Biallelic loss-of-function variants of SLC12A9 cause lysosome dysfunction and a syndromic neurodevelopmental disorder.

PURPOSE: Pathogenic variants of FIG4 generate enlarged lysosomes and neurological and developmental disorders. To identify additional genes regulating lysosomal volume, we carried out a genome-wide activation screen to detect suppression of enlarged lysosomes in FIG4-/- cells. METHODS: The CRISPR-a gene activation screen utilized sgRNAs from the promoters of protein-coding genes. Fluorescence-activated cell sorting separated cells with correction of the enlarged lysosomes from uncorrected cells. Patient variants of SLC12A9 were identified by exome or genome sequencing and studied by segregation analysis and clinical characterization. RESULTS: Overexpression of SLC12A9, a solute co-transporter, corrected lysosomal swelling in FIG4-/- cells. SLC12A9 (NP_064631.2) colocalized with LAMP2 at the lysosome membrane. Biallelic variants of SLC12A9 were identified in 3 unrelated probands with neurodevelopmental disorders. Common features included intellectual disability, skeletal and brain structural abnormalities, congenital heart defects, and hypopigmented hair. Patient 1 was homozygous for nonsense variant p.(Arg615∗), patient 2 was compound heterozygous for p.(Ser109Lysfs∗20) and a large deletion, and proband 3 was compound heterozygous for p.(Glu290Glyfs∗36) and p.(Asn552Lys). Fibroblasts from proband 1 contained enlarged lysosomes that were corrected by wild-type SLC12A9 cDNA. Patient variant p.(Asn552Lys) failed to correct the lysosomal defect. CONCLUSION: Impaired function of SLC12A9 results in enlarged lysosomes and a recessive disorder with a recognizable neurodevelopmental phenotype.

Posthemorrhagic hydrocephalus management in patients with necrotizing enterocolitis: a monocentric experience.

PURPOSE: Posthemorrhagic hydrocephalus (PHH) and necrotizing enterocolitis (NEC) are two comorbidities associated with prematurity. The management of patients with both conditions is complex and it is necessary to intercept them to avoid meningitis and multilocular hydrocephalus. METHODS: In a single-center retrospective study, we analyzed 19 patients with NEC and PHH admitted from 2012 to 2022. We evaluated perinatal, imaging, and NEC-related data. We documented shunt obstruction and infection and deaths within 12 months of shunt insertion. RESULTS: We evaluated 19 patients with NEC and PHH. Six cases (31.58%) were male, the median birth weight was 880 g (650-3150), and the median gestational age was 26 weeks (23-38). Transfontanellar ultrasound was performed on 18 patients (94.74%) and Levine classification system was used: 3 cases (15.79%) had a mild Levine index, 11 cases (57.89%) had moderate, and 5 cases (26.32%) were graded as severe. Magnetic resonance showed intraventricular hemorrhage in 14 cases (73.68%) and ventricular dilatation in 15 cases (78.95%). The median age at shunt insertion was 24 days (9-122) and the median length of hospital stay was 120 days (11-316). Sepsis was present in 15 cases (78.95%). NEC-related infection involved the peritoneal shunt in 4 patients and 3 of them had subclinical NEC. At the last follow-up, 6 (31.58%) patients presented with psychomotor delay. No deaths were reported. CONCLUSIONS: Although recognition of subclinical NEC is challenging, the insertion of a ventriculoperitoneal shunt is not recommended in these cases and alternative treatments should be considered to reduce the risk of meningitis and shunt malfunction.

A case report of hemorrhagic presentation of diffuse neonatal hemangiomatosis (DNH) associated to obstructive hydrocephalus: Medical and neurosurgical considerations.

BACKGROUND: Diffuse neonatal hemangiomatosis (DNH) is a rare disorder typically recognized at birth or during the neonatal period. DNH involves three or more organ systems, including the central nervous system (CNS). In these cases, serious complications such as hemorrhages and obstructive hydrocephalus can develop. CASE REPORT: We present a case of DNH with intracranial hypertension and CNS hemorrhagic lesions on the mesencephalic aqueduct, resulting in triventricular hydrocephalus, treated with endoscopic ventriculocisternostomy (ETV) and medical therapy. DISCUSSION: DNH is a rare condition that can involve the CNS with serious complications. From a review of the literature, we highlighted only two cases of DNH with brain involvement treated surgically. We report the successful outcome of ETV, along with surgical considerations, imaging findings, and the complete resolution of cerebral and skin lesions following medical therapy. CONCLUSIONS: Medical therapy is not standardized and must be individualized. In patients who develop severe neurological symptoms such as obstructive hydrocephalus, surgery may be considered to avoid neurological sequelae.

Pathogenesis and treatment of a giant occipital bone defect with meningoencephalocele in an NF1 child: case report and review of the literature.

Autosomal dominantly inherited neurofibromatosis type I (NF1) is a systemic disorder caused by a mutation of a gene on chromosome 17q11.2 and characterized by multiple café-au-lait spots, lentiginous macules, Lisch nodules of the iris, and tumors of the nervous system. Bony manifestations such as scoliosis, dysplasia of the greater sphenoidal wing, tibial pseudoarthrosis, short stature, and macrocephaly have been reported in approximately 50% of patients. However, calvarial bone defects are rare. After screening 324 articles, 23 cases (12 adult and 11 pediatric patients) of occipital bone defects in NF1 patients were selected. All patients had a single/multiple bone defect over the lambdoid suture. Adjacent benign plexiform neurofibromas were observed in 14 patients (60.8%, 7 adults and 7 children); one adult patient was diagnosed with neurofibrosarcoma. Meningoencephalocele over the occipital defect was noted in 8 cases (34.78%, all adults). Cranioplasty was performed in only 17.39% of patients. Histologic examination was performed in 7 of the 15 patients with associated neurofibromas/neurofibrosarcomas. Biopsy of the bone margins surrounding the defect was performed in only one case. Pathologic examination of the herniated parieto-occipital or cerebellar tissue was not performed in any of the patients studied. We report the case of a 9-year-old girl with NF1 and a significant occipital bone defect and performed a systematic review of the relevant literature to highlight the challenges in treating this condition and to investigate the underlying mechanisms contributing to bone defects or dysplasia in NF1.

Surgical limits, pitfalls, and potential solutions in kyphectomy in myelomeningocele: three cases and systematic review of the literature.

OBJECTIVES: To describe surgical treatment of 3 cases of severe and progressive thoracolumbar kyphosis in myelomeningocele and provide a systematic review of the available literature on the topic. METHODS: Medical records and pre- and post-operative imaging of 3 patients with thoracolumbar kyphosis and myelomeningocele were reviewed. A database search was performed for all manuscripts published on kyphectomy and/or surgical treatment of kyphosis in myelomeningocele. Patients' information, preoperative kyphosis angle, type of surgery, levels of surgery degrees of correction after surgery and at follow-up, and complications were reviewed for the included studies. RESULTS: Three cases underwent posterior vertebral column resection (pVCR) of 2-4 segments at the apex of the kyphosis (kyphectomy). Long instrumentation was performed with all pedicle screws constructed from the thoracic spine to the pelvis using iliac screws. According to literature review, a total of 586 children were treated for vertebral kyphosis related to myelomeningocele. At least one vertebra was excised to gain some degree of correction of the deformity. Different types of instrumentation were used over time and none of them demonstrated to be superior over the other. CONCLUSION: Surgical treatment of progressive kyphosis in myelomeningocele has evolved over the years incorporating all major advances in spinal instrumentation techniques. Certainly, the best results in terms of preservation of correction after surgery and less revision rates were obtained with long construct and screws. However, complication rate remains high with skin problems being the most common complication. The use of low-profile instrumentation remains critical for treatment of these patients.

Navigating the complexities of encephalocraniocutaneous lipomatosis: a case series and review.

INTRODUCTION: Encephalocraniocutaneous lipomatosis (ECCL) is a rare congenital syndrome with complex skin, eye, and central nervous system (CNS) symptoms. Diagnosis and treatment are challenging due to its rarity and diverse manifestations. It often involves issues like porencephalic cysts, cortical atrophy, and low-grade gliomas in the CNS, resulting in developmental delays. The spinal cord is frequently affected, leading to problems like medullary compression and radiculopathy, causing back pain and sensory/motor deficits. Surgical interventions are reserved for symptomatic cases to address hydrocephalus or alleviate spinal lipomas. This article reviews a case series to assess surgical risks and neurological outcomes. CASE SERIES: We present a case series ECCL, focusing on the diffuse lipomatosis of the spinal cord and the intricate surgical procedures involved. A multi-stage surgical approach was adopted, with continuous neuromonitoring employed to safeguard motor pathways. We discuss clinical characteristics, imaging studies, and indications for neurosurgical interventions. DISCUSSION: ECCL is a complex syndrome. Diagnosis is challenging and includes clinical evaluation, neuroimaging, and genetic testing. Treatment targets specific symptoms, often requiring surgery for issues like lipomas or cerebral cysts. Surgery involves laminectomies, spinal fusion, and motor pathway monitoring. Thorough follow-up is crucial due to potential CNS complications like low-grade gliomas. Hydrocephalus occurs in some cases, with endoscopic third ventriculostomy (ETV) preferred over ventriculoperitoneal shunt placement. CONCLUSION: Neurosurgery for ECCL is for symptomatic cases. ETV is preferred for hydrocephalus, while the treatment for lipoma is based on the presence of symptoms; the follow-up should assess growth and prevent deformities.

Rathke's cyst with xanthogranulomatous change or chronic cystic craniopharingioma? A rare case.

A 9-year-old girl presented to our neurosurgery clinic complaining of visual disturbances for a week. Magnetic resonance imaging showed an extensive sellar lesion with suprasellar involvement and compression of the optic chiasm. Based on these findings, a cystic craniopharyngioma, a pituitary macroadenoma and - less likely - a Rathke's cleft cyst were considered as differential diagnoses. In view of the progressive loss of vision, the parents agreed to resection of the lesion through an endoscopic endonasal transtubercular approach, with the aim of a gross total resection. Microscopic examination revealed that the lesion was cystic, surrounded by an epithelium that was partly composed of columnar ciliated cells with interspersed mucous cells and partly had a flattened appearance. The observed findings were complex to interpret: if, on the one hand, the clinical-surgical and neuroradiologic data suggested a craniopharyngioma, this hypothesis was not supported by the microscopic data, because the presence of columnar ciliated epithelium associated with mucous cells was a microscopic feature inconsistent with a craniopharyngioma and was instead consistent with a Rathke's cleft cyst, a histologic diagnosis that was made. The incidence of Rathke's cleft cyst, which mimics clinical and neuroradiologic aspects of craniopharyngiomas, is extremely unusual, as only 2 cases have been described in the literature.

Surgical revascularization as a procedure to prevent neurological complications in children with moyamoya syndrome associated with neurofibromatosis I: a single institution case series.

BACKGROUND: The optimal timing and surgical approach for surgical revascularization in patients with moyamoya syndrome (MMS) associated with neurofibromatosis type I (NF1) remain so far elusive. We aimed to compare the long-term clinical, radiological, and cognitive effects of different revascularization procedures in a pediatric cohort of NF1-associated MMS. METHODS: We reviewed the clinical, radiological, and surgical data of 26 patients with NF1-associated MMS diagnosed at our institution between 2012 and 2022, at the clinical onset and last follow-up. RESULTS: Indirect bypasses were performed in 12/26 patients (57.1%), while combined direct and indirect procedures in 9/26 subjects (42.9%); 5 patients did not undergo surgery. Through logistic regression analysis, pathological Wechsler Intelligence Scale for Children (WISC) at onset was found to be associated with symptom improvement at 1-year follow up (p = 0.006). No significant differences were found in long-term neurocognitive outcome and stroke rate in patients receiving combined or indirect bypass (p > 0.05). CONCLUSIONS: Currently, whether combined or indirect bypass should be considered the treatment of choice in pediatric patients with NF1-associated MMS remains unclear, as well as the optimal time approach. In our series, no significant differences were found in long-term neurocognitive outcome and stroke rate between patients treated with either of these two approaches. Clinical evidence supports the crucial role of early diagnosis and surgical revascularization in subjects with MMS-associated NF1, even in case of mildly symptomatic vasculopathy. This allows to achieve a good long-term outcome with improved intellectual function and prevention of stroke and seizure in these patients.

Surgical treatment of cavernous malformation-related epilepsy in children: case series, systematic review, and meta-analysis.

OBJECTIVE: Cerebral cavernous malformations (CCMs) are cerebral vascular lesions that occasionally occur with seizures. We present a retrospective case series from IRCCS Gaslini Children's Hospital, a systematic review, and meta-analysis of the literature with the goal of elucidating the post-surgery seizure outcome in children with CCMs. METHODS: a retrospective review of children with cavernous malformation related epilepsy who underwent surgery at Gaslini Children's Hospital from 2005 to 2022 was conducted. We also conducted a comprehensive search on PubMed/MEDLINE and Scopus databases from January 1989 to August 2022. Inclusion criteria were: presence of CCMs-related epilepsy, in under 18 years old subjects with a clear lesion site. Presence of post-surgery seizure outcome and follow-up ≥ 12 months. RESULTS: we identified 30 manuscripts and 223 patients with CCMs-related epilepsy, including 17 patients reported in our series. We identified 85.7% Engel class I subjects. The risk of expected neurological deficits was 3.7%; that of unexpected neurological deficits 2.8%. We found no statistically significant correlations between Engel class and the following factors: site of lesion, type of seizure, drug resistance, duration of disease, type of surgery, presence of multiple CCMs. However, we found some interesting trends: longer disease duration and drug resistance seem to be more frequent in subjects in Engel class II, III and IV; multiple cavernomas would not seem to influence seizure outcome. CONCLUSIONS: epilepsy surgery in children with CCMs is a safe and successful treatment option. Further studies are necessary to define the impact of clinical features on seizure prognosis.

Practical Algorithm for the Management of Multisutural Craniosynostosis with Associated Chiari Malformation and/or Hydrocephalus.

INTRODUCTION: The association between multisutural craniosynostosis with Chiari malformation (CM), venous hypertension, and hydrocephalus is widely described in the literature, especially in children with paediatric craniofacial syndromes. Some efforts have been done in the last years to understand the complex pathogenetic mechanisms underlying this association, and several theories have been proposed. In particular, it is now accepted that the hypothesis of the overcrowding of the posterior fossa due to precocious suture fusion is the cause of the cerebellar herniation in syndromic and non-syndromic patients, against the theory of intrinsic cerebellar anomalies, ventriculomegaly, and venous hypertension. However, whatever the pathophysiological mechanism, it is still unclear what the best management and treatment of CM and hydrocephalus are in multisutural craniosynostosis patients. The aim of this study was to report our 25 years' experience in treating paediatric patients affected by these rare pathologies in order to propose a simple and effective therapeutic flow chart for their management. MATERIALS AND METHODS: We retrospectively collected data of each patient who underwent a cranial vault remodelling (CVR) for complex multisutural craniosynostosis in our institution in the last 25 years, while monosutural craniosynostosis was excluded. We recorded data concerning type of craniosynostosis and craniofacial syndromes, presence of ventriculomegaly, and CM at presentation and clinical and radiological follow-up. Therefore, we evaluated the final outcomes (improved, stable, deteriorated) of these patients and created a practical flow chart that could help physicians choose the best surgical treatment when different pathological conditions, as Chiari malformation I (CMI) or hydrocephalus, affect complex craniosynostosis children. RESULTS: Thirty-nine patients (39 out of 55; 70.9%), with an isolated multisutural craniosynostosis at presentation, underwent a two-step CVR as first surgery; 36 patients (92.3%) had an improved outcome, 2 patients (5.1%) had a stable outcome, and 1 patient (2.56%) had a deteriorated outcome. Other eight children (8 out of 55; 14.5%) had a radiological evidence of asymptomatic CMI at presentation. In this group, we performed CVR as first surgery. As for the final outcome, 7 patients had an improved outcome (87.5%) with good aesthetic result and stability or resolution of CMI. Finally, 7 patients (7 out of 55; 12.7%) presented a various combination of CMI and ventriculomegaly or hydrocephalus at presentation. Among them, 3 patients had an improved outcome (42.8%), and 4 patients had a deteriorated outcome (57.1%). DISCUSSION: The prevalence of one pathological condition with associated symptoms over the others was the key factor leading our therapeutic strategy. When craniosynostosis is associated with a radiological CM, the assessment of clinical symptoms is of capital importance. When asymptomatic or pauci-symptomatic, we suggest a CVR as first step, for its efficacy in reducing tonsillar herniation and solving CM symptoms. When craniosynostosis is associated with ventricular enlargement, the presence of intracranial hypertension signs and symptoms forces physicians to first treat hydrocephalus with a ventriculo-peritoneal shunt or endoscopic third ventriculostomy. For patients with various degrees and severity of ventriculomegaly and associated CM, the outcomes were very heterogeneous, even when the same therapeutic strategy was applied to patients with similar starting conditions and symptoms. This is maybe the most unexpected and least clear part of our results. Despite the proposed algorithm comes from a clinical experience on 85% successfully treated patients with multiple craniosynostosis, more extensive and deep studies are needed to better understand CM and hydrocephalus development in such conditions.

Imaging characteristics and neurosurgical outcome in subjects with agenesis of the corpus callosum and interhemispheric cysts.

PURPOSE: To explore the relationships between clinical-radiological features and surgical outcomes in subjects with interhemispheric cysts (IHC) and corpus callosum anomalies. METHODS: We reviewed the clinico-radiological and neurosurgical data of 38 patients surgically treated with endoscopic fenestration, shunting, or combined approaches from 2000 to 2018 (24 males, median age 9 years). Pre- and postoperative changes in IHC volume were calculated. Outcome assessment was based on clinico-radiological data. Group comparisons were performed using χ2, Fisher exact, Mann-Whitney U, and Kruskal-Wallis tests. RESULTS: Median age at first surgery was 4 months (mean follow-up 8.3 years). Eighteen individuals (47.3%) required > 1 intervention due to IHC regrowth and/or shunt malfunction. Larger preoperative IHC volume (P = .008) and younger age at surgery (P = .016) were associated with cyst regrowth. At last follow-up, mean cystic volume was 307.8 cm3, with IHC volume reduction > 66% in 19/38 (50%) subjects. The neurological outcome was good in 14/38 subjects (36.8%), fair in 18/38 (47.3%), and poor in 6/38 (15.7%). There were no differences in the postoperative cyst volume with respect to either the type of first surgery or overall surgery type. Higher absolute postoperative IHC reduction was observed in subjects who underwent both IHC fenestration and shunting procedures (P < .0001). No differences in neurological outcome were found according to patient age at surgery or degree of IHC reduction. CONCLUSION: Endoscopic fenestration and shunting approaches are both effective but often require multiple procedures especially in younger patients. Larger IHC are more frequently complicated by cyst regrowth after surgery.

Diagnosis and treatment of Chiari malformation type 1 in children: the International Consensus Document.

BACKGROUND: Chiari malformation type 1 (CM1) is a rare condition where agreed classification and treatment are still missing. The goal of this study is to achieve a consensus on the diagnosis and treatment of CM1 in children. METHODS: A multidisciplinary panel formulated 57 provisional statements based on a review of the literature. Thirty-four international experts (IE) participated in a Delphi study by independently rating each statement on a 4-point Likert scale ("strongly disagree," "disagree," "agree," "strongly agree"). Statements that were endorsed ("agree" or "strongly agree") by < 75% of raters were re-formulated, or new statements were added, and another Delphi round followed (up to a maximum of three). RESULTS: Thirty-five IE were contacted and 34 agreed to participate. A consensus was reached on 30/57 statements (52.6%) after round 1. Three statements were added, and one removed. After round 2, agreement was reached on 56/59 statements (94.9%). Finally, after round 3, which took place during the 2019 Chiari Consensus Conference (Milan, Italy), agreement was reached on 58/59 statements (98.3%) about four main sections (Definition and Classification, Planning, Surgery, Isolated Syringomyelia). Only one statement did not gain a consensus, which is the "definition of radiological failure 24 month post-surgery." CONCLUSIONS: The consensus document consists of 58 statements (24 on diagnosis, 34 on treatment), serving clinicians and researchers following children with CM1. There is a clear need for establishing an international network and registry and to promote collaborative studies to increase the evidence base and optimize the long-term care of this patient population.

Early molecular diagnosis of BRAF status drives the neurosurgical management in BRAF V600E-mutant pediatric low-grade gliomas: a case report.

BACKGROUND: To date, this is the only report showing with close and consecutive magnetic resonance images the extremely rapid response of two types of pediatric low-grade gliomas (PLGG) to vemurafenib and its impact on the surgical approach. CASES PRESENTATION: We report two cases of symptomatic PLGG treated with vemurafenib, a BRAF inhibitor: in a 12-year-old girl it was used as first-line medical treatment, reducing the tumor by 45% within a month and stabilizing to 76% after a year; in a 3-year-old boy with no improvement after SIOP LGG 2004 Protocol, vemurafenib induced in only one week a 34% shrinkage and solved the hydrocephalus, avoiding surgical operation. DISCUSSION AND CONCLUSIONS: Our cases demonstrate how an early molecular diagnosis of BRAF mutations through the neurosurgical biopsy is essential to promptly start targeted therapies., whose effect can influence both therapeutic and surgical decisions, hopefully reducing the occurrence of second neurosurgery with associated risks of neurological sequelae.

Stepwise approach for vertebral hemangioma in children: case-reports and treatment algorithm proposal.

PURPOSE: To discuss a treatment algorithm for vertebral hemangioma in children. METHODS: Vertebral hemangioma (VH) is a rare cause of low back pain in children. In most cases, VHs present as incidental findings and do not require invasive diagnostic procedure. In case of symptomatic presentation, different approaches can be used. Over the years, we have developed a treatment algorithm for VH in children based on our clinical experience. In this manuscript, we propose a stepwise approach to treatment of VHs based on tumor extension and the degree of spinal cord/nerves compression with or without neurological deficit. RESULTS: According to the proposed protocol, we discuss two cases of aggressive VH treated at our institution by a multidisciplinary team. The first case is about a young girl treated with percutaneous one-level posterior instrumentation followed by medical adjuvant therapy for an L4 "Stage 3" VH. The second case is about an 8-year-old boy with rapidly progressive myelopathy due to T11 "Stage 4" VH treated with a combined anterior and posterior surgery (i.e., posterior decompression and fusion followed by vertebrectomy and expandable cage placement) after preoperative arterial embolization. CONCLUSION: Given the lack of international guidelines and consensus with regard to treatment of VHs in children, we believe our proposal for a stepwise approach combining clinical and radiological characteristics of the lesion may help guide treatment of this condition in children.

From Henry Shrapnel (1761-1842) to today's neurosurgery: how antipersonnel weapons have laid the foundation of clinical and surgical management of head injury fractures and penetrating brain injuries.

Henry Shrapnel invented an antipersonnel weapon capable of defragmenting with the explosion of charge. Modern grenades or improvised explosive devices may be seen as an evolution of Shrapnel's ammunition. Starting by analyzing the ballistics of these weapons, it is possible to understand the historical evolution of the management of skull fractures and penetrating brain injuries (PBIs). A circular crack line with a splinter at the center, depressed in bone, was a characteristic feature of fractures due to Shrapnel's bullet. Three longitudinal fissures, one medial and two lateral, may be present due to tangential blows. Craniectomy and/or fracture reduction were almost always necessary in these cases. The first document describing medical examination and therapeutic strategies for head-injured patients dates back to 1600 bc (the Edwin Smith Papyrus). Several doctors from the past century, such as Puppe, Matson, and Cushing, proposed different theories about skull fractures and the management of craniocerebral injuries, paving the way for diagnosing and treating these injuries. Shrapnel fractures required wider craniotomies and in the past surgeons had to deal with more severe injuries. Based on past military experiences during what could be called the postshrapnel age, guidelines for the management of PBIs were introduced in 2001. In these guidelines various concepts were reviewed, such as the importance of antibiotics and seizure prevention; included as well were prognostic factors such as hypotension, coagulopathy, respiratory distress, and Glasgow Coma Scale score. Furthermore, they highlight how it has not been possible to reach a common viewpoint on surgical management. Nevertheless, in contrast with the past, it is preferable to be less aggressive regarding retained fragments if there is no intracranial mass effect. Although military situations were useful in building basic principles for PBI guidelines, civilian PBIs differ noticeably from military ones. Therefore, there is a need to review modern guidelines in order to apply them in every situation.

Pediatric pituitary adenoma with mixed FSH and TSH immunostaining and FSH hypersecretion in a 6 year-old girl with precocious puberty: case report and multidisciplinary management.

OBJECTIVE: We describe a rare case of functioning gonadotropins-producing pediatric adenoma immunostaining positively for FSH and focally for TSH causing central precocious puberty associated to central hypothyroidism in a 6 year-old girl. MATERIALS AND METHODS: Clinical evaluation revealed precocious puberty, as confirmed by hormonal determination with elevated FSH and estradiol, while central hypothyroidism was biochemically diagnosed by a low fT4 and normal TSH. Head MRI showed the presence of a hyperintense pituitary lesion. The patient successfully underwent transsphenoidal endoscopic resection of the pituitary macroadenoma. RESULTS: Pathologic evaluation of the tissue resected at surgery confirmed the diagnosis of pituitary adenoma with positive immunohistochemistry for FSH and focally for TSH in a mixed pattern. Ten months after surgery, there were no neurological signs and symptoms. Postoperative head MRI showed no abnormalities and no evidence of tumor regrowth. CONCLUSIONS: Early and accurate diagnosis, multidisciplinary approach and close follow up are crucial factors for the favorable outcome.

Exome survey of individuals affected by VATER/VACTERL with renal phenotypes identifies phenocopies and novel candidate genes.

The acronym VATER/VACTERL refers to the rare nonrandom association of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac anomalies (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb anomalies (L). For the clinical diagnosis, the presence of at least three CFs is required, individuals presenting with only two CFs have been categorized as VATER/VACTERL-like. The majority of VATER/VACTERL individuals displays a renal phenotype. Hitherto, variants in FGF8, FOXF1, HOXD13, LPP, TRAP1, PTEN, and ZIC3 have been associated with the VATER/VACTERL association; however, large-scale re-sequencing could only confirm TRAP1 and ZIC3 as VATER/VACTERL disease genes, both associated with a renal phenotype. In this study, we performed exome sequencing in 21 individuals and their families with a renal VATER/VACTERL or VATER/VACTERL-like phenotype to identify potentially novel genetic causes. Exome analysis identified biallelic and X-chromosomal hemizygous potentially pathogenic variants in six individuals (29%) in B9D1, FREM1, ZNF157, SP8, ACOT9, and TTLL11, respectively. The online tool GeneMatcher revealed another individual with a variant in ZNF157. Our study suggests six biallelic and X-chromosomal hemizygous VATER/VACTERL disease genes implicating all six genes in the expression of human renal malformations.

A rare triad of morning glory disc anomaly, moyamoya vasculopathy, and transsphenoidal cephalocele: pathophysiological considerations and surgical management.

Morning glory disc anomaly is a congenital abnormality of the optic disc and peripapillary retina reported as an isolated condition or associated with various anomalies, including basal encephaloceles and moyamoya vasculopathy. However, the co-occurrence of these three entities is extremely rare and the pathogenesis is still poorly understood. Moreover, data on the surgical management and long-term follow-up of the intracranial anomalies are scarce. Here, we describe the case of a 11-year-old boy with morning glory disc anomaly, transsphenoidal cephalocele, and moyamoya vasculopathy, who underwent bilateral indirect revascularization with encephalo-duro-myo-arterio-pericranio-synangiosis at the age of 2 years, and endoscopic repair of the transsphenoidal cephalocele at the age of 6 years. A rare missense variant (c.1081T>C,p.Tyr361His) was found in OFD1, a gene responsible for a X-linked ciliopathy, the oral-facial-digital syndrome type 1 (OFD1; OMIM 311200). This case expands the complex phenotype of OFD1 syndrome and suggests a possible involvement of OFD1 gene and Shh pathway in the pathogenesis of these anomalies.

Limits and pitfalls of indirect revascularization in moyamoya disease and syndrome.

Moyamoya vasculopathy is a rare chronic cerebrovascular disorder characterized by the stenosis of the terminal branches of the internal carotid arteries and the proximal tracts of anterior and middle cerebral arteries. Although surgical revascularization does not significantly change the underlying pathogenic mechanisms, it plays a pivotal role in the management of affected individuals, allowing to decrease the risk of ischemic and hemorrhagic complications. Surgical approaches may be direct (extracranial-intracranial bypass), indirect, or a combination of the two. Several indirect techniques classifiable according to the tissue (muscle, periosteum, galea, dura mater, and extracranial tissues) or vessel (artery) used as a source of blood supply are currently available. In this study, we reviewed the pertinent literature and analyzed the advantages, disadvantages, and pitfalls of the most relevant indirect revascularization techniques. We discussed the technical aspects and the therapeutical implications of each procedure, providing a current state-of-the-art overview on the limits and pitfalls of indirect revascularization in the treatment of moyamoya vasculopathy.

Congenital posterior cervical spine malformation due to biallelic c.240-4T>G RIPPLY2 variant: A discrete entity.

The clinical and radiological spectrum of spondylocostal dysostosis syndromes encompasses distinctive costo-vertebral anomalies. RIPPLY2 biallelic pathogenic variants were described in two distinct cervical spine malformation syndromes: Klippel-Feil syndrome and posterior cervical spine malformation. RIPPLY2 is involved in the determination of rostro-caudal polarity and somite patterning during development. To date, only four cases have been reported. The current report aims at further delineating the posterior malformation in three new patients. Three patients from two unrelated families underwent clinical and radiological examination through X-ray, 3D computed tomography and brain magnetic resonance imaging. After informed consent was obtained, family-based whole exome sequencing (WES) was performed. Complex vertebral segmentation defects in the cervico-thoracic spine were observed in all patients. WES led to the identification of the homozygous splicing variant c.240-4T>G in all subjects. This variant is predicted to result in aberrant splicing of Exon 4. The current report highlights a subtype of cervical spine malformation with major atlo-axoidal malformation compromising spinal cord integrity. This distinctive mutation-specific pattern of malformation differs from Klippel-Feil syndrome and broadens the current classification, defining a sub-type of RIPPLY2-related skeletal disorder. Of note, the phenotype of one patient overlaps with oculo-auriculo-vertebral spectrum disorder.