Epiphyseal stippling is not a feature of 7‐dehydrocholesterol reductase deficiency (Smith‐Lemli‐Opitz syndrome)

Smith-Lemli-Opitz syndrome (OMIM 270400) is a malformation syndrome caused by a defect of distal cholesterol synthesis. Deficiency of 7-dehydrocholesterol reductase (7DHCR) as the biochemical defect underlying SLOS was discovered in 1993. Before that time, SLOS was diagnosed clinically based on the recognition of the typical facial features and pattern of malformation; since the discovery of the biochemical defect the phenotype has expanded to include much more severe, prenatally lethal forms and much milder patients with minimal clinical findings and normal intelligence [Porter, 2008]. There exists a large body of literature on SLOS dating before the discovery of the biochemical defect that includes many patients who did not have 7DHCR deficiency. Some features observed in those patients have become entrenched as part of the SLOS phenotype. One such feature is epiphyseal stippling or chondrodysplasia punctata. A review of the original literature shows a case of ‘‘Smith-LemliOpitz syndrome [. ] with dysplasia epiphysialis punctata’’ [Gibson, 1965] and a case with definite and generalized epiphyseal stippling [Meinecke et al., 1987]. The report by Gibson [1965] does not present any clinical photographs or radiographs, and while some of the described features are suggestive of SLOS (failure to thrive, broad and flattened nose, prominently anteverted nostrils, inner epicanthic folds, mild ptosis of the eyelids, broad and rugose maxillary alveolar ridges, relatively small mandible, cryptorchidism, small phallus, and hypoplastic scrotum), others are not: partial webbing of the second and third toes is present only on one side (right), and ‘‘exceptionally’’ short terminal phalanges of the second to the fourth fingers bilaterally. In fact, the extensive description of the calcifications and their reported resolution by age 16 months suggests the diagnosis of brachytelephalangic chondrodysplasia punctata (OMIM 302950). On the other hand, the clinical photographs of the proband reported by Meinecke et al. [1987] show facial features that are not consistent with severe, type II, SLOS that one would expect given the severity of malformations in this patient; the authors actually commented ‘‘the face appeared atypical to us and the intrauterine growth retardation, as well as the frequently observed syndactyly of toes 2–3 were also absent’’. Two other papers frequently cited as reporting epiphyseal stippling [Gemme et al., 1978; Wallace et al., 1994], do not, in fact, show stippling in the published radiographs; nor do they mention epiphyseal stippling in the clinical reports or reviews of the literature presented in their discussions. The only ossification abnormality that was reported in two patients who did look like SLOS [Herman et al., 1993] or who have subsequently been confirmed to have 7DHCR deficiency [Wallace et al., 1994] was an extra ossification center in the manubrium or abnormal sternal ossification. An informal survey of international clinicians caring for patients with SLOS (conducted partially through the SLOS Foundation http://www.smithlemliopitz.org/contact-lists/medical -advisory-board) determined that none have seen epiphyseal stippling in patients with biochemically proven SLOS. It would appear that chondrodysplasia punctata, although seen in other defects of cholesterol metabolism, is not a radiographic feature of SLOS. It is time to remove SLOS from the differential diagnosis of epiphyseal stippling. Furthermore, one may posit that the presence of epiphyseal stippling suggests a biochemical defect different from 7DHCR deficiency.