Differences in Cardiovascular Manifestation of Marfan Syndrome Between Children and Adults.

Marfan syndrome (MFS) is a connective tissue disorder characterized by a broad range of clinical manifestations. Cardiovascular involvement is the most life-threatening aspect of the syndrome. Although abnormalities within the cardiovascular system in adults are well documented, there is still a paucity of data regarding manifestation of MFS in childhood. The aim of the study was to compare cardiovascular manifestation of MFS between children and adults. The study population consisted of 236 patients (144 children and 92 adults), who were referred to our department with suspicion of MFS. All patients underwent complete clinical evaluation in order to confirm the diagnosis of MFS according to the modified Ghent criteria. MFS was diagnosed in 101 (44 children and 57 adults) out of the 236 patients. The other patients were diagnosed with Ehlers-Danlos syndrome, Loeys-Dietz syndrome, MASS phenotype, ectopia lentis syndrome, marfanoid habitus and other rare syndromes. The most common cardiovascular abnormality was aortic root dilatation (81.19% of patients). It was found that both adults and children had similar high rates of aortic root dilatation. Similarly, there was no significant difference with regard to the prevalence of aortic valve regurgitation and mitral valve prolapse among children and adults. These findings equivocally indicate that the aforementioned abnormalities develop in early childhood, therefore, they may be used in the early identification of patients with MFS. Other assessed abnormalities, which included mitral valve regurgitation, pulmonary artery dilation, aneurysms of aortic arch, descending thoracic aorta and abdominal aorta were found mostly in adults, and thus, are of less use in the early detection of MFS.

Hypomyelinating leukodystrophies - a molecular insight into the white matter pathology.

Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. In the past various classification systems for HLDs have been used, based on imaging findings, clinical manifestation, and organelle-specific disorders. Here we present a molecular insight into HLDs based on a defect in specific gene engaged in myelination. We discuss recent findings on pathogenesis, clinical presentation, and imaging related to these disorders. We focus on HLDs that are in use in differential diagnostics of Pelizaeus-Merzbacher disease (PMD), with a special emphasis on Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition with delayed myelination due to thyroid transport disturbances. On the background of previously published patients we describe a proband initially considered as presenting with a severe PMD, whose diagnosis of AHDS due to a novel nonsense SLC16A2 mutation unraveled two previously undiagnosed generations of affected males who died in infancy from unexplained reasons. Since AHDS is found to be a relatively frequent cause of X-linked intellectual disability, we emphasize the need for determining the whole thyroid profile especially in hypotonic males with a delay of psychomotor development.

Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction.

Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin-related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of 11 patients carrying 10 distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS-overlapping features. The phenotype of our patients is very broad, whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X-inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counseling and risk prediction.

The Marfan syndrome - features, natural history and treatment options - our experiences.

The Marfan syndrome (MFS) is one of the most common (1:3000-1:4000) heritable connective tissue disorders. It's still a rarely diagnosed syndrome, especially in childhood. Near all cases MFS results from mutations in the fibrillin-1 (FBN1) gene on chromosome 15q21.1, which encodes for the glycoprotein fibrillin. The FBN1 gene is a large protein that can cause more than 500 mutations and molecular examinations, finally confirming the diagnosis, are conducted extremely rare. We present prospective data concerning 66 patients with clinically-diagnosed MFS who have been controlled in Department of Pediatric Cardiology and Congenital Heart Diseases Medical University in Gdansk in 2000 - 2010. 29 patients (44%) had mitral valve regurgitations, 19 (29%) aneurysmal dilatation of the aorta, 13 (20%) had both these irregularities. In 7 cases (11%) diagnosis of mitral valve prolapse preceded appearance of an aneurysmal dilalation of the aortic bulb. During the observation 11 patients (17%) underwent cardiosurgical procedures for the sake of stopping crucial progressive mitral valve dysfunction and/or aneurysmal dilatation of the aortic bulb, which threatened with a rupture of aortic aneurysm. In 39 cases (59%) prophylactic treatment with beta - blockers was administered. The patients with MFS need a multidisciplinary system of care and the psychological supporting. The cardiosurgical treatment, which nowadays is bringing better results, due to the technological advancements is a new hope for this patient population.

The course of the dilated cardiomyopathy in three siblings - a rare case of familial non-compact left ventricle.

The dilated cardiomyopathy still remains a big problem in infant's cardiology. Almost a third of patients with this diagnosis die in infancy, 30% will suffer from the chronic heart failure that forces constant treatment or/and heart transplantations, and in remaining 30% we notice improvement during infancy. We presented the clinical course and progress of dilated cardiomyopathy based on the case of three siblings. Signs of the heart failure were nonspecific. Concluding: diagnostic vigilance must be shown in the cases of positive familial history.

8.6Mb interstitial deletion of chromosome 4q13.3q21.23 in a boy with cognitive impairment, short stature, hearing loss, skeletal abnormalities and facial dysmorphism.

We describe a 16-year-old boy with an 8.6Mb interstitial deletion of chromosome 4q 13.3q21.23 identified by oligo array-CGH. The patient presents psychomotor developmental delay, absent speech, marked progressive growth restriction, hearing loss, skeletal defects and minor facial anomalies. The patient required surgical treatment for cleft lip and palate, bilateral cryptorchidism and a neurofibroma. The analysis of the presented patient against previously published cases allowed us to expand further on the phenotype and to reevaluate previously proposed critical overlapping region at 4q21. As an addition to PRKG2 and RASGEFIB genes, we propose to include BMP3 gene as the principal determinant of the observed common phenotype. BMP3 haploinsufficiency appears to be causative of hearing loss and peculiar skeletal abnormalities including hemivertebrae and brachydactyly.

A new sporadic case of early-onset Loeys-Dietz syndrome due to the recurrent mutation p.R528C in the TGFBR2 gene substantiates interindividual clinical variability.

We report on a 2-year-old Polish girl with typical manifestations of Loeys-Dietz syndrome (LDS), a rare genetic condition belonging to the group of Marfan-related disorders. The characteristic LDS symptoms observed in the girl included craniofacial dysmorphism (craniosynostosis, cleft palate, hypertelorism), arachnodactyly, camptodactyly, scoliosis, joint laxity, talipes equinovarus, translucent and hyperelastic skin, and umbilical hernia. Mild dilatation of the ascending aorta and tortuous course of the left internal carotid artery were recognized during her second year of life. Molecular genetic testing revealed a heterozygous missense mutation (c.1582C>T, p.R528C) in the transforming growth factor beta receptor II gene (TGFBR2). This mutation has been previously associated with LDS in 5 unrelated cases, and was never reported in patients with other Marfan-related disorders. Comparison of the phenotypes of our patient and these 5 individuals with c.1582C>T showed that only the hallmark triad of the syndrome - consisting of hypertelorism, aortic root dilatation/aneurysm, and cleft palate or bifid uvula - was present in all 6 cases. Interestingly, none of the 5 individuals who underwent psychological evaluation showed developmental delay. The pattern of all other LDS features showed interindividual variability. Our data support the recently reported observation that symptoms of LDS can develop at a very young age, making early diagnosis and management essential for these patients. This is the first report on a Polish infant with typical LDS symptoms caused by a TGFBR2 mutation.

Clinical and molecular-cytogenetic studies in seven patients with ring chromosome 18.

We report the results of detailed clinical and molecular-cytogenetic studies in seven patients with ring chromosome 18. Classical cytogenetics and fluorescence in situ hybridization (FISH) analysis with the chromosome 18 painting probe identified five non-mosaic and two complex mosaic 46,XX,dup(18)(p11.2)/47,XX,dup(18)(p11.2),+r(18) and 46,XX,dup(18)(p11.32)/47,XX,dup(18)(p11.32),+r(18) cases. FISH analysis was performed for precise characterization of the chromosome 18 breakpoints using chromosome 18-specific short-arm paint, centromeric, subtelomeric, and a panel of fifteen Alu- and DOP-PCR YAC probes. The breakpoints were assessed with an average resolution of approximately 2.2 Mb. In all r(18) chromosomes, the 18q terminal deletions ranging from 18q21.2 to 18q22.3 ( approximately 35 and 9 Mb, respectively) were found, whereas only in four cases could the loss of 18p material be demonstrated. In two cases the dup(18) chromosomes were identified as inv dup(18)(qter-->p11.32::q21.3-->qter) and inv dup(18)(qter-->p11.32::p11.32-->p11.1: :q21.3-->qter)pat, with no evidence of an 18p deletion. A novel inter-intrachromatid mechanism of formation of duplications and ring chromosomes is proposed. Although the effect of "ring instability syndrome" cannot be excluded, the phenotypes of our patients with characteristic features of 18q- and 18p- syndromes are compared and correlated with the analyzed genotypes. It has been observed that a short neck with absence of cardiac anomalies may be related to the deletion of the 18p material from the r(18) chromosome.

Mutations in the EDA gene in three unrelated families reveal no apparent correlation between phenotype and genotype in the patients with an X-linked anhidrotic ectodermal dysplasia.

Anhidrotic ectodermal dysplasia (EDA) is caused by mutations in the EDA gene encoding ectodysplasin A, a member of the TNF ligand superfamily involved in the communication between the cells. The structure of the EDA gene was investigated in three patients exhibiting clinical symptoms of EDA in an attempt to correlate the molecular findings with the phenotype of the patients. Genomic DNA was analyzed by single stranded conformation polymorphism (SSCP) followed by direct sequencing. In one of the patients, as well as in his heterozygous mother and sister, a single T insertion was evidenced in exon 3 between nucleotides 713 and 714 that changed Lys codon (AAA) into a termination codon TAA (Lys158Ter). In the other patient, A1321T transversion was demonstrated. The same mutation was found in his heterozygous mother and resulted in a change of Ileu360Asn that might generate an additional glycosylation site. In the third patient an A1285G transition was revealed. This mutation that originated de novo was localized in a region that is highly conserved in TNF ligand family and caused substitution of Ala349Thr. Localization of the mutations in the extracellular domain of ectodysplasin A suggested that the primary cause of EDA is a defect in communication between the cells responsible for the development of skin appendages. Despite a different character and localization of the mutations, no apparent correlation between phenotype and genotype of the patients was evidenced. Some differences in the patients' phenotype were observed.

[A severe adverse event after vaccine for diphtheria, tetanus, pertussis and poliomyelitis (DTP + polio) in a 4.5 month old infant]. / Powiklanie o ciezkim przebiegu po szczepieniu przeciw Blonicy, Tezcowi, Krztuscowi oraz Poliomyelitis (DTP + Polio) u 4,5 miesiecznego niemowlecia.

Neurological complications of immunisation are rare. We report the case of neuroallergic reaction 5 days after receiving the second course of DTP + Polio vaccine in a 4.5 month old girl. The pathological signs developed 48 hours after the vaccination. On admission the infant demonstrated a persistent fever (39 degrees C), resistant to Paracetamol, unusual crying, irritability, consciousness disorder, and opistotonus. Physical examination showed generalised mild, macular rash and redness and swelling at the injection site. The neurological assessment revealed weakness of upper and lower limbs, meningeal signs such as stiff neck, Kernigs and Brudzinski signs. There were no pathological changes in the CSF. The diagnosis was established as the neuro-allergic Adverse Event Following DPT + Polio Immunisation. After 10 day treatment with Dexamethasone and Phenobarbital the infant was discharged with no neurological changes. A psychomotorical development is good.

A case with 47,XXY,del(11)(q23) karotype-coexistence of Jacobsen and Klinefelter syndromes.

A case with 47,XXY, del(11)(q23) karyotype-coexistence of Jacobsen and Klinefelter syndromes: A two-year-old dysmorphic male child was found to have 47,XXY,del(11)(q23) karyotype. Domination of the clinical features of Jacobsen syndrome was observed: mild mental retardation, trigonocephaly, ptosis, downward slanting palpebral fissures, low set ears, carp-shape mouth and micrognathia. Transient thrombocytopenia and leukopenia were also present. Over the following five years gynecomastia and eunuchoid body proportions became evident as clinical features of Klinefelter syndrome. This is the first description of the coexistence of both syndromes.

[Thrombus of the right ventricle simulating a cardiac tumor--case report]. / Skrzeplina w prawej komorze symulujaca guz serca--opis przypadku.

A nine day infant with Down syndrome and congenital heart disease is presented in whom the course of neonatal sepsis was complicated by the presence of difficult to diagnose pathological masses in the right ventricle. The etiology of pathological masses was difficult to establish in survival investigations. Histopathological examinations revealed the presence of thrombus in the right heart and foci of granulation on a muscle of right ventricle outflow, probably after a septic embolus.

[Acute leukemia in children with Down syndrome: analysis of cases]. / Ostra bialaczka u dzieci z zespolem Downa--analiza przypadków wlasnych.

An analysis of clinical and laboratory parameters and the results of treatment of 14 children with Down Syndrome and acute leukaemia was performed. The children were treated between 1986-1997. Their age ranged from 1 day to 13 years (average 5.5). There were 9 girls and 5 boys. Four of them had congenital heart disease. ALL was observed in 10, AML in 3 and TAM (Transient Abnormal Myelopoesis) in 1. Half of the children with ALL was classified as L1 according to FAB with the majority of common phenotypes and M6 in ANLL group. Remission was achieved in all ALL patients, six of them are still free of symptoms, the remaining four died of brain haemorrhage as a consequence of myelosuppression. Only 1 of 3 children with ANLL achieved remission. The child died of cardiac arrest after induction phase of BFM 95 programme (ADE). The 2 remaining children with ANLL also died of circulation failure before initiation of chemotherapy. The children had complicated cyanotic heart disease. The neonate with TAM is in clinical and hematological remission. In conclusion all children with ALL achieved hematological remission but tolerance of treatment was a problem. The majority of patients had diminished bone marrow reserve. Mortality was frequently related to circulatory failure in children with associated heart defects. It seems necessary to discuss the modification of accepted programmes for leukemia for the treatment of children with Down Syndrome.

[Thrombus in the right ventricle in an infant--a good result of thrombolytic therapy with recombinant tissue plasminogen activator]. / Skrzeplina w prawej komorze u niemowlecia-dobry wynik leczenia tkankowym aktywatorem plazminogenu.

In a 2 month-old infant presenting with the symptoms of cardio-respiratory failure in the course of staphylococcal septicaemia a thrombus in the right ventricle was detected in an echocardiographic examination. Scintigraphy of the lungs revealed of microthrombosis. Thrombolytic therapy with recombinant tissue plasminogen activator (Actylise) was started on the dose of 0.5 mg/kg/hour in 7-hour constant infusion. After 5 days of treatment the thrombus was completely dissolved. No complication were observed. Indicators of serum clothing remained normal during the treatment.

[The clinical course of fungal urinary tract infection in neonates]. / Grzybica ukladu moczowego noworodków--obserwacje wlasne.

The authors present the clinical course of 8 cases of fungal infection of the urinary tract in newborns. Three of the investigated children were premature or with intrauterine hypotrophy, a congenital defect of the urinary tract was detected in one child. In 5 cases the fungal infection followed bacterial septicaemia. Two of the 8 children required peritoneal dialysis, another two required insertion of intravenous catheters for parenteral feeding, and four required bladder catheterisation. The diagnosis of fungal urinary tract infection was established on the basis of urine culture, the presence of specific serum anti-candida antibodies and results of ultrasonographic examination (vs). In 7 of 8 cases the possibility of fungal infection was suggested by US examination. Seven children were treated with fluconazole combined with 5-fluorocytosine, one was treated with fluconazole. Pyelostomy was performed, in two of the patients all of them received supportive treatment. Our clinical observations point to the necessity of prophylaxis in case of predisposing factors to fungal infection and the use of abdominal ultrasonography for detection of early stages of fungal urinary tract infection.