To the Editor: We appreciate the points raised by Dr. Khan in response to our recent article, as well as the opportunity to clarify our findings in an effort to provide a thorough phenotypic characterization of patients within the holoprosencephaly (HPE) spectrum [Pineda-Alvarez et al., 2011; Solomon et al., 2010b]. One question raised by Dr. Khan pertained to the methods of corneal measurements. The horizontal corneal diameters of the patients in our study were measured using digital scaled-photography technique. Despite arguments of lack of precision and overestimation of the horizontal corneal diameters, there is extensive evidence that this technique correlates with gold-standard techniques, for example, via calipers under general anesthesia [Lagreze and Zobor, 2007; Puvanachandra and Lyons, 2009; Robinson et al., 1989]. In response to Dr. Khan’s questions about specific ocular phenotypes we described in our article, Patient 1 was a 34-year-old woman at the time of the exam and presented with horizontal corneal diameters of 10.5 mm OU, which are in the lower end of “relative” microcornea. Patient 2 was a 12-year-old boy who presented with smaller than average ocular axial lengths (below the 5th centile in the right eye measuring 21.69 mm, and approximately at the 5th centile in the left eye measuring 22.48 mm). These latter measurements can be classified as “simple microphthalmos” since the use of the term nanophthalmos has acquired a different connotation [Khan and Zafar, 2009; Khan, 2008]. In addition, Patient 2 has a small peripapillary crescent in OS and a blood vessel running very close to the fovea centralis in OD, with a vision of 20/30 that was not improvable with manifest refraction. These findings suggest mild foveal hypoplasia in the right eye [Pineda-Alvarez et al., 2011]. While we agree with Dr. Khan that the ocular anomalies in these two patients are not typical for the general population, we also believe that the presentation of phenotypic features in patients with HPE are unusual and that most of these features have not been meticulously characterized. Furthermore, there is evidence that Sonic Hedgehog (SHH), an important morphogen implicated in the pathogenesis of HPE, also plays key role in the causality of several ophthalmologic anomalies. As we described, SHH regulates several aspects of the development of the eye, including ventral-dorsal patterning, eye field separation, and optic fissure closure, among other processes [Carlson, 2009; England et al., 2006; Hallonet et al., 1999; Kobayashi et al., 2010; Zhao et al., 2010]. Consequently, insults that affect directly or indirectly the generation of a proper SHH morphogenic gradient may alter the normal development of the eye and result in unusual ophthalmologic features, such as seen in the patients we described. These anomalies have been mentioned in the literature with varying degrees of detail, but they have not been consistently evaluated in the rest of the patients of our large cohort (over 1,000 individuals with HPE) [Bakrania et al., 2010; Horn et al., 2004; Lacbawan et al., 2009; Schimmenti et al., 2003; Solomon et al., 2010a]. We also concur that further research should be conducted in order to improve our understanding of the broad phenotypic variability among patients with mutations in HPE-associated genes. However, we feel strongly that relegating the unraveling of our patients’ ocular phenotypes to the marvels of newly available genomic sequencing technologies violates Occam’s razor, and is a potentially overly simplistic reaction to any incomplete etiologic explanation. Among the limitations of this approach are the immense genetic heterogeneity and the broad phenotypic variability of HPE, as well as perhaps-related ocular conditions. Lastly, and most importantly, we would like to emphasize that ocular anomalies are prevalent among patients with HPE; therefore, we encourage clinicians to refer these patients to an ophthalmologist familiar with this disorder in order to promptly characterize any anomalies, initiate an adequate treatment and avoid possible complications.