Pfeiffer type 2 syndrome: review with updates on its genetics and molecular biology.

INTRODUCTION: Pfeiffer syndrome is a rare autosomal dominant inherited disorder associated with craniosynostosis, midfacial hypoplasia, and broad thumbs and toes. The syndrome has been divided into three clinical subtypes based on clinical findings. METHODS: This review will specifically examine the most severe type, Pfeiffer syndrome type 2, focusing on its genetics and molecular biology. CONCLUSION: This subtype of the syndrome is caused by de novo sporadic mutations, the majority of which occur in the fibroblast growth factor receptor type 1 and 2 (FGFR1/2) genes. There is not one specific mutation, however. This disorder is genetically heterogeneous and may have varying phenotypic expressions that in various cases have overlapped with other similar craniosynostoses. A specific missense mutation of FGFR2 causing both Pfeiffer and Crouzon syndromes has been identified, with findings suggesting that gene expression may be affected by polymorphism within the same gene. Compared to other craniosynostosis-related disorders, Pfeiffer syndrome is the most extreme phenotype, as the underlying mutations cause wider effects on the secondary and tertiary protein structures and exhibit harsher clinical findings.

Pfeiffer type 2 syndrome: review with updates on its genetics and molecular biology.

INTRODUCTION: Pfeiffer syndrome is a rare autosomal dominant inherited disorder associated with craniosynostosis, midfacial hypoplasia, and broad thumbs and toes. The syndrome has been divided into three clinical subtypes based on clinical findings. METHODS: This review will specifically examine the most severe type, Pfeiffer syndrome type 2, focusing on its genetics and molecular biology. CONCLUSION: This subtype of the syndrome is caused by de novo sporadic mutations, the majority of which occur in the fibroblast growth factor receptor type 1 and 2 (FGFR1/2) genes. There is not one specific mutation, however. This disorder is genetically heterogeneous and may have varying phenotypic expressions that in various cases have overlapped with other similar craniosynostoses. A specific missense mutation of FGFR2 causing both Pfeiffer and Crouzon syndromes has been identified, with findings suggesting that gene expression may be affected by polymorphism within the same gene. Compared to other craniosynostosis-related disorders, Pfeiffer syndrome is the most extreme phenotype, as the underlying mutations cause wider effects on the secondary and tertiary protein structures and exhibit harsher clinical findings.

A comprehensive review of Mongolian spots with an update on atypical presentations.

PURPOSE: Mongolian spots (MS) are grayish-blue macules that typically present in the lumbosacral and gluteal regions of newborns. They are mostly benign and tend to resolve with age. This review brings to light recent findings and disorders associated MS. METHODS: In this paper, we review the literature, highlight recent cases and disorders associated with MS, and emphasize how newborns presenting with atypical MS should undergo appropriate screening. RESULTS: Atypical MS on other body parts are more likely to persist and might be an indication for further screening. Recent studies have shown persistent and extensive MS to be associated with various genetic disorders such as lysosomal storage diseases (LSDs) and phakomatosis pigmentovascularis. CONCLUSION: Physicians should be aware of atypical MS and related conditions in order to further assess these patients for risk of any underlying genetic disorders.

Embryology and pathophysiology of the Chiari I and II malformations: A comprehensive review.

Although the Chiari malformations are well-studied and described developmental anomalies, there remains some incongruity in regards to their underlying etiologies. A number of theories have been proposed with the purpose of accounting for the embryology and pathogenesis of the Chiari I and II malformations and their associated complications and clinical syndromes. The present review aims to review the pertinent literature for all of the main theories that have been proposed, and outline their validity and relevance to our contemporary understanding of these anomalies. Clin. Anat. 31:202-215, 2018. © 2017 Wiley Periodicals, Inc.

Embryology of the craniocervical junction and posterior cranial fossa, part II: Embryogenesis of the hindbrain.

Although pathology of the hindbrain and its derivatives can have life altering effects on a patient, a comprehensive review on its embryology is difficult to find in the peer-reviewed medical literature. Therefore, this review article, using standard search engines, seemed timely. The embryology of the hindbrain is complex and relies on a unique timing of various neurovascular and bony elements. Derailment of these developmental processes can lead to a wide range of malformations such as the Chiari malformations. Therefore, a good working knowledge of this embryology as outlined in this review of the hindbrain is important for those treating patients with involvement of this region of the central nervous system. Clin. Anat. 31:488-500, 2018. © 2018 Wiley Periodicals, Inc.

Embryology of the craniocervical junction and posterior cranial fossa, part I: Development of the upper vertebrae and skull.

Although the embryology of the posterior cranial fossa can have life altering effects on a patient, a comprehensive review on this topic is difficult to find in the peer-reviewed medical literature. Therefore, this review article, using standard search engines, seemed timely. The embryology of the posterior cranial fossa is complex and relies on a unique timing of various neurovascular and bony elements. Derailment of these developmental processes can lead to a wide range of malformations such as the Chiari malformations. Therefore, a good working knowledge of this embryology as outlined in this review of its bony architecture is important for those treating patients with involvement of this region of the cranium. Clin. Anat. 31:466-487, 2018. © 2018 Wiley Periodicals, Inc.

Development of profound Chiari I malformation and cerebellar tissue loss and resolution following shunting of posterior fossa extra-axial cyst. Case report.

INTRODUCTION: Chiari I malformation can be due to a multitude of etiologies such as craniosynostosis or hydrocephalus. A posterior fossa extra-axial cyst (PFEAC) appears to be an extremely rare cause of this form of hindbrain herniation. CASE REPORT: Herein, we report a case of PFEAC that presented with no Chiari I malformation and then presented months later with a significant Chiari I malformation. Following shunt placement of a PFEAC, striking reversal of the Chiari malformation as well as reconstitution of the cerebellum was noted. CONCLUSIONS: Patients with PFEAC might develop a Chiari I malformation and this might be treated with shunting of the PFEAC alone.

Junctional neural tube defect in a newborn: report of a fourth case.

INTRODUCTION: A discontinuous, functionally disconnected spinal cord is an extremely rare finding, with only three known reports in the literature. Titled junctional neural tube defect (JNTD), this newly reported dysraphism is believed to arise from a developmental error occurring during junctional neurulation, a transitory stage of development marked by the end of primary neurulation and the beginning of secondary neurulation. Herein, we report a newborn case of JNTD. CASE REPORT: We report a newborn boy born with anorectal atresia. Physical examination revealed normal movement in the upper and lower extremities. Imaging revealed distal sacral agenesis and a spinal cord that was discontinuous at the thoracolumbar junction. Three vertebral segments inferiorly, at the L2 vertebral level, the distal end of the spinal cord (i.e., conus medullaris) were visualized. No signs of a tethered cord were identified. CONCLUSIONS: Characterized by an error in junctional neurulation in which the primary and secondary NT fail to integrate appropriately, JNTD has been recently classified. We believe the current patient to represent only the fourth reported case of JNTD in the literature.

Radiological evolution of peri-odontoid pannus in a patient with Chiari I malformation: a case-based review.

INTRODUCTION: The Chiari I malformation (CIM) is commonly encountered by neurosurgeons and can have different etiologies and clinical presentations. CASE REPORT: We report a CIM patient who presented with symptoms of ventral brain stem compression and was found to have a large peri-odontoid pannus. Posterior fossa decompression was performed with a planned second-stage odontoidectomy. However, at the 6-month follow-up, postoperative images demonstrated a mostly resolved pannus and improvement of the brain stem compression symptoms, and the patient progressed uneventfully without the need for odontoidectomy. CONCLUSIONS: This case illustrates the resolution of a significant and symptomatic peri-odontoid pannus in a patient with CIM without craniocervical fusion or odontoidectomy. Such a case indicates that not all peri-odontoid pannus formations in CIM patients are due to hypermobility at the craniocervical junction.

Meningocele manqué: a comprehensive review of this enigmatic finding in occult spinal dysraphism.

The term meningocele manqué (MM) was coined in 1972 to describe a broad range of surgical findings characterized by intradural bands tethering neural structures to the dorsal dura. Over the following decades, reports continued to lump intradural tethering bands associated with a variety of comorbidities under the umbrella term MM. In more recent years, disorders previously called MM have been identified as embryologically distinct and were reclassified. While this sectioning continues, there remains a set of intradural tethering disorders for which no better term than MM exists. Herein, we comprehensively review the literature surrounding MM, including embryological disorders, clinical, radiographic, and surgical presentation, as well as alternative classification methods and MM treatment.

Simultaneous Umbilical Hernia Repair with Transumbilical Ventriculoperitoneal Shunt Placement.

INTRODUCTION: Recently, placement of a ventriculoperitoneal shunt via a transumbilical approach has been reported. PATIENTS AND METHODS: Herein, we report the repair of an umbilical hernia via the same incision and introduction of the distal end of a ventricultoperitoneal shunt into the peritoneal cavity in 3 patients. A case illustration is included. RESULTS: Both hernia repair and placement of the distal end of the ventriculoperitoneal shunt were uncomplicated in our small case series. CONCLUSIONS: To our knowledge, simultaneous repair of an umbilical hernia followed by transumbilical shunt placement has not been reported. As umbilical hernias are so common in infants, this finding, based on our experience, should not exclude placement of peritoneal tubing in the same setting.

Symptomatic retethering of the spinal cord in postoperative lipomyelomeningocele patients: a meta-analysis.

BACKGROUND: Timing of surgical treatment for tethered cord syndrome due to a lipomyelomeningocele (LMM) has been controversial. The purpose of this study was to evaluate populations of patients treated surgically for LMM in a meta-analysis in order to better understand how outcomes differ based on follow-up time, symptomatology, and LMM classification. METHODS: An extensive search on PubMed and Google Scholar was performed for LMM and surgical outcomes to identify case series of patients for inclusion in this analysis. Patients were sorted based upon symptomatology prior to surgery and Chapman's LMM classification, where possible. Deterioration rates were determined by symptomatic retethering of the spinal cord that led to repeat surgery. RESULTS: Of 608 (19 %) patients, 115 were included in the study experienced deterioration leading to repeat surgery. Symptomatic and asymptomatic patients did not experience significantly different rates of deterioration after surgical untethering. There was a significant positive linear correlation between follow-up time of studies and percentage of patients deteriorating with an increase of 3.3 % per year of follow-up. Transitional LMM had a significantly higher rate of deterioration compared to the caudal type along with the entire patient pool. CONCLUSIONS: Outcomes of primary surgical treatment in regard to late deterioration are not significantly affected by patient symptomatology. Patient deterioration increases linearly over time. Additional studies should be performed to adequately determine the natural history of asymptomatic patients that are treated conservatively for LMM.

The Chiari 3.5 malformation: a review of the only reported case.

INTRODUCTION: In 1894, Giuseppe Muscatello described what we believe to be the only case of an occipitocervical encephalocele with a communication to the stomach. This case and its history and context compared to the Chiari 3 malformation as described 3 years earlier by Hans Chiari are presented. CONCLUSIONS: Based on the uniqueness of this case, we propose the term Chiari 3.5 malformation be used to describe its anatomical derailment.

Histological study of the occipital bone from patients with Chiari I malformation.

BACKGROUND: This study is focused on the histologic characteristics of occipital bone removed during Chiari I decompression in the hope of discovering unique features that may be related to the pathogenesis of this condition. METHODS: Ten consecutive pediatric patients with Chiari I malformation underwent standard posterior fossa decompression surgery. Bone that was removed from the posterior fossa was sent for histological examination. Bone from age-matched controls also underwent histological analysis. RESULTS: For all study and control specimens, bony samples were found to be made up of dense lamellar bone without marrow elements. In all aspects, histologically, the bone tissue had a normal appearance compared to control samples. CONCLUSIONS: Although many authors have mentioned that the occipital bone in patients with Chiari I malformation is abnormal on imaging or at operation (e.g., thinned, thickened), based on our study, there is no histological difference between the occipital bone removed at operation and controls.

Evolution of cerebellar tonsillar ischemia to cerebellar tonsillar cysts in the Chiari I malformation: radiological, surgical, and histological evidence.

BACKGROUND: Rare reports in the literature have documented the presence of a cyst at the tip of the cerebellar tonsil in patients with Chiari I malformation. The current study aimed to better elucidate these cysts and identify their etiology via a histological and radiologically analysis. PATIENTS AND METHODS: We prospectively reviewed all new Chiari I malformation (CM-I) patients who presented to our clinic during a 2-year period. This was a pediatric cohort made up of 340 children aged 3 to 18 years. Specifically, all patients were screened for ischemic or cystic lesions of the herniated cerebellar tonsils on MRI. RESULTS: Out of 340 patients, 2.9 % were found to have signal changes on MRI consistent with ischemia or cysts in the cerebellar tonsils. Of the 340 patients, 20 % underwent posterior fossa decompression. Of the 67 patients, cerebellar tonsillar ischemia was observed in 10.4 % and cerebellar tonsillar cysts were seen in 6 %. Four of the seven operative patients with cerebellar tonsillar ischemia and concomitant syringomyelia and three of these patients with tonsillar cysts concomitant syringomyelia and cerebellar tonsillar cysts underwent subpial dissection of some cerebellar tonsil to ensure that CSF egress from the fourth ventricle to the cervical subarachnoid space, and this transected tissue was also sent for histological analysis. Three of the four patients found to have intraoperative tonsillar cysts were noted to have tonsillar ischemic changes on preoperative imaging in this same region. For both ischemic and cystic cerebellar tonsils, histologically, the tissue demonstrated loss of Purkinje cells with concomitant Bergmann gliosis. The ischemic and cystic tissues were virtually the same, histologically. CONCLUSIONS: Based on our findings, cerebellar tonsillar ischemia and cysts in patients with CM-I can often be seen radiologically. Histologically, these ischemic and cystic tissues are the same. Moreover, we document patients where ischemic lesions progressed to cysts, radiologically. Taken together, cerebellar tonsillar ischemia and cysts are on a continuum and represent chronic compression of this herniated part of the cerebellum.

Do the cerebellar tonsils move during flexion and extension of the neck in patients with Chiari I malformation? A radiological study with clinical implications.

BACKGROUND: In the past, diagnosis of the Chiari I malformation has primarily been made on midsagittal MRI. We hypothesized that based on the frequent presentation of opisthotonos in patients with hindbrain hernia (primarily Chiari II malformation but sometimes Chiari I malformation) that the hyperextension might be a compensatory technique used by such patients to bring the cerebellar tonsils up out of the cervical spine. PATIENTS AND METHODS: This prospective study reviewed imaging of patients with Chiari I malformation who underwent flexion/extension MRI for evaluation of their hindbrain herniation. Age-matched controls were used for comparison. RESULTS: In general, there was elevation of the cerebellar tonsils with extension and increased descent with flexion of the cervical spine. In 72 % of patients, flexion of the neck resulted in descent of the cerebellar tonsils. In 64 % of patients, extension of the neck resulted in ascent of the cerebellar tonsils. In the 14 patients with an associated syrinx, 71 % were found to have caudal movement of the cerebellar tonsils with neck flexion, and only 43 % were observed to have any movement of the cerebellar tonsils in neck extension compared to patients without a syrinx where ascent of the tonsils was seen in only nine during neck extension. Two patients were observed to have the reverse finding of ascent of the cerebellar tonsils with neck flexion and descent of the cerebellar tonsils with neck extension. Five patients had no movement of the cerebellar tonsils in either flexion or extension of the neck, and one of these had a small syrinx. CONCLUSIONS: Although minimal and not in all patients, we observed elevation of the herniated cerebellar tonsils with extension of the cervical spine in patients with Chiari I malformation. This finding provides evidence as to why some patients with hindbrain herniation present with opisthotonos and supports earlier findings that CSF flow is reduced at the craniocervical junction in flexion in patients with Chiari I malformation.

Sagittal MRI often overestimates the degree of cerebellar tonsillar ectopia: a potential for misdiagnosis of the Chiari I malformation.

BACKGROUND: We hypothesized that by using coronal MRI, Chiari I malformation could be more precisely diagnosed, would provide simple anatomic landmarks, would provide information regarding asymmetry of hindbrain herniation, and would be a better method for analyzing the tonsillar herniation postoperatively when the opisthion has been removed. METHODS: Fifty consecutive pediatric patients diagnosed with Chiari I malformation had comparison between the measurements of their caudally descended cerebellar tonsils on midsagittal and coronal MRI images. RESULTS: On MRI coronal imaging, tonsillar asymmetry was found in 48 patients. Maximal left tonsillar descent was 20.9 mm, and maximal right tonsillar descent was 17.4 mm. On MRI sagittal imaging, tonsillar descent ranged from 5 to 27.4 mm. Fifty-eight % of patients had syringomyelia. Five patients (10 %) on coronal MRI were found to have both cerebellar tonsils that were less than 3 mm below the foramen magnum. However, all of these patients had greater than 3 mm of tonsillar ectopia on sagittal imaging. Nineteen patients (38 %) on coronal MRI were found to have one of the cerebellar tonsils that were less than 3 mm below the foramen magnum. Similarly, each of these had greater than 3 mm of tonsillar ecotpia as measured on midsagittal MRI. Also, based on these findings, Chiari I malformation is almost always an asymmetrical tonsillar ectopia. CONCLUSIONS: Sagittal MRI overestimates the degree of tonsillar ectopia in patients with Chiari I malformation. Misdiagnosis may occur if sagittal imaging alone is used. The cerebellar tonsils are paramedian structures, and this should be kept in mind when interpreting midline sagittal MRI.

Alexander Monro Tertius and his works on hydrocephalus.

INTRODUCTION: The Monros of the University of Edinburgh reigned over anatomy instruction for over a century. The last of these men, Monro Tertius, was the weaker teacher of the family but still contributed to the anatomical and surgical literature. Herein, we describe the life of Alexander Monro Tertius and his writings, particularly on childhood hydrocephalus. CONCLUSIONS: Monro Tertius will not be remembered as a great anatomist or teacher. However, he collected and published important books on his observations and those of others on hydrocephalus. These texts contained the knowledge of his era on this topic.

Chiari III malformation: a comprehensive review of this enigmatic anomaly.

INTRODUCTION: Chiari III is one of the rarest of the Chiari malformations and is characterized by a high cervical or low occipital encephalocele and osseous defect with or without spinal cord involvement and may include many of the anatomical characteristics seen in the Chiari II malformation. Herein, we provide a comprehensive review of this rare anomaly as well as a translation of Chiari's original description. METHODS: We review all reported cases of Chiari III malformation found in the extant literature. CONCLUSIONS: Out of 57 reported cases of Chiari III malformation, encephaloceles were in a high cervical/low occipital position in 23, 8 were in a high cervical position, 17 were in low occipital position, and the position in 9 cases was not reported. The pathogenesis of Chiari III malformation remains unclear. The majority of patients have concomitant hydrocephalus. Brain parts occurring in the sac from the most to least common include the following: cerebellum, occipital lobe, and parietal lobe. The severity of symptoms is correlated with the amount of brain structures within the encephalocele. Neurologic functional outcomes have been varied and depend on the neurological status of the patient before surgery.

Relationship between pharyngitis and peri-odontoid pannus: A new etiology for some Chiari I malformations?

The pathophysiology underlying Chiari I malformations (CIMs) provides room for debate with several theories attempting to address this issue. We retrospectively reviewed many of our past patients with pediatric CIMs (specifically, those with peri-odontoid pannus), and present a hypothesis for the development of the malformation in some of said patients. Our experience with the pediatric CIM has shown that almost 1 in 20 patients who present with symptoms is found to have a peri-odontoid pannus. These masses ranged in size from 4 to 11 mm in diameter. Forty percent had a history of clinically significant pharyngitis or pharyngeal abscess. Pannus formation around the dens (odontoid) resulted in ventral compression of the craniocervical junction in each of these patients. Highlighting the hypermobility that causes such lesions, following fusion, the pannus and symptoms in several patients were diminished. Impairment of normal cerebrospinal fluid circulation out of the fourth ventricle and across the craniocervical junction appears to be a plausible endpoint in this discussion and a suitable explanation for some patients with CIM. Still, the mechanisms by which cerebrospinal fluid circulation is compromised may be variable and are not well understood. This is the first study dedicated to the evaluation of pannus formation in the CIM population. We hypothesize that pharyngeal inflammatory conditions contribute to the formation and progression of hindbrain herniation in a small subset of patients with CIMs.