An Osteosclerotic form of Robinow Syndrome Kieran J. Bunn,1 Angeline Lai,2 Azza Al-Ani,3 Mauro Farella,3 Susan Craw,4 and Stephen P. Robertson1* 1
Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
Genetics Service, Department of Paediatrics, KK Women’s and Children’s Hospital, Singapore Department of Oral Sciences, School of Dentistry, University of Otago, Dunedin, New Zealand
Department of Radiology, Dunedin Hospital, Dunedin, New Zealand
Manuscript Received: 16 March 2014; Manuscript Accepted: 16 June 2014
Robinow syndrome (RS) is a clinically and genetically heterogenous condition primarily characterized by short stature, mesomelia, genital hypoplasia, oral abnormalities, and a facial gestalt that includes hypertelorism, a short nose, and a broad mouth. The disorder exists in both a dominant and a more severe recessive form. Here two unrelated cases of sporadic RS are described with the additional finding of axial and appendicular osteosclerosis. These two patients, coupled with three additional patients previously described in the literature, may represent a distinct sub-phenotype of this condition. Ó 2014 Wiley Periodicals, Inc.
Key words: Robinow syndrome; osteosclerosis; oligodontia; hyperosteosis
INTRODUCTION Robinow syndrome (RS), first described in 1969 [Robinow et al., 1969], is a phenotypically heterogeneous condition principally characterized by a variable combination of mesomelic limb shortening, genital hypoplasia, and a facial gestalt that includes hypertelorism, a short nose, and a broad mouth. While the disorder originally defined by Robinow shows autosomal dominant inheritance, a phenotypically more severe recessive variant was identified in 1978 [Wadia et al., 1978] and originally termed Covesdem syndrome. Now more commonly referred to as recessive RS, this condition also presents with the characteristic facial appearance and mesomelic dysplasia but is discriminated from its dominant counterpart by its inheritance pattern, severity, and the presence of significant vertebral anomalies as well as rib fusions [Mazzeu et al., 2007]. Recessive RS is caused by biallelic loss-of-function mutations in ROR2, which encodes for the orphan receptor tyrosine kinase, ROR2 [van Bokhoven et al., 2000; Afzal et al., 2000b]. ROR2 participates in the transduction of non-canonical WNT signaling by interacting with extracellular soluble ligands, most classically WNT5A [Oishi et al., 2003]. In the face of substantial phenotypic heterogeneity, the genetic loci that underlie dominant RS have proved elusive. Two families with the classical presentation of dominant RS have had missense variants in WNT5A identified,
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Bunn KJ, Lai A, Al-Ani A, Farella M, Craw S, Robertson SP. 2014. An osteosclerotic form of Robinow syndrome. Am J Med Genet Part A. 164A:2638–2642.
but mutations at this locus do not explain the majority of individuals with this phenotype [Person et al., 2010], suggestive of locus heterogeneity for this disorder. Here two unrelated isolated patients with the RS phenotype are described. The most striking features are gingival hypertrophy, facial dysmorphism (hypertelorism, a broad short and upturned nose, and wide mouth), disordered dentition and substantial axial, and appendicular osteosclerosis. This latter finding is not a common accompaniment of the disorder with only three previous descriptions being identifiable in the literature. It may represent a subcategory of RS with its own distinct etiology.
CLINICAL REPORT Patient 1 This patient, a female, was born at term to unaffected nonconsanguineous parents after an unremarkable pregnancy. The maternal and paternal ages at birth were 31 and 42 years. respectively. Her birth weight was 3.2 kg. It was noted at delivery that the tongue was Conflicts of Interest: None. Ethical approval for this study was obtained from the Southern Regional Ethics Committee, NZ. Grant sponsor: Curekids (NZ). Correspondence to: Stephen P. Robertson, Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand. E-mail: [email protected]
Article first published online in Wiley Online Library (wileyonlinelibrary.com): 14 July 2014 DOI 10.1002/ajmg.a.36677
BUNN ET AL. bilobed and hypomobile, the uvula was hypoplastic, the nose short, and the mouth wide. Camptodactyly, clinodactyly, and brachydactyly were also observed. Recurrent chest infections resulted in frequent admissions to hospital throughout childhood. Chronic otitis media was treated twice with grommets. Bilateral mixed conductive and sensorineural hearing loss was diagnosed. There was an unsuccessful surgical attempt to correct her camptodactyly. All primary teeth failed to exfoliate, and consequently were removed surgically. Subsequently the patient was found to be oligodontic, with agenesis of 12 secondary teeth. On examination at age 13 years the patient weighed 40 kg (10th centile), had a height of 147.8 cm (97th centile). She had down-slanting palpebral fissures with hypertelorism (IC distance 4 cm, >97th centile), mid-face hypoplasia, a wide and depressed nasal bridge, a short nose, narrow nares, and excessive anterior lower facial height (Fig. 1). Oral examination revealed moderate tooth crowding, severe mesial rotation of the upper left incisor, the absence of 12 permanent teeth, and marked gingival exposure on smile with hypertrophy, especially around the lower teeth (Fig. 2). Brachydactyly (middle finger: hand length ratio 97th centile). He had apparent hypertelorism, a broad nasal root, a flattened nasal tip and narrow
FIG. 1. Clinical images of Patient 1 at age 16. A: Hypertelorism, down-slanting palpebral fissures, broad nasal bridge, and midface hypoplasia are evident. B: Depressed nasal bridge. C: Brachydactyly, camptodactyly, and clinodactyly. D: Hypoplastic toes [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmga].
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
FIG. 2. Intraoral findings of Patient 1 at age 14. A: A frontal extra-oral photograph showing the gingival hyperplasia and dental disarray B: An orthopantomogram showing 12 missing teeth including all four wisdom teeth. The arrows indicate the following missing teeth: bilateral upper second permanent molars, upper and lower second permanent premolars, and upper lateral incisors [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmga].
nares. Oral findings included a short tongue, gingival hyperplasia, dental crowding, and a repaired cleft lip and palate on the left. Brachydactyly, broad thumbs, camptodactyly and bilateral flat feet were observed. Limb segments and the genitalia were normal. He drooled excessively, but did not have any difficulties eating, swallowing or with his speech. His cognitive functioning was normal, but he had mild motor impairments which were improving with physical therapy. Radiographs showed widespread osteosclerosis,
particularly of the skull base and cortices of the long bones, which themselves were undertubulated. The distal phalanges of the hands and feet were hypoplastic with the terminal phalanx of both thumbs being partially bifid. A DEXA scan at 11 years of age showed increased bone density of the lumbar spine, with a bone mineral density (BMD) of 1.264 g/cm2 (Z-score þ 7.6). The BMD of the left hip and left femoral neck were 0.937 g/cm2 (Z-score þ 1.8) and 1.015 g/cm2 (Z-score þ 3.0), respectively. No mutations were
FIG. 3. Radiographs of Patient 1 at age 16. A: Lateral X-ray of the skull showing osteosclerosis of the cranial vault most marked at the base and hypoplastic frontal sinuses. B: Coronal CT scan of the head showing sclerotic and thickened bone. C: X-ray of the feet, showing the hypoplastic distal phalanges and the bilateral bifid distal phalanx of the great toe. D: Left hand, demonstrating camptodactyly, clinodactyly, brachydactyly, and the bifid distal phalanx of the thumb E: Generalized osteosclerosis of the pelvis and mild undertubulation of the metaphyses. F: Undertubulation and osteosclerosis affecting the distal femoral and proximal tibial metaphyses. G: Osteosclerosis of the lumbar and lower thoracic spine, a mild scoliosis, but no segmentation defects [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmga].
BUNN ET AL. found on direct sequencing of WNT5A. The absence of severe mesomelia, vertebral abnormalities, or rib fusions makes recessive RS unlikely, so mutations in ROR2 were not sought.
DISCUSSION Two comprehensive studies that sought to phenotypically characterize RS [Butler and Wadlington, 1987; Mazzeu et al., 2007] identified a number of key criteria which are found in a high frequency in both dominant and recessive forms of the condition. These features are short stature, hypertelorism, a wide and depressed nasal bridge, short and upturned nares, hypoplasia of the midface, brachydactyly, clinodactyly, genital hypoplasia, and mesomelic limb shortening. The facies of the two individuals described here align well with the above criteria but significantly these patients lack mesomelia, and the male does not have a micropenis. While these signs are certainly common features of RS they are not obligatory for the diagnosis with up to 20% of individuals with dominant RS having no limb segment disproportion and 16% of males with dominant RS not having genital hypoplasia [Bain et al., 1986; Mazzeu et al., 2007]. Severe short stature, rib fusions, and morphological vertebral anomalies are considered obligatory components of the recessive RS phenotype [Mazzeu et al., 2007], and these features are not present in either of the patients described here. While recessive RS is generally more severe it has been reported that the intra-oral findings are more striking in the dominant form of the condition [Beiraghi et al., 2011]. Although there is some conflict in the literature as to the relative frequency of oral findings in the dominant and recessive variants [Mazzeu et al., 2007; Beiraghi et al., 2011], the gingival hypertrophy, malocclusion, and dental crowding observed in our patients fit well within the broad diagnosis of dominant RS. The extent of the oligodontia in Patient 1 is unusual, with 12 missing teeth. Oligodontia of this severity only occurs in 0.14% of the population [Polder et al., 2004]. There are three previous reports of RS with osteosclerosis identified in the literature. In one instance the sclerosis was limited to the mastoids, but like Patient 1 this patient also had severe tooth agenesis, with the congenital absence of 11 permanent teeth [Kelly et al., 1975]. A second case, a 23-year-old male, had a more generalized osteosclerotic phenotype. Significantly in this second report the proband had a son, who had a more severe RS phenotype, yet lacked the osteosclerosis. This led the authors to conclude that the osteosclerosis may be a progressive aspect of the condition [Shprintzen et al., 1982], a suggestion that is supported by our observation of a progression in the osteosclerosis as documented by DEXA scanning of Patient 1.The final and most recent report is of a patient with RS but without mutations in either ROR2 or WNT5A and a phenotype very similar to the cases discussed here. Only osteosclerosis of the skull was described in this report, which focused on the otological manifestations of this disorder [Eijkenboom et al., 2012]. Interestingly, chronic otitis media and hearing loss are features of the patients presented here, and two of the previously reported patients with osteosclerosis [Kelly et al., 1975; Eijkenboom et al., 2012]. Recessive RS is caused by truncating mutations in ROR2 [van Bokhoven et al., 2000; Afzal et al., 2000a]. The ROR2 receptor
2641 mediates some aspects of non-canonical WNT signaling, via an interaction with the soluble extracellular WNT ligands, the prototypical example being WNT5A [Oishi et al., 2003]. Putative mutations in WNT5A were found in the original family identified by Robinow and in an unrelated family, and on this basis mutations in WNT5A were sought in the two individuals described here but no mutations were identified reflecting the experience with other study cohorts of individuals with dominant RS [Person et al., 2010]. While the molecular etiology of most instances of dominant RS remains elusive, given the similarity in phenotype to recessive RS and the involvement of WNT5A in some instances, it seems plausible that a defect in WNT activity may underlie the phenotype described here. A link between WNT signaling and bone development is well established (see [Baron and Kneissel 2013] for a recent review). Of particular note, gain-of-function mutations in LRP5 that produce an osteosclerotic phenotype [Little et al., 2002], formerly called Worth endosteal hyperostosis [Worth and Wollin, 1966], has strong radiological similarities to the individuals described here. Given the involvement of non-canonical WNT signaling in RS and canonical WNT signaling in osteosclerosis [Little et al., 2002], these individuals may have mutations at a locus that impacts signal transduction in both of these pathways.
ACKNOWLEDGMENTS The authors would like to acknowledge the willing participation of the families described here.
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