Autistic Phenotype and Hyperphagia in an Adolescent Male with Paternal Microdeletion of GABRB3

Janice Forster, Linda Gourash

Pittsburgh Partnership: Specialists in Prader-Willi Syndrome, Pittsburgh, PA

BG is an 18 year old man with mental retardation and autistic disorder.  He has a chromosome abnormality consisting of a paternal deletion of the GABRB3 locus that is located in the region of 15q11-13.  Because of the proximity of the GABRB3 locus to SNRPN (PWS locus), he has been labeled as having PWS since the age of 7 years. Developmental factors supporting a diagnosis of PWS at that time included food acquisition behaviors, temper tantrums, and moderate developmental delays.  BG never displayed the hypotonia, poor suck, or cryptorchidism that are found in the PWS phenotype.  Weight gain was noted at age 2 years and a diagnosis of PWS was considered. He has not displayed the hypogonadal hypopituitarism seen in PWS, and his muscular habitus suggests that he has developed with adequate levels of growth hormone.  There has been a deterioration in his behavior across settings over the past two years.  This deterioration may have been associated with the onset of puberty, as he is currently Tanner 4-5.  Physical examination revealed brachycephaly (HC=55 cm) with a flattened occiput and ridging along the sagittal suture.  He has widening of the palpebral fissures and alternating strabismus.  He had a well developed beard and normal musculature.  Hypothenar eminences were minimally flattened, and he displayed bilateral clinodactyly.  

BG never demonstrated prosocial skills, and he currently presents with the full spectrum of autistic thought and behavior.  He meets criteria for a social communication disturbance associated with noncontextual verbalizations (delayed echolalia), stereotypic movements (banging objects with the back of his hand or head; pinching the skin on the back of his hand and his cheeks; biting his fingers and hands), and emotional upset in response to environmental change because of a desire for sameness. There was no evidence of hallucinations or delusions on mental status exam.  He has developed symptoms of mood activation with SSRI's (Prozac and Zoloft) in the past.

The original genetic testing from 1992 demonstrated a lack of paternal inheritance at the GABRB3 locus.  Molecular probes at two other loci (IR10-1and MS620) demonstrated normal biparental inheritance.  Both his mother and father were subsequently studied with additional probes, and no abnormalities were detected.  Subsequent DNA methylation for SNRPN gene on chromosome 15 showed a normal methylation pattern (January, 2004).  

Although BG has been labeled as having PWS through his developmental years, he does not meet the clinical criteria except for food seeking behaviors and rapid weight gain.  He has met the criteria for autistic disorder.  It has only been in recent years that various abnormalities of the GABRB3 locus have been associated with autistic spectrum disorders. Most of the case reports have described inverted duplication, trisomy or tetrasomy of the maternal locus.  BG is the only known case report of a paternal microdeletion of GABRB3 locus.  His physical and behavioral phenotype is described to further our understanding of the role of this locus in human development and behavior.