Microcephaly type 22 and autism spectrum disorder: A case report and review of literature.

INTRODUCTION: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with a multifaceted etiology. This case report explores the ischemic cryptogenic vascular dissection as a potential underlying cause of ASD. METHODS: A 9-year-old child presented with symptoms of ASD, including social interaction difficulties, repetitive behaviors, and cognitive challenges. Despite conventional ASD treatments, significant improvement was only observed after addressing an underlying ischemic cryptogenic vascular dissection identified through DCE-CT. RESULTS: Following a reconstructive treatment approach to the vascular dissection, the patient showed marked improvement in cognitive functions, social abilities, and a reduction in ASD-related symptoms whether during the perioperative period or during approximately 5-month follow-up. CONCLUSION: This case suggests that ischemic cryptogenic vascular dissection may contribute to the symptoms of ASD. Identifying and treating underlying vascular anomalies may offer a new avenue for mitigating ASD symptoms, emphasizing the need for comprehensive diagnostic estimations in ASD management.

Management of an older Marshall-Smith syndrome patient: a review of literature of MSS and craniosynostosis.

Marshall-Smith Syndrome (MSS) is a rare progressive developmental disorder that severely impairs a patient's intellectual development and physical health. The only known cause for MSS is a mutation in the nuclear factor 1 X (NFIX) gene. This mutation affects neuronal development and protein transcription. Historically, most patients with MSS do not survive beyond 3 years of age. Reports of ocular findings are limited. We report a case of a 9-year-old MSS patient with progressive craniosynostosis, elevated intracranial pressure, and catastrophic ocular complications. A comprehensive PubMed literature search from 2018 to August 2022 updating a previous review of older literature produced 72 articles relating to MSS, which are reviewed.

Unilateral progressive anterior iris adhesions in Mowat-Wilson syndrome: a new ocular finding.

Ocular associations in Mowat-Wilson syndrome (MWS) are rare. Those involving the anterior segment are scarce in the literature. We describe a child with genetic confirmation of MWS that presented with acquired onset of unilateral anterior iris adhesions with no known trauma.

Exacerbated Zika virus-induced neuropathology and microcephaly in fetuses of dengue-immune nonhuman primates.

Zika virus (ZIKV) is a mosquito-borne flavivirus that can vertically transmit from mother to fetus, potentially causing congenital defects, including microcephaly. It is not fully understood why some fetuses experience severe complications after in utero exposure to ZIKV, whereas others do not. Given the antigenic similarity between ZIKV and the closely related virus dengue (DENV) and the potential of DENV-specific antibodies to enhance ZIKV disease severity in mice, we questioned whether maternal DENV immunity could influence fetal outcomes in a nonhuman primate model of ZIKV vertical transmission. We found significantly increased severity of congenital Zika syndrome (CZS) in fetuses of DENV-immune cynomolgus macaques infected with ZIKV in early pregnancy compared with naïve controls, which occurred despite no effect on maternal ZIKV infection or antibody responses. Ultrasound measurements of head circumference and biparietal diameter measurements taken sequentially throughout pregnancy demonstrated CZS in fetuses of DENV-immune pregnant macaques. Furthermore, severe CZS enhanced by DENV immunity was typified by reduced cortical thickness and increased frequency of neuronal death, hemorrhaging, cellular infiltrations, calcifications, and lissencephaly in fetal brains. This study shows that maternal immunity to DENV can worsen ZIKV neurological outcomes in fetal primates, and it provides an animal model of vertical transmission closely approximating human developmental timelines that could be used to investigate severe ZIKV disease outcomes and interventions in fetuses.

Safe use of the ketogenic diet in an infant with microcephaly, epilepsy, and diabetes syndrome: a case report.

BACKGROUND: Microcephaly, epilepsy, and diabetes syndrome (MEDS) is a rare syndromic form of monogenic diabetes caused by bi-allelic loss of function mutations in IER3IP1. In vitro studies have shown that loss of IER31P leads to apoptosis in both neurons and pancreatic ß-cells. Simultaneous management of seizures and diabetes is challenging in patients with MEDS. We present the challenges and successes in the use of ketogenic diet in an infant with insulinopenic diabetes. CASE PRESENTATION: Our term female proband presented at 2 months of age with new onset multifocal seizures followed by the onset of infantile spasms (IS) at 4 months of age. An epilepsy gene panel identified bi-allelic variants, c.239T > G (p.Leu80*) and c.2T > A (initiator codon), in IER3IP1 that were subsequently shown to be inherited in trans. Following initiation of steroid therapy for IS, the patient developed clinically apparent insulin requiring diabetes. Her epilepsy was ultimately refractory to multiple antiseizure medications, thus the ketogenic diet (KD) was initiated. We were able to successfully titrate to a therapeutic KD ratio of 3:1 and maintain a ketotic state without diabetic ketoacidosis (DKA). With intercurrent illnesses, however, the patient had rapid decompensation and mild DKA due to delays in treatment, and for this reason, KD was discontinued after 5 months. CONCLUSIONS: We report two novel IER31P1 mutations in a patient with MEDS and the successful management of the cooccurring conditions of IS and insulinopenic diabetes with the KD. Our experience underscores the importance of careful monitoring during KD as our patient had DKA more easily when on the KD.

Craniofacial and dental features in children aged 3-5 years with congenital Zika syndrome.

OBJECTIVE: Zika virus infection has been associated to congenital zika syndrome (CZS) in newborns and is characterized by microcephaly, central/axial motor and sensory dysfunction, dysphagia among other previously described severe health complications. CZS is usually diagnosed postpartum by evident/apparent neural development problems. Although there are some reports of craniofacial/dentition development in CZS, several clinical oral aspects are still unknown. This study describes some structural and functional characteristics of facial and cranial growth and deciduous dentition in CZS-affected children. MATERIAL AND METHODS: Some cranial, facial and dental characteristics were determined in 14 children with CZS aged 3-5 years and compared them against 12 apparently healthy children paired by age and gender. RESULTS: Fourteen CZS cases presented microcephaly, maxillary prognathism, altered facial thirds, asymmetric pupillary line, bruxism (p = 0.006), deep and anterior open bite and distal step decidual molar relationship (p = 0.031). CZS children cannot feed by themselves and most cannot walk and have not develop coordinated and intelligible language according to their chronological age. In contrast, controls presented normal skull features, have autonomous locomotion skills, speak intelligible language, feed by themselves, presented a harmonic intermaxillary relationship and have symmetrical facial thirds. CONCLUSION: Microcephaly, dysphagia, bruxism, mandibular retrognathia, altered facial proportions and malocclusion are the main craniofacial and oral features at CZS. CLINICAL RELEVANCE: The complications of CZS including those related with the face and the oral cavity are still being identified. This study revealed some cranial, facial and oral features in children affected by CSZ. Interdisciplinary rehabilitation protocols must address these syndromic features that could improve children and parents living conditions.

Novel association of Dandy-Walker malformation with CAPN15 variants expands the phenotype of oculogastrointestinal neurodevelopmental syndrome.

Oculogastrointestinal neurodevelopmental syndrome has been described in seven previously published individuals who harbor biallelic pathogenic variants in the CAPN15 gene. Biallelic missense variants have been reported to demonstrate a phenotype of eye abnormalities and developmental delay, while biallelic loss of function variants exhibit phenotypes including microcephaly and craniofacial abnormalities, cardiac and genitourinary malformations, and abnormal neurologic activity. We report six individuals from three unrelated families harboring biallelic deleterious variants in CAPN15 with phenotypes overlapping those previously described for this disorder. Of the individuals affected, four demonstrate radiographic evidence of the classical triad of Dandy-Walker malformation including hypoplastic vermis, fourth ventricle enlargement, and torcular elevation. Cerebellar anomalies have not been previously reported in association with CAPN15-related disease. Here, we present three unrelated families with findings consistent with oculogastrointestinal neurodevelopmental syndrome and cerebellar pathology including Dandy-Walker malformation. To corroborate these novel clinical findings, we present supporting data from the mouse model suggesting an important role for this protein in normal cerebellar development. Our findings add six molecularly confirmed cases to the literature and additionally establish a new association of Dandy-Walker malformation with biallelic CAPN15 variants, thereby expanding the neurologic spectrum among patients affected by CAPN15-related disease.

TANGO2 Deficiency Disorder: Two Cases of Developmental Delay Preceding Metabolic Crisis.

BACKGROUND: TANGO2 deficiency disorder is a rare genetic disease caused by biallelic defects in TANGO2 gene. METHODS: We report the clinical phenotype of two children with TANGO2 deficiency disorder. RESULTS: Patient 1 is a female child presenting with developmental delay and microcephaly during the second year of life, who evolved with severe cognitive impairment, facial dysmorphisms, spastic paraparesis, and atonic seizures. At age 13 years, she was hospitalized due to an episode of rhabdomyolysis complicated with cardiac arrhythmia and hypothyroidism. Patient 2 is a female child with dysmorphic facial features, cleft palate, and developmental delay who was diagnosed with DiGeorge syndrome. At age three years, she presented with an acute episode of severe rhabdomyolysis in the context of human herpesvirus 6 infection. After the resolution of this acute episode, she maintained recurrent muscle weakness with axial hypotonia and progressive spasticity of the lower extremities. In both patients, diagnosis of TANGO2 deficiency disorder was only confirmed after an acute metabolic crisis. CONCLUSIONS: A high index of suspicion for TANGO2 deficiency disorder is needed in patients with developmental delay or other neurological symptoms and episodic rhabdomyolysis.

Generation and characterization of a knock-in mouse model for spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM).

Solute carrier family 1 member 4 (SLC1A4), also referred to as Alanine/Serine/Cysteine/Threonine-preferring Transporter 1 (ASCT1), is a sodium-dependent neutral amino acid transporter. It is expressed in many tissues, including the brain, where it is expressed primarily on astrocytes and plays key roles in neuronal differentiation and development, maintaining neurotransmitter homeostasis, and N-methyl-D-aspartate neurotransmission, through regulation of L- and D-serine. Mutations in SLC1A4 are associated with the rare autosomal recessive neurodevelopmental disorder spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM, OMIM 616657). Psychomotor development and speech are significantly impaired in these patients, and many develop seizures. We generated and characterized a knock-in mouse model for the most common mutant allele, which results in a single amino acid change (p.Glu256Lys, or E256K). Homozygous mutants had increased D-serine uptake in the brain, microcephaly, and thin corpus callosum and cortex layer 1. While p.E256K homozygotes showed some significant differences in exploratory behavior relative to wildtype mice, their performance in assays for motor coordination, endurance, learning, and memory was normal, and they showed no significant differences in long-term potentiation. Taken together, these results indicate that the impact of the p.E256K mutation on cognition and motor function is minimal in mice, but other aspects of SLC1A4 function in the brain are conserved. Mice homozygous for p.E256K may be a good model for understanding the developmental basis of the corpus callosum and microcephaly phenotypes observed in SPATCCM patients and assessing whether they are rescued by serine supplementation.

Case Report: short stature, kidney anomalies, and cerebral aneurysms in a novel homozygous mutation in the PCNT gene associated with microcephalic osteodysplastic primordial dwarfism type II.

We report the case of a boy (aged 3 years and 7 months) with severe growth failure (length: -9.53 SDS; weight: -9.36 SDS), microcephaly, intellectual disability, distinctive craniofacial features, multiple skeletal anomalies, micropenis, cryptorchidism, generalized hypotonia, and tendon retraction. Abdominal US showed bilateral increased echogenicity of the kidneys, with poor corticomedullary differentiation, and a slightly enlarged liver with diffuse irregular echotexture. Initial MRI of the brain, performed at presentation, showed areas of gliosis with encephalomalacia and diffused hypo/delayed myelination, and a thinned appearance of the middle and anterior cerebral arteries. Genetic analysis evidenced a novel homozygous pathogenic variant of the pericentrin (PCNT) gene. PCNT is a structural protein expressed in the centrosome that plays a role in anchoring of protein complexes, regulation of the mitotic cycle, and cell proliferation. Loss-of-function variants of this gene are responsible for microcephalic osteodysplastic primordial dwarfism type II (MOPDII), a rare inherited autosomal recessive disorder. The boy died at 8 years of age as a result of an intracranial hemorrhage due to a cerebral aneurism associated with the Moyamoya malformation. In confirmation of previously published results, intracranial anomalies and kidney findings were evidenced very early in life. For this reason, we suggest including MRI of the brain with angiography as soon as possible after diagnosis in follow-up of MODPII, in order to identify and prevent complications related to vascular anomalies and multiorgan failure.

Ketogenic diet-responsive drug-resistant epilepsy in a case of asparagine synthetase deficiency with a novel compound heterozygous missense variant.

Asparagine synthetase deficiency (ASNSD) is a rare autosomal recessive neurometabolic disorder caused by homozygous or compound heterozygous mutations in the ASNS gene. Most of the patients have early-onset intractable seizures. A 7-year-old boy was first admitted to our clinic with intractable febrile and afebrile seizures that started when he was 6 months old. He had axial hypotonia with spastic quadriparesis, mild facial dysmorphism, and acquired microcephaly at 1 year-old. Metabolic tests showed a borderline-low serum asparagine level. The electroencephalogram demonstrated epileptic discharges with a high incidence of multifocal spike-wave activity. Brain MRI showed mild cerebral atrophy. His seizures continued despite combinations of multiple antiseizure agents. Whole-exome sequencing (WES) revealed a novel compound heterozygous missense variant of the ASNS gene, and the variants were confirmed by Sanger sequencing. He was started on a ketogenic diet at five years and six months of age. In the first month of the ketogenic diet, we observed that the frequency of seizures significantly decreased. He showed a remarkable improvement in seizures and milder improvement in cognitive skills. To our knowledge, our case is the first report describing significant improvement with a ketogenic diet in intractable seizures due to ASNSD.

The outcome of surgical management for the patient with giant occipital encephalocele: a case illustration and systematic review.

PURPOSE: Occipital encephalocele (OE) is one of congenital malformation of the central nervous system. However, giant OE, mostly defines as bigger-than-head OE, is extremely rare and carries a worse prognosis. Here, we presented our systematic review of the management of the giant OE and illustrated our case. METHOD: The systematic review was carried out under PRISMA guidelines. Publications were searched under "occipital encephalocele" from 1959 to April 2021. Our primary area of interest was the outcome of patients who have undergone surgery for giant OE. Variables of interest included age, sex, size of the sac, presentations, associated anomalies, management, outcome, and follow-up period were collected. RESULT: We collected 35 articles, consisting of 74 cases (including 1 case from our illustrative case), to perform a systematic review. The mean age at the time of surgery was 3.53 ± 8.22 months. The mean circumference of the sac was 52.41 ± 18.6 cm. The three most common associated anomalies were microcephaly, corpus callosal agenesis/dysgenesis, and Chiari malformation. After the surgery, survival was reported in 64 (90.1%) patients. Postoperative complications were reported in 14 cases (16 events). Age above 1 month at the time of surgery was significantly associated with survival (p = 0.02) but not with complication (p = 0.22). In contrast, the type of surgery was not associated with survival (p = 0.18) or complications (p = 0.41). CONCLUSION: Despite a rare condition with a poor prognosis, our reported case and systematic review revealed promising outcomes of surgery regardless of surgical strategies, especially in patients older than 1 month. Thus, appropriate planning is essential for the treatment of this condition.

Pyoderma gangrenosum in a patient with Dubowitz syndrome: a new comorbidity?

INTRODUCTION: Dubowitz syndrome is a rare genetic disease with only a few cases reported in the literature. It is characterized by growth retardation, microcephaly, facial dysmorphism and higher risk of developing cancer and cardiomyopathies. PG is an autoinflammatory disorder that causes painful ulcers to develop on the skin and has not been previously associated with Dubowitz syndrome. CASE PRESENTATION: The authors report the case of a 50-year-old female with Dubowitz syndrome who developed painful ulcerative lesions. An incisional biopsy was performed to rule out other diagnoses, and a subsequent clinical diagnosis of PG was made. The patient was treated with specialized wound dressings and oral glucocorticoids. The clinical picture improved consistently after 7 weeks of therapy. CONCLUSIONS: This case report, to the authors' knowledge, is the first to suggest a possible association between Dubowitz syndrome and PG and also to indicate an effective treatment.

Biallelic variants in TUBGCP6 result in microcephaly and chorioretinopathy 1: Report of four cases and a literature review.

Autosomal recessive microcephaly and chorioretinopathy-1 (MCCRP1) is a rare Mendelian disorder resulting from biallelic loss of function variants in Tubulin-Gamma Complex Associated Protein 6 (TUBGCP6, MIM#610053). Clinical features of this disorder include microcephaly, cognitive impairment, dysmorphic features, and variable ophthalmological anomalies including chorioretinopathy. Microcephaly can be recognized prenatally and visual impairment becomes evident during the first year of life. The clinical presentation resembles the findings in some acquired conditions such as congenital toxoplasmosis and cytomegalovirus infections; thus, it is important to recognize and diagnose this syndrome in view of its impact on patient health management and familial reproductive plans. To date, only seven molecularly confirmed patients from five unrelated families have been reported. We report an additional four unrelated patients with TUBGCP6 variants including one prenatal diagnosis and review the clinical phenotypes and genotypes of all the known cases. This report expands the molecular and phenotypic spectrum of TUBGCP6 and includes additional prenatal findings associated with MCCRP1.

Whole-exome sequencing revealed a novel homozygous missense variant in OSGEP gene: a case report of Galloway-Mowat syndrome in Iran.

Galloway-Mowat syndrome is a rare autosomal-recessive genetic disorder that is characterized by variety of complications such as neurological abnormalities and early-onset progressive kidney disease. Studies have been shown that pathogenic mutations in genes that belong to the KEOPS complex lead to Galloway-Mowat syndrome. Several pathogenic mutations in OSGEP gene, a member of the KEOPS complex, have been detected in Galloway-Mowat syndrome. Here we describe a 12-year-old male with intellectual disability, poor speech, seizures, microcephaly, and nephrotic syndrome that were in favor of Galloway-Mowat syndrome, born to a healthy Iranian consanguineous parents. Extracted genomic DNA from blood sample was used to perform whole-exome sequencing in the patient. The mutational screening revealed a novel homozygote OSGEP gene missense variant. Our finding established whole-exome sequencing as a valuable technic for the detection of rare variants.

Massive subgaleal hematoma: a potentially fatal rare entity-a case-based review.

BACKGROUND: Massive subgaleal hematoma is defined as profuse bleeding in the subgaleal layer of the scalp, causing excessive accumulation of hematoma, thus progressively increasing the size of head circumference. If not immediately diagnosed and managed carefully, continuous bleeding will lead to hematoma enlargement, impairing the functions of surrounding organ(s) and general homeostasis. In severe cases, subgaleal hematoma could lead to severe morbidity or even death. CASE REPORT: We describe the case of an 11-year-old girl with a history of microcephaly and intellectual disability, presented with massive soft tissue swelling on more than half of her cranial circumference, accompanied with intermittent fever, anemia, and leukocytosis. The initial cerebral CT scan identified a mixed density extracranial lesion with multilobulated cystic appearance. The initial effort to aspirate the mass by a needle failed, and the patient was initially diagnosed with Pott's puffy tumor. Intraoperative findings confirmed the presence of massive subgaleal hematoma, and complete removal of the hematoma was achieved. The post-surgical period was uneventful, and the patient was discharged without any complications. CONCLUSION: Massive subgaleal hematoma should be considered in cases where children's head circumference increases rapidly, with or without a clear history of trauma and the presence of any possible risk factors. Missed diagnosis and inappropriate therapy could lead to unfavorable outcome. Hence, it is important for any clinicians to be familiar with this entity, so timely diagnosis and treatment can be made.