A novel splicing acceptor variant of the FBN2 gene contributes to a case of congenital contractural arachnodactyly / 中华医学遗传学杂志

OBJECTIVE@#To identify the pathogenic variants from a patient with suspected congenital contractural arachnodactyly, and to explore the possible molecular genetic pathogenesis, so as to provide evidence for clinical diagnosis.@*METHODS@#Whole exome sequencing was performed for the patient. The splicing site variation of candidate pathogenic genes was verified by Sanger sequencing, and the new transcript sequence was determined by RT-PCR and TA-cloning sequencing.@*RESULTS@#The patient carried a heterozygous c.533-1G>C variant of FBN2 gene, which was not reported. The sequencing of mRNA showed that the variant leaded to the disappearance of the canonical splice acceptor site of FBN2 gene and the activation of a cryptic splice acceptor site at c.533-71, resulting in the insertion of 70 bp sequence in the new transcript. It was speculated that the polypeptide encoded by the new transcript changed from valine (Val) to serine (Ser) at amino acid 179, and prematurely terminated after 26 aminoacids. According to the guidelines of American College of Medical Genetics and Genomics, the variant of FBN2 gene c. 533-1G>C was determined as pathogenic (PVS1+PM2+PP3 ).@*CONCLUSION@#A novel splicing variant of FBN2 gene (c.533-1G>C) was identified, which can lead to congenital contractural arachnodactyly.

Pathological variant of FBN2 gene identified in a pedigree affected with congenital contracture arachnodactyly / 中华医学遗传学杂志

OBJECTIVE@#To detect pathological variant in a Chinese pedigree affected with congenital contractural arachnodactyly (CCA).@*METHODS@#Next generation sequencing (NGS) was used to scan the whole exome of the proband. Potential variant of the FBN2 gene was also detected in all members of the pedigree and 100 healthy controls by Sanger sequencing. With the determination of the genotype, prenatal diagnosis was carried out by amniotic fluid sampling.@*RESULTS@#A c.3528C>A (p.Asn1176Lys) variant was identified in the FBN2 gene of the proband, other patients from this pedigree, as well as the fetus. The same variant was not found among healthy members from this pedigree and the 100 healthy controls.@*CONCLUSION@#The c.3528C>A (p.Asn1176Lys) variant of the FBN2 gene probably underlies the pathogenesis of CCA in our case. The new variant has enriched pathological spectrum of the FBN2 gene.

Atypical Neonatal Marfan Syndrome with p.Glu1073Lys Mutation of FBN1: the First Case in Korea

Neonatal Marfan syndrome (nMFS) is considered to be on the most severe end of the spectrum of type I fibrillinopathies. The common features of nMFS include ascending aortic dilatation, severe mitral and/or tricuspid valve insufficiency, ectopia lentis, arachnodactyly, joint contractures, crumpled ear, loose skin, and pulmonary emphysema.We describe a newborn male diagnosed with nMFS. He presented several atypical features, such as diaphragmatic eventration, severe hydronephrosis with hydroureter, and dilated cisterna magna. Molecular analysis revealed a missense mutation at nucleotide 3217 (c.3217G>A) in exon 26 of the fibrillin-1 (FBN1) gene, resulting in the substitution of a glutamate for a lysine at codon 1073 (E1073K) in the 12th calcium binding epidermal growth factor-like domain of the FBN1 protein. Here we report a rare case of Nmfs with several combined atypical features, such as diaphragmatic eventration, severe hydronephrosis with hydroureter, and dilated cisterna magna. Our report is the first atypical nMFS case with p.Glu1073Lys mutation of FBN1 in Korea and may help clinicians with the diagnosis and follow-up of atypical nMFS.

A novel FBN1 gene mutation associated with early-onset pneumothorax in Marfan syndrome

Marfan syndrome (MFS) is an inherited connective tissue disorder with a mutation in the fibrillin-1 (FBN1) gene. Fibrillin is a major building block of microfibrils, which constitute the structural component of the connective tissues. A 10-year-old girl visited our hospital with the chief complaint of precocious puberty. According to her medical history, she had a pulmonary wedge resection for a pneumothorax at 9 years of age. There was no family history of MFS. Mid parental height was 161.5 cm. The patient's height was 162 cm (>97th percentile), and her weight was 40 kg (75th-90th percentile). At the time of initial presentation, her bone age was approximately 11 years. From the ophthalmologic examination, there were no abnormal findings except myopia. There was no wrist sign. At the age of 14 years, she revisited the hospital with the chief complaint of scoliosis. Her height and weight were 170 cm and 50 kg, respectively, and she had arachnodactyly and wrist sign. We performed an echocardiograph and a test for the FBN1 gene mutation with direct sequencing of 65 coding exons, suspecting MFS. There were no cardiac abnormalities including mitral valve prolapse. A cytosine residue deletion in exon 7 (c.660delC) was detected. This is a novel mutation causing a frameshift in protein synthesis and predicted to create a premature stop codon. We report the case of a patient with MFS with a novel FBN1 gene missense mutation and a history of pneumothorax at a young age without cardiac abnormalities during her teenage years.

A Case of Aortic Dissection with Marfan Syndrome and Ankylosing Spondylitis / 대한내과학회지

A 33-year-old male presented with an acute onset of back pain and abdominal pain. He was 189.9 cm tall and had an arm span of 194 cm, and had mild pectus carinatum as well as arachnodactyly. Plain radiographs showed kyphoscoliosis of the lumbar spine, bamboo spine of the thoracic spine, and sacroiliitis of the pelvis. Abdominal computed tomography revealed debakey type 3 aortic dissection. We prescribed beta blockers to control his blood pressure. According to the modified New York criteria, we diagnosed him with HLA negative ankylosing spondylitis and initiated therapy with nabumetone and sulfasalazine. We later diagnosed Marfan syndrome based on the Ghent criteria and mutation screening at the fibrillin-1. After treatment, he has been followed up without symptoms or complications.

Unusual manifestation of Marden-walker syndrome.

Marden-Walker syndrome (MWS) is characterized by multiple joint contractures, a mask-like face with blepharophimosis, micrognathia, high-arched or cleft palate, low-set ears, decreased muscular bulk, arachnodactyly, and kyphoscoliosis. We report a case of MWS along with unusual manifestation of neurological, cardiovascular, and genitourinary system.

A Case Report of Beals Syndrome with Hydrocephalus / 대한주산의학회잡지

Beals syndrome, also known as Beals-Hecht syndrome or congenital contractural arachnodactyly, is a rare, autosomal dominant connective tissue disorder. It is characterized by crumpled ears, arachnodactyly, congenital contractures and scoliosis. A male infant of 37+5 weeks of gestation, and with birth weight of 3170 grams, had features of a long and narrow face, bilateral crumpled inferior helix, prominent antihelix of the ears, bilateral arachnodactyly, clenched position of the hands and flexion contractures of the elbows and knees. The infant had tachypnea and chest retractions shortly after birth, and was diagnosed with transient tachypnea of newborn with pneumothorax. He was subsequently treated with positive pressure ventilation and chest tube insertion. Chromosomal karyotype analysis was normal and screening for Marfan syndrome was negative. Echocardiographic findings were unremarkable. Cranial ultrasonography showed a left lateral ventricle dilatation of 0.5 cm and increase up to 1.2 cm on follow up. Brain MRI showed a progression of dilatation of the left ventricle, and a ventriculo-peritoneal shunt was done at 3 months of age. We present a case of a newborn male with Beals syndrome, accompanied with ventricular dilatation and progression to hydrocephalus that has not been previously reported.

A case of de novo duplication of 15q24-q26.3 / 소아과

Distal duplication, or trisomy 15q, is an extremely rare chromosomal disorder characterized by prenatal and postnatal overgrowth, mental retardation, and craniofacial malformations. Additional abnormalities typically include an unusually short neck, malformations of the fingers and toes, scoliosis and skeletal malformations, genital abnormalities, particularly in affected males, and, in some cases, cardiac defects. The range and severity of symptoms and physical findings may vary from case to case, depending upon the length and location of the duplicated portion of chromosome 15q. Most reported cases of duplication of the long arm of chromosome 15 frequently have more than one segmental imbalance resulting from unbalanced translocations involving chromosome 15 and deletions in another chromosome, as well as other structural chromosomal abnormalities. We report a female newborn with a de novo duplication, 15q24-q26.3, showing intrauterine overgrowth, a narrow asymmetric face with down-slanting palpebral fissures, a large, prominent nose, and micrognathia, arachnodactyly, camptodactyly, congenital heart disease, hydronephrosis, and hydroureter. Chromosomal analysis showed a 46,XX,inv(9)(p12q13),dup(15)(q24q26.3). Array comparative genomic hybridization analysis revealed a gain of 42 clones on 15q24-q26.3. This case represents the only reported patient with a de novo 15q24-q26.3 duplication that did not result from an unbalanced translocation and did not have a concomitant monosomic component in Korea.

Cranioplasty in Frontometaphyseal Dysplasia

Frontometaphyseal dysplasia is a rare genetic syndrome first described by Gorlin and Cohen in 1969. This disease affects the skeletal system and connective tissue, and could be characterized by hyperostosis of the skull, prominence of supraorbital ridges, additional skeletal and extraskeletal abnormalities. It is believed that the condition is an X-linked dominant trait with severe manifextations in males and extreme variability in females. We described a case of 15-year-old boy manifested a pronounced supraorbital ridge associated with exorbitism. He also had bilateral progressive hearing deficit, thoracic spine scoliosis, chest wall deformity, bilateral maxillary sinusitis and both 5th finger arachnodactyly. The patient underwent a fronto-temporo-orbital cranioplasty through a coronal incision. The frontal bone including supraorbital region, orbital lateral rim and temporal bone were extensively contoured with burr. And then, burring of the medial aspect of lateral orbital wall was made to increase both orbital volume for correction of exorbitism. Postoperative results show well corrected prominent supraorbital ridge, hyperostosis of frontotemporal bone and exorbitism. The patient was satisfied with the improved appearance. No recurrence occurred during the 6 months of follow-up period. We report this case as it shows esthetically good result without any complication.

A Case of Beals-Hecht syndrome

Beals-Hecht syndrome, also known as congenital contractural arachnodactyly, is a rare autosomal dominant, connective tissue disorder characterized by congenital joint contractures, arachnodactyly, dolichostenomelia, crumpled ear, and kyphoscoliosis. We report a case of Beals-Hecht syndrome in a 4 days old female newborn baby, associated with congenital knee and elbow joint contractures, arachnodactyly, dolichostenomelia, crumpled ear, and 4 umbilical arteries, with brief review of the related literatures.

A Case of Marden-Walker Syndrome

Marden-Walder syndrome is characterized by a mask-like face, blepharophimosis, joint contractures, and psychometer retardation. We report a newborn infant with the clinical features of the syndrome. He was diagnosed with clinical findings of mask-like face, blepharophimosis, micrognathia, camptodactyly, arachnodactyly, multiple contractures, and hypotonia. The infant died of aspiration pneumonia at 5 months. A brief review of related literature is also presented.

Intracranial Aneurysms Associated with Polycystic Kidney, and Marfan's Syndrome: Case Report

A case of an anterior communicating(Acom) artery aneurysm in a 36-year-old woman with polycystic kidney, and a case of multiple aneurysms(Acom. And anterior choroidal artery aneurysm) in a 49-year-old man with Marfan's syndrome are reported. Polycystic kidney was confirmed by abdominal ultrasonography and computed tomography. Marfan's syndrome was diagnosed with skeletal abnormalities(dolichocephaly, highly arched palate, cleft palate, arachnodactyly and tall slender height with excessive length of limbs) and marked elongation and tortuosity of the vertebral artery on cerebral angiography. Those patients were treated with the clipping of aneurysms. We will discuss the pathogenesis of cerebral aneurysm in those diseases with stress on the important points of management.

A Case of Marfan Syndrome

The Marfan syndrome is classified as a heritable disorder of connective tissue with clinical and pathological alterations involving supporting elements. In its classic form, the Marfan syndrome is associated with abnormalities of the eye(ectopia lentis), aorta(aortic dilatation and aortic regurgitation) and skeleton(dolichostenomelia, arachnodactyly and pectus deformity). The authers have experienced a case of marfan syndrome recently. The patient was 30-years-old male complaining of anterior chest pain radiating to upper back. Physical examination showed tall status, increased length of the limbs as compared with the trunk and arachnodactyly. On auscultation, heart sound was normal without murmur. He wore glasses because of moderate myopia. Roentgenogram of the chest P-A revealed normal cardiac and aortic contours and lung fields. Left lateral view of chest X-ray revealed concave depression of sternum showing mild pectus excavatum, fusiform dilatation of aorta from aortic root to mid portion of thoracic aorta and resulting in obliteration of retrosternal clear space. Echocardiogram demonstrated moderate dilatation of aortic root A-P diameter(4.5cm) without aortic or mitral valvular abnormalities and normal size of left ventricular cavity(EDD:5.3cm). These data coupled with a distinct family history could permit the diagnosis of Marfan syndrome.

The Relationship between hand and foot Length and Other Anthropometric Measurements in Neonates

The hand length, foot length, middle finger length as percentage of total hand length, palm length, height, birth weight head circumference of 143 neonates of gestational ages ranging from twen-five to fourty-two weeks were measured between 12 hours and 5 days of life in order to find out normal values and correation between them. The subjects were devided into three groups of term babies with weight appropriate for gestational age, of term babies with weight light for dates and of premature babies. The following results were obtained. 1. The means, standard deviations & percentile values of hand length, foot length, palm length, middle finger length, middle finger length as percentage of total hand length in term babies(n=110) were obtained(Table 3). The sexual difference was statistically insignificant(p<0.05) in all. 2. There was a positive linear correlation between foot and hand length and other indices of anthropometric measurements in all groups. In premature babies, the correlation between foot length hadd length(r=0.79), foot length and height(r=0.64) as well as foot length and birth weight(r=0.82) were excellent. The 95percent confidence limits of the regression lines were+/-0.66cm,+/-0.66cm, and+/-374g, respectively. The birth weight and height of premature babies can theoretically be estimated from a measurement of foot length which can be performed easily and rapidly. 3. A positive linear correlation(r=0.79) between foot length and gestational age exist and the foot length of 7.0cm serves as a reliable index of prematurity. Its diagnosi bility was 0.998, 0.612. 4. The normal values of hand length, foot length, palm length, middle finger length, middle finger length as percentage of total hand length, which were obtained in this study, will be helpful to diagnose as brachydactyly or arachnodactyly.

A Case of Madan's Syndrome

Marfan's syndrome is another name of arachnodactyly and was firstly noted by Marfan in 1896. Salle found that ocular signs are also accompanied by this syndrome. Since then, many cases of this syndrome have been reported even in this country. The etiology of this syndrome is not exactly classified but is thought as an hereditorical and general developemental abnormalities of mesodermal origin. Authors report here a case of this syndrome in which ectopia lentis, lens opacity, organization of vitreous and iridodonesis are present.

A Case Report of Madan's Syndrome

Marfan's Syndrome was a collagenous hereditary disorder affected by the long bone, heart and eyes. This typical arachnodactyly patient was 8 year old boy who has had visual disturbance due to central opacitous lens subluxation of both eyes. We performed successfull intracapsular lens extraction by use of cryolens extractor for both eyes. X-ray chest suggested the evidence of aortic aneurysm. Electron microscopic study for the zonular fibers of the lens showed a relative loose aggregated zonular fibers with small amount of its bundles, but chromosomal study for this patient showed no abnormality.