By clinical anecdote, macrocephaly is an accepted component of CS and BRRS. In the only population-based clinical epidemiologic study of CS in the Amsterdam area in the 1980's, the prevalence of macrocephaly was estimated at 25%.2
This epidemiologic study was undertaken before PTEN
was identified as the CS predisposition gene. Taken together with review studies, prevalence estimates for macrocephaly in CS range from 25 to 38%.1, 13, 14
However, a systematic prospective study of OFC in a series of individuals carrying germline PTEN
mutations has never been undertaken. We found that 94% of our prospective series of individuals with PHTS have OFC +2.0 to +6.9 SD (mean +3.5 SD) over population norms. In the paediatric PHTS patients, average OFC was almost +5 SD over population norms. In our prospective series of 3042 probands accrued with classic CS or Cowden-like features, macrocephaly was identified in only 33% of PTEN
mutation-negative research participants (compared with 83% in mutation-positive individuals; P
<0.0001). We concluded that macrocephaly was a necessary, but not sufficient, criterion for PTEN
mutation testing in the paediatric population and carried significant weight towards recommending testing in the adult population.15
OFC is a straightforward measurement that can be easily performed by any health caregiver. However, our understanding of its relationship to height in the adult population and ethnic background remains rudimentary. Studies of paediatric populations in different countries find differences in OFC norms that one would think would continue into adulthood. Interestingly, the data from our murine model show little variation in brain weight despite different genetic backgrounds for each Pten genotype. Therefore, data from a large study of adult human head circumference and correlation with height and ethnicity would be helpful to have for more accurate comparative purposes and to better understand whether differences in ethnic background contributes to significant differences in OFC measurement in an adult population.
In the patient presenting to genetics clinic with macrocephaly as a chief complaint, the clinician's syndromic differential diagnosis is extensive. An OMIM search for syndromes with ‘macrocephaly' within the clinical synopsis reveals 103 syndromes for which clinical testing is available or a diagnosis could be made based on clinical and laboratory assessment. Head circumference has been systematically assessed in patients with Fragile X,16
Nevoid Basal Cell Carcinoma (NBCCS),17
and Sotos19, 20
syndromes. In Fragile X syndrome, OFC for most patients falls into the normal range, with the 5th, 50th, and 95th centiles for the patient population being consistently just slightly above the respective normal centiles. A small series of patients with NBCCS found only probands to be macrocephalic, with many family members having an OFC that fell within the normal range, leading the authors to conclude that NBCCS is more consistent with a generalised overgrowth disorder than a true macrocephaly syndrome. A study of 436 patients from the National NF Foundation Database found macrocephaly in 24%, with the remainder falling into the normal range.
OFC parameters in patients with Sotos syndrome revealed the greatest similarity to our patients with PHTS. An early paper found macrocephaly in all 33 patients with a clinical diagnosis studied, with OFC ranging from +2.0 to +6.9 SD with a mean of +3.5 SD.19
A larger analysis of patients with NSD1
mutations found macrocephaly in 146/192 (76%) of patients.20
The characteristic facial appearance of patients with Sotos syndrome was observed in 99% of mutation-positive patients; to date, similar studies have not been carried out to determine whether a particular facies exists in PHTS patients. Other common findings in Sotos syndrome include advanced bone age (76%), neonatal problems (70%), seizures (25%), and cardiac anomalies (21%); these are all findings not known to be associated with PHTS, but their precise frequencies have not been investigated in a large patient series.
Missense germline mutations in PTEN
have, to date, been far less prevalent than truncating mutations; thus, it is notable that there is a trend demonstrating less dramatic macrocephaly in adults with missense mutations compared with those with other mutation types. Interestingly, a subset of these missense mutations affect one of the two ATP-binding motifs of PTEN, which results in inability of PTEN to bind ATP and inability to exit the nucleus.21, 22, 23
These types of mutants result in relative instability of PTEN, increased double-strand DNA breaks and increased reactive oxygen species.23
constitutional knock-in mouse was created to model defective nuclear–cytoplasmic localisation, and one of its phenotypes is megencephaly. The life span for the homozygous mutant mice averages 8 weeks or less, with very few of these mice surviving past this point. Among the advantages of our model compared with tissue-specific or heterozygous models of Pten
is the fact that this is a germline mutation expressed under the endogenous promoter, leading to a functional disruption also observed in a subset of PHTS patients. This advantage allows exploration of the impacts of a missense mutation expressed from the earliest embryonic time points through adulthood, a situation where protein function is reduced but absolute levels are not as low as in murine models of heterozygous or tissue-specific deletion.
We also found it notable that 5 of our 181 mutation-positive patients have missense mutations in exon 9, an exon that is rarely affected by mutations.5, 26, 27
As the final exon in PTEN
, missense mutations in this region would be predicted to only cause a slight alteration in protein structure and function. All three patients with exon 9 missense mutations and normal OFC had an invasive cancer that led their clinicians to consider a diagnosis of PHTS, but none had a family history that would have caused increased suspicion for PHTS before their cancers were diagnosed. It is plausible that exon 9 missense mutations may result in an attenuated PHTS phenotype.
Finding macrocephaly in 94% of our PHTS series confirms that this feature should be considered a major component phenotype in this population. It is possible that selection bias could lead to the identification of an abundance of PHTS patients with extreme macrocephaly, particularly as a presenting feature within the paediatric or young adult population who have not yet developed the full phenotypic features of PHTS. This was supported among the females in this study, where OFC SD values were significantly greater for patients ≤18 years (P=0.0047). However, a similar pattern was not identified in males (P=0.36).
Identifying nine patients with PHTS and normal head circumference should remind clinicians not to exclude this diagnosis in a patient with normal OFC. Among our seven normocephalic adult patients, all but two adult females would meet clinical diagnostic criteria for Cowden syndrome based on their other features. One of the two male children would be diagnosed with BRRS based on the finding of tan macules on the glans penis; the other would likely be considered Proteus-like because of the findings of hemihyperplasia and lipomas, leading their clinicians to consider PTEN molecular analysis despite the absence of macrocephaly. Notably all nine normocephalic patients were probands, implying that selecting patients for analysis based on macrocephaly did not confound these findings.
In any hereditary syndrome, early diagnosis is critical to provide optimal screening and medical recommendations. In particular, recognising extreme macrocephaly as a hallmark feature of PHTS should encourage clinicians to consider germline PTEN
testing at an early point in the diagnostic work-up for patients with this characteristic, and should prompt them to investigate for other features of PHTS within the personal and family histories. Evaluation by both a geneticist and dermatologist is ideal to fully investigate patients for subtle syndromic manifestations and to rule out other syndromes associated with macrocephaly. Current recommendations by the National Comprehensive Cancer Network (http://www.nccn.org
) advocate for increased surveillance for breast and thyroid cancers in patients with CS. Appropriately, these same recommendations are made for any patient with a known PTEN
mutation regardless of whether they meet CS diagnostic criteria. Early diagnosis of PHTS can lead to the patient and their family members gaining the ability to take advantage of this high-risk screening, thereby reducing potential morbidity and mortality of this difficult-to-recognise syndrome. Because the clinical manifestation of PHTS is protean and broad, finding straightforward ‘most frequent' phenotypes associated with PTEN
germline mutations is helpful. In this study, we provide evidence that macrocephaly, likely secondary to megencephaly, is an important component of PHTS and is more prevalent than previously appreciated, with extreme macrocephaly being a defining phenotype caused by germline PTEN