Goldenhar syndrome associated with growth hormone deficiency

Goldenhar syndrome is a rare disorder of unknown etiology. The most frequent findings are vertebral defects, hemifacial microsomia and ear abnormalities. We present an 8-year-old boy with oculo-auriculo-vertebral (Goldenhar) syndrome. He also had a parachute mitral valve and growth hormone deficiency. Parachute mitral valve is a previously unreported finding while growth hormone deficiency was reported just in one case in the literature.     

Hydrocephalus and the Goldenhar syndrome

Two female babies with Goldenhar syndrome have, the first an aqueductal stenosis, the second repetitive spells of pain and strain of the anterior fontanel. Aqueductal stenosis, hydrocephalus or intracranial hypertension are not previously described in this syndrome.     

Reproduction abnormalities and twin pregnancies in parents of sporadic patients with oculo-auriculo-vertebral spectrum/Goldenhar syndrome

A great number of case reports on concordant and discordant twins with oculo-auriculo-vertebral spectrum (OAVS) suggest that there might be an association between reproductive abnormalities, twinning and OAVS. The etiology of OAVS is unknown, but may involve epigenetic dysregulation of the oocyte or early embryo. We collected data on fertility and pregnancy outcome of 72 parents of patients with sporadic OAVS. We also evaluated prospective follow-up data on 3.372 fetuses and children conceived by intracytoplasmatic sperm injection (ICSI). Parental age, duration of menstrual cycle and the incidence of spontaneous abortion was not different when compared to the German population. However, there is an excess of parents who have used assisted reproductive techniques (ART; retrospective P = 0.038, prospective P = 0.023) and an excess of twins among naturally conceived patients with OAVS (P = 0.0025). An excess of ART conceptions and monozygotic twinning in OAVS is compatible with the concept of overripeness ovopathy as proposed by Jongbloet (Maandschr Kindergeneeskd 36:352–367, 1968).     

Partial trisomy (11;22) syndrome with manifestations of Goldenhar sequence due to maternal balanced t(11;22)

Here we report a 15-year-old girl patient who had severe mental and growth retardation, cleft palate, hemifacial microsomia, skin tags, hypoplasia of the external auditory canal, scoliosis and renal agenesis. Our patient was the fourth child of nonconsanguineous marriage. Peripheral blood chromosomal analysis of the patient revealed 47,XX,+der(22)t(11;22)(q23;q11). The maternal karyotype was reported as 46,XX,t(11;22)(q23;q11). Maternal balanced translocation t(11;22)(q23;q11) causing Goldenhar syndrome with 47,XX,+der(22) has not been reported previously. The presented case clearly indicates that in every case with Goldenhar syndrome, chromosome analysis should be done for the possibility of unbalanced translocations.     

Cardiac ion channel gene mutations in Greek long QT syndrome patients

The long QT syndrome (LQTS) is an inherited cardiac arrhythmia that may lead to sudden death in the absence of structural heart disease. Mutations in the cardiac potassium and sodium channel genes can be found in approximately 70% of patients with a highly probable clinical diagnosis. In this study, we aimed to genotype and explore the yield of genetic testing of LQTS patients from Greece, for whom there are no collective published data available. We clinically evaluated and genetically screened 17 unrelated patients for mutations in theKCNQ1, KCNH2, SCN5A, KCNE1, andKCNE2 cardiac ion channel genes. Genetic testing was positive in 6 out of 8 patients with a highly probable clinical diagnosis of LQTS and negative for all the other patients. Two patients carriedKCNQ1 mutations (c.580G>C, c.1022C>T), while 4 patients carriedKCNH2 mutations (c.202T>C, c.1714G>A, c.3103delC, c.3136C>T). To the best of our knowledge, the last mentioned mutation (c.3136C>T) is novel. Moreover, 27 single-nucleotide polymorphisms (SNPs) were detected, 5 of which are novel. Our preliminary data indicate a low genetic diversity of the Greek LQTS genetic pool, and are in accordance with international data that genetic testing of the major LQTS genes is efficient in genotyping the majority of patients with a strong clinical diagnosis. Therefore, the transition of an LQTS genetic screening program from research to the diagnostic setting within our ethnic background is feasible.     

Detection of submicroscopic deletions in band 17p13 in patients with the Miller-Dieker syndrome

The Miller-Dieker syndrome (MDS), a syndrome with lissencephaly, distinctive craniofacial features, growth impairment, and profound developmental failure, has been associated with a deletion of the distal part of chromosome band 17p13. A minority of patients with the syndrome do not have a deletion detectable with current cytogenetic techniques. Using three highly polymorphic DNA probes (pYNZ22, pYNH37.3, and p144D6) we have detected microdeletions in three MDS patients, two of whom had no visible abnormalities of chromosome 17. Loci defined by two of the DNA probes, pYNZ22 and pYNH37.3, were deleted in all three patients. The most distal locus, defined by p144D6, was present in one MDS patient, possibly defining the distal limits of the MDS region in band 17p13.3. None of these loci were absent in one case of lissencephaly without MDS.     

Radiological evidence of Goldenhar syndrome in a paleopathological case from a South German ossuary

We investigated the skull of a juvenile living in Southern Germany between 1400 and 1800 A.D. A remarkable hemifacial microsomia led to further detailed computed tomographic examination especially of the petrous bone revealing a total bony atresia of the external auditory canal as well as distinct anomalies of the middle ear on the same side. The combination of these findings strongly suggests the diagnosis of Goldenhar syndrome. This very heterogeneous syndrome affects primarily aural, ocular, oral and mandibular development, whereby the constellation of anomalies indicate their origin at approximately 30-45 days of gestation, caused by genetic or intrauterine factors. Despite the lack of clinical information and the absence of soft tissue it was possible to perform a differential diagnosis in this palaeopathological case. Thereby, the use of modern modalities of image reconstructions in this computed tomographic clearly enhanced the supposed diagnosis.     

Analysis of mutation in exon 17 of PTCH in patients with nevoid basal cell carcinoma syndrome

Abnormalities in sonic hedgehog (SHH) signaling pathway components are major contributing factors in the development of nevoid basal cell carcinoma syndromes (NBCCS) that include SHH, PTCH, SMO and GLI. The novel patched homologue (PTCH) mutation and clinical manifestations with NBCCS links PTCH haplosufficiency and aberrant activation of the sonic hedgehog/Patched/smoothened pathway. To investigate further the molecular genetics of NBCCS, we performed mutation analysis of PTCH gene in a family case with five affected members. These clinical manifestations might be associated with a novel constitutional mutation of the PTCH gene, 3146A → T (1049N → I), in exon 17. The analyzed results of tumor tissue show a high expression of GLI. Our findings suggested that the mutation of 3146A → T may be the cause of high expression of GLI and permit SMO to transmit signal to the nucleus through SHH/PTCH/SMO pathway.     

Pseudoexfoliation syndrome, a systemic disorder with ocular manifestations

This report is of a round-table discussion held in Cardiff in September 2009 for Cesagen, a research centre within the Genomics Network of the UK??s Economic and Social Research Council. The meeting was arranged to explore ideas as to the likely future course of human genomics. The achievements of genomics research were reviewed, and the likely constraints on the pace of future progress were explored. New knowledge is transforming biology and our understanding of evolution and human disease. The difficulties we face now concern the interpretation rather than the generation of new sequence data. Our understanding of gene-environment interaction is held back by our current primitive tools for measuring environmental factors, and in addition, there may be fundamental constraints on what can be known about these complex interactions.     

Clinical, endocrine, and molecular genetic findings in patients with 17beta-hydroxysteroid dehydrogenase deficiency

Mutations in the 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 3 gene are associated with the clinical findings of 17beta-HSD deficiency. We investigated 5 patients of German descent with 46,XY karyotype and predominantly female phenotype. Androstenedione (A) and testosterone (T) levels in serum were determined before and after stimulation with human chorionic gonadotropin. DNA analysis of the whole coding region of the 17beta-HSD type 3 gene was performed by PCR, single-strand conformation analysis, and direct sequencing. In all patients we found highly variable A and T levels before and after stimulation. However, the A-to-T ratio was abnormal in all cases suggestive of 17beta-HSD deficiency. Molecular genetic analysis revealed mutations in all patients. We conclude that A and T levels may be highly variable in patients with 17beta-HSD deficiency. Molecular genetic analysis of the 17beta-HSD gene may support the diagnosis of this disorder.     

Morquio syndrome: Clinical findings in 11 patients with MPS IVA and 2 patients with MPS IVB

Summary Genetic heterogeneity of the Morquio syndrome has been known since deficiency of -galactosidase was detected in some patients in addition to the deficiency of N-acetylgalactosamine-6-sulphate sulphatase in the classical form of Morquio syndrome. The clinical findings of 11 patients with MPS IVA, the classical form, and 2 patients with MPS IV B, a variant form, are described. All of the patients with MPS IV A showed extraskeletal manifestations of their disease. The patients with MPS IV B seem to be less severely affected.     

Goldenhar syndrome, anterior encephalocele, and aqueductal stenosis following fetal primidone exposure

Fetal exposure to primidone was associated with Goldenhar syndrome, hemifacial microsomia, tetralogy of Fallot, aqueductal stenosis, and anterior encephalocele in this male infant. No similar cases in anticonvulsant-exposed pregnancies were found on literature review, despite the increased incidence of other anomalies following such exposure. Goldenhar syndrome, especially related to rare central nervous system anomalies, is reviewed. Experimental production of hemifacial microsomia by a folic acid antagonist, triaxene, is mediated via hemorrhage in the fetus. Intraventricular hemorrhage was noted in this infant as were dilated lateral and third ventricles. The hemorrhagic diathesis and/or the folic acid depletion of newborns following fetal anticonvulsant exposure may have been the underlying mechanism.     

Quantification by flow cytometry of chromosome-17 deletions in Smith-Magenis syndrome patients

We have used bivariate flow karyotyping to quantify the deletions involving chromosome 17 in sixteen patients with Smith-Magenis syndrome (SMS). The fluorescence intensities of mitotic chromosomes stained with Hoechst 33258 and chromomycin were quantified in a dual-beam flow cytometer. For each patient, the position of the peak representing the deleted chromosome 17 was compared to those of the normal homologs of an unaffected parent. The patients could be classified into four groups based on the size of their deletions. The deletions ranged from ∼9–10 Mb (∼10–11% of the chromosome) to below the detection limit of the technique (2 Mb). Different deletion sizes were detected among patients whose high-resolution banding results were similar. Some deletions detected by banding were not detected by flow analyses. Deletion estimates are largely consistent with the results of molecular analyses. Patients with larger deletions that extend into band 17p12 have abnormal electrophysiologic studies of peripheral nerves. Deletion size does not appear to correlate with the degree of mental retardation, presence of behavioral abnormalities, craniofacial anomalies or common skeletal findings in SMS. By identifying patients with varying deletion sizes, these data will aid the construction of a long-range deletion-based map of 17p11.2 and identification of the genes involved in this syndrome. Received: 19 March 1996 / Revised: 21 June 1996