To the Editor:

We read with interest the guidelines on the clinical evaluation of the etiology of autism spectrum disorders by Schaefer et al.1 Although we congratulate the authors on the development of these guidelines, we question the need for routine studies for chromosome anomalies and fragile X syndrome for patients with Asperger syndrome (AspS). The authors state that the generally reported rate of success for identifying a specific diagnosis for evaluations of patients with various categories of autism spectrum disorders including AspS is 6–15%. The authors cite three references in support of this. The study by Abdul-Rahman and Hudgins2 reported on 101 patients including 63 with pervasive developmental delay (PDD)/autism, 7 with AspS, 7 with autistic features, 20 with developmental delay/mental retardation, and 4 with other conditions. None of the patients with AspS had an underlying genetic diagnosis identified. Battaglia and Carey3 described 65 patients with autism, 18 with PDD-not otherwise specified, and 2 with AspS. An etiologic diagnosis was made for nine of these patients. The report does not say if either of the AspS patients had an underlying diagnosis. Schaefer and Lutz4 recommend an evaluation protocol for children with AspS or PDD yet their study reports on 32 patients with autism. None were reported to have AspS. They did however refer to six other studies in the development of their recommendations. One of the studies cited was the Battaglia and Carey3 study described above. The other studies (Refs. 5–9) were reviewed. Challman et al.5 collected data on five AspS patients but did not report those results. According to our review, we are not aware of any patients with AspS in those studies identified with a chromosome anomaly or fragile X syndrome.

To determine if AspS patients have been reported with a chromosome anomaly, we did a Medline search (as of July 2008), for “Asperger* Chromosome,” “Asperger* Chromosomal,” and “Asperger fragile X.” The following cases reports were identified. Robertson et al.10 reported on a woman with Gilles de la Tourette syndrome who had developmental delays and some features of AspS or autism spectrum disorder. She had a 22q11.2 deletion. Fontenelle et al.11 reported a patient with AspS, obsessive-compulsive disorder, major depression, and 45,X/46,XY mosaicism. Tentler et al.12 described two AspS patients with balanced translocations [t(13;17)(q14;p13) and t(17;19)(p13.3;cen)]. Their second patient was previously described by Annerén et al.13 Saliba and Griffiths14 found an inherited fragile site on chromosome 2 in a patient with AspS. We found several other studies15–23 that evaluated a series of patients with autism spectrum disorders including AspS where fragile X testing and/or chromosome studies were done on all or part of the group. These studies are summarized in the Table. We also checked the Autism Chromosome Rearrangement Database.24 There were two additional unbalanced karyotypes found in AspS patients. One unpublished case with possible AspS with growth delay and dysmorphic features had a 47,XY,+mar/46,XY karyotype. The marker was identified as der(7)(q11.1q11.23). Another patient described by Akefeldt and Gillberg25 had atypical autism/AspS in addition to hypomelanosis of Ito had various clonal chromosomal abnormalities. In our own laboratory, we have done chromosome studies on 24 patients whose diagnosis was stated to be AspS. All had normal karyotypes. Nineteen of these patients had fragile X molecular testing. None had fragile X syndrome. One female patient was a premutation carrier (55 CGG repeats). One male patient had 51 CGG repeats which is considered in the gray zone.

Table 1 Summary of published AspS case series
Full size table

COMMENT

Most of the chromosome anomalies described are likely coincidental rather than causative, and most are considered to be normal variants that would normally not be associated with any phenotypic effects, e.g., long Y; fragile sites; single cell low grade mosaicism (query cultural artifact). The anomalies that may be clinically significant are the XYY, the 45,X mosaic and the “major abnormality of 5p,” the 22q deletion and the mosaic derivative 7. The first two are unlikely etiologically causative of AspS, but comorbid conditions. It is difficult to comment on the significance the 5p abnormality without further details. The patient with 22q deletion had more complex problems including intellectual deficiency that would normally warrant further genetic investigations. The patient with a mosaic derivative 7 chromosome also had additional features. The chromosome anomalies seen in the patient with hypomelanosis of Ito likely relate to that diagnosis rather than the AspS.26 Our finding of one fragile X female carrier and one male with 51 CGG repeats is interesting. Farzin et al.27 did report a higher frequency of autism spectrum disorders in fragile X premutation carriers although none were diagnosed with AspS. More research in the area is needed before testing for a fragile X premutation becomes a standard of practice for AspS.

One limitation of a literature review is that the diagnostic criteria for AspS used in the studies vary and have changed with time. Kopra et al.28 described four diagnostic criteria for AspS, i.e., International Classification of Disease-10, Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition, the Gillberg & Gillberg, and the Szatmari criteria. The International Classification of Disease-10 criteria require lack of clinically significant delay in language or cognitive development in childhood. The Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria state that there must be no clinically significant delay in cognitive development in childhood. The other two criteria sets do not specifically require a normal IQ.

Based on our review of the literature and our own experience we recommend a detailed history and physical examination of patients with AspS. If there are dysmorphic features, intellectual impairment, or other concerns, including a family history to suggest an X-linked disorder, further investigations such as chromosome analysis, array CGH, fragile X testing, and possibly other genetic studies associated with X-linked mental retardation is recommended. In our opinion, routine genetic investigations in uncomplicated AspS, in the absence of any of the above findings, is not recommended. However, this group of individuals may be useful for research using genetic markers to identify genes that lead to susceptibility to autism spectrum disorders.