Richard J. Redett

Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate.

Nonsyndromic cleft palate (CP) is a common birth defect with a complex and heterogeneous etiology involving both genetic and environmental risk factors. We conducted a genome‐wide association study (GWAS) using 550 case‐parent trios, ascertained through a CP case collected in an international consortium. Family‐based association tests of single nucleotide polymorphisms (SNP) and three common maternal exposures (maternal smoking, alcohol consumption, and multivitamin supplementation) were used in a combined 2 df test for gene (G) and gene‐environment (G × E) interaction simultaneously, plus a separate 1 df test for G × E interaction alone. Conditional logistic regression models were used to estimate effects on risk to exposed and unexposed children. While no SNP achieved genome‐wide significance when considered alone, markers in several genes attained or approached genome‐wide significance when G × E interaction was included. Among these, MLLT3 and SMC2 on chromosome 9 showed multiple SNPs resulting in an increased risk if the mother consumed alcohol during the peri‐conceptual period (3 months prior to conception through the first trimester). TBK1 on chr. 12 and ZNF236 on chr. 18 showed multiple SNPs associated with higher risk of CP in the presence of maternal smoking. Additional evidence of reduced risk due to G × E interaction in the presence of multivitamin supplementation was observed for SNPs in BAALC on chr. 8. These results emphasize the need to consider G × E interaction when searching for genes influencing risk to complex and heterogeneous disorders, such as nonsyndromic CP. Genet. Epidemiol. 2011.  © 2011 Wiley‐Liss, Inc. 35: 469‐478, 2011

Methods and results of rhinophyma treatment.

Rhinophyma is a disfiguring soft‐tissue hypertrophy of the nose. It is an uncommon disease that primarily affects Caucasian men in the fifth to seventh decades of life. Nine cases from the authors’ series and a comparison of results following various treatment modalities are presented. Eight of the patients were Caucasian and one was African American. Excision of the diseased tissue with a scalpel or Goulian dermatome using loupe magnification provided the safest means of preserving the underlying sebaceous gland fundi that permit spontaneous re‐epithelialization with the least scarring. (Plast. Reconstr. Surg. 107: 1115, 2001.)

Limb salvage of lower-extremity wounds using free gracilis muscle reconstruction.

&NA; An extensive series reviewing the benefits and drawbacks of use of the gracilis muscle in lower‐extremity trauma has not previously been collected. In this series of 50 patients, the use of microvascular free transfer of the gracilis muscle for lower‐extremity salvage in acute traumatic wounds and posttraumatic chronic wounds is reviewed. In addition, the wound size, injury patterns, problems, and results unique to the use of the gracilis as a donor muscle for lower‐extremity reconstruction are identified. In a 7‐year period from 1991 to 1998, 50 patients underwent lower‐extremity reconstruction using microvascular free gracilis transfer at the University of Maryland Shock Trauma Center, Johns Hopkins Hospital, and Johns Hopkins Bayview Medical Center. There were 22 patients who underwent reconstruction for coverage of acute lower‐extremity traumatic soft‐tissue defects associated with open fractures. The majority of patients were victims of high‐energy injuries with 91 percent involving motor vehicle or motorcycle accidents, gunshot wounds, or pedestrians struck by vehicles. Ninety‐one percent of the injuries were Gustilo type IIIb tibial fractures and 9 percent were Gustilo type IIIc. The mean soft‐tissue defect size was 92.2 cm2. Successful limb salvage was achieved in 95 percent of patients. Twenty‐eight patients with previous Gustilo type IIIb tibia‐fibula fractures presented with posttraumatic chronic wounds characterized by osteomyelitis or deep soft‐tissue infection. Successful free‐tissue transfer was accomplished in 26 of 28 patients (93 percent). All but one of the patients in this group who underwent successful limb salvage (26 of 27, or 96 percent) are now free of infection. Use of the gracilis muscle as a free‐tissue transfer has been shown to be a reliable and predictable tool in lower‐extremity reconstruction, with a flap success and limb salvage rate comparable to those in other large studies. (Plast. Reconstr. Surg. 106: 1507, 2000.)

Prevalence and severity of obstructive sleep apnea and snoring in infants with Pierre Robin sequence.

Objective To evaluate the prevalence and severity of obstructive sleep apnea in infants with Pierre Robin sequence prior to airway intervention and determine whether snoring correlates with the presence of obstructive sleep apnea in this population. Design Retrospective case series. Setting Urban tertiary care teaching hospital. Participants/Methods Review of infants with Pierre Robin sequence who underwent polysomnography in the first year of life from 2002 to 2007. Only results from the initial polysomnography were analyzed. A subgroup of consecutive prospectively tested patients was also evaluated. Results A total of 33 infants with Pierre Robin sequence were identified. Of these, 13 (39%), 11 girls and two boys, underwent polysomnography in the first year of life. The mean age at evaluation was 48 days (range, 7 to 214 days). Seven nonconsecutive and six consecutive patients were included, and no significant differences were seen between groups. Obstructive sleep apnea was identified in 11 of 13 (85%) infants. The mean obstructive apnea-hypopnea index was 33.5 (range, 0 to 85.7). Obstructive sleep apnea severity was mild in 2 of 11 (18%), moderate in 3 of 11 (27%), and severe in 6 of 11 (55%). Mean end-tidal Pco2 measurements were elevated at 59 mm Hg (range, 47 to 76 mm Hg). Mean oxygen saturation nadir was decreased at 80% (range, 68% to 93%). Snoring occurred in only 7 of 13 (54%). Of the subjects with obstructive sleep apnea, snoring occurred in 6 of 11 (55%). Conclusion The high incidence of obstructive sleep apnea in this group suggests that polysomnography should be promptly performed in children with Pierre Robin sequence. Although snoring was seen in the majority, the absence of snoring did not exclude the presence of obstructive sleep apnea.

Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations

Isolated oral clefts, including cleft lip with/without cleft palate (CL/P) and cleft palate (CP), have a complex and heterogeneous etiology. Case-parent trios from three populations were used to study genes spanning chromosome 2, where single nucleotide polymorphic (SNP) markers were analyzed individually and as haplotypes. Case-parent trios from three populations (74 from Maryland, 64 from Singapore and 95 from Taiwan) were genotyped for 962 SNPs in 104 genes on chromosome 2, including two well-recognized candidate genes: TGFA and SATB2. Individual SNPs and haplotypes (in sliding windows of 2–5 SNPs) were used to test for linkage and disequilibrium separately in CL/P and CP trios. A novel candidate gene (ZNF533) showed consistent evidence of linkage and disequilibrium in all three populations for both CL/P and CP. SNPs in key regions of ZNF533 showed considerable variability in estimated genotypic odds ratios and their significance, suggesting allelic heterogeneity. Haplotype frequencies for regions of ZNF533 were estimated and used to partition genetic variance into among-and within-population components. Wright’s fixation index, a measure of genetic diversity, showed little difference between Singapore and Taiwan compared with Maryland. The tensin-1 gene (TNS1) also showed evidence of linkage and disequilibrium among both CL/P and CP trios in all three populations, albeit at a lower level of significance. Additional genes (VAX2, GLI2, ZHFX1B on 2p; WNT6–WNT10A and COL4A3–COL4A4 on 2q) showed consistent evidence of linkage and disequilibrium only among CL/P trios in all three populations, and TGFA showed significant evidence in two of three populations.

The management of patients on anticoagulants prior to cutaneous surgery: case report of a thromboembolic complication, review of the literature, and evidence-based recommendations.

Minor cutaneous surgery is commonly performed by plastic surgeons. Approximately 1.5 to 3.7 percent1,2 of patients having cutaneous surgery take warfarin and an estimated 25 percent take aspirin.2 Temporarily stopping these anticoagulants before cutaneous surgery is a common practice extrapolated from the experiences of thoracic, abdominal, and gynecologic surgery to avoid a bleeding complication. A survey of cutaneous surgeons found that 80 percent discontinue warfarin selectively on patients, of whom 90 percent do not prescribe heparin as bridging therapy.3 The same survey also showed that 26 percent of surgeons always discontinue aspirin preoperatively and another 70 percent discontinue it when they deem it medically unnecessary. Halting anticoagulation, however, increases the risk of thromboembolic complications, especially around the time of surgery, because of the thrombogenic nature of surgery and the potential rebound hypercoagulation from warfarin stoppage.4 Kovich and Otley estimate this thromboembolic risk may be as high as one in 6219 patients in whom warfarin is stopped and 1 in 21,448 in whom aspirin is stopped.5 Although the estimated risk may seem low, the combined high incidence of skin malignancy and high prevalence of anticoagulant use quickly translates into significant numbers of potential thromboembolic complications. The surgeon, therefore, is faced with a choice to accept a theoretically higher likelihood of bleeding should the patient be anticoagulated or subject the patient to the thromboembolic risks that the anticoagulation was seeking to avoid. The decision is often deferred to the caretaker prescribing the anticoagulation or to the physician or provider performing the preoperative evaluation. These providers, in turn, are unable to make an informed decision without knowing the likelihood, expected severity, and expected consequence of a bleeding complication. Recent reports have explored a range of surgical procedures that can be safely and effectively performed in the setting of anticoagulation. Surgeons must be familiar with those procedures that can be safely performed without stopping anticoagulation, to avoid unnecessary and potentially life-threatening thromboembolic complications. Presented here is a case report of a devastating neurologic complication after anticoagulation was withheld for cutaneous surgery. The current literature regarding cutaneous surgery in the presence of anticoagulation is reviewed. Also presented are evidence-based recommendations to assist the plastic surgeon in making an appropriate decision when faced with performing cutaneous surgery on patients taking anticoagulation.

The Two-dermal-flap Umbilical Transposition: A Natural and Aesthetic Umbilicus after Abdominoplasty

Background: The aesthetic and natural appearance of the transposed umbilicus after abdominoplasty is a key factor to the overall result and satisfaction of patient and surgeon alike. In this article, the authors present a technique in umbilical transposition that creates a natural-appearing umbilicus. Methods: The skin in the neoumbilical position is deepithelialized and incised in the midline, thus creating two dermal flaps that are sutured down to the abdominal fascia, thereby creating a natural periumbilical concavity, inconspicuous scars, and a tension-free closure, resulting in a decreased chance for cicatricial umbilical scarring. Twenty patients underwent umbilical transposition during abdominoplasty with this technique between 2003 and 2005. Results: Both patient and surgeon satisfaction were very high, with three senior surgeons changing their surgical technique after being introduced to that described in this article. One complication culminated in partial skin dehiscence early in our experience when deep dermal sutures were not used for skin closure. Conclusion: The technique described is simple, safe, and easily learned, and results in a very satisfying aesthetic and natural-appearing umbilicus in patients after abdominoplasty.

Characterization of Obstructive Sleep Apnea Before and After Tongue-Lip Adhesion in Children With Micrognathia

Objectives To characterize airway obstruction before and after tongue-lip adhesion in children with micrognathia using polysomnography. Design Retrospective pilot case series. Participants and Methods Evaluation of all children with micrognathia who underwent tongue-lip adhesion and polysomnography before and after surgery from 2002 to 2007 (N = 8). Results Eight children met inclusion criteria; six were girls. The mean interval between polysomnography and tongue-lip adhesion was 6 days (range, 2 to 13 days) preoperatively and 17 days (range, 5 to 32 days) postoperatively. Severe obstructive sleep apnea was identified in seven of eight (88%) children, with a mean preoperative obstructive apnea hypopnea index of 52.6 events per hour (range, 7.1 to 85.7 events per hour). None had significant central sleep apneas (>5 per hour). Tongue-lip adhesion resulted in a mean decrease of 34.5 events per hour (range, −65.8 to 71.6 events per hour). After tongue-lip adhesion, seven of eight (87.5%) patients had an improved obstructive apnea hypopnea index, with resolution of obstructive sleep apnea in one child and improvement to mild (two) and moderate (two) obstructive sleep apnea in four others. Only one child had an obstructive apnea hypopnea index that increased after tongue-lip adhesion. Peak end-tidal pCO2 measurements were elevated in all eight children before surgery at a mean of 60 mm Hg (range, 52 to 76 mm Hg) that improved to 51 mm Hg (range, 45 to 59 mm Hg), with normal peak levels in four children. Oxygen saturation nadir improved from 73% (range, 58% to 81%) to 82% (range, 65% to 94%). Conclusions Tongue-lip adhesion may be performed in micrognathic infants to alleviate airway obstruction. Polysomnographic evaluation in this pilot study before and after surgery suggests that tongue-lip adhesion usually improves obstructive sleep apnea, but only 38% had complete resolution. Future studies of tongue-lip adhesion efficacy should include Polysomnographic evaluation.

Facial palsy: Anatomy, etiology, grading, and surgical treatment

The modern microvascular reconstructive surgeon has quite an arsenal when managing the paralyzed face and injury to the facial nerve. After a brief description of the anatomy, etiology, facial nerve syndromes, and grading schemes, we detail our approach to the patient with facial paralysis. In reviewing our methods, we discuss the organ-based timing protocol, along with recent advancements in surgical technique.

The FGF and FGFR Gene Family and Risk of Cleft Lip With or Without Cleft Palate

Background Isolated, nonsyndromic cleft lip with or without cleft palate is a common human congenital malformation with a complex and heterogeneous etiology. Genes coding for fibroblast growth factors and their receptors (FGF/FGFR genes) are excellent candidate genes. Methods We tested single-nucleotide polymorphic markers in 10 FGF/FGFR genes (including FGFBP1, FGF2, FGF10, FGF18, FGFR1, FGFR2, FGF19, FGF4, FGF3, and FGF9) for genotypic effects, interactions with one another, and with common maternal environmental exposures in 221 Asian and 76 Maryland case-parent trios ascertained through a child with isolated, nonsyndromic cleft lip with or without cleft palate. Results Both FGFR1 and FGF19 yielded evidence of linkage and association in the transmission disequilibrium test, confirming previous evidence. Haplotypes of three single-nucleotide polymorphisms in FGFR1 were nominally significant among Asian trios. Estimated odds ratios for individual single-nucleotide polymorphic markers and haplotypes of multiple markers in FGF19 ranged from 1.31 to 1.87. We also found suggestive evidence of maternal genotypic effects for markers in FGF2 and FGF10 among Asian trios. Tests for gene-environment (G x E) interaction between markers in FGFR2 and maternal smoking or multivitamin supplementation yielded significant evidence of G x E interaction separately. Tests of gene-gene (G x G) interaction using Cordells method yielded significant evidence between single-nucleotide polymorphisms in FGF9 and FGF18, which was confirmed in an independent sample of trios from an international consortium. Conclusion Our results suggest several genes in the FGF/FGFR family may influence risk for isolated, nonsyndromic cleft lip with or without cleft palate through distinct biological mechanisms.