Screening of the NSD1 gene in a cohort of 88 familial and sporadic cases of autism and macrocephaly did not reveal any intragenic mutations or deletions, indicating that Sotos syndrome is a rare cause of autism spectrum disorders. The three missense variants identified in one individual each (R604L, S822C and E1499G), were inherited from unaffected parents, suggesting that they are likely to be polymorphisms. In addition, none of these variants is located in a known functional domain , further suggesting that they are nonpathogenic. Previous studies have shown that missense mutations are pathogenic only if they occur within functional domains of the protein involved in chromatin regulation .
Our negative findings are in agreement with recent studies showing that virtually all patients with a NSD1 mutation or deletion have the characteristic facial features of Sotos syndrome (broad forehead, sparse frontotemporal hair, long narrow face, malar flushing, down-slanted palpebral fissures, prominent jaw, pointed chin) [4, 29, 30]. However, the facial features are subtle and are difficult to recognize by clinicians with limited experience with this condition. The patients in our study presumably did not have the facial gestalt of Sotos syndrome, although most had not been evaluated by a clinical geneticist and it is likely that the psychiatrists that evaluated the patients were not all familiar with Sotos syndrome because of the relative rarity of this condition.
The other key clinical features of Sotos syndrome are the macrocephaly and the developmental delay. HC and height are increased in the majority of children with Sotos syndrome. By adulthood, height may fall within normal limits, but macrocephaly usually persists. However, recent studies have shown that HC and height are normal in 10% of NSD1 mutation-positive patients, indicating that overgrowth, previously considered as a major criterion of the disorder, is not necessary for the diagnosis of Sotos syndrome .
Our series included a high proportion of familial cases of autism spectrum disorders, as compared to singletons (51 vs. 37). Because Sotos syndrome is mostly a sporadic disorder, this could have contributed to the negative results of this study. However, several familial cases of Sotos syndrome with NSD1 mutations have been described in the past years [4, 27, 30–35], suggesting that familial, usually milder, forms of the disorder might be underdiagnosed.
Besides Sotos syndrome, there are several other syndromes presenting with macrocephaly and developmental delay, which are sometimes associated with autism. Among the better known is the fragile X syndrome, which is the most frequent genetic disorder identified in patients with autism spectrum disorders, accounting for about 2% of cases . Molecular analysis for fragile X is routinely performed in patients with autism and mental retardation, and was ruled out in the patients participating in our study. Another disorder associated with autism and macrocephaly is the PTEN hamartoma tumor syndrome, which includes Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. The PTEN gene has recently been found to be mutated in several children with autism spectrum disorders and macrocephaly [37–40]. We screened PTEN for mutations and deletions in the 88 individuals with autism spectrum disorders and macrocephaly reported in this study and identified one patient with extreme macrocephaly carrying a de novo missense mutation .
Other examples of disorders associated with macrocephaly which carry an increased risk for the development of autism include neurofibromatosis type I [41, 42] and 22q13 deletions . In addition, there are several reports in the literature of cases with progressive postnatal macrocephaly with autism, marked speech delay and mental retardation, referred to as the Cole-Hughes macrocephaly syndrome [44, 45]. The Orstavik syndrome, described by Orstavik et al. , is characterized by macrocephaly, epilepsy, autism, mental retardation and dysmorphic features. Several other cases of the same syndrome were reported later by another group . As Sotos syndrome, these disorders account for only a small number of patients with autism and macrocephaly.
The macrocephaly observed in about 20% of patients with autism appears to be an independent clinical trait, not related to sex, presence of morphological abnormalities, IQ, occurrence of seizures, or severity of autistic symptoms [20, 21]. Converging evidence from HC measurements, MRI studies and postmortem brain weight indicates that an even greater proportion of children with autism have an abnormal regulation of brain growth, resulting in enlarged brains during early childhood . At birth, HC is typically normal or slightly reduced, followed by accelerated growth during the first years of life. This early phase of excessive growth is followed by slowed growth after 2–4 years of age, so that in adolescents and adults HC measures are usually within normal range . Other studies, however, have found increased brain volume in older populations of individuals with autism [49, 50], so the timing of brain enlargement is not settled yet. Similarly, the pattern of enlargement across the brain lobes and cerebellum and the involvement of gray versus white matter remain unclear at present. Elucidation of the mechanisms involved in the pathological postnatal brain overgrowth may prove critical for understanding the emergence of autistic symptoms during the same time frame.