Macrocephaly/autism Syndrome

A number sign (#) is used with this entry because of evidence that macrocephaly/autism syndrome is caused by heterozygous mutation in the PTEN gene (601728) on chromosome 10q23.

Heterozygous mutation in the PTEN gene can also cause Cowden syndrome (CWS1; 158350), which shows some overlapping features.

Description

Macrocephaly/autism syndrome is an autosomal dominant disorder characterized by increased head circumference, abnormal facial features, and delayed psychomotor development resulting in autistic behavior or mental retardation (Herman et al., 2007). Some patients may have a primary immunodeficiency disorder with recurrent infections associated with variably abnormal T- and B-cell function (Tsujita et al., 2016).

Clinical Features

In the course of a clinical study of Sotos syndrome (117550), Cole and Hughes (1991) found that 6 of 79 probands who failed to fit that phenotype showed remarkable similarities to each other and to some of their first- and second-degree relatives. In addition to macrocephaly, affected individuals had typical facies characterized by square outline with frontal bossing, 'dished-out' midface, biparietal narrowing, and long philtrum. Birth weight and length were normal or near normal with subsequent obesity. Cole and Hughes (1991) were uncertain whether this represented a new entity or benign familial macrocephaly (153470).

Naqvi et al. (2000) reported 2 patients who had the same clinical features as the patients described by Cole and Hughes (1991) in addition to autistic characteristics with attention deficit disorder. The authors noted that the patients described by Cole and Hughes (1991) with adequate psychometric data had delays in language and social development much more prominent than delays in motor function, suggesting that some of these patients may have had autistic features. They also noted that Stevenson et al. (1997) had found progressive postnatal macrocephaly in 24% of 100 patients with autism and that 62% of such cases had a family history of macrocephaly. Naqvi et al. (2000) suggested that this may represent a recognizable syndrome within the autism behavioral phenotype.

Butler et al. (2005) studied 18 subjects from 3 to 18 years of age who had autism spectrum disorders and macrocephaly, with head circumferences ranging from +2.5 to +8 SD for age and sex (average head circumference, +4.0 SD). There were no features suggestive of Cowden syndrome (158350) except for pigmented macules on the glans penis of 1 boy.

Herman et al. (2007) reported 2 unrelated patients with macrocephaly and autism due to PTEN mutation. A 27-month-old affected girl had developmental delay, autistic features, and mild dysmorphism with broad forehead, mild hypertelorism, midface hypoplasia, depressed nasal bridge, and short nose. She did not resemble either of her parents. An unrelated 4-year-old boy with macrocephaly/autism syndrome was found to have an R130X mutation (601728.0007), which had also been found in patients with Cowden syndrome and BRRS. This child inherited the mutation from his unaffected father. Herman et al. (2007) noted that both children may develop further clinical manifestations of other PTEN-associated syndromes and emphasized that the second family was counseled on the possibility of increased tumor risk in the boy and the mutation-carrying father.

Macrocephaly and Mental Retardation With Immunodeficiency

Tsujita et al. (2016) reported 2 unrelated Japanese children with macrocephaly and mental retardation associated with primary immunodeficiency. Common features included recurrent infections, fever, and lymphadenopathy; 1 patient had hepatosplenomegaly and transient pancytopenia. Both patients had opportunistic infections, i.e., pneumocystic pneumonia (PCP) and pulmonary aspergillosis, respectively. The immunologic defects varied. The first patient (P1) patient was suspected to have severe combined immunodeficiency, and laboratory studies showed lymphopenia, an inverted CD4/CD8 ratio, and low NK cells with normal or increased Ig levels. The other patient (P2) was given a diagnosis of common variable immunodeficiency, and laboratory studies showed hypogammaglobulinemia with normal B- and T-cell counts, but decreased numbers of memory B cells and class-switched B cells. Whole-exome sequencing of the patients identified a de novo heterozygous loss-of-function mutation in each patient (R233X, 601728.0002 and c.41insGA, 601728.0045, respectively). Activated patient T cells showed decreased levels of PTEN protein, and T and B cells showed aberrant activation of the AKT (164730)/mTOR (601231) pathway compared to controls, suggesting that PTEN mutations cause increased PI3K signaling in lymphocytes. The findings were similar to that observed in patients with IMD14 (615513), who have activating mutations in the PIK3CD gene (602839).

Molecular Genetics

Butler et al. (2005) analyzed the PTEN gene in 18 subjects with autism spectrum disorders and macrocephaly. They identified heterozygosity for germline PTEN mutations in 3 boys: H93R (601728.0037), D252G (601728.0038), and F241S (601728.0039), respectively. One mutation-positive boy had pigmented macules on his glans penis, but there were no other features or family history suggestive of CS or BRRS in these patients. No PTEN mutations were found in the 3 parents who were available for testing.

Herman et al. (2007) reported 2 unrelated patients with macrocephaly and autism associated with heterozygous mutations in the PTEN gene (601728.0007 and 610728.0040).

O'Roak et al. (2012) identified 3 de novo mutations in the PTEN gene while sequencing 44 candidate genes among 2,446 autism spectrum disorder probands. There were 2 missense and 1 frameshift mutation identified. All 3 patients were macrocephalic.

Animal Model

Kwon et al. (2006) found that mice with targeted inactivation of the Pten gene in differentiated neurons of the cerebral cortex and hippocampus demonstrated abnormal social interaction and exaggerated responses to sensory stimuli. The mice also showed macrocephaly and neuronal hypertrophy, including hypertrophic and ectopic dendrites and axon tracts with increased synapses. The findings suggested that Pten defects in mice can result in macrocephaly and autistic-like behavior.

Page et al. (2009) showed that haploinsufficient Pten +/- mice were macrocephalic and that female, but not male, Pten +/- mice were impaired in social approach behavior. This phenotype was exacerbated in Pten +/- Slc6a4 (182138) +/- double-haploinsufficient mice. While increased brain size correlated with decreased sociability across these genotypes in females, within each genotype, increased brain size correlated with increased sociability, suggesting that epigenetic influences interact with genetic factors in influencing the phenotype. The findings suggested an interaction between 2 autism spectrum disorder candidate genes during brain development.

Clipperton-Allen and Page (2014) found that Pten +/- mice showed widespread brain overgrowth and deficits in social behavior. In addition, Pten +/- males showed repetitive behavior and abnormalities related to mood or anxiety, whereas Pten +/- females showed abnormal circadian activity and emotional learning. Conditional deletion of Pten in dopaminergic neurons resulted in abnormal social interactions similar to those found in Pten +/- mice. Clipperton-Allen and Page (2015) found that Pten +/- males showed reduced aggression, in addition to elevated repetitive behavior. Chen et al. (2015) found that haploinsufficiency in beta-catenin (CTNNB1; 116806), but not Mtor (601231), reduced cortical overgrowth in Pten +/- mice.