT/WT mice (stars). Note that brain weights of heterozygotes begin to differ from wild-type mice only by 3 months of age.