Published papers

© 2018 Wiley Periodicals, Inc. The TWIST family is a group of highly conserved basic helix–loop–helix transcription factors. In humans, TWIST1 haploinsufficiency causes Saethre–Chotzen syndrome, which is characterized by craniosynostosis. Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney–Cox syndrome, Barber–Say syndrome, and ablepharon-macrostomia syndrome, respectively. Sweeney–Cox syndrome, Barber–Say syndrome, and ablepharon-macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth. Existence of phenotypic overlap between Saethre–Chotzen syndrome and Sweeney–Cox syndrome remains unknown. Herein, we document a male infant with the distinctive facial features of ablepharon, hypertelorism, cheek pads adjacent to the corners of the mouth, and bilateral coronal suture craniosynostosis who had a de novo heterozygous mutation in the basic domain of TWIST1, that is, c.351C>G p.Glu117Asp. The pathogenicity of this variant was supported by in silico and in vivo evidence. Our review showed that Sweeney–Cox syndrome appears to share many characteristics with Barber–Say syndrome and ablepharon-macrostomia syndrome except for craniosynostosis, which is a cardinal feature of Saethre–Chotzen syndrome. An amino acid substitution from Glu117 to Asp, both of which are the sole members of negatively charged amino acids, resulted in a prototypic Sweeney–Cox syndrome phenotype. This suggests that any amino acid substitutions at Glu117 would likely lead to the Sweeney–Cox syndrome phenotype or lethality. The present observation suggests that a localized TWIST1 basic domain substitution, that is, p.Glu117Asp, in TWIST1 may exert a mild antimorphic effect similar to that of haploinsufficiency, leading to craniosynostosis and ablepharon.

© 2019 Elsevier Ltd Midface advancement with distraction osteogenesis is more routinely used for faciocraniosynostosis. Distraction devices are generally classified into external and internal types. Compared with external distractors, internal distractors are smaller and better tolerated, but their removal is complicated. Here, we introduce a refined internal distraction device and describe its applicability. Unlike the previous anterior fixation plate that utilises screws, the refined internal distraction (type Z'gok) has 3 claws. This anterior point of the distractor is positioned behind the malar eminence, or the lateral orbital wall. Eight patients with syndromic craniosynostosis underwent midface distraction osteogenesis using the type Z'gok between 2016 and 2017 (Z'gok group). Twelve patients were treated using conventional internal distractors (control group). Patient age ranged from 6 to 21 years. Among them, 4 patients underwent Le Fort III distraction osteogenesis, while the others underwent Le Fort IV distraction osteogenesis. The operative time to remove the distractors in the Z'gok group was 65 ± 18 min, shorter than 89 ± 12 min in the control group. The blood loss per kilogram of body weight in the Z'gok and control groups was 3.6 ± 3.3 mL/kg and 4.7 ± 1.7 mL/kg, respectively. In conclusion, the type Z'gok is a reliable and effective internal distractor for midface distraction osteogenesis.

Copyright © 2018 by Mutaz B. Habal, MD Purpose: To evaluate the utility and efficacy of bioabsorbable hydroxyapatite and collagen complex (HA/Col) for cranioplasty repair of cranial bone defects in children. Methods: Two patients (a 6-year-old male and 11-year-old female) with Treacher Collins syndrome received zygoma and orbital floor reconstruction using a full thickness of parietal bone. The bone grafts were taken from each patient’s parietal cranium. The right parietal cranial defect was repaired with autologous bone dust, and the left side was repaired with HA/Col in each patient. Computed tomography scans were taken immediately after and at 12 months following surgery. The osteosynthesis areas and thicknesses were measured using computer-aided engineering. Results: Both patients experienced no complications, including infection. In the 6- and 11-year-old patients, the extent of osteosynthesis for HA/Col was 92.2% and 89.4%, respectively; and for the autologous bone dust was 78.5% and 53.2%, respectively. Because of the small sample size, a significant difference could not be calculated; however, the percentage of osteosynthesis for HA/Col was higher than for the autologous bone dust. Conclusion: This study showed that HA/Col can be effectively used in cranial defects and can be considered an alternative graft material for cranial reconstruction.

© 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Purpose: Detection of optic canal fractures is often difficult because of the subtleness of the fracture. If we could clarify impact on which region around the orbit is likely to accompany the fracture of the optic canal, the knowledge should be useful to make early diagnosis of optic canal fractures. The present study was conducted to elucidate this issue. Methods: Ten finite element models were produced simulating the skulls of ten humans (8 males and 2 females; 43.8 ± 10.2 y/o). The peri-orbital area of each of the ten models was divided into eight regions in a clockwise fashion per 45 degrees. These regions were defined as Superior-Medial (0–45 degrees), Medial-Superior (45–90 degrees), Medial-Inferior (90 to 135 degrees), Inferior-Medial (135 to 180 degrees), Inferior-Lateral (180–225 degrees), Lateral-Inferior (225 to 270 degrees), Lateral-Superior (270–315 degrees), and Superior-Lateral regions (315–360 degrees), respectively. Dynamic simulation of applying traumatic energy on each of these regions was conducted. Resultant fracture patterns were evaluated using finite element analyses. Thereafter, frequencies of fracture involvement of the optic canal were evaluated for each of the eight regions. Results: The involvement of the optic canal was most frequent for the Superior-Medial region (7/10), followed by the Medial-Superior region (5/10). Conclusion: Optic canal fracture is likely to occur when the area between the supra-orbital notch and the medial canthus are strongly impacted. When evident fracture or serious damage of soft tissue is observed in this area, occurrence of optic canal fracture should be suspected.

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: The primitive tentorial, occipital, and falcine sinuses are thought to attain the adult pattern or regress between the fetal stage and adulthood. The anatomy of these three primitive dural sinuses has seldom been studied in the infant population, and it remains unclear when these dural sinuses reach the adult condition. Using computed tomography digital subtraction venography (CT-DSV), we analyzed the anatomy of these embryonic dural sinuses in infants. Methods: We included 13 infants who underwent CT-DSV prior to neurosurgery and 35 cases with unruptured cerebral aneurysms as normal adult controls. Three embryonic dural sinuses, i.e., the primitive tentorial, occipital, and falcine sinuses, were retrospectively analyzed in CT-DSV images of infants and adults. We also analyzed the drainage patterns of the superficial middle cerebral vein (SMCV), determined by the connection between the primitive tentorial sinus and the cavernous sinus. Results: The primitive tentorial, occipital, and falcine sinuses were present in 15.4%, 46.2%, and none of the infants, respectively, and in 10.0, 8.6, and 2.9% of the adults, respectively. The difference in SMCV draining pattern between infants and adults was insignificant. The incidence of the occipital sinus was significantly higher in infants than in adults. Conclusions: The connection between the primitive tentorial sinus and the cavernous sinus appears to be established before birth. The occipital sinus is formed at the embryonic stage and mostly regresses after infancy. The falcine sinus is usually obliterated prenatally. Our findings form the basis for interventions by pediatric interventional neuroradiologists and neurosurgeons.

Copyright © 2018 by Mutaz B. Habal, MD Hydroxyapatite and poly-L-lactide plates are often used for maxillofacial surgery. These plates take 3 to 4 years to resorb completely, leading to the possibility of a foreign-body reaction. A 20-year-old woman who developed a foreign-body reaction to the plates was reported. Based on review of the relevant literature, foreign-body reactions have often been reported with this plate. Long-term follow-up is warranted to evaluate patients using this plate in maxillofacial surgery.

© 2018 Wiley Periodicals, Inc. NCOR1 (nuclear receptor corepressor 1) is a transcriptional coregulatory protein that regulates the balance between histone acetylation and histone deacetylation. NCOR1 is listed as one of the 3,230 dose-sensitive genes which very rarely show truncating mutations in the pediatric population without severe diseases, even in a heterozygous state. In a large cohort study of intellectual disability/autism spectrum disorder, splicing mutations were identified in two individuals, however, the truncating effects of these splicing mutations have not been examined at the transcription level. We describe a 3-year-old girl who had behavior consistent with autism spectrum disorder, a bifid uvula, and early-onset scoliosis. Trio exome analysis showed a de novo heterozygous mutation at the splice donor site in exon 19 of NCOR1, c.2182 + 1G > T (NM_00190440.1). Reverse transcription polymerase chain reaction assay confirmed that the splicing mutation results in skipping of exon 19, a shift in the reading frame and then to nonsense-mediated mRNA decay. This patient represents the first patient who has had unequivocal documentation of haploinsufficient for the NCOR1 gene. Based on our observations, we conclude that NCOR1 is indeed a human disease-causing gene. We further suggest that bifid uvula, a micro form of cleft palate, may well be causally related to de novo NCOR1 haploinsufficiency, in that a previously reported deletion mapping study of atypical Smith-Magenis syndrome patients with large deletions and cleft palate identified that NCOR1, the only loss-of-function-intolerant gene within the region, is located in the smallest region of overlap.

© 2018 by Mutaz B. Habal, MD. Postoperative radiation can cause ulcer formation, leading to the denudation of skin over alloplastic materials. The influence of backscatter radiation from fixation devices has not been investigated. The aim of this study is to evaluate backscatter dose variations for different cranial bone fixation devices in an experimental model designed to simulate postoperative radiotherapy. The authors assessed the radiation backscatter doses associated with resorbable (PLLA-PGA) and titanium plates. The samples were irradiated with 6 and 10 MV photon beams from a linear accelerator. Measurements were obtained using an ionization chamber and radiochromic films cut from the same batch. As a result, the backscatter radiation of water and PLLA-PGA proportionally decreased as the depth increased. However, the backscatter radiation of the titanium plate increased just above the plate. This depth lies in the region of the scalp. Each material showed a dose of radioactivity that was higher at 10 MV than that at 6 MV. These devices showed a significant difference, which suggested that these materials amplified the dose compared with water at 6 MV. In conclusion, it is supposed that PLLA-PGA should be used to fix the cranium to decrease the potential for radiation ulcers.

© 2019 by The Japan Neurosurgical Society. Cranioplasty following decompressive craniectomy is highly associated with complications. Methods for avoiding these complications have been well-documented; however, approaching reconstruction through the previous incision, especially if it was on or very near the bone defect, can sometimes lead to wound dehiscence and infection, with exposure of the artificial bone. For such complicated cases, we propose a multi-staged preparation that includes creating a delayed skin flap for the actual skull reconstruction. Flap was elevated in three stages, with 4 week intervals between each stage to allow for adequate blood supply. Cranioplasty using custom-made implants was then performed. Four patients (age range, 10-25 years) were prepared for skull reconstruction using this technique. During follow-up period for 12 months, no complications, including infections, exposure of the artificial bone, or flap necrosis, were observed. Despite the multiple stages required, we consider that our technique makes a significant contribution to the literature because it suggests a technique for cranioplasty following decompressive craniectomy that may avoid many of the complications following such cranioplasty using current methods.

© Copyright 2017 by Mutaz B. Habal, MD. Synthetic hydroxyapatite (HAP) implants are common in craniofacial surgery; the major problem with HAP implants is fixation instability. An ultrasound-assisted pinned resorbable fixation system has recently been introduced. The authors hypothesized that this resorbable system could be used to fix HAP implants. The authors evaluated the optimal HAP porosity and resorbable pin using the pull-out test and microscopic analysis. Hydroxyapatite blocks were synthesized with 0% (dense type), 35% (fine pore type), and 50% (large pore type) porosity. Bioabsorbable pins of 4 sizes were tested: diameters of 1.6 or 2.1mm and lengths of 4 or 7mm. Among the 1.6mm diameter pins, the 7-mm length pins showed higher pull-out strength (large pore, 6.5±1.2 kgf; fine pore, 4.1±0.7 kgf; dense, 2.4±0.4 kgf) than the 4-mm length pins (large pore, 2.1±1.0 kgf; fine pore, 1.3±0.4 kgf; dense, 1.5±0.9 kgf) with all 3 HAP types (P<0.01). Among 2.1-mm diameter pins, all were removed from the large and fine pore HAP types without any resistance. Only three of seven 2.1×7mm pins inserted into the dense type HAP showed pull-out strength (3.9±2.1 kgf). Among all conditions, the 7-mm length, 1.6-mm diameter pin in large pore type HAP showed the highest pull-out strength. Microscopically, the large pore type HAP showed the liquefying pin flowing into the large pore adjacent to the pilot hole. By contrast, the fine pore and dense pore types of HAP did not allow flow, and the pins did not change in structure 3-dimensionally. The authors found that pull-out strength depends on HAP porosity, and pin length and diameter.

Copyright © 2018 by Mutaz B. Habal, MD Purpose: Posterior calvarial vault expansion using distraction osteogenesis is performed for syndromic craniosynostosis as the first choice. This procedure allows far greater intracranial volume than fronto-orbital advancement (FOA). This study aimed to determine the most suitable timing of posterior distraction or FOA to sufficiently increase the intracranial volume and remodel the skull shape. Patients and Methods: From 2014 to 2017, the authors performed posterior distraction in 13 patients with syndromic craniosynostosis. Data on premature suture fusion, age at first visit, age at surgery, skull thickness, and complications were collected. Results: Five patients underwent posterior distraction at approximately 12 months of age and had no complications, including cerebrospinal fluid leakage or gull wing deformity. However, during the waiting period for the operation, the skull deformity continues to extend upward (turribrachycephaly). To prevent progress of the skull deformity, the authors performed the operation at approximately 6 months of age in 7 patients. However, in 3 of 7 patients whose lambdoid sutures were opening, gull wing deformity occurred. From these results, in a patient with severe Beare-Stevenson syndrome, the authors performed FOA first at 5 months of age, followed by posterior distraction at 12 months of age, and achieved favorable results. Conclusions: Treatment patterns are patient specific and should be tailored to premature suture fusion, specific skull deformity, and required intracranial volume of each patient.

Copyright © 2018 by Mutaz B. Habal, MD. Background: The management of fronto-orbital fibrous dysplasia involves total excision of the dysplastic bone and bone reconstruction using implants. Custom-made implants are used to achieve good contouring. However, the remnant defect after excising the lesion often does not match the implant. Methods: To design the craniotomy line, a template was prepared by preoperative computed surgical simulation. The template was overlaid on the preoperative cranium, such that its inner surface fits exactly with the cranial surface. After excising the lesion by performing osteotomy, the implant was placed in the defect and fixed. Both template and implant were made of hydroxyapatite. Results: The authors treated 4 patients, with fibrous dysplasia involving the fronto-facial region by using the template. Intraoperative trimming of the implant or bone defect was not required in 2 patients, while the third patient required mild trimming. They did not have any complications and obtained good contouring. Conclusion: The hydroxyapatite templates reduced the surgical time by determining the precise craniotomy line preoperatively, thus avoiding needless trimming of the implant and bone defect. Therefore, they can enhance the efficacy of treatment for fronto-orbital fibrous dysplasia lesion.

Copyright © 2018 by Mutaz B. Habal, MD. Transcranial vertical orbital translocation is useful for correcting vertical orbital dysplasia. However, the technique is limited by the degree of uncertainty regarding the amount of vertical movement required after the osteotomy. As for landmark movement, Z osteotomy is performed as part of a box osteotomy. This technique is useful in that it is easy to know how far the orbit should be moved, and stabilization can be obtained.