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Commentary: Recognizing syndromes with overlapping features: How difficult is it? Considerations generated by the article on differential diagnosis of Smith–Magenis syndrome by Vieira and colleagues

In my clinical research work, I have had the opportunity to study over 60 patients with the deletion 1p36 [Battaglia et al., 2008]. Based on this experience, I considered the facial features as distinct and characteristic, allowing for the clinical diagnosis of this newly recognized MCA/ID (intellectual disability) syndrome, even before laboratory confirmation. This was based on a number of features that altogether allowed for a prompt recognition of the syndrome. Such facial manifestations include: straight eyebrows, deep-set eyes, mid-face hypoplasia, broad nasal/root bridge, long philtrum, pointed chin, and facial hypotonia [Gajecka et al., 2007; Battaglia and Shaffer, 2008; Battaglia et al., 2008]. Evaluation of the face constitutes a central theme in diagnosing syndromes, and the facial features are often the most relevant element in the diagnostic criteria of a number of MCA/ID conditions [Carey, 2010]. However, recently, I happened to evaluate two patients whose facial features were suggestive of the 1p36 deletion syndrome. On examination, both had straight eyebrows, deep-set eyes, mid-face hypoplasia, broad nasal/root bridge, and facial hypotonia (Fig. 1). Therefore, I pursued array-CGH for diagnostic confirmation. To my surprise, the array-CGH of both patients showed a microdeletion on the short arm of chromosome 17, at 17p11.2, sizing almost 3.4 and 3.5 Mb, respectively, including the RAI1 gene. The microdeletion was confirmed by FISH and was shown to be de novo in both patients. In one patient (reported separately) the 17p11.2 microdeletion was associated with a microdeletion on the long arm of chromosome 15, at 15q13.2q13.3, sizing almost 1.5 Mb, de novo. The patient with only the 17p11.2 microdeletion did not have a disrupted sleep–wake cycle, while the other could only sleep from 11.00 pm till 4.00 am, and would go to sleep during the day. Very recently, as Associate Editor, I was asked by the Editor-inChief of the Journal to govern the review process of a paper by Vieira and colleagues on ‘‘Differential diagnosis of Smith–Magenis syndrome: 1p36 deletion syndrome.’’ As I went through the article, I jumped on my chair, since, in my clinic, I had had an experience similar to that reported by Vieira and colleagues. These authors documented a patient who had been recognized as having clinical features consistent with SMS, but lacked 17p11.2 deletion or a RAI1 gene mutation, and had a 1p36 deletion shown on whole genome array-CGH. Their proposita was a 15-year-old female with developmental delay, hypotonia, sleep disturbance, seizures, behavior problems, and dysmorphic craniofacial features characterized by microbrachycephaly, straight eyebrows, deep-set eyes, mid-face hypoplasia, and prognathism. However, judging from her photo (especially the lateral view of the face), she looked to me as a probable deletion 1p36 syndrome. The discrepancy in the clinical recognition of the possible syndrome between Vieira and colleagues and myself could be explained by the following: (1) different clinical experience with a given malformation pattern and (2) overlapping features of the two syndromes. The latter are represented by: brachycephaly, deep-set eyes, midface hypoplasia, broad nasal bridge, relative prognathism with age,