Level 4, therapeutic study (retrospective case series).

Growth and differentiation factors (GDFs) are secreted signaling molecules within the BMP family that have critical roles in joint morphogenesis during skeletal development in mice and humans. Using genetic data obtained from a six-generation Chinese family, we identified a missense variant in GDF6 (NP_001001557.1; p.Y444N) that fully segregates with a novel autosomal dominant synostoses (SYNS) phenotype, which we designate as SYNS4. Affected individuals display bilateral wrist and ankle deformities at birth and progressive conductive deafness after age 40 years. We find that the Y444N variant affects a highly conserved residue of GDF6 in a region critical for binding of GDF6 to its receptor(s) and to the BMP antagonist NOG, and show that this mutant GDF6 is a more potent stimulator of the canonical BMP signaling pathway compared with wild-type GDF6. Further, we determine that the enhanced BMP activity exhibited by mutant GDF6 is attributable to resistance to NOG-mediated antagonism. Collectively, our findings indicate that increased BMP signaling owing to a GDF6 gain-of-function mutation is responsible for loss of joint formation and profound functional impairment in patients with SYNS4. More broadly, our study highlights the delicate balance of BMP signaling required for proper joint morphogenesis and reinforces the critical role of BMP signaling in skeletal development.

Background: Although there are several predominantly single-center case series in the literature, relatively little prospectively collected data exist regarding the outcomes of open hip reduction (OR) for infantile developmental dysplasia of the hip (DDH). The purpose of this prospective, multi-center study was to determine the outcomes after OR in a diverse patient population. Methods: The prospectively collected database of an international multicenter study group was queried for all patients treated with OR for DDH. Minimum follow-up was 1 year. Proximal femoral growth disturbance (PFGD) was defined by consensus review using Salter’s criteria. Persistent acetabular dysplasia was defined as an acetabular index >90th percentile for age. Statistical analyses were performed to compare preoperative and operative characteristics that predicted re-dislocation, PFGD, and residual acetabular dysplasia. Results: A cohort of 232 hips (195 patients) was identified; median age at OR was 19 months (interquartile range 13 to 28) and median follow-up length was 21 months (interquartile range 16 to 32). Re-dislocation occurred in 7% of hips (n=16/228). The majority (81%; n=13/16) occurred in the first year after initial OR. Excluding patients with repeat dislocation, 94.5% of hips were IHDI 1 at most recent follow-up. On the basis of strict radiographic review, some degree of PFGD was present in 44% of hips (n=101/230) at most recent follow-up. Seventy-eight hips (55%) demonstrated residual dysplasia compared with established normative data. Hips that had a pelvic osteotomy at index surgery had about half the rate of residual dysplasia (39%; n=32/82) versus those without a pelvic osteotomy with at least 2 years follow-up (78%; n=46/59). Conclusions: In the largest prospective, multicenter study to date, OR for infantile DDH was associated with a 7% risk of re-dislocation, 44% risk of PFGD, and 55% risk of residual acetabular dysplasia at short term follow-up. The incidence of these adverse outcomes is higher than previous reports. Patients treated with concomitant pelvic osteotomy had lower rates of residual dysplasia. These prospectively collected, multicenter data provide better generalizable information to improve family education and appropriately set expectations. Level of Evidence: Level II, prospective comparative study.

Background Mutations in CNKSR2 have been described in patients with neurodevelopmental disorders characterized by childhood epilepsy, language deficits, and attention problems. The encoded protein plays an important role in synaptic function. Case presentation Whole-exome sequencing was applied to detect pathogenic variants in a patient with clinical symptoms of psychomotor development, attention deficit, poor logical thinking ability, and an introverted personality, but without epilepsy or any significant electroencephalogram changes. Genetic study revealed a splicing mutation (c.1904 + 1G > A) and RT-PCR revealed aberrant splicing of exon 16, leading to a reading-frame shift and a truncated protein in the PH domain. Conclusions This is the first report of a splicing variant of CNKSR2, and the unique clinical features of this pedigree will help extend our understanding of the genetic and phenotypic spectra of CNKSR2-related disorders.

Aarskog-Scott syndrome (ASS) is a rare, X-linked recessive inherited disorder. Affected individuals may develop short stature and exhibit distinctive skeletal and genital development. Mutations in the FYVE, rhogef and pleckstrin homology domain-containing protein 1 (FGD1) gene, located within the Xp11.21 region, are responsible for the occurrence of ASS. Since it is rare and complex, it can take a long time to obtain a definitive clinical diagnosis unless clinicians are familiar with the disease. In the present study, whole-exome sequencing (WES) was performed to screen for causal variants in a Chinese pediatric patient who exhibited a number of clinical symptoms of ASS, including short stature, facial abnormalities, stubby metacarpals and swollen testis. DNA sequencing revealed a novel c.1270 A>G mutation in exon 6 of the FGD1 gene, which led to an amino acid conversion of asparagine to aspartic acid on codon 424 and in silico analysis indicated that this novel missense mutation was pathogenic. The present study identified a novel variant of the FGD1 gene and to the best of our knowledge, is the first report of ASS in a Chinese individual. The results indicated that WES is an effective tool for the diagnosis of rare and complex syndromes such as ASS.