Prevalence of craniosynostosis in Finland, 1987-2010: A population-based study.

BACKGROUND: Craniosynostosis is a prevalent craniofacial malformation in Finland; however, comprehensive population-based epidemiological data are limited. This study aimed to estimate the total and birth prevalence of craniosynostosis in Finland from 1987 to 2010 and examine temporal trends. METHODS: We collected the data from nationwide registers maintained by the Finnish Institute for Health and Welfare and Statistics Finland, as well as treating hospitals, encompassing live births, stillbirths, terminations for fetal anomalies, and infant deaths with suspected or diagnosed craniosynostosis or skull deformation. A craniofacial surgeon and a clinical geneticist reviewed 1878 medical records for diagnostic confirmation. RESULTS: Out of 877 craniosynostosis cases, 83% were single-suture synostoses (all live births), 10% craniosynostosis syndromes, and 7% multisutural non-syndromic synostoses. Live birth prevalence from 1987 to 2010 was 6.0/10,000 live births, ranging from 5.0/10,000 in 1987 to 7.5/10,000 in 2010. Total prevalence, including live births, stillbirths, and terminations, varied from 5.0/10,000 in 1987 to 8.0/10,000 in 2010. Sagittal synostosis was the most common synostosis, with a prevalence of 3.9/10,000 live births, followed by metopic (0.6/10,000), unicoronal (0.4/10,000), and unilambdoid (0.1/10,000) synostoses. CONCLUSIONS: The total combined prevalence of all craniosynostosis types significantly increased driven by a nonsignificant rise across all subgroups and a significant increase in the syndrome group. In live births increase was significant only within the syndrome subgroup, primarily due to an increase in Muenke syndrome patients. The rising prevalence of syndromes necessitates further investigation. Contrasting with trends in Europe, Australia, and the USA, Finland showed no significant increase in metopic craniosynostosis.

Outcomes of Primary Furlow Double-Opposing Z-plasty for the Treatment of Symptomatic Submucous Cleft Palate.

BACKGROUND: Submucous cleft palate (SMCP) requires surgical repair if symptomatic. The Furlow double-opposing Z-plasty is the preferred method in Helsinki cleft center. AIMS: To assess the efficacy and complications of Furlow Z-plasty in the treatment of symptomatic SMCP. METHODS: This retrospective study reviewed documentation of 40 consecutive patients with symptomatic SMCP who underwent primary Furlow Z-plasty by 2 high-volume cleft surgeons at a single center between 2008 and 2017. Patients underwent perceptual and instrumental evaluation of velopharyngeal function (VPF) by speech pathologists preoperatively and postoperatively. RESULTS: The median age at Furlow Z-plasty was 4.8 years (SD 2.6, range 3.1-13.6). The overall success rate, including postoperative competent or borderline competent VPF, was 83%, and 10% required secondary surgery for residual velopharyngeal insufficiency. The success rate was 85% in nonsyndromic, and 67% in syndromic patients with no significant difference ( P =0.279). Complications arose in only 2 (5%) patients. No children were found to have obstructive sleep apnea postoperatively. CONCLUSION: Furlow primary Z-plasty is a safe and effective operation for symptomatic SMCP with a success rate of 83% with only 5% rate of complications.

ErbB signaling is a potential therapeutic target for vascular lesions with fibrous component.

Background: Sporadic venous malformation (VM) and angiomatosis of soft tissue (AST) are benign, congenital vascular anomalies affecting venous vasculature. Depending on the size and location of the lesion, symptoms vary from motility disturbances to pain and disfigurement. Due to the high recurrence of the lesions, more effective therapies are needed. Methods: As targeting stromal cells has been an emerging concept in anti-angiogenic therapies, here, by using VM/AST patient samples, RNA-sequencing, cell culture techniques, and a xenograft mouse model, we investigated the crosstalk of endothelial cells (EC) and fibroblasts and its effect on vascular lesion growth. Results: We report, for the first time, the expression and secretion of transforming growth factor A (TGFA) in ECs or intervascular stromal cells in AST and VM lesions. TGFA induced secretion of vascular endothelial growth factor (VEGF-A) in paracrine fashion, and regulated EC proliferation. Oncogenic PIK3CA variant in p.H1047R, a common somatic mutation found in these lesions, increased TGFA expression, enrichment of hallmark hypoxia, and in a mouse xenograft model, lesion size, and vascularization. Treatment with afatinib, a pan-ErbB tyrosine-kinase inhibitor, decreased vascularization and lesion size in a mouse xenograft model with ECs expressing oncogenic PIK3CA p.H1047R variant and fibroblasts. Conclusions: Based on the data, we suggest that targeting of both intervascular stromal cells and ECs is a potential treatment strategy for vascular lesions having a fibrous component. Funding: Academy of Finland, Ella and Georg Ehnrooth foundation, the ERC grants, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Jane and Aatos Erkko Foundation, GeneCellNano Flagship program, and Department of Musculoskeletal and Plastic Surgery, Helsinki University Hospital.

How Early Can We Predict the Need for VPI Surgery?

Velopharyngeal dimensions change as a child with cleft palate (CP) grows. The aim of this study was to assess if the decision for velopharyngeal insufficiency (VPI) surgery can be made by the age of 3 years among CP children with moderate-to-severe VPI. In addition, we sought to clarify if speech therapy before VPI surgery is beneficial for VPI speech characteristics. Methods: This retrospective study reviewed documentation of children with moderate-to-severe VPI at age 3 years who did not undergo VPI surgery until age 5 years. Based on the national cleft register, 959 patients with syndromic and nonsyndromic CP were treated by the craniofacial team at Helsinki University Hospital, Finland between 2000 and 2014. Eighty-six patients fulfilled the study inclusion criteria. The speech pathologist evaluated velopharyngeal function at age 3, 5, and 8 years. Results: Of the 86 children presenting with moderate-to-severe VPI at age 3 years, 94% still had moderate-to-severe VPI at age 5 years, even though speech therapy was offered to 77%. Of those whose velopharyngeal function improved by age 5 years, function regressed to incompetent over time. Overall, 93% underwent VPI surgery and 82% underwent VPI surgery between ages 5 and 8 years. Only 23% at age 8 years still had moderate-to-severe VPI. Speech therapy alone did not improve VPI speech characteristics. Conclusions: Moderate-to-severe VPI did not improve from 3 to 5 years or improved but subsequently relapsed. This suggests that the decision for VPI surgery can be made for children aged 3 years with moderate-to-severe VPI.

Pierre Robin sequence causes position-dependent obstructive sleep apnoea in infants.

INTRODUCTION: Obstructive sleep apnoea (OSA) and feeding difficulties are key problems for Pierre Robin sequence (PRS) infants. OSA management varies between treatment centres. Sleep positioning represents the traditional OSA treatment, although its effectiveness remains insufficiently evaluated. DESIGN: To complete a polysomnographic (PSG) evaluation of effect of sleep position on OSA in PRS infants less than 3 months of age. We analysed a 10-year national reference centre dataset of 76 PRS infants. PSG was performed as daytime recordings for 67 in the supine, side and prone sleeping position when possible. In most cases, recording included one cycle of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep in each position. RESULTS: One-third of infants (9/76, 12%) had severe OSA needing treatment intervention prior to PSG. During PSG, OSA with an obstructive apnoea and hypopnoea index (OAHI) >5 per hour was noted in 82% (55/67) of infants. OSA was most severe in the supine and mildest in the side or in the prone positions. The median OAHI in the supine, side and prone positions were 31, 16 and 19 per hour of sleep (p=0.003). For 68% (52/67) of the infants, either no treatment or positional treatment alone was considered sufficient. CONCLUSIONS: The incidence of OSA was 84% (64/76) including the nine infants with severe OSA diagnosed prior to PSG. For the most infants, the OSA was sleep position dependent. Our study results support the use of PSG in the evaluation of OSA and the use of sleep positioning as a part of OSA treatment.

Speech Characteristics and Oromyofunctional Outcomes in Two Bimaxillary Face Transplantation Patients in Helsinki.

OBJECTIVES/HYPOTHESIS: Facial functional restoration is one of the main goals in face transplantation. We report the oromyofacial function outcomes of two bimaxillary face transplantation (FT) patients in Helsinki. STUDY DESIGN: Outcome Study. METHODS: Two male patients, aged 34 and 59, had severe functional facial disabilities following self-inflicted gunshot injuries sustained to their mid and lower faces several years earlier. Both underwent tooth-bearing maxillomandibular face transplantation in 2016 and 2018. We collected data regarding speech, swallowing, sensory recovery, motor recovery, and olfaction prior to transplantation. Patient charts were reviewed from the follow-up period of 4 and 2 years, respectively. RESULTS: Speech intelligibility, acceptability, and articulation continued to improve during follow-up for both patients. Voice quality and resonance were mainly normal at last follow-up. Swallowing improved once lip occlusion was regained, with only minor aspiration evident on videofluorography. Both patients had significant improvement in facial mimic muscle function after FT. The first patient who only had buccal sensory nerves connected has only recovered protective facial sensation, whereas our second patient with buccal, infraorbital, and alveolar nerves connected has almost complete facial two-point discrimination. CONCLUSION: Both patients have regained satisfactory facial sensory and motor function. Sensory recovery seems to be faster and more precise if multiple sensory nerve coaptations are performed. Swallowing and speech have continued to improve over time although not reaching the level of the normal population. We demonstrate how speech-corrective surgery can safely be performed in a FT patient and can improve speech recovery. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E2643-E2649, 2021.

Palatal Re-Repair With Z-Plasty in Treatment of Velopharyngeal Insufficiency of Syndromic and Nonsyndromic Patients With Cleft Palate.

BACKGROUND: Velopharyngeal insufficiency (VPI) often results from palatal shortening or insufficient levator function after cleft palate repair. AIMS: To assess the efficacy of palatal re-repair with Z-plasty in treatment of VPI for patients with isolated cleft palate (ICP). METHODS: This retrospective analysis comprised 130 consecutive patients who had ICP with VPI that required Z-plasty as secondary surgery between 2008 and 2017. Pre- and post-operative evaluation of velopharyngeal function was done perceptually and instrumentally by Nasometer. RESULTS: Median patient age at Z-plasty was 6.8 years (range 3.0-20.1). Of the 130 patients, preoperatively VPI was severe in 73 (56%), mild-to-moderate in 55 (42%), and borderline in 2 (2%). Postoperatively, 105 (81%) of patients achieved adequate (normal or borderline) velopharyngeal competence and 16 (12%) required second operation for residual VPI. The success rate was 84% in nonsyndromic patients, 79% in nonsyndromic Pierre Robin sequence patients, and 58% in syndromic patients. In syndromic children, the speech outcome was significantly worse than in nonsyndromic children (P = 0.014). Complications included wound healing problems in 3 patients (2%), mild infection in 1 patient (1%), postoperative bleeding in 1 (1%), and postoperative fistula in 2 (2%). CONCLUSION: Palatal re-repair with Z-plasty is a safe operation for VPI correction in patients with ICP with a success rate of 81%. In syndromic patients, the procedure did not seem to work as well as in nonsyndromic patients.

Pierre Robin Sequence: Incidence of Speech-Correcting Surgeries and Fistula Formation.

OBJECTIVE: Children with Pierre Robin sequence (PRS) and cleft palate have a high rate of velopharyngeal insufficiency (VPI) following primary palatoplasty. Our purpose was to determine the long-term incidence of speech-correcting surgeries (SCSs) and fistula rates in PRS after primary palatoplasty and the influence of possible causal factors. DESIGN: A retrospective single-center, observational chart review study. PARTICIPANTS: After exclusion, the study cohort comprised 78 nonsyndromic PRS children (48 females) born between 1990 and 2009 and treated at the Cleft Palate and Craniofacial Center of Helsinki University Hospital, Finland. Causal factors included gender, surgeon, age at primary palatoplasty, surgical technique, airway obstruction in infancy, and cleft severity. We analyzed the outcome at age 8 years and at data retrieval, with a median follow-up of 14 years (range: 8-27 years). RESULTS: Thirty-four (43.6%) children received SCS by age 8 years, and of the 19 (24.4%) postoperative fistulas, 6 (7.7%) underwent closure. At data retrieval, 37 (47.4%) children had undergone SCS and 8 (10.3%) had a fistula closure. Median age at SCS was 6 years. The results showed no significant association for gender, surgeon, age at primary palatoplasty, surgical technique, cleft severity, or airway obstruction in infancy regarding incidence of SCS, fistulas, or repaired fistulas. CONCLUSION: Pierre Robin sequence in children is associated with a high incidence of SCS and fistula formation, which necessitates accurate clinical follow-up and observation of speech development. The development of VPI in PRS is complex and most likely involving multiple factors.

Length of synostosis and segmented intracranial volume correlate with age in patients with non-syndromic sagittal synostosis.

PURPOSE: The aim of this study is to compare the length of synostosis and segmented intracranial volume (SIV) with age in children with non-syndromic sagittal synostosis. METHODS: Thirty-three consecutive patients (22 boys) who had been operated by cranial vault remodeling because of sagittal synostosis were compared retrospectively from 3D-CT imaging data sets obtained from volumetric CT. The mean age of the patients at preoperative CT imaging was 0.49 (range 0.13-1.3) years and at 1-year postoperative imaging 1.8 (range 1.3-3) years. The mean interval between preoperative CT imaging and surgery was 0.25 (range 0-0.8) years. Pearson's correlation and Student's t test were used in the statistical analyses. RESULTS: Length of sagittal synostosis correlated positively with age at preoperative CT (r = 0.688, p < 0.01). Children with total synostosis (n = 9) were significantly older (mean age 0.74 vs. 0.4 years, p < 0.01) than those with partial synostosis. Of partial synostoses, 9 were located anteriorly, 3 in the middle, and 12 posteriorly. The mean synostosis ratio (synostosis length/total sagittal suture length × 100) was 83%. Preoperative SIV correlated positively with age at preoperative CT (r = 0.788, p < 0.01), whereas the 1-year postoperative SIV did not correlate with age at operation. The older the child at the time of the operation, the less the percentage SIV increased. CONCLUSIONS: Length of sagittal synostosis and SIV increased with age.

Angiomatosis of soft tissue as an important differential diagnosis for intramuscular venous malformations.

Background We aimed to improve management of extremity low-flow vascular malformations by analyzing the histology and imaging of venous malformations (VMs) not responsive to sclerotherapy. Method We reviewed patient records of 102 consecutive patients treated with sclerotherapy for extremity VM in our institution to identify patients who had undergone surgery due to insufficient response. We semi-quantitatively analysed the tissue specimens and compared histological findings to those in preoperative imaging. Result The number of patients operated on was 19 (18.6%); 15 of them had lower-extremity intramuscular lesions. The histological pattern of 13 of these 15 lesions corresponded to angiomatosis of soft tissue (AST). All other lesions treated surgically were VMs. The histology of AST was distinctive but magnetic resonance imaging findings often overlapped with those of VM. Conclusion AST is easily mixed with intramuscular VM. The differentiation of these two entities has therapeutic importance. We emphasize the role of histology in the differential diagnostics of intramuscular slow-flow vascular malformations.

Sclerotherapy complications of peripheral venous malformations.

Background Sclerotherapy is often the primary treatment for peripheral venous malformations. It is mostly sufficient alone, but can be combined with other endovascular techniques. Despite its mini-invasiveness, it is not without potentially severe complications. Here, we systematically report sclerotherapy complications in trunk and extremity venous malformations. Methods We retrospectively assessed the complications of 127 consecutive patients who had received sclerotherapy for peripheral venous malformation in our tertiary care unit (January 2007-August 2013). We applied the Clavien-Dindo classification to grade the severity of complications. We mostly used detergent sclerosants (85.7%), and less often ethanol (5.7%) or bleomycin (4.2%). In 4.2% of the procedures, we combined glue, coils, endovascular laser or particles to sclerotherapy. Results The overall complication rate per procedure was 12.5%. Most complications (83.3%) were local and managed conservatively. We encountered four severe complications, all related to blood coagulopathy. Subcutaneous lesion location and use of ethanol significantly increased the risk of local complications. Conclusion Sclerotherapy alone or combined with other endovascular techniques is a safe method for local venous malformations with moderate risk for conservatively manageable complications. Blood coagulopathy constitutes a risk for, otherwise rare, severe complications.

Complications of sclerotherapy for 75 head and neck venous malformations.

Sclerotherapy is one treatment option for head and neck venous malformations (VMs). Evaluation of complication risks is, however, essential to improve its safety. We aimed to systematically report sclerotherapy complications by means of the Clavien-Dindo classification and to distinguish factors predisposing to complications. We identified our institution's head and neck VM patients who received sclerotherapy between 1 January 2007 and 31 August 2013, analyzed patient reports retrospectively, and applied to them the Clavien-Dindo classification. Our 75 VM patients underwent a total of 150 sclerotherapy sessions. The most common sclerosants were 3 % sodium tetradecyl sulfate and polidocanol. Complications occurred in 13 patients (17.3 %) and in 15 sessions (10.0 %); 3 complications required extensive postprocedural treatment and caused permanent morbidity, whereas 12 received conservative treatment. Patients with sclerotherapy complications underwent more treatments (p = 0.009) and more often needed further surgery (p = 0.007). We thus consider sclerotherapy a relatively safe treatment modality for head and neck VMs. To avoid complications, evaluation of VM characteristics and optimal treatment technique in a multidisciplinary team is vital.

An interdisciplinary specialist team leads to improved diagnostics and treatment for paediatric patients with vascular anomalies.

AIM: Patients with vascular anomalies are often misdiagnosed, leading to delayed or improper treatment. The aim of this study was to evaluate the impact of an interdisciplinary team on the diagnosis and treatment of paediatric patients with vascular anomalies. METHODS: We reviewed the paediatric patients evaluated by our interdisciplinary team between 2002 and 2012, analysing the referral diagnosis, final diagnosis, patient age, sex, clinical history, laboratory tests, imaging studies and treatments. RESULTS: Of the 480 patients who were evaluated, 435 (90.6%) had a vascular anomaly: 30.7% of all patients had a tumour and 55.2% had a malformation. Haemangiomas comprised 93.2% of all tumours, while malformations included capillary (9.8%), lymphatic (30.1%), venous (36.8%), arteriovenous (3.8%) and combined slow-flow (7.9%) malformations. Tumours were initially diagnosed correctly in 89.2% of the patients, but only 38.0% of the malformations were diagnosed correctly. Improper treatment was given to 1.4%, due to incorrect diagnoses. CONCLUSION: This study showed that haemangiomas were likely to be diagnosed correctly, but other tumours and vascular malformations were likely to be misdiagnosed. Misdiagnosis seldom led to improper treatment, but probably led to delayed treatment in many cases. The interdisciplinary approach led to improved diagnostics and treatment.

Neuropilin-2 and vascular endothelial growth factor receptor-3 are up-regulated in human vascular malformations.

Despite multiple previous studies in the field of vascular anomalies, the mechanism(s) leading to their development, progression and maintenance has remained unclear. In this study, we have characterized the expression levels of vascular endothelial growth factors and their receptors in 33 human vascular anomalies. Analysis with quantitative real-time PCR and gene-specific assays showed higher expression of neuropilin-2 (NRP2) and VEGF-receptor-3 (VEGFR-3) mRNAs in vascular malformations (VascM) as compared to infantile hemangiomas (Hem). In addition, the expression levels of PlGF and VEGF-C mRNA were significantly higher in venous VascM when compared to the other VascM and Hem. Higher expression of NRP2 and VEGFR-3 were confirmed by immunohistochemistry. To further study the importance of NRP2 and VEGFR-3, endothelial cell (EC) cultures were established from vascular anomalies. It was found that NRP2 and VEGFR-3 mRNA levels were significantly higher in some of the VascM ECs as compared to human umbilical vein ECs which were used as control cells in the study. Furthermore, adenoviral delivery of soluble decoy NRP2 prevented the proliferation of ECs isolated from most of the vascular anomalies. Our findings suggest that NRP2 functions as a factor maintaining the pathological vascular network in these anomalies. Thus, NRP2 could become a potential therapeutic target for the diagnosis and treatment of vascular anomalies.

[Treatment of hemangiomas]. / Hemangioomien hoito.

Hemangioma is the most common benign tumor in infancy. Over 90% of hemangiomas require no treatment, but there is a need to recognize those that may require even quick measures to secure vital functions or normal development of organs. Propranolol has established itself as the first-line treatment. Pulsed dye laser has proven effective in the treatment of ulcerated hemangiomas. Corticosteroid therapy is applied only rarely, but surgical treatment or angiography and embolization therapy associated with it may sometimes be indicated.