Co-occurrence of X-Linked Congenital Adrenal Hypoplasia and Autistic Disorder

To the Editor: One form of congenital adrenal hypoplasia is associated with the Xp21 chromosomal region. These patients have clinical abnormalities including mental retardation, hearing loss, hypogonadism, glycerol kinase deficiency, ornithine transcarbamoylase deficiency, and Duchenne muscular dystrophy. This letter presents a case of a patient with X-linked congenital adrenal hypoplasia whose mental status as a preadolescent male was also consistent with the diagnosis of autistic disorder.

Case Report

A 12-year-old Caucasian boy presented with features of autistic disorder including marked lack of awareness of the feelings of others; no seeking of comfort in times of distress; gross impairment in ability to make peer friendships; abnormal nonverbal communication; abnormalities in speech production including perseveration and echolalia; stereotyped body movements including flapping, clapping, and rocking; and persistent preoccupation with parts of objects reflecting a restricted range of interests. His Autism Behavior Checklist total score was 126 with the following subscale profile results: sensory 15, relating 33, body and object use 31, language 25, social and self-help 22. Speech and language testing indicated an age equivalency of 2.8 to 3.0 years old with severe delays of receptive and expressive language as well as speech articulation. MRI brain scan was unremarkable. Chromosomal analysis had confirmed a deletion at the Xp21 region. His family pedigree noted several female congenital adrenal hypoplasia carriers including his mother as well as male infants who had died from congenital adrenal hypoplasia with no family history of autism, nor other developmental, neurologic, or psychiatric conditions. The patient had been prenatally diagnosed with congenital adrenal hypoplasia and survived with in utero replacement therapy initiated at 40 weeks gestation with 100 mg of dehydroepiandrosterone sulfate infused into the amniotic space. Subsequent assessments revealed normalizing maternal estriol excretion. After birth at 43.5 weeks gestation, mineralocorticoid replacement therapy was administered during infancy. Later evaluations revealed steroid deficiencies as well as chronic failure to thrive. Progressive motor, language, and socialization delays followed as described.

Comment

Despite receiving replacement treatment, it is conceivable that congenital adrenal hypoplasia-related neurophysiologic abnormalities may have already been staged. Adrenal hormone imbalances have been linked to disturbances of development, language, memory, and mood. 1 Congenital adrenal hypoplasia can impact the function of the mineralocorticoid and glucocorticoid receptor systems for cortisol binding in the limbic system. The mineralocorticoid receptors, located in the lateral septum and hippocampus, affect tonic influences on brain function. 2 They demonstrate a 10-fold higher binding affinity for cortisol over glucocorticoid receptors. 1 Glucocorticoid receptors are more widely distributed in the lateral septum, central amygdala, locus coeruleus, and dentate nucleus having involvement with feedback action on stress-activated brain mechanisms. 2 Other studies demonstrated the selective loss of hippocampal granule cells after adrenalectomy suggesting adrenal hormones are a requirement for limbic structural integrity. 3 Adrenal deficiency causes hippocampal serotonin receptor density to selectively increase along with development of subsensitivity at presynaptic receptors. 4 Such impacts on serotonin receptors are particularly significant as alterations of serotonergic neurotransmission have been implicated in both autistic disorder and mental retardation. 5