On macrocephaly, epilepsy, autism, specific facial features, and mental retardation
To the Editor:
Autism is a complex neurobehavioral disorder. The clinical picture is quite variable among affected individuals and may include commom features such as mental retardation in 75% [Gillberg, 1988], epilepsy in 30% [Minshew, 1991], and macrocephaly in 10–15% [Fidler et al., 2000]. These comorbid symptoms suggest the occurrence of extensive brain alteration and go against the “psychogenic origin” model, supporting the idea that most cases of autism are due to neurobiological factors. Probably the majority of individuals with autism present a combination of genetic and non-genetic factors following a multifactorial model, but in about 15% of the patients a specific cause can be detected, including chromosomal abnormalities, monogenic disorders, and non-genetic conditions.
In 1997, Orstavik et al. described a combination of macrocephaly, epilepsy, autism, dysmorphic features, and mental retardation in two sisters as a possible new autosomal recessive syndrome. Craniofacial features included high and broad forehead, deep-set eyes, short philtrum, bushy eyebrows, and hairy upper lip. The younger sister had sudden death at age 5 probably due to a nocturnal epileptic attack.
Recently, we have evaluated a family with similar findings. The parents were healthy, young, and non-consanguineous, although consanguinity has been reported in the maternal grandparents, which where first-cousins.
The proposita were an 8-year-old girl and her twin sister. Their pregnancy was uneventful and delivery was at term by caesarian section due to pelvic presentation of one of the twins. There is no information about placenta or amniotic membranes. Both were born with 2,520 g. In the neonatal period, one of the sisters had three episodes of apnea with spontaneous resolution. Their neurological development was delayed and included autistic symptoms: poor language, echolalia, social isolation, absence of imaginative games, repetitive motor movements (body shaking, flapping), and stereotyped handling of objects, like spinning a piece of string or a ball. They met 11 of the 12 DSM-IV criteria for infantile autism.
The examination showed macrocephaly (OFC = 57 cm, > P98), high and broad forehead, hypertelorism, wide nasal root, anteverted nostrils, high arched palate, short philtrum, prominent upper central incisors, pectus excavatum, spatulated distal phalanges, increased distance between first and second toes, as well as several blue nevi from 0.3 to 0.5 mm in scalp. One of the sisters has a small café-au-lait spot on the left leg.
The 4-year-old younger brother presented similar dysmorphic features, including macrocephaly (OFC = 58 cm, > P98), frontal bossing, hypertelorism, long palpebral fissures, short philtrum, open mouth, prominent upper central incisors, spatulated phalanges, diastasis of abdominal muscles, and undescended testes. He also has mild to moderate mental retardation but no impairment in language or social interaction. The 6-year-old middle brother has normal development and no dysmorphic features.
Complementary tests performed in one of the twin sisters included a brain computed tomography scan (normal), screening for inborn errors of metabolism and amino acid chromatography (normal), chromosomal analysis on peripheral lymphocytes with G-banding technique (46,XX 400 bands resolution), molecular tests for the FRAXA, FRAXE, and FRAXF mutations (all showing normal alleles), and cerebral SPECT (revealing hypoperfusion of the inferior portion of the right frontal lobe). Unfortunately, we could not perform molecular test to confirm the monozygosity and the family did not allow us to take pictures.
Although epilepsy was not present in our cases, we believe that this family represents an additional report on the rare condition described by Orstavik et al. [1997], since the main features including autism, mental retardation, macrocephaly, frontal bossing, hypertelorism, and short philtrum were present. Recurrence in the sibship affecting both sexes with normal parents supports the proposed autosomal recessive inheritance pattern. Variability in clinical expression may occur, since autistic features were present in the female sisters but not in the affected brother. Description of further cases are necessary to better delineate the phenotype of this condition.
