Noonan syndrome (NS) is a pleomorphic genetic disorder. Up to 50-80% of individuals have associated congenital heart disease. The scope of cardiac disease in NS is quite variable depending on the gene mutation. The most common forms of cardiac defects include pulmonary stenosis, hypertrophic cardiomyopathy (HCM), atrial septal defect and left-sided lesions. Amongst the rare vascular abnormalities few case reports have been mentioned about coronary artery lesions apart from sinus of Valsalva aneurysm, aortic dissection, intracranial aneurysm. This is a case report a rare case of asymptomatic coronary artery aneurysm in a young male with NS. There is lack of unified protocol for the screening, diagnosis, treatment, and follow-up of coronary artery disease in patients with NS. We conclude, echocardiography is sufficient in most cases in children. But a CT scan is appropriate in adults or when other lesions are suspected.

Noonan syndrome (NS) is a dominantly inherited genetic disorder with mutations in genes encoding components or regulators of the Rat sarcoma virus/mitogen-activated protein kinase pathway. Its diagnosis is based on characteristic features, including typical facial features, a short stature, congenital heart disease, mild developmental delay, and cryptorchidism. Patients with NS sometimes develop autoimmune diseases, such as Hashimoto\'s thyroiditis and, rarely, systemic lupus erythematosus (SLE). We herein present a 29-year-old Japanese female with NS complicated by SLE and repeated severe hypoglycaemia. The patient was diagnosed with SLE based on thrombocytopenia, nephritis, a positive antinuclear antibody titre (1:640), and a positive anti-dsDNA antibody. The patient was treated with a glucocorticoid, mycophenolate mofetil, and tacrolimus, which attenuated both SLE and hypoglycaemia. Since insulin receptor antibody levels were higher to the upper normal range and decreased after treatment, hypoglycaemia probably appeared to be attributed to type B insulin resistance syndrome. We herein present the first case of SLE in NS complicated by type B insulin resistance syndrome. Although NS is a rare disease, we need to consider the complication of autoimmune diseases, including SLE.

Neurofibromatosis-Noonan syndrome is a rare RASopathy syndrome. It occurs due to the mutation in the NF1 gene and the patients present with the phenotypic features of both Neurofibromatosis and Noonan syndrome. Here a case of an early adolescent girl is described who presented with the chief complaint of primary amenorrhoea and on evaluation was diagnosed to be a patient of Neurofibromatosis-Noonan syndrome. The index case was short-statured with a short and broad neck. Physical examination revealed a pointed pinna, hypertelorism, telecanthus, characteristic facies, and multiple freckles all over the body. She also had numerous atypical café-au-lait spots. Whole genome sequencing revealed Neurofibromatosis-Noonan syndrome which was likely a pathogenic variant causative of the typical phenotype present with a mutation in the neurofibromin gene (NF1) on chromosome 17q11. We discuss here the management and follow-up of the case.

This case report provides a detailed examination of a rare co-occurrence of Costello syndrome, euryblepharon, and Moyamoya syndrome in a 14-year-old female. Costello syndrome, a rare genetic disorder characterized by developmental delays, distinctive facial characteristics, and a predisposition to certain malignancies, presents an array of ocular manifestations, including downward-slanting palpebral fissures. A significant similarity is noted with euryblepharon, a rare periocular anomaly marked by the downward slanting of the eyelids. Despite these striking resemblances, the association between euryblepharon and Costello syndrome is yet to be documented in the literature. Furthermore, the coexistence of Costello syndrome and Moyamoya syndrome, a cerebrovascular disorder, is exceedingly rare. This report provides an in-depth analysis of the patient\'s ocular and periocular manifestations, establishing a potential association of euryblepharon within the phenotypic spectrum of Costello syndrome and documenting the unusual co-occurrence with Moyamoya syndrome. These findings aim to augment our understanding of Costello syndrome\'s phenotypic variability and potential associations.

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous disorder caused by somatic FGFR1 and KRAS variants. It shares significant phenotypic overlap with several closely related disorders caused by mutations in the RAS-MAPK pathway (mosaic RASopathies). We report a diagnostically challenging case of ECCL in which next-generation sequencing of affected tissue identified a pathologic FGFR1 p.K656E variant, thereby establishing a molecular diagnosis. Patients with FGFR1-associated ECCL carry a risk of developing malignant brain tumors; thus, genetic testing of patients with suspected ECCL has important management implications.

暂无摘要。

Noonan syndrome (NS) is the most common disease among RASopathies, characterized by short stature, distinctive facial features, congenital cardiac defects, and variable developmental delay. NS rarely presents with overt neurologic manifestations, in particular hydrocephalus. Recent evidence suggests that pathogenic variants in the gene RRAS2 are a rare cause of NS. Specifically, an RRAS2 pathogenic variant, p.Q72L, may be particularly severe, manifesting with lethal neurologic findings. Here, we report a NS patient with documented p.Q72L variant in RRAS2. The patient was identified in utero to have hydrocephalus and a Dandy Walker malformation. Postnatal examination revealed multiple dysmorphic features, some reminiscent of NS including low-set posteriorly rotated ears, redundant nuchal skin, widely spaced nipples, and cryptorchidism. Despite suspicion of NS, results of a 14-gene Noonan syndrome panel (Invitae) were negative. Follow-up rapid whole exome sequencing revealed a de novo p.Q72L variant in RRAS2, a poorly studied gene recently identified as a cause of NS. The patient herein reported brings to three the total number of cases reported with the RRAS2 p.Q72L pathogenic variant. All three documented patients presented with a particularly fulminant course of NS, which included hydrocephalus. RRAS2, specifically p.Q72L, should be considered in severe NS cases with neurologic manifestations.

BACKGROUND: In the fetus, the ductus venosus (DV) connects the umbilical vein and the portal veins to the inferior vena cava in order to bypass the high-resistance hepatic vascular network. Via the Eustachian valve, the DV directs umbilical venous blood with the highest oxygen content preferentially towards the myocardium and the brain. An absence (agenesis) or a secondary obliteration of an initially normally developed DV (atresia) is associated with various shunt types and may lead to severe hydrops.
METHODS: A routine check-up of a healthy 34-year-old woman at 27 5/7 wks GA revealed a severe hydrops fetalis with pleural effusions and ascites. After birth at 28 0/7 wks GA, the bilateral pleural effusions needed drainage via thoracic drains. Arterial hypotension was initially treated with volume replacement and dopamine, later on adrenaline and hydrocortisone were added. The initial echocardiography showed normal anatomic structures and normal bi-ventricular function. Despite maximal intensive care treatment, a global respiratory and cardiovascular insufficiency developed. The girl died on fourth day of life. At autopsy, a secondary atresia of the DV was identified, and moreover a pathogenic de novo heterozygous mutation in the KRAS gene was found in the chorion biopsy probe.
CONCLUSIONS: For all cases of non-haemolytic hydrops fetalis, a prenatal or postnatal sonography with Doppler examination of the venous system and of the heart should be performed. Furthermore, testing for RASopathies should be recommended especially in presence of increased nuchal translucency thickness and polyhydramnios.

Antenatal diagnosis of cardio-facio-cutaneous syndrome: prenatal characteristics and contribution of fetal facial dysmorphic signs in utero. This paper is a case study and review of literature. \"RASopathies\" is the term coined for a group of genetic diseases that share modulation inside the MAPKinase pathway. Mutations inside the coding sequence of any of these genes may be responsible for the upregulation of the RAS pathway, leading on the clinical level to Type 1 Neurofibromatosis (NF1), Noonan syndrome (NS), Costello syndrome (CS), Multiple Lentigines, Loose Anagen Hair syndrome, Cardio-Facio-Cutaneous syndrome (CFCS), and, more recently, Legius syndrome. While the postnatal presentation of this group is well-known, prenatal findings are less well recognized. The presence of a RASopathy during the prenatal period can be suspected on account of non-specific abnormalities: polyhydramnios, cystic hygroma or high nuchal translucency, macrosomia with proportionate short long bones, macrocephaly, renal, lymphatic, or cardiac defects. The current case report underlines the characteristic dysmorphic facial features on 3D-ultrasound (hypertelorism, down-slanting palpebral fissures, a long and marked philtrum, and low-set posteriorly rotated ears) that allow for a \"RASopathy\" to be postulated. After detecting a copy number variation (CNV) absence on a CGH array, we performed a RASopathy gene panel analysis, which identified a so-far unreported heterozygous de novo mutation in the BRAF gene (namely NM_004333.4 : c.1396 G > C ; p.Gly466Arg). Genetic counseling has, therefore, focused on the diagnosis of a RASopathy and predictable phenotype of CFCS, a distinct entity characterized by an increased risk of intellectual disability and early-onset feeding problems. We suggest that a more detailed prenatal facial evaluation should be performed in fetuses presenting high nuchal thickness, heart defects, or unusual findings, along with the absence of a CNV on a CGH array. Due to the dysmorphic facial features, targeted RASopathy genes are presumed to likely to be responsible for NS, CFCS, and CS.

Schimmelpenning syndrome is a rare, well-defined constellation of clinical phenotypes associated with the presence of nevus sebaceous and multisystem abnormalities most commonly manifested as cerebral, ocular, and skeletal defects [1]. A single nucleotide mutation in the HRAS or KRAS genes resulting in genetic mosaicism is responsible for the clinical manifestations of this syndrome in the majority of cases. We report a case of an adolescent boy with Schimmelpenning syndrome with a multifocal pilocytic astrocytoma. No HRAS or KRAS gene mutations were noted in the tumor on genetic sequencing. However, glial tumors have been associated with genetic mutations of RAS upregulation, which may imply a common pathway.