We report on the follow-up and radiological characterization of the first and largest reported family with TODPD, refinement of the linkage region, and exclusion of two candidate genes.
As noted in the original description of this condition, and as confirmed by later reports, the most striking skeletal abnormality is the involvement of the hands and the digital fibromas [Horii et al., 1998
; Bacino et al., 2000
; Breuning et al., 2000
; Drut et al., 2005
; Baroncini et al., 2007
; Kokitsu-Nakata et al., 2008
]. The digital fibromas appear to be prevalent in infancy and they tend to regress with age in many cases, making them an inconsistent feature in adults. This is clearly exemplified by our proposita exhibiting the fibromas only in the first years of life and not at later evaluations. The carpal and tarsal coalitions were particularly striking in the proposita of our family (). This feature was not noted in the early report as the carpal bones were not ossified yet [Bacino et al., 2000
]. The abnormal bony texture and the localized areas of osteoporosis also point to an unusual bone process involved in the pathogenesis of the disorder.
Although the skeletal manifestations of TODPD mostly involve hands and feet, a more generalized bone involvement including bowing, mesomelic shortening, abnormal bony texture, areas of localized osteoporosis, cytic lesions, and amorphous ossification suggest a more generalized bone involvement and it may point to a defect of matrix degradation, because of similarities with the radiologic features of the osteolysis syndromes [Superti-Furga and Unger, 2007
], which may be due to defects in genes involved in degradation of bone matrix [Zankl et al., 2007
]. Interestingly, it also appears in our family that the degree of hand and foot involvement on the ulnar side is more severe.
Linkage analysis has indicated that the mutated gene in this disorder maps to Xq27.3-qter within a very gene-rich region [Zhang et al., 2000
]. However, the genetic defect of TODPD remains unknown. In the effort to identify the gene responsible for this condition, we further defined in our family the linkage region using a high density SNP array which allowed us to restrict the linkage to Xq28qter. Because of clinical overlap between STAR syndrome (OMIM 300707), an X-linked dominant condition presenting with anogenital and renal malformations, dysmorphic facial features, normal intellect, and syndactyly of toes [Unger et al., 2008
], we sequenced the FAM58A
gene, responsible for STAR syndrome. However, no mutations were found in the exons and intro/exon boundaries of this gene in the TODPD affected patients.
Filamin A (FLNA
) gene, which is also included within the linkage region, is involved in signaling pathways that mediate organogenesis in multiple systems including the skeleton. Some of the generalized skeletal features of our proband and the patient's first cousin suggested Melnick–Needles syndrome (OMIM 309350) like changes, while hand and foot changes radiographically, such as the carpal and tarsal coalitions and flexion contractures [Robertson et al., 2006
], suggest similarity to frontometaphyseal dysplasia (OMIM 305620). FLNA
mutations that conserve the reading frame result in a broad range of congenital malformations observed in four X-linked human disorders: otopalatodigital syndrome types I (OMIM 311300) and II (OMIM 304120), frontometaphyseal dysplasia, and Melnick–Needles syndrome. Given the clinical similarities between some of these disorders and TODPD, we have also considered FLNA
as a candidate gene. However, direct sequencing of this gene failed to reveal pathogenic mutations.
The development of the human skeleton is regulated by intricate signaling pathways involving secreted molecules that bind to cell surface receptors to elicit a response in the target cell. Bone morphogenetic proteins (BMPs) are an important part of this process. Their signaling capacity is regulated on several levels including the extracellular space where inhibitors such as Noggin (NOG) prevent BMPs from binding to their cognate receptors. The importance of the signaling pathway for the development of joints was shown by the identification of mutations in GDF5
, a member of BMP family, and NOG
in patients with symphalangism (OMIM 185800) and multiple synostosis syndrome (OMIM 186500) [Groppe et al., 2002
; Seemann et al., 2005
; Dawson et al., 2006
]. The presence of multiple joint fusions in TODPD may lead to the hypothesis that a dysregulation of the BMP pathway may play a role in the pathogenesis in this disorder as well.
The identification of the responsible gene will allow more accurate genetic counseling to the affected families and will shed light on the molecular pathways leading to the various clinical and radiographic anomalies of TODPD, in particular this rather unique skeletal phenotype.