A Mosaic Variant in CTNNB1/ß-catenin as a Novel Cause for Osteopathia Striata With Cranial Sclerosis.

CONTEXT: Osteopathia striata with cranial sclerosis (OSCS) is a rare bone disorder with X-linked dominant inheritance, characterized by a generalized hyperostosis in the skull and long bones and typical metaphyseal striations in the long bones. So far, loss-of-function variants in AMER1 (also known as WTX or FAM123B), encoding the APC membrane recruitment protein 1 (AMER1), have been described as the only molecular cause for OSCS. AMER1 promotes the degradation of ß-catenin via AXIN stabilization, acting as a negative regulator of the WNT/ß-catenin signaling pathway, a central pathway in bone formation. OBJECTIVE: In this study, we describe a Dutch adult woman with an OSCS-like phenotype, namely, generalized high bone mass and characteristic metaphyseal striations, but no genetic variant affecting AMER1. RESULTS: Whole exome sequencing led to the identification of a mosaic missense variant (c.876A > C; p.Lys292Asn) in CTNNB1, coding for ß-catenin. The variant disrupts an amino acid known to be crucial for interaction with AXIN, a key factor in the ß-catenin destruction complex. Western blotting experiments demonstrate that the p.Lys292Asn variant does not significantly affect the ß-catenin phosphorylation status, and hence stability in the cytoplasm. Additionally, luciferase reporter assays were performed to investigate the effect of p.Lys292Asn ß-catenin on canonical WNT signaling. These studies indicate an average 70-fold increase in canonical WNT signaling activity by p.Lys292Asn ß-catenin. CONCLUSION: In conclusion, this study indicates that somatic variants in the CTNNB1 gene could explain the pathogenesis of unsolved cases of osteopathia striata.

Osteopathia striata with cranial sclerosis causing a compressive optic neuropathy.

BACKGROUND: Osteopathia striata combined with cranial sclerosis (OS-CS) is an inherited skeletal dysplasia that manifests with macrocephaly, orofacial abnormalities, thickened craniofacial bones, and vertically oriented radiodensities of the long bones. CASE REPORT: Here, we present a severe case of OS-CS in a 4-year-old girl causing optic neuropathy as shown by radiographic evidence, ophthalmic findings, and histopathology. Previous genetic testing in this patient revealed a de novo heterozygous mutation in AMER1 (c.1057C>T, p.Arg353Ter). Although the patient had a pre-existing, appropriately functioning, ventriculoperitoneal (VP) shunt, a subsequent MRI of the brain and orbits showed narrowing of the bilateral optic nerve canals secondary to osseous thickening causing bilateral optic nerve atrophy, worse on the left. The patient underwent staged bilateral orbital osteotomies, optic canal decompression, and bilateral frontal craniotomy, and at 11 months postoperatively, her vision remained stable. Conclusions: While up to 50% of the patients with OS-CS may experience hearing loss due to cranial nerve compression, we present a case of severe visual loss secondary to OS-CS-associated optic nerve compression.

Special manifestations and treatment of rare cases of snoring with special facial features and hearing loss in children.

This current case report describes two rare cases of children with both hearing loss and snoring. Case 1, a 17-month-old male patient, and case 2, an 11-year-old male patient, both presented with nasal obstruction, snoring and hearing loss. Physical examinations showed obvious enlargement of the head circumference and special facial features. The two children underwent otolaryngology examinations, endoscopy, hearing tests, laboratory examinations for bone metabolism markers, cranial computed tomography, X-rays and genome-wide exon sequencing. The first case was diagnosed with craniometaphyseal dysplasia, which was relieved after giving a low-calcium diet. The second case was diagnosed with osteopathia striata with cranial sclerosis by gene sequencing. Snoring improved after medication and the speech and quality of life improved with a hearing aid. Paediatric otolaryngological physicians need to have a deeper understanding of congenital diseases involving the bones. Only by genetic testing to determine the pathogenesis can those children be given the correct treatment, which is of great importance for improving their prognosis.

Osteopathia Striata with Cranial Sclerosis: A Face-to-Radiograph-to-Gene Diagnosis.

Osteopathia striata with cranial sclerosis is an X-linked dominant bone dysplasia with osteosclerosis. It should be suspected in girls with macrocephaly, intellectual disability with unique facial dysmorphic features. We described the clinical and radiological profile of a patient with this rare disorder. A novel heterozygous variant was identified in the AMER1 gene which leads to premature truncation of the AMER1 protein. Facial gestalt recognition using artificial intelligence and radiographic features were used to narrow the differential diagnosis.

The phenotypic spectrum of AMER1-related osteopathia striata with cranial sclerosis: The first Canadian cohort.

Osteopathia striata with cranial sclerosis (OSCS; OMIM# 300373) is a rare X-linked disorder caused by mutations of the AMER1 gene. OSCS is traditionally considered a skeletal dysplasia, characterized by cranial sclerosis and longitudinal striations in the long bone metaphyses. However, OSCS affects many body systems and varies significantly in phenotypic severity between individuals. This case series focuses on the phenotypic presentation and development of individuals with OSCS. We provide an account of 12 patients with OSCS, ranging from 5 months to 38 years of age. These patients were diagnosed with OSCS after genetic testing confirmed pathogenic mutations in AMER1. Patient consent was obtained for photos and participation. Data were collected regarding perinatal history, dysmorphic features, and review of systems. This case series documents common facial dysmorphology, as well as rare extraskeletal features of OSCS, including two patients with intestinal malrotation and two patients with pyloric stenosis. We share four apparently nonmosaic males with OSCS (one de novo and three maternal variants). We also provide a clinical update on a patient who was previously published by Chénier et al. (2012). American Journal of Medical Genetics Part A, 158, 2946-2952. More research is needed to investigate the links between genotype and phenotype and assess the long-term comorbidities and overall quality of life of individuals with OSCS.

Whole Exome Sequencing Provides the Correct Diagnosis in a Case of Osteopathia Striata with Cranial Sclerosis: Case Report of a Novel Frameshift Mutation in AMER1.

The diagnosis of rare diseases with multisystem manifestations can constitute a difficult process that delays the determination of the underlying cause. Whole exome sequencing (WES) provides a suitable option to examine multiple target genes associated with several disorders that display common features. In this study, we report the case of a female patient suspected of having Sotos syndrome. Screening for the initially selected genes, considering Sotos syndrome and Sotos-like disorders, did not identify any pathogenic variants that could explain the phenotype. The extended analysis, which considered all genes in the exome associated with features consistent with those shown by the studied patient, revealed a novel frameshift variant in the AMER1 gene, responsible for osteopathia striata with cranial sclerosis. WES analysis and an updated revision of previously reported disease-causing mutations, proved useful to reach an accurate diagnosis and guide further examination to identify critical abnormalities.

Osteopathia striata in the mandible with cranial sclerosis: a case report and review of the literature.

Osteopathia striata with cranial sclerosis (OS-CS) is a bone dysplasia characterized by a linear striated pattern of sclerosis, especially in the long bones, and cranial sclerosis. It has variable clinical findings but distinctive radiological findings. Multiple oral and dental findings have been associated with this disease and can be seen during dental and/or medical imaging of the head and neck. Dentists and clinicians must be familiar with these signs to differentiate them from pathosis or erroneous radiographs. In the following case, we present a patient with OS-CS that presented at The University of Florida College of Dentistry with multiple craniofacial manifestations of this syndrome that were seen on a panoramic radiograph, which is one of the most commonly requested radiographs by dentists.

Deletion of Exon 1 in AMER1 in Osteopathia Striata with Cranial Sclerosis.

Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant condition characterised by metaphyseal striations, macrocephaly, cleft palate, and developmental delay in affected females. Males have a more severe phenotype with multi-organ malformations, and rarely survive. To date, only frameshift and nonsense variants in exon 2, the single coding exon of AMER1, or whole gene deletions have been reported to cause OSCS. In this study, we describe two families with phenotypic features typical of OSCS. Exome sequencing and multiplex ligation-dependent probe amplification (MLPA) did not identify pathogenic variants in AMER1. Therefore, genome sequencing was employed which identified two deletions containing the non-coding exon 1 of AMER1 in the families. These families highlight the importance of considering variants or deletions of upstream non-coding exons in conditions such as OSCS, noting that often such exons are not captured on probe or enrichment-based platforms because of their high G/C content.

Male child with somatic mosaic Osteopathia Striata with Cranial Sclerosis caused by a novel pathogenic AMER1 frameshift mutation.

Osteopathia striata with cranial sclerosis (OSCS; OMIM #300373) is a rare X-linked dominant condition caused by mutations in the AMER1 gene (also known as WTX or FAM123B). It is a condition which usually affects females in whom the clinical phenotype can be extremely variable. Conversely affected males typically die in utero or during the neonatal period [Perdu et al. (); Clinical Genetics 80: 383-388; Vasiljevic et al. (); Prenatal Diagnosis 35: 302-304]. There have been a small number of reported cases of surviving males, including three patients who are somatic mosaic for the condition [Chénier, Noor, Dupuis, Stavropoulos, & Mendoza-Londono, (); American Journal of Medical Genetics Part A 158A: 2946-2952; Holman et al. (); American Journal of Medical Genetics Part A 155A: 2397-2408; Joseph, Shoji, & Econs, (); The Journal of Clinical Endocrinology and Metabolism 95: 1506-1507]. We report a case of a male child who has proven somatic mosaicism for OSCS associated with a novel pathogenic frameshift mutation, c.607_611delAGGCC (p.Arg203 fs) in AMER1. We describe the multisystemic clinical features which include macrocephaly with ventriculomegaly and requirement for ventriculoperitoneal shunt, cleft palate, and respiratory difficulties after birth requiring tracheostomy insertion, persistent patent ductus arteriosus, failure to thrive and gastrostomy insertion, growth retardation, ophthalmoplegia, kidney malformation, cryptorchidism, and developmental delay. The use of new technologies with next generation sequencing (NGS) may improve the detection rate of mosaicism in rare conditions.

Osteopathia striata with cranial sclerosis (OSCS): review of the literature and case report demonstrating challenges of spinal fusion after trauma.

Osteopathia striata with cranial sclerosis (OSCS) is a rare but well-described pathology characterized by abnormalities in bone deposition in the axial and cranial skeleton as well as other abnormalities and associated deficits. These skeletal abnormalities can lead to significant intra-operative challenges for the surgeon and influence outcomes for the patient. In this report, we present a case of a patient with OSCS who was involved in a traumatic motor vehicle crash and underwent posterior cervico-thoracic fusion for a T4 chance fracture. Bony abnormalities in the cervico-thoracic spine presented a significant operative challenge due to alterations in bony anatomy and bone architecture. This case serves as an example of the challenges that the spine surgeon faces when dealing with OSCS, and highlights the differences between OSCS and commoner skeletal hyperplasias such as osteopetrosis.

A novel WTX mutation in a female patient with osteopathia striata with cranial sclerosis and hepatoblastoma.

Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant sclerosing bone dysplasia. Typically affected females show macrocephaly, characteristic facial appearance, cleft palate, mild learning difficulties, hearing loss, sclerosis of the long bones and skull, and longitudinal striations visible on radiographs of the long bones, pelvis and scapulae. Typically affected males usually die at the fetal or early neonatal stage. Because of its variable expressivity, which ranges from asymptomatic to fetal death, clinical diagnosis of OSCS can be difficult. Here, we identify a unique female patient presenting with severe macrocephaly, characteristic facial appearance, developmental delay, and hepatoblastoma. Exome sequencing identified a novel de novo nonsense mutation (c.1045C>T, p.Glu349*) in the WTX gene associated with OSCS. The OSCS diagnosis was confirmed in this patient based on the hallmark appearance of longitudinal striations in long bones when viewed by X-ray. WTX is also known as a tumor suppressor gene, and somatic mutations in that gene have been identified in Wilms tumors. In addition to this patient, although two patients with OSCS have been reported to have colorectal cancer or ovarian cancer, Wilms tumor has never been reported in association with this disorder. Tumor susceptibility in patients with OSCS is discussed.