Management of Craniosynostosis in Lethal Perinatal Hypophosphatasia.

Although perinatal lethal hypophosphatasia (HPP) was once a disease with a universally poor prognosis, it has now become a rare but treatable condition with the advent of enzyme replacement therapy with asfotase alfa. As a result, a greater population of patients with perinatal HPP are presenting with abnormal head shape and craniosynostosis. The authors present here 3 cases of perinatal lethal HPP, 1 treated with traditional open cranial vault remodeling and 2 treated utilizing distraction osteogenesis techniques. All patients demonstrated outcomes comparable to those previously reported with traditional observation or open cranial vault repair. Thorough consideration and discussion between the surgical team and patient's family is needed to determine a treatment plan that best addresses the goals of patient and family in light of recent advances in medical treatment in this rare patient population in which surgical interventions were previously nearly impossible. This article further supports the safety and efficacy of surgical intervention and explores the utility of distraction osteogenesis to address craniosynostosis in this patient population.

To Operate or Not to Operate? Reconstructive Surgical Burden and Quality of Life of Pediatric Patients with Facial Differences.

OBJECTIVE: The Craniofacial Condition Quality of Life Scale (CFC-QoL) was used to evaluate the relationship between surgical burden and quality of life (QoL). DESIGN: Patient-parent dyads completed the CFC-QoL which queries the following QoL domains: Bullying, Peer Problems, Psychological Impact, Family Support, Appearance Satisfaction, and Desire for Appearance Change. Stepwise multivariate linear regressions were performed for each QoL domain. SETTING: Urban tertiary care center. PATIENTS, PARTICIPANTS: Pediatric patients with facial differences, and their parents. INTERVENTION: Survey study. MAIN OUTCOME MEASURE(S): Demographic, diagnostic, and surgical characteristics were collected. Surgical burden was calculated as the standard deviation from the mean number of surgeries per diagnostic cohort. RESULT: Patients (N = 168) were majority female (57.1%) and Hispanic (64.3%). Diagnoses were cleft lip and/or palate (CLP,n = 99) or other craniofacial conditions (CFC,n = 69). Average patient age was 2.3 ± 5.6 years at first reconstructive surgery and 12.3 ± 3.4 years at study enrollment. Patients received an average of 4.3 ± 4.1 reconstructive surgeries.Worse Bullying was associated with higher surgical burden. Worse Peer Problems was associated with higher surgical burden, but only for children with non-CLP CFCs. Worse Family Support was associated with CFC diagnosis, female sex, and higher surgical burden. Worse Psychological Impact was associated with higher surgical burden. Worse Appearance Satisfaction was associated with younger age and with lower surgical burden. Greater Desire for Appearance Change was associated with older age, higher surgical burden, CLP diagnosis, female sex, and non-Hispanic ethnicity. Socioeconomic status did not predict QoL per patient self- or parent-proxy report. CONCLUSIONS: Higher surgical burden was associated with worse QoL outcomes in multiple domains.

Psychosocial Burden of Pediatric and Adult Patients With Congenital Versus Traumatic Facial Differences: Assessment of Psychiatric Distress and Healthcare Utilization in the United States From 2004 to 2012.

BACKGROUND: Psychiatric distress and its effects on healthcare utilization in pediatric patients with congenital and traumatic facial differences remain poorly understood. This study analyzes the psychosocial burden along with mental health and reconstructive surgery services utilization of this patient population in comparison with adult patients with such facial differences. METHODS: The 2004-2012 Medical Expenditures Panel Survey was queried for all patients with facial differences. Socioeconomic variables, Patient Health Questionnaire 2 and Kessler 6 scores, responses from validated screening surveys, and utilization of mental health and reconstructive surgery (ie, plastic surgery and otolaryngology) services were compared between pediatric and adult patients with congenital and traumatic facial differences. RESULTS: Children ages 5 to 12 years were more likely to be affected by facial trauma, whereas adolescents aged 13 to 17 years were more affected by congenital facial conditions. Pediatric patients with congenital facial conditions had higher rates of medical care, education, and special therapy utilization ( P < 0.0001), although their facial trauma counterparts used mental health services more often ( P < 0.0001). In adults, more facial trauma patients reported poorer perceived mental health status ( P = 0.01). Among patients with any facial difference, distressed adult patients were less likely to see a reconstructive surgeon even when controlling for socioeconomic variables (0.55 [0.31-0.97], P = 0.04). CONCLUSIONS: In the pediatric population, psychosocial considerations should include both age and etiology of facial differences to best optimize care. Among adults with facial trauma, poor mental health may contribute to lower rates of surgical follow-up, highlighting a potential benefit for provision of mental health services earlier for these patient populations.

The Effects of Chronic Steroid Use on Postoperative Complications Following Thyroidectomy.

BACKGROUND: Patients undergoing thyroidectomy are sometimes on chronic steroids for underlying disease. This study examined the postoperative risk profile of thyroidectomy patients on chronic steroids. METHODS: Patients in the National Surgical Quality Improvement Program (NSQIP) database who underwent thyroidectomy were sorted by presence or absence of chronic steroid use. Clinicodemographics, comorbidities, and postoperative complications were recorded and compared between the two. Univariate and multivariate analyses compared the groups and calculated odds ratios (OR). RESULTS: We identified 42,857 patients. 41,903 (97.8%) patients were not on chronic steroids, while 954 (2.2%) were. Most underwent total thyroidectomy (18,748, 43.75%) or total lobectomy (16,323, 38.09%). Following univariate and multivariate analyses, patients on chronic steroids had increased risk of postoperative bleeding and transfusions (OR = 0.375, p = 0.046, 95% CI 0.223-0.988), open wound infection (OR = 0.226, p < 0.001, 95% CI 0.117-0.437), pulmonary embolism (OR = 0.312, p = 0.034, 95% CI 0.106-0.918), and ventilator use > 48 h (OR = 0.401, p < 0.008, 95% CI 0.205-0.785). CONCLUSIONS: Chronic steroid use prior to thyroidectomy is an independent risk factor for multiple postoperative complications, namely postoperative bleeding and transfusions, open wound infection, pulmonary embolism, and ventilator use over 48 h. Patients on chronic steroids should be medically optimized before thyroidectomy to reduce the risk of potentially life-threatening complications.

Surgical ergonomics: Assessment of surgeon posture and impact of training device during otolaryngology procedures.

Objective: To identify factors associated with cervical-thoracic spine posture in otolaryngology surgeries and evaluate the efficacy of a commercially available posture-training device in enhancing surgeon ergonomics. Methods: Over 3 months, neck and spine posture from individuals performing otolaryngology surgeries was recorded using UpRight Go 2™. Average baseline posture was first recorded and biofeedback was later introduced to attempt to correct posture. The proportion of time spent in upright/neutral cervical-thoracic spine posture was correlated with surgeon and procedure characteristics and compared to proportion of upright posture time after biofeedback intervention. Results: The proportion of upright operating time was significantly different between procedure subtypes and surgical approaches with best performance in rhinology procedures and worst performance in head and neck surgeries (90% vs. 62%; both p < .001). Female gender, shorter stature, and use of sitting stools were associated with greater proportion of surgery spent upright (all p < .05). Loupes use was associated with less time in upright posture (p < .001). With biofeedback intervention, 8 of 10 subjects demonstrated an average of 5% improvement in operating upright, with most improvement found when performing laryngology procedures (7%) and least improvement in head and neck procedures (2%). Conclusions: While surgeon posture varies across otolaryngology surgeries, sitting and minimizing the use of loupes may help promote a more ergonomic operating environment and improve surgeon posture. Although the efficacy of biofeedback intervention from a commercially available posture-training device differs among otolaryngologists, exploration of alternative interventions and incorporation of an ergonomics curriculum is warranted to address postural issues experienced by many surgeons. Level of Evidence: 3.

Accelerated subcutaneous abdominal stem cell adipogenesis predicts insulin sensitivity in normal-weight women with polycystic ovary syndrome.

OBJECTIVE: To examine whether subcutaneous (SC) abdominal adipose stem cell differentiation into adipocytes in vitro predicts insulin sensitivity (Si) in vivo in normal-weight women with polycystic ovary syndrome (PCOS) and controls. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENT(S): Eight normal-weight women with PCOS and 8 age- and body mass index-matched controls. INTERVENTION(S): Women underwent circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total-body dual-energy x-ray absorptiometry, and SC abdominal fat biopsy. MAIN OUTCOME MEASURE(S): PPARγ and CEBPa gene expression and lipid content of adipocytes matured in vitro were compared between women with PCOS and control women, and correlated with patient characteristics, systemic Si, and adipose insulin resistance (adipose-IR). RESULT(S): Serum androgen levels, adipose-IR, and percentage of android fat were greater in women with PCOS than control women. Stem cell PPARγ and CEBPa gene expression increased maximally by day 12 without a female-type effect. In control cells, gene expression positively correlated with fasting serum insulin levels (both genes) and adipose-IR (CEBPa) and negatively correlated with Si (CEBPa). Conversely, CEBPa gene expression in PCOS cells negatively correlated with adipose-IR and serum free testosterone, whereas total lipid accumulation in these cells positively corelated with Si. CONCLUSION: In normal-weight women with PCOS, accelerated SC abdominal adipose stem cell differentiation into adipocytes in vitro favors Si in vivo, suggesting a role for hyperandrogenism in the evolution of metabolic thrift to enhance fat storage through increased cellular glucose uptake.

Dynamic changes in chromatin accessibility, altered adipogenic gene expression, and total versus de novo fatty acid synthesis in subcutaneous adipose stem cells of normal-weight polycystic ovary syndrome (PCOS) women during adipogenesis: evidence of cellular programming.

BACKGROUND: Normal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro. The present study examines chromatin accessibility, RNA expression and fatty acid (FA) synthesis during SC abdominal ASC differentiation into adipocytes in vitro of normal-weight PCOS versus age- and body mass index-matched normoandrogenic ovulatory (control) women to study epigenetic/genetic characteristics as well as functional alterations of PCOS and control ASCs during adipogenesis. RESULTS: SC abdominal ASCs from PCOS women versus controls exhibited dynamic chromatin accessibility during adipogenesis, from significantly less chromatin accessibility at day 0 to greater chromatin accessibility by day 12, with enrichment of binding motifs for transcription factors (TFs) of the AP-1 subfamily at days 0, 3, and 12. In PCOS versus control cells, expression of genes governing adipocyte differentiation (PPARγ, CEBPα, AGPAT2) and function (ADIPOQ, FABP4, LPL, PLIN1, SLC2A4) was increased two-sixfold at days 3, 7, and 12, while that involving Wnt signaling (FZD1, SFRP1, and WNT10B) was decreased. Differential gene expression in PCOS cells at these time points involved triacylglycerol synthesis, lipid oxidation, free fatty acid beta-oxidation, and oxidative phosphorylation of the TCA cycle, with TGFB1 as a significant upstream regulator. There was a broad correspondence between increased chromatin accessibility and increased RNA expression of those 12 genes involved in adipocyte differentiation and function, Wnt signaling, as well as genes involved in the triacylglycerol synthesis functional group at day 12 of adipogenesis. Total content and de novo synthesis of myristic (C14:0), palmitic (C16:0), palmitoleic (C16:1), and oleic (C18:1) acid increased from day 7 to day 12 in all cells, with total content and de novo synthesis of FAs significantly greater in PCOS than controls cells at day 12. CONCLUSIONS: In normal-weight PCOS women, dynamic chromatin remodeling of SC abdominal ASCs during adipogenesis may enhance adipogenic gene expression as a programmed mechanism to promote greater fat storage.

Adipose Insulin Resistance in Normal-Weight Women With Polycystic Ovary Syndrome.

CONTEXT: Normal-weight women with polycystic ovary syndrome (PCOS) may have adipose tissue insulin resistance (adipose-IR). OBJECTIVE: To examine whether adipose-IR and subcutaneous (SC) abdominal adipose stem cell (ASC) gene expression are altered in normal-weight women with PCOS and correlated with hyperandrogenemia and/or whole-body IR. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENTS: Ten normal-weight women with PCOS and 18 control subjects matched for age and body mass index. INTERVENTION(S): Women underwent circulating hormone and metabolic measurements, IV glucose tolerance testing, total-body dual-energy x-ray absorptiometry, and SC abdominal fat biopsy. MAIN OUTCOME MEASURE(S): Adipose-IR (fasting insulin × total fatty acid levels) and SC abdominal ASC gene expression were compared between groups and correlated with clinical outcomes. RESULTS: Adipose-IR was greater in women with PCOS than in control subjects (P < 0.01), with 29 pmol/L × mmol/L providing 94% specificity and 80% sensitivity in discriminating the two groups (P < 0.001). Adipose-IR positively correlated with serum androgen and log of fasting triglyceride (TG) levels, percentage of small adipocytes (P < 0.01, all correlations), and acute insulin response to glucose (P < 0.05); and negatively correlated with insulin sensitivity (Si; P < 0.025) and serum adiponectin levels (P < 0.05). Adjusting for serum androgens, adipose-IR correlations with Si and log TG levels remained significant. ASC genes were differentially expressed by the two groups. Expression of functionally critical genes was associated with serum testosterone and/or fasting insulin levels. CONCLUSION: Normal-weight women with PCOS have increased adipose-IR and altered ASC gene expression related to hyperandrogenism and IR.

Precocious subcutaneous abdominal stem cell development to adipocytes in normal-weight women with polycystic ovary syndrome.

OBJECTIVE: To examine whether abnormal subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes in polycystic ovary syndrome (PCOS) correlates with hyperandrogenism. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENT(S): Eight normal-weight women with PCOS and eight normoandrogenic ovulatory (control) women matched for age and body mass index. INTERVENTION(S): Circulating hormone and metabolic measurements, intravenous glucose tolerance testing, total body dual-energy X-ray absorptiometry, and SC abdominal fat biopsy. MAIN OUTCOME MEASURE(S): In vitro ASC commitment to preadipocytes (ZFP423 protein expression, day 0.5), preadipocyte differentiation to adipocytes (PPARγ gene expression, day 3) and adipocyte lipid content (Oil-Red-O fluorescence, day 12) comparisons correlated with clinical outcomes. RESULT(S): In women with PCOS, SC abdominal ASCs compared with those of control women showed exaggerated commitment to preadipocytes and had greater lipid content in newly formed adipocytes after in vitro maturation. In all women combined, ZFP423 protein expression negatively correlated with fasting plasma glucose levels whereas the lipid content of newly formed adipocytes positively correlated with both PPARγ gene expression and serum free testosterone levels. CONCLUSION(S): In normal-weight women with PCOS compared with the control group, exaggerated SC abdominal ASC commitment to preadipocytes and enhanced adipocyte lipid content during maturation in vitro negatively and positively correlate with circulating fasting glucose and androgen levels, respectively, as a possible mechanism to maintain glucose-insulin homeostasis when fat accretion is accelerated.