Comparative Analysis of 2D and 3D Metrics for Evaluation of Postoperative Outcomes Following Endoscopic Suturectomy for Sagittal Craniosynostosis.

To assess whether 3-dimensional (3D) volumetrics can be used to track and evaluate postoperative course of patients treated with endoscopic suturectomy for nonsyndromic sagittal synostosis, we compared changes in 2-dimensional (2D) measurements along with 3D volumetric correlates throughout the period of helmet therapy. Forty-six patients treated at our institution with endoscopic suturectomy for sagittal synostosis were retrospectively reviewed. Head circumference (HC), cephalic index (CI), and total cranial volumes (TCVs) were measured at 3 timepoints following surgery using optical surface scans obtained for helmet orthotics. All measurements showed significant differences between timepoints on the analysis of variance ( P <0.001). There was a significant correlation between CI and TCV (r=0.35, P =0.004) and between HC and TCV (r=0.81, P <0.001). The normalized rate of change over the course of treatment was significantly higher for TCV (36.7%) than for CI (8.8%) and HC (8.4%, P <0.001), with no difference between HC and CI. The authors conclude that 3D metrics were able to reliably follow the course of postoperative 2D metrics. There was a direct and linear correlation between HC and CI with TCV. Total cranial volumes showed the highest rate of sustained change at every timepoint. Although CI and HC plateau after the first measurement, TCV continues to adapt over the course of treatment. These results demonstrate the feasibility and value of volumetrics from 3D imaging to provide a more comprehensive evaluation of postoperative surgical outcomes than traditional 2D metrics without the ionizing radiation traditionally utilized for CT to obtain 3D metrics.

A Systematic Review of Idiopathic Secondary Stenosis Following Index Surgery for Craniosynostosis.

BACKGROUND: Primary craniosynostosis is a congenital craniofacial disorder in which cranial sutures prematurely close. Iatrogenic secondary stenosis is abnormal cranial suture closure caused by surgical manipulation of the suture. In contrast, idiopathic secondary stenosis develops in a suture that did not undergo surgical manipulation. The objective of this systematic review was to consolidate and characterize the incidence, classification, and management of idiopathic secondary stenosis in the literature. METHODS: Literature from PubMed, Web Of Science, and EMBASE from 1970 to March 2022 was reviewed. The following information was extracted for individual patients: incidence of idiopathic secondary stenosis, index primary craniosynostosis, primary surgical correction, presenting signs of secondary stenosis, management, and further complications. RESULTS: Seventeen articles detailing 1181 patients were included. Ninety-one developed idiopathic secondary stenosis (7.7%). Only 3 of these patients were syndromic. The most common index craniosynostosis was sagittal synostosis (83.5%). The most common suture undergoing idiopathic secondary stenosis was the coronal suture (91.2%). Patients presented at a median age of 24 months. The most common presenting sign was a radiologic finding (85.7%), although some patients presented with headache or head deformity. Only 2 patients, both syndromic, had complications following surgical correction of secondary stenosis. CONCLUSIONS: Idiopathic secondary stenosis is a rare, long-term complication following index surgical repair of craniosynostosis. It can occur following any surgical technique. It most commonly affects the coronal suture but can affect any of the sutures, including pansynostosis. Surgical correction is curative in nonsyndromic patients.

Inferiorly Directed Posterior Cranial Vault Distraction for Treatment of Chiari Malformations.

OBJECTIVE: The authors present a case series of patients with Chiari I malformations treated with distraction osteogenesis of the posterior cranial vault, utilizing a vertical distraction vector for appropriate cranial vault expansion while mitigating the risks of scaphocephaly and cerebellar ptosis. PATIENTS AND METHODS: Patients with syndromic and nonsyndromic Chiari I malformations treated with vertical-vector distraction osteogenesis of the posterior cranial vault were identified from 2008 to 2014. Demographics, preoperative and postoperative clinical symptoms, and perioperative details were assessed. Long-term esthetic outcomes, complications, and symptomatic improvement were evaluated in conjunction with neurosurgery. RESULTS: Nine patients were identified. Five had known syndromes, 2 likely had unidentified syndromes, and 2 were nonsyndromic. Seven had prior Chiari-related surgeries. Most presented with hydrocephalus, motor symptoms, and developmental delay. Operatively, 2 to 3 internal distraction fixators were applied such that the vector of distraction was along a cephalad-caudad axis. Devices were activated on postoperative day 5 and distracted 1 mm per day. Three postoperative complications were found within the first 3 months which included a dislodged distraction arm, a device extrusion, and a local cellulitis. No complications affected the clinical outcome. Radiographic follow-up showed good bone formation, decompression of the posterior fossa, improved cerebrospinal fluid flow, and no cerebellar ptosis. Neurological surveillance showed improvement in intracranial pressure, hydrocephalus, motor symptoms, and behavioral problems. CONCLUSION: The authors have presented 9 patients with Chiari I malformations treated with distraction osteogenesis, along with a novel technique to safely and effectively expand the posterior fossa while minimizing the risk of cerebellar ptosis. LEVEL OF EVIDENCE: Level II (prognostic/risk studies).

The Simultaneous Use of Spring-Mediated Cranioplasty and Distraction Osteogenesis as a Safe Modality for Multi-Suture Craniosynostosis.

ABSTRACT: Craniosynostosis caused by premature fusion of the cranial sutures most commonly involves a single suture. Less commonly, multiple sutures may fuse prematurely resulting in complex craniosynostosis. The authors present 1 case of a patient with unilateral sagittal and unilateral lambdoid craniosynostosis treated safely simultaneous with spring-mediated cranioplasty and distraction osteogenesis.

Paediatric skull growth models: A systematic review of applications to normal skulls and craniosynostoses.

INTRODUCTION: Craniosynostoses affect 1/2000 births and their incidence is currently increasing. Without surgery, craniosynostosis can lead to neurological issues due to restrained brain growth and social stigma due to abnormal head shapes. Understanding growth patterns is essential to develop surgical planning approaches and predict short- and long-term post-operative results. Here we provide a systematic review of normal and pathological cranial vault growth models. MATERIAL AND METHODS: The systematic review of the literature identified descriptive and comprehensive skull growth models with the following criteria: full text articles dedicated to the skull vault of children under 2 years of age, without focus on molecular and cellular mechanisms. Models were analysed based on initial geometry, numerical method, age determination method and validation process. RESULTS: A total of 14 articles including 17 models was reviewed. Four descriptive models were assessed, including 3 models using statistical analyses and 1 based on deformational methods. Thirteen comprehensive models were assessed including 7 finite element models and 6 diffusion models. Results from the current literature showed that successful models combined analyses of cranial vault shape and suture bone formation. DISCUSSION: Growth modelling is central when assessing craniofacial architecture in young patients and will be a key factor in the development of future customized treatment strategies. Recurrent technical difficulties were encountered by most authors when generalizing a specific craniosynostosis model to all types of craniosynostoses, when assessing the role of the brain and when attempting to relate the age with different stages of growth.

The Dura Split Technique in the Treatment of Craniosynostosis: Is It Still an Option?

BACKGROUND: The aim of this study was to report the outcome and the complications for patients operated on for craniosynostosis using the dura split technique. Specifically, the authors aimed to evaluate the safety of this technique, which is currently not in use, and to determine whether it is still useable. METHODS: The data was collected from the hospital patient records of all children surgically treated for craniosynostosis using the dura split technique in Turku University Hospital during the period 1975 to 2015. The data was analyzed to determine the clinical and radiological outcomes of the surgical procedure, the need for reoperations, and the rate of complications. RESULTS: During the study period, the dura split technique was used in the surgery of 65 patients. The outcome was either good or acceptable in most patients and reoperation was needed in only 2 patients (3.1%). Surgical complications included significant blood loss (26.2%), lesions on the inner layer of the dura (21.5%), leakage of cerebrospinal fluid (13.8%), and persistent bone defects (15.4% on palpation and 63.1% radiologically). CONCLUSIONS: Although the outcome of surgery for craniosynostosis using the dura split technique was mostly acceptable and the need for reoperations rare, the technique cannot, however, be recommended in the future due to high rates of bone defects, frequent problems with lesions on the inner layer of the dura, and consequent perioperative leakage of cerebrospinal fluid.

Characterization of Treatment Modalities for Patients With Syndromic Craniosynostosis in Relation to Degree of Midface Hypoplasia and Patient's Age Using Longitudinal Follow-Up Data.

ABSTRACT: The purpose of this study was to investigate the type and frequency of use of treatment modalities (Tx-Mods) in patients with syndromic craniosynostosis (SC) using longitudinal follow-up data. A total of 28 patients with SC (24 Crouzon, 2 Apert, and 2 Antley-Bixler syndromes), who were treated at the Department of Orthodontics, Seoul National University Dental Hospital, Seoul, South Korea between 1998 and 2020, was included. According to the degree of midface hypoplasia (MH) at the initial visit (T1), the patients were divided into the mild-MH (78°≤SNA < 80°, n = 8), moderate-MH (76≤SNA < 78°, n = 7), and severe-MH (SNA < 76°, n = 13) groups. T1-age and Tx-Mods, including cal-varial surgery (CALS), orthopedic treatment (OPT), fixed orthodontic treatment, and midface advancement surgery in childhood (MAS-child) and adulthood (MAS-adult), were investigated. Complexity of MAS-adult was graded as follows: 0, no surgery; 1, orthognathic surgery; 2, distraction osteogenesis (DOG); 3, combination of distraction osteogenesis and orthognathic surgery. Then, statistical analysis was performed. Percentage distribution of Tx-Mods was 71.4% in CALS, 21.4% in MAS-child, 42.9% in OPT, 100% in fixed orthodontic treatment, and 89.3% in MAS-adult. 92.9% of patients underwent MAS more than once. The number of MAS increased according to the severity of MH ( P < 0.05). The complexity of MAS-adult increased as T1-age and severity of MH increased (all P < 0.05); whereas it decreased when CALS and OPT were performed (all P < 0.05). However, MAS in childhood did not guarantee the avoidance of additional MAS in adulthood ( P > 0.05). These findings may be used as basic guidelines for successful treatment planning and prognosis prediction in patients with SC.

Hereditary hypophosphatemic rickets and craniosynostosis.

BACKGROUND: Craniosynostosis is an underdiagnosed complication associated with hypophosphatemic rickets. The study aims to describe the clinical and auxological characteristic of children with hypophosphatemic rickets and craniosynostosis, describe the usual treatment, and compare the characteristics with those of children without craniosynostosis. METHODS AND PATIENTS: An observational and retrospective cohort study was conducted. Clinical notes and cranial images were reviewed. Out of 96 children, only the 50 patients who had skull images were included. RESULTS: Out of 50 patients, 26 (15 males) had craniosynostosis (52%). No differences were observed in birth size, age, height, body proportions, alkaline phosphatase, serum phosphate, or percent tubular reabsorption of phosphate at first appointment among children with or without craniosynostosis. Among patients with craniosynostosis, dolichocephaly was prevalent. The sagittal suture was affected in all patients with craniosynostosis, with 19 of 26 children (73%) affected with isolated scaphocephaly. Pan-sutural craniosynostosis was present in 7 children (27%). None of the children had microcephaly, 7 of them presented macrocephaly and, in the remaining subjects, head circumference was normal. Five patients had undergone at least 1 cranial remodeling surgery. One patient with craniosynostosis was diagnosed with a Chiari I malformation. Molecular characterization of PHEX gene was performed in 14 cases. CONCLUSIONS: Craniosynostosis is an underdiagnosed complication of hypophosphatemic rickets. Many patients with normal head size and growth may go undiagnosed, thus it is important to consider this association for early diagnosis and possible surgical treatment. A multidisciplinary approach is necessary for a correct long-term follow-up.

Craniosynostosis Develops in Half of Infants Treated for Hydrocephalus with a Ventriculoperitoneal Shunt.

BACKGROUND: Craniosynostosis following placement of a ventriculoperitoneal shunt for hydrocephalus has been sporadically described. The purpose of this investigation was to determine the general risk of developing craniosynostosis in this patient population. METHODS: The authors retrospectively reviewed records and radiographs of infants who underwent ventriculoperitoneal shunt placement for hydrocephalus from 2006 to 2012. Recorded variables included date of shunt placement, demographics, comorbidities, cause of hydrocephalus, shunt type, and number of shunt revisions. Axial computed tomographic images obtained before and immediately after shunt placement and 2 to 4 years after shunt placement were evaluated by a panel of clinicians for evidence of craniosynostosis. Patients with preshunt craniosynostosis, craniosynostosis syndromes, or poor-quality computed tomographic images were excluded. Data were analyzed using STATA Version 15.1 statistical software. RESULTS: One hundred twenty-five patients (69 male and 56 female patients) were included. Average age at shunt placement was 2.3 ± 2.58 months. Sixty-one patients (48.8 percent) developed craniosynostosis at a median of 26 months after shunt placement. Of these, 28 patients fused one suture; the majority involved the sagittal suture (n = 25). Thirty-three patients fused multiple sutures; the most common were the coronal (n = 32) and the sagittal (n = 30) sutures. Multivariable logistic regression identified older age at shunt placement and more shunt revisions as independent predictors of craniosynostosis. Shunt valve type was not significant. CONCLUSIONS: Craniosynostosis developed in nearly half of infants who underwent ventriculoperitoneal shunt placement for hydrocephalus. The sagittal suture was most commonly involved. The effect of suture fusion on subsequent cranial growth, shunt failure, or the development of intracranial pressure is unclear. CLINICAL QUESITON/LEVEL OF EVIDENCE: Risk, III.

Short report: craniosynostosis, a late complication of nutritional rickets.

OBJECTIVES: Nutritional rickets may be a preventable cause of craniosynostosis. This potential association is under-recognised. A late diagnosis of craniosynostosis may result in reduced brain growth, raised intracranial pressure and long-term psychosocial problems. CASE PRESENTATION: We present four cases of craniosynostosis associated with nutritional rickets. Those who had delayed presentation underwent emergency craniotomy. CONCLUSIONS: Treatment of nutritional rickets and early identification of craniosynostosis can reduce morbidity in these children.

KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice.

Somatic KRAS mutations are highly prevalent in many cancers. In addition, a distinct spectrum of germline KRAS mutations causes developmental disorders called RASopathies. The mutant proteins encoded by these germline KRAS mutations are less biochemically and functionally activated than those in cancer. We generated mice harboring conditional KrasLSL-P34Rand KrasLSL-T58I knock-in alleles and characterized the consequences of each mutation in vivo. Embryonic expression of KrasT58I resulted in craniofacial abnormalities reminiscent of those seen in RASopathy disorders, and these mice exhibited hyperplastic growth of multiple organs, modest alterations in cardiac valvulogenesis, myocardial hypertrophy, and myeloproliferation. By contrast, embryonic KrasP34R expression resulted in early perinatal lethality from respiratory failure due to defective lung sacculation, which was associated with aberrant ERK activity in lung epithelial cells. Somatic Mx1-Cre-mediated activation in the hematopoietic compartment showed that KrasP34R and KrasT58I expression had distinct signaling effects, despite causing a similar spectrum of hematologic diseases. These potentially novel strains are robust models for investigating the consequences of expressing endogenous levels of hyperactive K-Ras in different developing and adult tissues, for comparing how oncogenic and germline K-Ras proteins perturb signaling networks and cell fate decisions, and for performing preclinical therapeutic trials.

Identifying the Misshapen Head: Craniosynostosis and Related Disorders.

Pediatric care providers, pediatricians, pediatric subspecialty physicians, and other health care providers should be able to recognize children with abnormal head shapes that occur as a result of both synostotic and deformational processes. The purpose of this clinical report is to review the characteristic head shape changes, as well as secondary craniofacial characteristics, that occur in the setting of the various primary craniosynostoses and deformations. As an introduction, the physiology and genetics of skull growth as well as the pathophysiology underlying craniosynostosis are reviewed. This is followed by a description of each type of primary craniosynostosis (metopic, unicoronal, bicoronal, sagittal, lambdoid, and frontosphenoidal) and their resultant head shape changes, with an emphasis on differentiating conditions that require surgical correction from those (bathrocephaly, deformational plagiocephaly/brachycephaly, and neonatal intensive care unit-associated skill deformation, known as NICUcephaly) that do not. The report ends with a brief discussion of microcephaly as it relates to craniosynostosis as well as fontanelle closure. The intent is to improve pediatric care providers' recognition and timely referral for craniosynostosis and their differentiation of synostotic from deformational and other nonoperative head shape changes.

Craniosynostosis and metabolic bone disorder. A review.

INTRODUCTION: Some metabolic bone disorders may result in the premature closure of one or more calvarial sutures during childhood, potentially leading to a cranioencephalic disproportion. The aim of this paper is to review the characteristics and consequences of craniosynostosis associated with metabolic disorder. MATERIAL AND METHODS: A review of the literature on metabolic forms of craniosynostosis was performed. RESULTS: The most common forms of craniosynostosis associated with metabolic bone disorder were isolated sagittal suture fusion with or without scaphocephaly, and sagittal suture fusion associated with coronal suture fusion (oxycephaly) or also with lambdoid suture fusion (pansynostosis). Synostosis may be well-tolerated, but in some subjects results in neurodevelopmental and functional impairment that is sometimes severe. CONCLUSION: The impact of metabolic synostosis is very variable, depending on the specific underlying metabolic disease, with a large spectrum of morphological and functional consequences. Diagnosis should be early and management should be carried out by a multidisciplinary team with expertise in both rare skeletal disorders and craniosynostosis. The impact of emergent medical therapies recently developed for some of these diseases will be assessed by systematic coherent follow-up of international registries.

Pharmacological exposures may precipitate craniosynostosis through targeted stem cell depletion.

The Centers for Disease Control and Prevention, National Birth Defects Study suggests that environmental exposures including maternal thyroid diseases, maternal nicotine use, and use of selective serotonin reuptake inhibitors (SSRIs) may exacerbate incidence and or severity of craniofacial abnormalities including craniosynostosis. Premature fusion of a suture(s) of the skull defines the birth defect craniosynostosis which occurs in 1:1800-2500 births. A proposed mechanism of craniosynostosis is the disruption of proliferation and differentiation of cells in the perisutural area. Here, we hypothesize that pharmacological exposures including excess thyroid hormone, nicotine, and SSRIs lead to an alteration of stem cells within the sutures resulting in premature fusion. In utero exposure to nicotine and citalopram (SSRI) increased the risk of premature suture fusion in a wild-type murine model. Gli1+ stem cells were reduced, stem cell populations were depleted, and homeostasis of the suture mesenchyme was altered with exposure. Thus, although these pharmacological exposures can deplete calvarial stem cell populations leading to craniosynostosis, depletion of stem cells is not a unifying mechanism for pharmacological exposure associated craniosynostosis.

The first Korean case report with scaphocephaly as the initial sign of X-linked hypophosphatemic rickets.

INTRODUCTION: X-linked hypophosphatemic rickets (XLH) can occasionally cause premature fusion of cranial sutures through an increased level of fibroblast growth factor 23 (FGF-23), which leads to the dysregulation of phosphate and vitamin D metabolism. Secondary craniosynostosis has long been considered to present late after XLH has already been diagnosed either clinically or genetically. CASE PRESENTATION: We present observations of a male infant showing sagittal synostosis as the first sign of XLH. Our patient did not show any other skeletal deformities except macrocephaly with a long head shape. There is a family history of genetically unconfirmed hypophosphatemic rickets in his mother. Direct sequencing by genomic polymerase chain reaction revealed that the patient has a large deletion comprising exons 1-3 of the phosphate regulating endopeptidase homolog X-linked (PHEX) gene. CONCLUSION: Our observations suggest that craniosynostosis secondary to rickets can develop in early infancy. Careful monitoring of head shape and growth is therefore critical for early detection of craniosynostosis in XLH.

PLGA-based control release of Noggin blocks the premature fusion of cranial sutures caused by retinoic acid.

Craniosynostosis (CS), the premature and pathological fusion of cranial sutures, is a relatively common developmental disorder. Elucidation of the pathways involved and thus therapeutically targeting it would be promising for the prevention of CS. In the present study, we examined the role of BMP pathway in the all-trans retinoic acid (atRA)-induced CS model and tried to target the pathway in vivo via PLGA-based control release. As expected, the posterior frontal suture was found to fuse prematurely in the atRA subcutaneous injection mouse model. Further mechanism study revealed that atRA could repress the proliferation while promote the osteogenic differentiation of suture-derived mesenchymal cells (SMCs). Moreover, BMP signal pathway was found to be activated by atRA, as seen from increased expression of BMPR-2 and pSMAD1/5/9. Recombinant mouse Noggin blocked the atRA-induced enhancement of osteogenesis of SMCs in vitro. In vivo, PLGA microsphere encapsulated with Noggin significantly prevented the atRA-induced suture fusion. Collectively, these data support the hypothesis that BMP signaling is involved in retinoic acid-induced premature fusion of cranial sutures, while PLGA microsphere-based control release of Noggin emerges as a promising strategy for prevention of atRA-induced suture fusion.

Characterization of Perinatal Risk Factors and Complications Associated With Nonsyndromic Craniosynostosis.

BACKGROUND: Certain intrauterine risk factors are known to increase the risk of premature cranial suture fusion and may cause complications during birth. Some of these risk factors may be modifiable. Therefore, the authors sought to characterize the institutional patterns of prenatal risk factors and perinatal complications in nonsyndromic craniosynostosis patients compared to normal births from the surrounding area to identify areas for possible intervention or prevention. METHODS: The medical records of all infants with nonsyndromic craniosynostosis and full birth records born at Duke University Health System from 2006 to 2017 were retrospectively reviewed. Maternal comorbidities, prenatal risk factors, and perinatal complications were collected. The North Carolina State Center for Health Statistics was queried for perinatal statistics from Durham county and the Northeastern Perinatal Care Region to represent a control cohort of normal births from the same time period and region. The primary outcome investigated was the incidence of prenatal risk factors and complications at birth associated with premature fusion of cranial sutures. RESULTS: Eighty births with nonsyndromic craniosynostosis were included in this study. The majority of these patients were males (61.7%) and born via cesarean section (55.0%). Intrauterine growth restriction occurred in 10.0% and head trauma during delivery occurred in 2.5%. Twinning (14.8% vs 3.6%, P < 0.0001), cesarean births (55.5% vs 30.0%, P < 0.0001), and breech presentation (17.3% vs 3.2%, P < 0.0001) were significantly more common in craniosynostosis patients. Prenatally, mothers of craniosynostosis infants had higher incidence of gestational diabetes (13.5% vs 5.0%, P < 0.0001) and oligohydramnios (6.1% vs 1.3%, P < 0.0001) compared to regional controls. CONCLUSION: This study demonstrates that premature suture fusion is associated with prenatal risk factors such as gestational diabetes and oligohydramnios. Continued research into potentially modifiable prenatal risk factors and more refined prenatal diagnostic tools has the potential to reduce both the incidence of premature suture fusion and the sequelae of birth complications in this population.

Craniosynostosis as the Presenting Feature of X-linked Hypophosphatemic Rickets.

Craniosynostosis is the premature closure of cranial sutures. Primary, or congenital, craniosynostosis is often sporadic but may be associated with genetic or chromosomal abnormalities. Secondary craniosynostosis presents after gestation, and can occur in metabolic bone diseases, including rickets. We describe the first reported cases of primary craniosynostosis in 2 unrelated, term infants with X-linked hypophosphatemic rickets (XLH). The diagnosis of XLH in both patients was confirmed by genetic testing. At the time craniosynostosis was detected, the patient in the first case did not have any other clinical features of XLH. The second patient developed clinical findings of craniosynostosis, followed by rickets. These are the earliest reported cases of craniosynostosis in XLH and demonstrate that craniosynostosis may be a presenting feature of this disease.