Expanding the phenotypic spectrum of Mendelian connective tissue disorders to include prominent kidney phenotypes.

Heritable connective tissue disorders are a group of diseases, each rare, characterized by various combinations of skin, joint, musculoskeletal, organ, and vascular involvement. Although kidney abnormalities have been reported in some connective tissue disorders, they are rarely a presenting feature. Here we present three patients with prominent kidney phenotypes who were found by whole exome sequencing to have variants in established connective tissue genes associated with Loeys-Dietz syndrome and congenital contractural arachnodactyly. These cases highlight the importance of considering connective tissue disease in children presenting with structural kidney disease and also serves to expand the phenotype of Loeys-Dietz syndrome and possibly congenital contractural arachnodactyly to include cystic kidney disease and cystic kidney dysplasia, respectively.

The Genetic Epidemiology of Pediatric Pulmonary Arterial Hypertension.

OBJECTIVE: To describe the prevalence of pulmonary arterial hypertension (PAH)-associated gene mutations, and other genetic characteristics in a national cohort of children with PAH from the Dutch National registry and to explore genotype-phenotype associations and outcomes. STUDY DESIGN: Children (n = 70) diagnosed with idiopathic PAH, heritable PAH, PAH associated with congenital heart disease with coincidental shunt (PAH-congenital heart disease group 3), PAH after closure of a cardiac shunt (PAH-congenital heart disease group 4), or PAH associated with other noncardiac conditions were enrolled. Targeted next-generation sequencing was performed on PAH-associated genes (BMPR2, ACVRL1, EIF2AK4, CAV1, ENG, KCNK3, SMAD9, and TBX4). Also, children were tested for specific genetic disorders in case of clinical suspicion. Additionally, children were tested for copy number variations. RESULTS: Nineteen children (27%) had a PAH-associated gene mutation/variant: BMPR2 n = 7, TBX4 n = 8, ACVRL1 n = 1, KCNK3 n = 1, and EIF2AK4 n = 2. Twelve children (17%) had a genetic disorder with an established association with PAH (including trisomy 21 and cobalamin C deficiency). In another 16 children (23%), genetic disorders without an established association with PAH were identified (including Noonan syndrome, Beals syndrome, and various copy number variations). Survival rates differed between groups and was most favorable in TBX4 variant carriers. CONCLUSIONS: Children with PAH show a high prevalence of genetic disorders, not restricted to established PAH-associated genes. Genetic architecture could play a role in risk-stratified care management in pediatric PAH.

Double heterozygous variants in FBN1 and FBN2 in a Thai woman with Marfan and Beals syndromes.

A phenotype of an individual is resulted from an interaction among variants in several genes. Advanced molecular technologies allow us to identify more patients with mutations in more than one genes. Here, we studied a Thai woman with combined clinical features of Marfan (MFS) and Beals (BS) syndromes including frontal bossing, enophthalmos, myopia, the crumpled appearance to the top of the pinnae, midface hypoplasia, high arched palate, dermal stretch marks, aortic enlargement, mitral valve prolapse and regurgitation, aortic root dilatation, and progressive scoliosis. The aortic root enlargement was progressive to a diameter of 7.2 cm requiring an aortic root replacement at the age of 8 years. At her last visit when she was 19 years old, she had moderate aortic regurgitation. Exome sequencing revealed that she carried the c.3159C > G (p.Cys1053Trp) in exon 26 of FBN1 and c.2638G > A (p. Gly880Ser) in exon 20 of FBN2. The variant in FBN1 was de novo, while that in FBN2 was inherited from her unaffected mother. Both genes encode for fibrillins, which are essential for elastic fibers and can form the heterotypic microfibrils. Two defective fibrillins may synergistically worsen cardiovascular manifestations seen in our patient. In this study, we identified the fourth patient with both MFS and BS, carrying mutations in both FBN1 and FBN2.

[Pathological variant of FBN2 gene identified in a pedigree affected with congenital contracture arachnodactyly].

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.

22q11.2 deletion syndrome and congenital heart disease.

The 22q11.2 deletion syndrome has an estimated prevalence of 1 in 4-6,000 livebirths. The phenotype varies widely; the most common features include: facial dysmorphia, hypocalcemia, palate and speech disorders, feeding and gastrointestinal disorders, immunodeficiency, recurrent infections, neurodevelopmental and psychiatric disorders, and congenital heart disease. Approximately 60-80% of patients have a cardiac malformation most commonly including a subset of conotruncal defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B), conoventricular and/or atrial septal defects, and aortic arch anomalies. Cardiac patients with a 22q11.2 deletion do not generally experience higher mortality upon surgical intervention but suffer more peri-operative complications than their non-syndromic counterparts. New guidelines suggest screening for a 22q11.2 deletion in the patient with tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, conoventricular septal defects as well as those with an isolated aortic arch anomaly. Early identification of a 22q11.2 deletion in the neonate or infant when other syndromic features may not be apparent allows for timely parental screening for reproductive counseling and anticipatory evaluation of cardiac and noncardiac features. Screening the at-risk child or adult allows for important age-specific clinical, neurodevelopmental, psychiatric, and reproductive issues to be addressed.

Beals syndrome with middle and inner ear dysplasia and encephalocele: A case report and review of imaging findings.

A 10-year-old male with history of Beals syndrome presented with hearing loss and was found to have middle and inner ear dysplasia and left temporal encephalocele on imaging. Beals syndrome is a rare autosomal dominant connective tissue disorder caused by a mutation in the fibrillin-2 gene. Skeletal manifestations of Beals have been reported, including anomalies of the long bones, calvarium, and spine. External ear abnormalities with "crumpled ear" deformity are seen in the majority of patients. This is the first case to report imaging findings of the middle and inner ear in a patient with Beals.

Aortic Root Dilation: Do Patients With Marfan Syndrome Fare Worse Than Those With Marfanoid Features?

OBJECTIVE: To discover whether patients with aortic root dilation and leptosomic features but without a diagnosis of Marfan syndrome (MFS) fare similarly to patients with MFS. METHODS: Of 124 patients with aortic root dilation identified from August 1, 1994, through October 31, 2012, 66 had MFS and 58 had leptosomic features but did not meet the Ghent criteria. Genetic testing was performed in 35% of patients (n=43). We compared z scores and aortic root diameters for patients who presented with aortic root dilation with and without an MFS diagnosis and with and without aortic root repair. RESULTS: No difference existed in initial aortic root diameters between groups (P=.15); however, mean ± SD z scores for patients without MFS and with MFS were 3.1±2.3 vs 4.5±3.2 (P=.005). Fourteen of 58 patients (24%) without MFS and 35 (53%) with MFS underwent aortic root operations (P<.05). For both groups who did not have surgery, aortic root diameters and z scores remained similar at follow-up (P=.20), as did 10-year survival: MFS, 100%; no MFS, 94.1% (P=.98). No significant difference was found for mean ± SD root diameter (no MFS, 38.9±7.3 mm; MFS, 35±8.6 mm; P=.06) or z score (no MFS, 2.4±2.0; MFS, 2.1±2.0; P=.53) for patients who underwent surgery. Two patients in each group had aortic root dissections. CONCLUSION: Similar rates of aortic dissection between the 2 groups warrant further study regarding patients with leptosomic features but no diagnosis of MFS. Aortic root dilation progressed similarly in patients who did not undergo surgery.

Thoraco-abdominal aortic aneurysm rupture in a patient with Shprintzen-Goldberg syndrome.

Shprintzen-Goldberg syndrome is a rare systemic connective tissue disorder characterized by craniosynostosis, skeletal abnormalities, infantile hypotonia, mild-to-moderate intellectual disability and cardiovascular anomalies. To our knowledge, this is the first report of a Shprintzen-Goldberg syndrome patient who developed a thoraco-abdominal aortic aneurysm. The aneurysm grew rapidly necessitating emergent thoraco-abdominal aortic replacement. The postoperative course was uneventful, and a careful lifetime follow-up was planned.

Congenital contractural arachnodactyly complicated with aortic dilatation and dissection: Case report and review of literature.

Congenital contractural arachnodactyly (CCA) is a connective tissue disease caused by mutations of the FBN2, which encodes fibrillin-2. CCA patients have a marfanoid habitus; however, aortic dilatation and/or dissection as observed in Marfan syndrome have been rarely documented. Here, we report on a Japanese familial case of CCA resulting from a FBN2 splicing mutation (IVS32+5g→a), which leads to exon 32 being skipped, and the patients developed aortic dilatation and type A dissection. Although CCA patients have been believed to have favorable prognoses, repetitive aortic imaging studies must be performed in some patients to detect possible aortic disease early, and genetic testing of FBN2 might be useful to identify such high-risk patients.

Congenital Contractural Arachnodactyly without FBN1 or FBN2 Gene Mutations Complicated by Dilated Cardiomyopathy.

Congenital contractural arachnodactyly (CCA) is a rare connective tissue disorder characterized by marfanoid habitus with camptodactyly. However, cardiac features have rarely been documented in adults. We herein report a sporadic case of CCA in a 20-year-old woman who developed decompensated dilated cardiomyopathy. The patient did not have any mutations in the FBN1 or FBN2 genes, which are most commonly associated with Marfan syndrome and CCA, respectively. Although whether these two diseases are caused by a mutation(s) in the same gene or two different genes remains unknown, this case provides new clinical insight into the cardiovascular management of CCA.

Beals-Hecht syndrome (congenital contractural arachnodactyly) with additional craniospinal abnormality: a case report.

Beals syndrome is an autosomal-dominant connective tissue disorder, characterized by multiple flexion contractures, arachnodactyly, severe kyphoscoliosis, crumpled ear, and muscular hypoplasia. It has similarities to Marfan syndrome (MFS) in many respects. It has much fewer incidences of eye and heart anomalies compared with MFS. Beals syndrome is caused by a mutation in the fibrillin-2 gene (FBN2) in 5q23; MFS is caused by mutations in fibrillin-1. With time, there is spontaneous improvement in joint contractures, but kyphosis tends to be progressive. The neonatal form results from new mutations and tends to be severe. Prenatal molecular diagnosis is possible. Ultrasound could be used to demonstrate hypokinesia and joint contractures in presumptive cases. We present a case of a patient with Beals syndrome who presented to the emergency department with pneumonia and was found to have narrowing of the foramen magnum, with partial fusion of C2-C3 vertebral bodies. To our knowledge, this has not been documented in the literature and could be characteristic in relation to Beals syndrome.

Double-valve surgery in Shprintzen-Goldberg syndrome.

We describe the challenging case of a 28-year-old Jehovah's Witness patient who presented with symptomatic mitral and tricuspid valve disease and Shprintzen-Goldberg syndrome. This is the first reported double-valve surgery in such a patient who, apart from chest deformity, had a small body size, severe lung disease, difficult airway and vascular access, and to add to the complexity, refused blood and blood product use. The patient underwent a successful mitral valve replacement and tricuspid valve repair through a right thoracotomy. Apart from atrial fibrillation, he had a smooth hospital course and was discharged home on postoperative day 9.

Variabilidad fenotípica del síndrome de Marfan en una familia con una nueva mutación en el gen FBN1 / Phenotypic variability in Marfan syndrome in a family with a novel nonsense FBN1 gene mutation

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Novel findings in the Marden-Walker syndrome.

Reports about the Marden-Walker syndrome mainly consist of sporadic cases. We describe a 14-year-old girl with the Marden-Walker syndrome who presented with a huge scalp hematoma. The case and the corresponding images demonstrate an association with a defective hemostasis, skin hyperlaxity, and impaired wound healing.

Aracnodactilia contractural congénita / Congenital contractural arachnodactyly

La aracnodactilia contractural congénita (ACC) es un trastorno del tejido conectivo debido a una mutación autosómica dominante. La persona afectada de ACC presenta múltiples expresiones clínicas, incluidas las cardiacas y, principalmente, las musculoesqueléticas. Los progresos en el control de la gestación y la accesibilidad a técnicas de reproducción asistida llevan, cada vez más, a tener que atender situaciones como el caso clínico que se presenta: una gestación gemelar bicorial biamniótica obtenida por técnica de fertilización in vitro en una mujer afectada de dicha enfermedad. Los retos diagnósticos, las alternativas terapéuticas, el pronóstico materno y neonatal y las repercusiones sociales y éticas de estos casos son temas para la reflexión(AU)

Congenital contractural arachnodactyly (CCA) is a connective tissue disorder caused by an autosomal dominant mutation. Affected individuals show multiple involvement, including cardiac and, mainly, musculoskeletal abnormalities. Because of advances in pregnancy management and access to assisted reproduction techniques, situations such as that reported in the present article will become more frequent: we describe a dichorionic diamniotic twin gestation obtained by in vitro fertilization in a woman with CCA. The diagnostic challenges, therapeutic alternatives, maternal and neonatal outcomes, and the social and ethical repercussions of these cases are discussed(AU)

Lethal cutis laxa with contractural arachnodactyly, overgrowth and soft tissue bleeding due to a novel homozygous fibulin-4 gene mutation.

Cutis laxa is characterised by redundant, inelastic skin with deep wrinkling and additional variable systemic involvement. Mutations in fibulin-4 (EFEMP2) and fibulin-5 (FBLN5) were described to be causative for autosomal recessive cutis laxa type 1 in a few families each. The female patient was born to healthy consanguineous parents. Pregnancy was remarkable for fetal overgrowth and oligohydramnios. The newborn girl showed extreme bradycardia and died perinatally. Apart from overgrowth, cutis laxa, arachnodactyly of hands and feet with contractures of the third to fifth finger, medial rotation of feet, spina bifida of the os sacrum, microcephaly and facial dysmorphism were noted. Autopsy showed collapsed lungs with hypoplastic diaphragm and signs of cervical soft tissue bleedings due to fragility of vessels. Histologic examination showed fragmentation of elastic fibres with formation of cystic cavities in the medial layer of the aorta and central lung vessels. Sequencing of the elastin, fibulin-4 and fibulin-5 genes revealed a homozygous missense mutation (p.Cys267Tyr) in the fibulin-4 gene in the patient. Our observation increases the number of cases with fibulin-4 mutations to three and extends the phenotypic spectrum of fibulin-4 mutations by microcephaly, overgrowth and arachnodactyly.

Long-term survival in a child with severe congenital contractural arachnodactyly, autism and severe intellectual disability.

The severe form of congenital contractural arachnodactyly is usually associated with early mortality due to multisystem complications. Here, we report a 9-year-old male child with severe skeletal manifestations of congenital contractural arachnodactyly. He had none of the cardiovascular or gastrointestinal features that have been described in severe congenital contractural arachnodactyly. He had profound intellectual disability with autism. All exons of FBN2, the gene associated with congenital contractural arachnodactyly, were sequenced and no disease-causing mutation was found. When severe congenital contractural arachnodactyly is diagnosed in the newborn period, parents need to be aware that long-term survival is possible, particularly if no significant extraskeletal complications are present, and that significant neurodevelopmental delay may occur.