De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations.

PURPOSE: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. METHODS: An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. RESULTS: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. CONCLUSION: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability.

A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders.

OBJECTIVE: Neurodevelopmental disorders (NDDs) often associate with epilepsy or craniofacial malformations. Recent large-scale DNA analyses identified hundreds of candidate genes for NDDs, but a large portion of the cases still remain unexplained. We aimed to identify novel candidate genes for NDDs. METHODS: We performed exome sequencing of 95 patients with NDDs including 51 with trigonocephaly and subsequent targeted sequencing of additional 463 NDD patients, functional analyses of variant in vitro, and evaluations of autism spectrum disorder (ASD)-like phenotypes and seizure-related phenotypes in vivo. RESULTS: We identified de novo truncation variants in nine novel genes; CYP1A1, C14orf119, FLI1, CYB5R4, SEL1L2, RAB11FIP2, ZMYND8, ZNF143, and MSX2. MSX2 variants have been described in patients with cranial malformations, and our present patient with the MSX2 de novo truncation variant showed cranial meningocele and partial epilepsy. MSX2 protein is known to be ubiquitinated by an E3 ubiquitin ligase PJA1, and interestingly we found a PJA1 hemizygous p.Arg376Cys variant recurrently in seven Japanese NDD patients; five with trigonocephaly and one with partial epilepsy, and the variant was absent in 886 Japanese control individuals. Pja1 knock-in mice carrying p.Arg365Cys, which is equivalent to p.Arg376Cys in human, showed a significant decrease in PJA1 protein amount, suggesting a loss-of-function effect of the variant. Pja1 knockout mice displayed moderate deficits in isolation-induced ultrasonic vocalizations and increased seizure susceptibility to pentylenetetrazole. INTERPRETATION: These findings propose novel candidate genes including PJA1 and MSX2 for NDDs associated with craniofacial abnormalities and/or epilepsy.

Mild trigonocephaly associated with microcephaly: surgical outcomes for 15 cases.

BACKGROUND AND IMPORTANCE: Surgical treatment for mild trigonocephaly associated with microcephaly is often attempted if neuroradiological studies show evidence of increased intracranial pressure. However, it is difficult to decide how to approach surgically these patients. Herein, we report the surgical outcomes of the patients we have treated surgically in our center. CLINICAL PRESENTATION: We performed surgery on 15 patients (ten girls and five boys) who were all diagnosed as microcephalic during infancy. All patients presented clinical symptoms and evidence of short stature. Symptoms included mental retardation, language delay, hyperactivity, motor dysfunction, and self-mutilation (head banging). Head circumferences were > 2 standard deviations below the normal range for their sex and age at the time of surgery. All patients were diagnosed with mild trigonocephaly based on three-dimensional computed tomography (3D-CT). No abnormal findings could be observed in the brain of 14 patients, as assessed by magnetic resonance imaging (MRI). One patient showed brain atrophy. 3D-CT showed marked digital markings in all. Intracranial pressure (ICP) was measured under normocapnia. Increased ICP could be observed in 13 patients. Decompressive cranioplasty was performed in all patients. After surgery, evidence of enlargement of the head circumference could be observed in six patients. Some degree of intelligence problems remained. However, every patient made some improvement in at least one of the other symptoms. CONCLUSION: We suggest that decompressive cranioplasty may be indicated in patients with mild trigonocephaly associated with microcephaly, if pre-surgical evaluation shows high ICP and no abnormal brain findings can be identified on MRI.

De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies.

Potocki-Shaffer syndrome (PSS) is a contiguous gene syndrome caused by 11p11.2 deletions. PSS is clinically characterized by intellectual disability, craniofacial anomalies, enlarged parietal foramina, and multiple exostoses. PSS occasionally shows autism spectrum disorder, epilepsy, and overgrowth. Some of the clinical features are thought to be associated with haploinsufficiency of two genes in the 11p11.2 region; variants affecting the function of ALX4 cause enlarged parietal foramina and EXT2 lead to multiple exostoses. However, the remaining clinical features were still yet to be linked to specific genetic alterations. In this study, we identified de novo truncating variants in an 11p11.2 gene, PHF21A, in three cases with intellectual disability and craniofacial anomalies. Among these three cases, autism spectrum disorder was recognized in one case, epilepsy in one case, and overgrowth in two cases. This study shows that PHF21A haploinsufficiency results in intellectual disability and craniofacial anomalies and possibly contributes to susceptibility to autism spectrum disorder, epilepsy, and overgrowth, all of which are PSS features.

The metopic-sagittal craniosynostosis-report of 35 operative cases.

PURPOSE: We have diagnosed 35 cases of the supposedly rare condition metopic-sagittal synostosis in the past 20 years. Here, we introduce their clinical symptoms, neuroradiological findings, and surgical treatment methods, as well as discuss the relevant literature. METHODS: Subjects included 35 patients (33 boys and 2 girls; mean age 4.2 years; range 1-8 years). Magnetic resonance imaging (MRI) confirmed that there were no abnormal findings in the brain. Thirty patients presented with symptoms including speech delay, hyperactivity, autistic tendency, motor impairment, self-mutilation, and panic/temper tantrum behaviors. No other congenital malformation was observed, and all cases were considered to be the non-syndromic type. The final diagnosis was made using three-dimensional computed tomography (3D-CT) scans. The surgery was done the fronto-orbital advancement in addition to remove the large parts of sphenoid bones including sphenoid ridges at the skull base and trimmed the calvarium as necessary to reduce pressure. RESULTS: Surgical intervention improved clinical symptoms in nearly all 35 patients; cosmetic problems in patients with scaphocephaly were also corrected. CONCLUSIONS: In the cases of child patients with metopic-sagittal synostosis who had clinical symptoms, surgical intervention improved such symptoms, suggesting its potential utility for metopic-sagittal synostosis with clinical symptoms. A surgical procedure focusing on the skull base was important for our successes. Based on the fact that metopic-sagittal synostosis was diagnosed in 35 patients at one institution over a relatively short period of time, this pathological condition may not be as rare as is currently believed.

Analysis of pre- and post-operative symptoms of patients with mild trigonocephaly using several developmental and psychological tests.

PURPOSE: Over the past decade, we collected the cases where patients underwent decompressive cranioplasty for the treatment of mild metopic suture synostosis (mild trigonocephaly) with developmental delays. To evaluate the effectiveness of this surgery, we administered several developmental and psychological examinations to children with this condition who underwent decompressive cranioplasty. METHODS: Thirty-four children (32 boys and 2 girls) who had developmental disorders with mild trigonocephaly underwent four different tests at three different time points (pre-operation, 3 and 6 months after surgery) including the: (a) Kyoto form developmental test (2001) to calculate the developmental quotient (DQ), (b) National Rehabilitation Center Sign-Significance Test (NRC S-S test) to evaluate the patients' language use and acquisition, (c) Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) to identify autistic tendencies, and (d) Japanese Child Behavior Checklist (J-CBCL) to evaluate behavioral problems. The scores were initially analyzed using analyses of variance. When significant results were observed, Tukey-Kramer multiple comparison tests were applied for further statistical evaluation. RESULTS: Significant DQ improvements were observed, as assessed by the Kyoto form developmental test. Additionally, significant improvement in the expression of words (measured with the NRC S-S test), the scores on PARS, and some behavioral factors (measured with the J-CBCL) were observed. CONCLUSIONS: The results in this cohort suggest that decompressive cranioplasty may play an important role in supporting the improvement of developmental delays in these patients.

An intracranial pseudoaneurysm in the distal middle cerebral artery in a child.

Intracranial pseudoaneurysms are rare, particularly in children and adolescents. They are characterized by the presence of organizing hematoma and fibrosis without true vascular elements. Most pseudoaneurysms result from events such as major trauma or infectious illness, and the development of pseudoaneurysm without a preceding incident is rare. We here describe a patient with a large pseudoaneurysm arising in the distal middle cerebral artery. A 10-year-old boy experienced a sudden onset of headache, nausea, and vomiting followed by loss of consciousness and was referred to our medical center. Brain computed tomography showed massive subcortical hemorrhage in the left temporal lobe. Digital cerebral angiography revealed a huge aneurysmal dilatation of the distal left M1 segment of the middle cerebral artery, with delayed filling and emptying of contrast media. Surgical resection of the aneurysm with evacuation of the hematoma yielded restoration of consciousness. Although the cause of aneurysm in this case is uncertain, this type of patient is seldom encountered; its etiology and mechanisms of onset are discussed with reference to the literature.

Mild trigonocephaly and intracranial pressure: report of 56 patients.

INTRODUCTION: We report the surgical results in patients with mild trigonocephaly and clinical symptoms. Since high intracranial pressure (ICP) was noted during surgery in our previous patient series, we began to record intraoperative ICP. The importance of treating mild trigonocephaly with clinical symptoms is stressed. PATIENTS AND METHODS: Fifty-six children (44 boys, 12 girls) in whom ICP was measured were diagnosed with mild trigonocephaly (nonsyndromic type) with symptoms such as language delay, hyperactivity, autistic tendencies, self-mutilation, motor delay, etc. Their ages ranged from 2 to 8 (mean 5.1) years. ICP was measured after a burr hole was made under endotracheal general anesthesia and a sensor was inserted in the right frontal lobe epidurally immediately in front of the right coronal suture. The first recordings were made at around 30 mmHg of PCO(2) as for neuroanesthesia, and the second were at around 40 mmHg of PCO(2) as during natural breathing. We also investigated which factors accounted for the improvement of clinical symptoms. RESULTS: The first ICP records at 29.1 mmHg of PCO(2) indicated a mean ICP of 13.3 mmHg. The second changed to a mean 38.2 mmHg of PCO(2) for an increased mean ICP of 19.8 mmHg. The pulse pressures were a mean 7.1 mmHg in the first recordings and 8.5 mmHg in the second. The mean ICP and pulse pressure were thus high in these children. Clinically, 30 out of 56 patients improved markedly and 22 improved slightly, while 4 did not exhibit any change. Factors contributing to improvement were younger age, relatively higher development quotient, marked digital impressions on skull X-rays, abnormal findings on SPECT, and moderate degree of trigonocephaly. CONCLUSION: Although our patients had mild trigonocephaly, their ICP and pulse pressure were high. Decompressive cranioplasty in cases of mild trigonocephaly is feasible.

Mild trigonocephaly with clinical symptoms: analysis of surgical results in 65 patients.

INTRODUCTION: It has been believed that isolated, mild trigonocephaly rarely presents with clinical symptoms. PATIENTS AND METHODS: We diagnosed and operated on 65 patients with mild trigonocephaly and developmental delay up to July 2000. There were 47 boys and 18 girls in our series. All patients had symptoms such as delay in language development, hyperactivity, autistic tendencies, and motor dysfunctions. Their facial features were characterized by a metopic ridge, depressed temples, heel-shaped rather than keel-shaped forehead, and slight hypotelorism. The most important physical sign was the palpable metopic ridge. Most patients did not exhibit any symptoms until they were more than 1 year old. Fifteen patients showed regression in language acquisition and use. Three-dimensional computed tomography revealed the metopic ridge, depressed pterional regions, hypotelorism, and small anterior fossae. Magnetic resonance imaging was performed on all patients and demonstrated no abnormal findings in the brain. Single-photon emission computed tomography (SPECT) was performed on 83% of patients and revealed decreased cerebral blood flow (CBF) in the frontal lobes of 76% of those patients. Decompressive cranioplasty of the frontal bone involving the skull base was performed on all patients. RESULTS: In most (61 out of 65) patients a degree of postoperative improvement in clinical symptoms was noted, especially in behavioral problems. Postoperative SPECT demonstrated increased CBF in the frontal lobes in 95% of the patients. CONCLUSION: Based on these results, it can be postulated that mild trigonocephaly is frequently associated with developmental delays and that these symptoms can be improved to a certain degree by decompressive cranioplasty.