Autism spectrum disorders (ASD) represent a heterogeneous group of conditions. In addition to the classic triad of ASD (impaired language and communication and stereotyped behavior), some individuals show other phenotypes such as, accelerated head growth and macrocephaly, seizures (5-46%), developmental regression (15-30%) and various neurological deficits. Because females compose only about 20% of the ASD population, these female-specific characterizations may be overlooked when investigating the entire ASD group. We hypothesized that the presence of different clinical phenotypes represents more extensive brain involvement and will be associated with increased female's presentation in ASD.
Objectives: To examine the M:F ratio in specific clinical phenotypes commonly described in ASD, including macro-and microcephaly, seizures, developmental regression and minor neurological deficits (MND).
Methods:
The study included 611 participants aged 15m-18y (M=42.6m SD=28.4m) referred to a national autism center for diagnosis of ASD. Evaluation included neurological and behavioral assessments and obtaining of medical, developmental and familial histories from the parents. ASD diagnosis included the use of the Autism Diagnosis Interview-Revised (ADI-R) and the Autism Diagnosis Observation Schedule (ADOS) tests, and meeting criteria for autism/ASD based on DSM-IV criteria.
Results:
M:F ratio in the ASD group (n=537) was 6.8:1 and significantly higher than the ratio of 2.7:1 in the group that did not meet criteria for ASD (n=74). Mean head circumference (HC) percentile for males (50.0±26.2) was significantly larger (p=.01) than for females (42.0±29.0). Microcephaly (≤3%) and macrocephaly (≥97%) were more frequent in ASD than expected (5.9%, 22.4% respectively). The M:F ratio was significantly lower (p=.001) in the microcephalic group (2.1:1; n=31) compared to the >3 HC percentile group (7.7:1; n=496), indicating an increased rate of microcephaly among females with ASD compared with males. However, M:F ratios in the macrocephalic group (6.2:1; n=118) and the <97 HC percentile group (10.4:1; n=409) were not significantly different. Seizures were documented in 5.8% of the ASD group (n=502). The rate of seizures among females with ASD was 13.4%, higher than the rate of 4.6% in the male population. M:F ratio in the seizures group was significantly lower (p<.01)) than in the non-seizures group (2.5:1; 7.3:1 respectively). Regression was noted in 21.8% of the ASD group (n=532) and was significantly higher (p<.05) for females (31.9%) than for males (20.3%). M:F ratio for the group with social regression (4.3:1) was significantly lower (p<.05) than for the non-regressive group (8.4:1). M:F ratio differences were not observed for regression in other domains. MND was documented in 56.8% of the ASD cases and included hyperlaxity of joints (38.8%), hypotonia (28.0%), abnormal DTR (20.4%) and cerebellar dysfunction (27.0%). M:F ratio in the MND group (5.0:1) was significantly lower (p<.05) than the ratio for the group without MND (11.3:1).
Conclusions:
The higher proportion of microcephaly, seizures, developmental regression and MND in females suggests the existence of ‘female ASD’ that presents with unique clinical manifestations. This increased female representation in the examined phenotypes suggests that the etiologies and mechanism of ASD in females are different, broader and more associated with other neurological abnormalities than in males.
See more of: Clinical Phenotype
See more of: Symptoms, Diagnosis & Phenotype