Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

Background: Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. Methods: This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. Results: We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. Conclusions: This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation

Periareolar approach for the correction of congenital symmastia

This report elucidates the continued and relatively rare problem of congenital symmastia and its surgical repair without concomitant bilateral breast reduction. This case highlights the use of suction-assisted lipectomy techniques to address the excess fat in the presternal web and a periareolar approach for access to the intermammary space. The periareolar incision allows for the use of a concealed approach and the avoidance of a central scar that could result in hypertrophy or keloid formation, especially in this patient who is more prone to hypertrophic scarring. Furthermore, plication of the central web dermis to the sternal periosteum in a more superior position serves to not only correct the symmastia but also redrape the excess skin and restore the blunted inframammary folds

Corrective otoplasty for symptomatic prominent ears in U.S. soldiers

The purpose of this investigation was to evaluate U.S. Army soldiers who presented to the plastic surgery service with the inability to properly wear a government-issued Kevlar field helmet because of their prominent ear deformity. Between September 2000 and April 2002, four patients with prominent ears and helical rim skin abrasions with breakdown attributable to abutment from their helmets underwent open otoplasty with conchal bowl resection via a posterior approach. Symptomatic relief and cosmetic improvement were obtained, with no incidence of complications or recurrence during the follow-up period, which ranged from 9 to 22 months. All patients were able to wear their Army-issued Kevlar helmets without difficulty after surgery. Otoplasty is an effective, reliable procedure that has now been performed to alleviate symptoms in an otherwise asymptomatic patient population

Virtual Surgical Planning in Craniofacial Surgery

The complex three-dimensional anatomy of the craniofacial skeleton creates a formidable challenge for surgical reconstruction. Advances in computer-aided design and computer-aided manufacturing technology have created increasing applications for virtual surgical planning in craniofacial surgery, such as preoperative planning, fabrication of cutting guides, and stereolithographic models and fabrication of custom implants. In this review, the authors describe current and evolving uses of virtual surgical planning in craniofacial surgery

Mastodynia refractory to medical therapy: is there a role for mastectomy and breast reconstruction?

Mastodynia is among the most frequently reported symptoms in women with breast complaints; it is usually classified as cyclic, noncyclic, or nonbreast in origin. A useful response with medical or conservative therapy is obtained in the majority of these patients. There is a subset of patients, however, who have exhausted every medical effort and psychiatric counseling and will desire mastectomy with breast reconstruction in the hope of alleviating their chronic pain. Three patients with noncyclical, bilateral mastodynia referred for breast reconstruction options from December of 2000 to March of 2004 are presented in this article. Daily breast pain charts with a visual analogue scale for pain assessment were analyzed and recorded for all patients throughout the study period. Two patients underwent delayed reconstruction and had complete resolution of pain 6 to 8 weeks after bilateral mastectomy, with no recurrence of mastalgia after reconstruction. One patient underwent bilateral mastectomy with immediate reconstruction and achieved complete resolution of her pain 3 months postoperatively. Histopathologic findings of all breast specimens revealed benign breast tissue with proliferative breast disease consistent with mastodynia. This modality, which includes mastectomy with or without reconstruction, is a viable alternative after exhaustion of all other nonsurgical options and when quality of life is significantly affected. Although mastectomy for the treatment of mastodynia refractory to medical therapy does not guarantee alleviation of chronic breast pain, it should be considered in these often desperate patients

Flap monitoring and patient management

Complications in free-tissue transfer patients cannot be completely prevented; however, the incidence may be significantly reduced by a thorough preoperative evaluation and initiation of prophylactic strategies, meticulous surgical technique, and diligent postoperative monitoring. Emergent exploration must be performed soon after obstruction occurs if it is to be successful, and early exploration and repair is likely in compromised flaps if they are monitored frequently in the initial postoperative period. This article reviews the importance of clinical management in this patient population, the recommended frequency of flap monitoring, and the most commonly used methods of monitoring the transferred tissue whether or not the flap is readily visible. The authors also review the anticoagulants used and a postoperative flap monitoring protocol

Reconstruction of Head and Neck Defects: A Systematic Approach to Treatment

Reconstruction of composite maxillofacial defects after tumor excision or trauma is difficult. The role of the reconstructive surgeon is to have a diverse armamentarium of reconstructive options to enable an aesthetic and functional reconstruction while minimizing the morbidity to the patient. This article will present a systematic review of composite maxillofacial reconstruction with free tissue transfer

Vascularized composite allotransplant in the realm of regenerative plastic surgery

Vascularized composite allotransplant (VCA) has led to new treatment options for patients with severe upper extremity and facial injuries. Although VCA can restore form and function, it exposes the patient to the risks associated with lifelong immunosuppression. Hopefully, ongoing advances in regenerative medicine will someday obviate the need for VCA, but until that time, VCA remains an immediate means of reconstructing otherwise unreconstructable defects. We review the outcomes of hand and face transplants, as well as the recent developments in immunosuppression as it relates to the field of VCA