[Identification of TCTN1 gene variants in a fetus with Joubert syndrome 13].

OBJECTIVE: To explore the clinical characteristics and genetic basis for a fetus with Joubert syndrome. METHODS: A pregnant woman who had visited Suzhou Municipal Hospital on February 26, 2021 was selected as the study subject. The fetus and her parents were subjected to whole exome sequencing (WES), and candidate variants were verified by Sanger sequencing. cDNA analysis of her father and RNA sequencing of her sister were also carried out. RESULTS: The fetus was found to harbor compound heterozygous variants of the TCTN1 gene, namely c.624G>A and c.96dupA (p.Glu33Argfs*49), which were inherited from her father and mother, respectively. Her sister also carried the paternal c.624G>A variant, and mRNA transcripts with the c.624G>A variant of the TCTN1 gene were not detected by cDNA analysis of her father and RNA sequencing of her sister. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.624G>A and c.96dupA variants were both classified as likely pathogenic (PVS1+PM2_Supporting). CONCLUSION: The compound heterozygous variants of the TCTN1 gene probably underlay the pathogenesis in this fetus. Above finding has also expanded the mutational spectrum of the TCTN1 gene.

Fabry Disease Rat Model Develops Age- and Sex-Dependent Anterior Segment Ocular Abnormalities.

Purpose: Fabry disease is an X-linked lysosomal storage disorder that results in multi-systemic renal, cardiovascular, and neuropathological damage, including in the eyes. We evaluated anterior segment ocular abnormalities based on age, sex (male and female), and genotype (wild-type, knockout [KO] male, heterozygous [HET] female, and KO female) in a rat model of Fabry disease. Methods: The α-Gal A KO and WT rats were divided into young (6-24 weeks), adult (25-60 weeks), and aged (61+ weeks) groups. Intraocular pressure (IOP) was measured. Eyes were clinically scored for corneal and lens opacity as well as evaluated for corneal epithelial integrity and tear break-up time (TBUT). Anterior chamber depth (ACD) and central corneal thickness (CCT) using anterior segment-optical coherence tomography (AS-OCT). Results: The Fabry rats showed an age-dependent increase in IOP, predominantly in the male genotype. TBUT was decreased in both male and female groups with aging. Epithelial integrity was defective in KO males and HET females with age. However, it was highly compromised in KO females irrespective of age. Corneal and lens opacities were severely affected irrespective of sex or genotype in the aging Fabry rats. AS-OCT quantification of CCT and ACD also demonstrated age-dependent increases but were more pronounced in Fabry versus WT genotypes. Conclusions: Epithelial integrity, corneal, and lens opacities worsened in Fabry rats, whereas IOP and TBUT changes were age-dependent. Similarly, CCT and ACD were age-related but more pronounced in Fabry rats, providing newer insights into the anterior segment ocular abnormalities with age, sex, and genotype in a rat model of Fabry disease.

Expanding the Phenotypic Spectrum of Pathogenic KIAA0586 Variants: From Joubert Syndrome to Hydrolethalus Syndrome.

KIAA0586 variants have been associated with a wide range of ciliopathies, mainly Joubert syndrome (JS, OMIM #616490) and short-rib thoracic dysplasia syndrome (SRTD, OMIM #616546). However, the hypothesis that this gene is involved with hydrolethalus syndrome (HSL, OMIM #614120) and orofaciodigital syndrome IV (OMIM #258860) has already been raised. Ciliopathies' clinical features are often overlapped despite differing in phenotype severity. Besides KIAA0586, HYLS1 and KIF7 are also known for being causative of ciliopathies, indicating that all three genes may have similar or converging genomic pathways. Overall, the genotypic and phenotypic spectrum of ciliopathies becomes wider and conflicting while more and more new variants are added to this group of disorders' molecular pot. In this case report we discuss the first Brazilian individual clinically diagnosed with hydrolethalus syndrome and molecular findings that demonstrate the role of KIAA0586 as a causative gene of a group of genetic disorders. Also, recent reports on individuals with intronic and exonic variants combined leading to ciliopathies support our patient's molecular diagnosis. At the same time, we discuss variable expressivity and overlapping features in ciliopathies.

Mowat-Wilson syndrome: Case report.

BACKGROUND: Mowat-Wilson syndrome (MWS) is a rare genetic condition resulting in multiple congenital anomalies, including facial dysmorphism, structural anomalies of the internal organs, functional disorders, and, although less commonly, ocular abnormalities. To present a child with MWS and eye abnormalities. METHODS: A 3-year-old boy was born at 37 weeks of pregnancy with dysmorphic features, neurodevelopmental disorders, genetically confirmed MWS, nystagmus, strabismus, and suspicion of congenital glaucoma. Ophthalmic examination was carried out under general anesthesia; eyeball ultrasound and electrophysiological examination (flash visual evoked potentials) were also performed. RESULTS: The examinations revealed nystagmus, a normal response of pupils to light in both eyes, and normal intraocular pressure, that is, 17 and 18 mm Hg in the right and left eye, respectively. Corneal thickness was 606 µm in the right eye and 588 µm in the left eye. Gonioscopy revealed displacement of Schwalbe line anterior to the limbus of the cornea (posterior embryotoxon). Fundus examination revealed a pink optic disk with a cup-to-disc ratio of 0.5, macular pigment regrouping, and normal blood vessels. Flash visual evoked potentials: P2 latency was normal. P2 amplitude from the left hemisphere was reduced to 50%, and P2 amplitude over the right hemisphere was normal. CONCLUSION: Children with genetically determined congenital anomalies need regular ophthalmic checkups to accurately assess the eye and determine the prospects of vision function development.

Universal eye screening: perinatal risk factors and ocular abnormalities in 1795 newborns not meeting retinopathy of prematurity criteria.

OBJECTIVES: This prospective cohort study aimed to investigate the ocular outcomes of universal eye screening in newborns and assess the relationship between different perinatal risk factors and various ocular abnormalities in infants who do not meet the criteria for retinopathy of prematurity (ROP) screening. METHODS: An universal eye screening questionnaire was utilised to screen newborn babies who did not meet the ROP screening criteria within 72 h of birth at a public and private hospital between June 2016 and April 2018. The questionnaire covered demographic characteristics, neonatal history, and eye examination findings. A trained retina specialist conducted comprehensive anterior and posterior segment examinations utilising a binocular indirect ophthalmoscope. RESULTS: Out of the 1795 newborns screened, 55.2% were male, and 44.8% were female. The most prevalent ocular abnormality observed was retinal haemorrhage (RH), with a prevalence of 10.64% (95% CI: 9.25-12.16%). The prevalence of non-RH abnormality was 7.5% (95% CI: 6.34-8.84%). The retinal haemorrhages were associated with normal vaginal deliveries (OR: 9.91; 95% CI: 6.71-14.64, p-value < 0.001), while non-RH abnormalities were associated with pre-term babies (OR: 4.87; 95% CI: 3.03-7.83, p < 0.001), consanguinity (OR: 2.20; 95% CI: 1.28-3.8, p < 0.001), low birth weight (OR: 0.22; 95% CI: 0.14-0.34, p < 0.001) and systemic abnormalities (OR: 3.08; 95% CI: 1.94-4.91, p < 0.001). CONCLUSIONS: Sight-threatening ocular pathology in newborns may be linked to perinatal risk factors such as preterm birth, low birth weight, consanguinity, and systemic abnormalities. Accordingly, it may be prudent to consider specialized ocular screening protocols for neonates within this high-risk cohort in future prospective studies.

Modified Reverse Hatchet Flap for Ablepharon-Macrostomia Syndrome.

Ablepharon-macrostomia syndrome is a rare disorder characterized by TWIST2 mutations and anterior lamellar dysgenesis. Timely intervention is critical to prevent exposure keratopathy, corneal ulceration, and permanent vision loss. We report a novel approach to multiplanar eyelid reconstruction in ablepharon-macrostomia syndrome involving use of a modified reverse hatchet flap in 1 lower eyelid along with division at the eyelid margin, recession of the eyelid retractors in conjunction with preputial skin grafting for anterior lamellar restoration in the other 3 eyelids.

Primary cilia formation requires the Leigh syndrome-associated mitochondrial protein NDUFAF2.

Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.

Morning Glory Disc Anomaly: Expanding the MR Phenotype.

BACKGROUND AND PURPOSE: Morning glory disc anomaly (MGDA) is a congenital malformation characterized by a funnel-shaped optic disc excavation with radiating vessels and a central glial tuft. Imaging is essential to evaluate associated cephalocele and steno-occlusive vasculopathy. The goal of this study was to assess optic nerve, chiasmatic, and sphenoid bone morphology in MGDA. MATERIALS AND METHODS: This retrospective study examined all subjects with funduscopically confirmed MGDA diagnosed and imaged with brain MR imaging between 2008 and 2023. RESULTS: Thirty-two children met inclusion criteria. Ocular involvement was unilateral in 29 subjects and bilateral in 3. Segmental optic nerve enlargement ipsilateral to the MGDA was seen in 21 subjects, with 3 also demonstrating a segmental reduction in the size of the ipsilateral optic nerve. Segmental reduction in the size of the ipsilateral optic nerve was present in 3 additional subjects, one with bilateral MGDA. The optic chiasm appeared asymmetrically thickened in 21 subjects, often with deformity. The optic nerves appeared normal in signal intensity in all subjects, with faint peripheral chiasmatic enhancement in 4 of 20 patients who received contrast. Optic nerve findings were stable in 15 subjects with multiple examinations. A persistent craniopharyngeal canal was identified in 17 subjects with sphenoid cephalocele in 1 and mild inferior pituitary gland displacement in 4. Tubular or nodular nasopharyngeal lesions were seen in 10 subjects. One subject had an off-midline sphenoid bone cleft, midbrain deformity, and abnormal thickening of and enhancement around the left oculomotor nerve; the oculomotor nerve finding was present in 1 additional patient. CONCLUSIONS: MGDA often manifests with ipsilateral optic nerve thickening, leading to a potential misdiagnosis as optic glioma. MGDA is also commonly associated with a persistent craniopharyngeal canal with variable pituitary gland and infundibular deformity, cephalocele, and tubular or nodular nasopharyngeal lesions.

CEP41, a ciliopathy-linked centrosomal protein, regulates microtubule assembly and cell proliferation.

Centrosomal proteins play pivotal roles in orchestrating microtubule dynamics, and their dysregulation leads to disorders, including cancer and ciliopathies. Understanding the multifaceted roles of centrosomal proteins is vital to comprehend their involvement in disease development. Here, we report novel cellular functions of CEP41, a centrosomal and ciliary protein implicated in Joubert syndrome. We show that CEP41 is an essential microtubule-associated protein with microtubule-stabilizing activity. Purified CEP41 binds to preformed microtubules, promotes microtubule nucleation and suppresses microtubule disassembly. When overexpressed in cultured cells, CEP41 localizes to microtubules and promotes microtubule bundling. Conversely, shRNA-mediated knockdown of CEP41 disrupts the interphase microtubule network and delays microtubule reassembly, emphasizing its role in microtubule organization. Further, we demonstrate that the association of CEP41 with microtubules relies on its conserved rhodanese homology domain (RHOD) and the N-terminal region. Interestingly, a disease-causing mutation in the RHOD domain impairs CEP41-microtubule interaction. Moreover, depletion of CEP41 inhibits cell proliferation and disrupts cell cycle progression, suggesting its potential involvement in cell cycle regulation. These insights into the cellular functions of CEP41 hold promise for unraveling the impact of its mutations in ciliopathies.

Deciphering the etiology of undiagnosed ocular anomalies along with systemic alterations in pediatric patients through whole exome sequencing.

Inherited and developmental eye diseases are quite diverse and numerous, and determining their genetic cause is challenging due to their high allelic and locus heterogeneity. New molecular approaches, such as whole exome sequencing (WES), have proven to be powerful molecular tools for addressing these cases. The present study used WES to identify the genetic etiology in ten unrelated Mexican pediatric patients with complex ocular anomalies and other systemic alterations of unknown etiology. The WES approach allowed us to identify five clinically relevant variants in the GZF1, NFIX, TRRAP, FGFR2 and PAX2 genes associated with Larsen, Malan, developmental delay with or without dysmorphic facies and autism, LADD1 and papillorenal syndromes. Mutations located in GZF1 and NFIX were classified as pathogenic, those in TRRAP and FGFR2 were classified as likely pathogenic variants, and those in PAX2 were classified as variants of unknown significance. Protein modeling of the two missense FGFR2 p.(Arg210Gln) and PAX2 p.(Met3Thr) variants showed that these changes could induce potential structural alterations in important functional regions of the proteins. Notably, four out of the five variants were not previously reported, except for the TRRAP gene. Consequently, WES enabled the identification of the genetic cause in 40% of the cases reported. All the syndromes reported herein are very rare, with phenotypes that may overlap with other genetic entities.

An Eye into the Aorta: The Role of Extracellular Matrix Regulatory Genes ZNF469 and PRDM5, from Their Previous Association with Brittle Cornea Syndrome to Their Novel Association with Aortic and Arterial Aneurysmal Diseases.

The extracellular matrix is a complex network of proteins and other molecules that are essential for the support, integrity, and structure of cells and tissues within the human body. The genes ZNF469 and PRDM5 each produce extracellular-matrix-related proteins that, when mutated, have been shown to result in the development of brittle cornea syndrome. This dysfunction results from aberrant protein function resulting in extracellular matrix disruption. Our group recently identified and published the first known associations between variants in these genes and aortic/arterial aneurysms and dissection diseases. This paper delineates the proposed effects of mutated ZNF469 and PRDM5 on various essential extracellular matrix components, including various collagens, TGF-B, clusterin, thrombospondin, and HAPLN-1, and reviews our recent reports associating single-nucleotide variants to these genes' development of aneurysmal and dissection diseases.

PREVALENCE OF OCULAR ABNORMALITIES AND NORMAL DIAGNOSTIC PARAMETERS IN TWO GROUPS OF PANAMANIAN GOLDEN FROGS (ATELOPUS ZETEKI).

Panamanian golden frog (PGF) (Atelopus zeteki) is a critically endangered species. The Maryland Zoo in Baltimore houses two groups of PGF originating from distinct geographic locations as an assurance colony, with the goal of upholding genetics for future release of individuals back to their native environment. The purpose of this cross-sectional study was to characterize the prevalence of ocular abnormalities in these two zoo-housed populations of PGF as well as to establish normal parameters for selected diagnostic tests in these groups. Twenty-five females and 25 males were randomly selected from each group (100 PGF; 200 eyes in total) to undergo ocular examination using slit lamp biomicroscopy and direct ophthalmoscopy. Endodontic absorbent paper point test (EAPPT) and intraocular pressure (IOP) and Rose Bengal stain diagnostic tests were also performed. Reference ranges for tear production (EAPPT, 0.5-3 mm/min) and IOP (14-26 mmHg) were calculated in the nondiseased PGF eyes (n = 160 eyes). Rose Bengal stain uptake was negative on all eyes. In total, 40 eyes of 30 PGF were found to have some form of ocular abnormality (28% of PGF, 20% of eyes). The most frequently observed ocular abnormalities were cataract (9% of PGF, 6% of eyes) and keratitis (nonlipid keratopathy; 10% of PGF, 5.5% of eyes). There was no significant difference in overall ocular abnormality prevalence between the two groups studied (P = 0.37) or between the sexes (P = 0.76). The median age of an eye with cataract and keratitis (nonlipid keratopathy) was 10.35 and 7.7 yr, respectively. Ocular abnormalities are common in these two populations of PGF. Documentation of these ocular abnormalities and establishment of diagnostic reference ranges have not previously been published and may be important for maintaining the health of this endangered species.

Defects in diffusion barrier function of ciliary transition zone caused by ciliopathy variations of TMEM218.

Primary cilia are antenna-like structures protruding from the surface of various eukaryotic cells, and have distinct protein compositions in their membranes. This distinct protein composition is maintained by the presence of the transition zone (TZ) at the ciliary base, which acts as a diffusion barrier between the ciliary and plasma membranes. Defects in cilia and the TZ are known to cause a group of disorders collectively called the ciliopathies, which demonstrate a broad spectrum of clinical features, such as perinatally lethal Meckel syndrome (MKS), relatively mild Joubert syndrome (JBTS), and nonsyndromic nephronophthisis (NPHP). Proteins constituting the TZ can be grouped into the MKS and NPHP modules. The MKS module is composed of several transmembrane proteins and three soluble proteins. TMEM218 was recently reported to be mutated in individuals diagnosed as MKS and JBTS. However, little is known about how TMEM218 mutations found in MKS and JBTS affect the functions of cilia. In this study, we found that ciliary membrane proteins were not localized to cilia in TMEM218-knockout cells, indicating impaired barrier function of the TZ. Furthermore, the exogenous expression of JBTS-associated TMEM218 variants but not MKS-associated variants in TMEM218-knockout cells restored the localization of ciliary membrane proteins. In particular, when expressed in TMEM218-knockout cells, the TMEM218(R115H) variant found in JBTS was able to restore the barrier function of cells, whereas the MKS variant TMEM218(R115C) could not. Thus, the severity of symptoms of MKS and JBTS individuals appears to correlate with the degree of their ciliary defects at the cellular level.

Congenital Corneal Staphyloma: A Comprehensive Histopathologic Assessment Including Associated Anterior Segment Abnormalities.

Congenital corneal staphyloma is a rare congenital malformation with guarded visual potential. The cornea is opaque, markedly ectatic, and lined by uveal tissue with a variety of associated anterior segment abnormalities. In this case report, the detailed histopathology of this condition is highlighted with an unusual finding of the malformed lens. [J Pediatr Ophthalmol Strabismus. 2024;61(3):e28-e32.].

The EFEMEREYE Study: prenatal medication exposure and ocular anomaly occurrence in EFEMERIS health database.

PURPOSE: To describe ocular anomalies (OAs) in children and fetuses in a French general population, to estimate their prevalence, and to investigate a possible association between prenatal medication exposure and the occurrence of OA in utero or in early childhood. METHODS: We conducted a case-control study using the EFEMERIS cohort, a database containing pregnancies registered in Haute-Garonne and their outcomes. We collected OA descriptions of fetuses at the time of pregnancy termination or of children at birth and the results of eye examinations of children at 9 months and 2 years of age. RESULTS: The prevalence of overall OAs was 2.13%, of which 0.04% were congenital ocular malformations (COMs). A total of 2,968 cases and 136,619 controls were selected for analysis. There was a significant difference between the two groups with regard to prenatal exposure to medications for the digestive tract and metabolism, the cardiovascular system, and the respiratory system. Multivariable analysis revealed an increased risk of OA in children of mothers exposed to magnesium during and 1 month before pregnancy (OR = 1.24; 95% CI, 1.11-1.38). CONCLUSIONS: This first pharmaco-epidemiological study on OA in France suggests that OA may be associated with exposure to commonly used medications. Given the rarity of COM, larger, international studies are warranted.

Expanding the spectrum of LAMB2: Pierson syndrome associated with neuromuscular junction disorder in two patients.

LAMB2 gene disorders present with different phenotypes. Pierson syndrome (PS) is a common phenotype associated with LAMB2 variants. Neuromuscular phenotype has been reported including hypotonia and developmental delay. However, neuromuscular junction abnormalities represented as congenital myasthenic syndrome (CMS) was reported in one adult patient only. Here, in this paper, we present two pediatric cases with a severe presentation of PS and have CMS so expanding the knowledge of LAMB2 related phenotypes. The first patient had hypotonia and global developmental delay. Targeted genetic testing panel demonstrated homozygous pathogenic variant in the LAMB2 gene (c.5182C>T, pGln1728*) which was reported by Maselli et al. 2009. Repetitive nerve stimulation (RNS) showed a decremental response at low frequency of 3 Hz. On the other hand, the second patient had profound weakness since birth. Tri-Whole exome sequencing showed homozygous pathogenic variant in the LAMB2 gene c.2890C>T, pArg964*. A trial of salbutamol did not improve the symptoms. Both patients passed away from sequala of PS. The spectrum of phenotypic changes associated with LAMB2 mutations is still expanding, and further investigation into the various clinical and morphologic presentations associated with these mutations is important to better identify and manage affected individuals.

(What's the story) morning glory? MRI findings in morning glory disc anomaly.

PURPOSE: Morning glory disc anomaly (MGDA) is a rare congenital ophthalmologic disorder. Historically it has been diagnosed fundoscopically, with little in the literature regarding its imaging findings. The purpose of this study is to further characterize the orbital and associated intracranial magnetic resonance imaging (MRI) findings of MGDA in our tertiary pediatric center. METHODS: A retrospective review was performed of fundoscopically-diagnosed cases of MGDA, that had been referred for MRI. All MRI studies were scrutinized for orbital and other intracranial abnormalities known to occur in association with MGDA. RESULTS: 18 of 19 cases of MGDA showed three characteristic MRI findings: funnel-shaped morphology of the posterior optic disc, abnormal soft tissue associated with the retrobulbar optic nerve, and effacement of adjacent subarachnoid spaces. The ipsilateral (intraorbital) optic nerve was larger in one patient and smaller in six. The ipsilateral optic chiasm was larger in two patients and smaller in one. CONCLUSION: This study represents a comprehensive radiological-led investigation into MGDA. It describes the most frequently-encountered MRI findings in MGDA and emphasizes the importance of MRI in this cohort, i.e., in distinguishing MGDA from other posterior globe abnormalities, in assessing the visual pathway, and in screening for associated intracranial abnormalities - skull base/cerebral, vascular, and facial. It hypothesizes neurocristopathy as an underlying cause of MGDA and its associations. Caliber abnormalities of the ipsilateral optic nerve and chiasm are a frequent finding in MGDA. Optic pathway enlargement should not be labeled "glioma". (239/250).

Evaluating neural crest cell migration in a Col4a1 mutant mouse model of ocular anterior segment dysgenesis.

The periocular mesenchyme (POM) is a transient migratory embryonic tissue derived from neural crest cells (NCCs) and paraxial mesoderm that gives rise to most of the structures in front of the eye. Morphogenetic defects of these structures can impair aqueous humor outflow, leading to elevated intraocular pressure and glaucoma. Mutations in collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) cause Gould syndrome - a multisystem disorder often characterized by variable cerebrovascular, ocular, renal, and neuromuscular manifestations. Approximately one-third of individuals with COL4A1 and COL4A2 mutations have ocular anterior segment dysgenesis (ASD), including congenital glaucoma resulting from abnormalities of POM-derived structures. POM differentiation has been a major focus of ASD research, but the underlying cellular mechanisms are still unclear. Moreover, earlier events including NCC migration and survival defects have been implicated in ASD; however, their roles are not as well understood. Vascular defects are among the most common consequences of COL4A1 and COL4A2 mutations and can influence NCC survival and migration. We therefore hypothesized that NCC migration might be impaired by COL4A1 and COL4A2 mutations. In this study, we used 3D confocal microscopy, gross morphology, and quantitative analyses to test NCC migration in Col4a1 mutant mice. We show that homozygous Col4a1 mutant embryos have severe embryonic growth retardation and lethality, and we identified a potential maternal effect on embryo development. Cerebrovascular defects in heterozygous Col4a1 mutant embryos were present as early as E9.0, showing abnormal cerebral vasculature plexus remodeling compared to controls. We detected abnormal NCC migration within the diencephalic stream and the POM in heterozygous Col4a1 mutants whereby mutant NCCs formed smaller diencephalic migratory streams and POMs. In these settings, migratory NCCs within the diencephalic stream and POM localize farther away from the developing vasculature. Our results show for the first time that Col4a1 mutations lead to cranial NCCs migratory defects in the context of early onset defective angiogenesis without affecting cell numbers, possibly impacting the relation between NCCs and the blood vessels during ASD development.

PHACES syndrome and multi-regional odontodysplasia: a case report.

PHACES syndrome is an acronym for the syndromic presentation of Posterior fossa malformation, Hemangioma, Arterial anomalies, Coarctation of aorta/cardiac defects, Eye abnormalities and Sternal malformations. Infantile hemangiomas are the most common tumors of infancy. Regional odontodysplasia, commonly referred to as "ghost teeth", is a rare localized developmental malformation of enamel and dentin with varying levels of severity that results in unusual clinical and radiographic appearances of affected teeth. This report describes a rare case of a two-year-old Caucasian male diagnosed with PHACES syndrome also presenting with multi-regional odontodysplasia. Ten of twenty teeth were dysplastic. The patient was treated under general anesthesia in a hospital setting. All affected primary teeth were extracted due to sensitivity, abscess and extremely poor long-term prognosis. Moving forward, a long-term interdisciplinary approach will be necessary to address this child's dentition as it develops.

Intergenic sequences harboring potential enhancer elements contribute to Axenfeld-Rieger syndrome by regulating PITX2.

Recent studies have uncovered that noncoding sequence variants may relate to Axenfeld-Rieger syndrome (ARS), a rare developmental anomaly with genetic heterogeneity. However, how these genomic regions are functionally and structurally associated with ARS is still unclear. In this study, we performed genome-wide linkage analysis and whole-genome sequencing in a Chinese family with ARS and identified a heterozygous deletion of about 570 kb (termed LOH-1) in the intergenic sequence between paired-like homeodomain transcription factor 2 (PITX2) and family with sequence similarity 241 member A. Knockout of LOH-1 homologous sequences caused ARS phenotypes in mice. RNA-Seq and real-time quantitative PCR revealed a significant reduction in Pitx2 gene expression in LOH-1-/- mice, while forkhead box C1 expression remained unchanged. ChIP-Seq and bioinformatics analysis identified a potential enhancer region (LOH-E1) within LOH-1. Deletion of LOH-E1 led to a substantial downregulation of the PITX2 gene. Mechanistically, we found a sequence (hg38 chr4:111,399,594-111,399,691) that is on LOH-E1 could regulate PITX2 by binding to RAD21, a critical component of the cohesin complex. Knockdown of RAD21 resulted in reduced PITX2 expression. Collectively, our findings indicate that a potential enhancer sequence that is within LOH-1 may regulate PITX2 expression remotely through cohesin-mediated loop domains, leading to ARS when absent.