Difficulties in Diagnosing Fabry Disease in Patients with Unexplained Left Ventricular Hypertrophy (LVH): Is the Novel GLA Gene Mutation a Pathogenic Mutation or Polymorphism?

Fabry disease (FD) is an X-linked, lysosomal glycosphingolipid storage disorder that occurs very rarely. Cardiac involvement may comprise of left ventricular hypertrophy (LVH), arrhythmias, conduction abnormalities, heart failure and valvular abnormalities. The goal of this study was to conduct gene analysis for FD in patients suffering from unexplained LVH. 120 patients over the age of 30 who were diagnosed by echocardiography with idiopathic LVH were included in the study. Patients with severe hypertension, intermediate valve disease such as moderate aortic stenosis, known FD, and a family history of autosomal dominant hypertrophic cardiomyopathy were excluded from the study. GLA gene mutations were studied by Sanger sequence analysis in all patients. Of the 120 total patients included in this study, 69 were female (58%) and 51 were male (42%). The mean age was 60.3 ± 15.7. GLA gene mutations were detected in three male patients. The detected mutations are as follows: NM_000169.2:IVS6-10G>A (c.1000-10G>A), NM_000169.2:c.937G>T (p.D313Y) (p.Asp313Tyr) and NM_000169.2:c.941A>T (p.K314M) (p.Lys314Met). Early diagnosis is of vital importance in FD, which can be treated with enzyme replacement. Genetic screening in patients diagnosed with idiopathic LVH by echocardiography is important in the early diagnosis and treatment of FD. Patients over 30 years of age with idiopathic LVH should be screened for FD. Various new polymorphisms can be detected in genetic screening. Identifying new polymorphisms is important for knowing the true mutations in FD.

Do Gene Polymorphisms Play a Role in Newborn Hyperbilirubinemia?

Objectives: Polymorphisms of the uridine-diphospho-glucuronosyltransferase 1A1 (UGT1A1) gene, hepatic solute carrier organic anion transporter 1B1/B3 (SLCO1B1/3) gene, and glutathione S-transferase (GST) gene have been associated with significant hyperbilirubinemia in some populations. This study aims to determine whether the variation of UGT1A1, SLCO1B1/3 and GST genes play an important role in neonatal hyperbilirubinemia in Turkish newborn infants. Methods: The study included 61 idiopathic hyperbilirubinemia cases, 28 prolonged jaundice cases, and 41 controls. Ten common polymorphisms in four genes involved in bilirubin metabolism were examined. Polymerase chain reaction-restriction fragment length polymorphism method was used to detect variants of those genes. Results: No association was found between the variants of UGT1A1 at nt 211, the SLCO1B1 gene at nt 388, 463, 521, 1463, the SLCO1B3 gene at nt 334, 727+118, 1865+19721, and the GST gene at nt 313, 341, and neonatal hyperbilirubinemia. There was no difference between the case and control groups in terms of allele frequencies of these genes (except SLCO1B3 at nt 334) (p>0.05 in all comparisons). The presence of the G allele of the SLCO1B3 at nt 334 variant gene seemed to protect from jaundice in infants with idiopathic hyperbilirubinemia. Conclusion: These gene polymorphisms currently studied do not seem to modulate the risk of hyperbilirubinemia in Turkish newborn infants.

A familial case of Coffin-Lowry syndrome caused by RPS6KA3 C.898C>T mutation associated with multiple abnormal brain imaging findings.

Coffin-Lowry syndrome (CLS) is a rare X linked mental retardation syndrome characterised by severe psychomotor and growth retardation, distinct facial phenotype, and progressive skeletal malformations. It is caused by mutations in the RPS6KA3 gene located at Xp22.2. In this report we describe a family with CLS consists of three affected males, and two affected females, arising from c.898C>T mutation in RPS6KA3 gene. A 6 year-old, and a 3 year-old boy both had distinct clinical features of Coffin-Lowry syndrome; severe mental and motor retardation, microcephaly, prominent forehead, hypertelorism, large mouth, large ears, large soft hands, puffy tapered fingers, and pectus carinatum. In addition, they had multiple abnormal brain MRI findings. Other siblings presented with a mild and variable phenotype.

CITRIN DEFICIENCY: AN INFANT INCIDENTALLY DETECTED BY PHENYLKETONURIA SCREENING WITH A NOVEL MUTATION IN SLC25A13 GENE.

We report the first Turkish patient with citrin deficiency detected incidentally by phenylketonuria screening. Mild cholestasis, increased α-fetoprotein level, aminoacidemia including citrulline and coagulation disorder suggested citrin deficiency. Screening the SLC25A13 gene revealed compound heterozygosity harboring a novel mutation, c.851-854delGTAT (p.M285Pfs*2)/ p.I290T (c.869T>C). Progression to type II citrullinemia was considered due to hyperammonemia episodes resulting from high carbohydrate/low protein diet. High protein/low carbohydrate diet resulted in cessation of hyperammonemia episodes, reversal of hepatic dysfunction and steatohepatitis. Our report illustrates the importance of awareness on citrin deficiency.

REVERSIBLE CLINICAL AND MAGNETIC RESONANCE IMAGING FINDINGS IN LATE-ONSET COBALAMIN C DEFECT.

Cobalamin C (Cbl C) disease is an inborn error of intracellular cobalamin metabolism. Two distinct clinical types are defined according to the age of onset. We describe an 8 year old girl with late-onset Cbl C disease presenting with neuropsychiatric symptoms. Mutation analysis revealed homozygous c.394C>T (p.R132X) mutation in the MMACHC gene. Serial magnetic resonance imaging (MRI) before and after the treatment are provided. MRI of the brain before treatment showed bilateral patchy focal hyperintensities in the white matter and cortical atrophy. After treatment with intramuscular hydroxycobalamin, oral folinic acid, oral betaine, normalization of MRI findings can be achieved in addition to clinical improvement. We present this case to draw attention to the reversibility of clinical and MRI findings in the late onset Cbl C disease after treatment.

Prenatal diagnosis of Goldenhar syndrome with unusual features by 3D ultrasonography.

Oculoauriculo-vertebral spectrum, or Goldenhar syndrome, is characterized by varying degrees of prevalently unilateral underdevelopment of craniofacial structures (orbit, ear, and mandible) and spinal anomalies. We report a patient with unusual features diagnosed prenatally by 3D ultrasonography at 21 weeks' gestation without a family history. An early diagnosis was suggested by observation of a maxillary cleft-plate, multiple vertebral segmentation defects and hypoplastic thumb. Postnatal evaluation also revealed ambiguous genitalia and club feet in addition to the prenatally and postnatally diagnosed classical Goldenhar syndrome features like hemifacial microsomia, preauricular and facial skin tags, coloboma of eyelids, epibulbar dermoid.

Nephron-sparing surgery for renal cell carcinoma of the allograft after renal transplantation: report of two cases.

The risk of renal transplanation patients developing de novo malignancy is increased 100-fold compared with the healthy nontransplantation population. Renal cell carcinoma (RCC) arising from native kidneys is diagnosed among up to 4.6% of the renal transplant recipients as a consequence of immunosuppression. These tumors tend to behave more aggressively.(1) Although tumors occurring in allografted kidneys can be treated by partial (to save functional graft) or total nephrectomy, there is a paucity of data the outcomes. From 1978 to 2012, we performed 804 kidney transplantations including two cases in which RCC arose from the allografted kidney, both of which were treated with nephron-sparing surgery. The first patient has been followed for 30 months with a well functioning graft without an RCC recurrence. The second patient has returned to dialysis after 6 months due to an insufficient remnant nephron mass. In conclusion, nephron-sparing surgery is a novel alternative to total nephrectomy for allograft RCC. The remaining kidney can preserve function and the patient may not need chronic dialysis.

Acromesomelic dysplasia with cardiac and neurologic abnormalities: an association by chance, new features of maroteaux type or a new syndrome?

We report a patient with acromesomelic dysplasia, cardiac and neurologic abnormalities. This may be a new syndrome or cardiac and neurologic features may be undescribed rare features of acromesomelic dysplasia.

A new family with autosomal dominant porencephaly with a novel Col4A1 mutation. Are arachnoid cysts related to Col4A1 mutations?

Porencephaly is an extensively encountered condition in pediatric neurology practice and leads to serious morbidity with its complications. Important etiological factors are trauma, hemorrhage, infection and thrombophilic factors that may cause destruction in the developing brain. Col4A1 mutations were also shown in familial porencephaly cases. We describe two siblings with porencephaly, hemiparesis, epilepsy, atrophic kidney in one of the siblings and asymptomatic mothers with an arachnoid cyst. We performed Col4A1 gene mutation screening and detected a novel mutation in mother and both of the children. This family has some features previously undescribed in patients with mutations of Col4A1 gene like atrophic kidney in one sibling and arachnoid cyst in the mother. We discuss here the possible relationship between these abnormalities and the mutation.

A 7q11.23 microduplication patient with cerebral palsy and facial dysmorphism.

We report an 11year-old female with 7q11.23 microduplication detected by an array-CGH test performed because of her atypical facial appearance while being followed-up with diagnoses of epilepsy and cerebral palsy at the pediatric neurology department since she was 3 months old. We emphasize that the facial phenotype by itself should arise suspicion of the 7q11.23 duplication.

Ovulation induction with gonadotropins causes increased sister chromatid exchanges.

Gonadotropins are widely accepted agents for ovulation induction in infertile women. On the other hand, several authors discuss the possible effect of gonadotropins on the developmental mechanism of ovarian cancer. SCE is a method of genotoxicity investigation and it is an excellent parameter to monitor the DNA damage and repair. There are numbers of studies showing the relationship between endogenous or exogenous hormones and SCEs. The aim of this study was to investigate with SCE techniques the effects of long-term (6 months) use of gonadotropins on DNA as we couldn't find any other study on the effect of long term use. We found increased sister chromatid exchange rates in a study group as compared to a control group. This may be one of the causes of increased ovarian cancer risk in infertile population.

A novel mutation in the RPS6KA3 gene in a patient with Coffin-Lowry syndrome.

Coffin-Lowry syndrome is an X-linked disorder characterized by mental retardation, characteristic facial features, skeletal abnormalities, and tapering fingers. Herein we report a novel missense mutation in exon 7 at codon 180 in the RPS6KA3 gene in a boy with Coffin-Lowry syndrome.

A case of otocephaly with anencephaly and meningomyelocele.

A case of otocephaly with anencephaly and meningomyelocele: Otocephaly is a rare lethal syndrome with microstomia, aglossia, agnathia, and synotia as major clinical features due to arrest in development of the first branchial arch. Some associated anomalies may be present as cyclopia, holoprosencephaly, cerebellar hypoplasia, situs inversus, and other visceral anomalies. We describe a case of fetus, spontaneously aborted in the 14th week of gestation with otocephaly complex (agnathia, synotia, microstomia) and associated anencephaly and meningomyelocele.

Partial trisomy due to a de novo duplication 22q11.1-22q13.1: a cat-eye syndrome variant with brain anomalies.

We report a case of partial trisomy 22q with de novo duplication of chromosomal region 22q11.1-22q13.1, also confirmed by microarray comparative genomic hybridization (Array-CGH) analysis. The fetus had interhemispheric cyst and corpus callosum agenesis diagnosed by MRI which has not been reported in the literature. This novel phenotype differs from the reported cat eye syndromes by the absence of heart defects and the presence of brain anomalies.

A case of lower mesodermal defects sequence.

Here, we describe a stillborn fetus who had lower mesodermal defects sequence associated with craniorachischisis, anencephaly, bilateral pulmonary hypoplasia.

A Feingold syndrome case with previously undescribed features and a new mutation.

Feingold syndrome (FS) is a dominantly inherited combination of microcephaly with or without learning disabilities, hand and foot abnormalities, short palpebral fissures and esophageal/duodenal atresia. The syndrome has autosomal dominant inheritance with full penetrance, and variable expressivity. Digital anomalies are almost always present. The gene for FS is localized to a 2.2 cM region in 2p23-p24. We report on the first Turkish family with Feingold syndrome. The propositus is a male infant with microcephaly, frontal balding, brachymesophalangy of the second and fifth fingers, bilateral syndactyly of toes 2-3, facial anomalies, choanal atresia and focal epilepsy. His father has microcephaly, and more severe hands and feet abnormalities. One of his brothers died because of eosofageal atresia. Clinical presentation of the family was suggestive of Feingold syndrome, and genetic testing of the MYCN gene confirmed the diagnosis. The missense mutation we report here has not been described previously. FS is an autosomal dominant condition, and therefore, the diagnosis has important implications for genetic counseling.