Delusional and psychotic disorders in juvenile myotonic dystrophy type-1.

We investigated the clinically derived hypothesis of a relatively high incidence of delusional and psychotic disorders in adolescents with juvenile Myotonic Dystrophy type-1 (DM1). Twenty-seven subjects of age 16-25 with juvenile DM1 and their parents were invited to have a clinical psychiatric interview, and to complete an ASEBA behavior checklist (YSR, ASR, CBCL, and ABCL). We diagnosed a Delusional Disorder in 19% of our patients and a Psychotic Disorder not otherwise specified in another 19%. These two groups of patients had a significantly worse level of clinically defined general functioning. It is clinically relevant to investigate in patients with juvenile DM the symptom of delusions and the presence of a delusional and psychotic disorder, and to consider the presence of juvenile DM in youngsters presenting with such a thought disorder. These disorders compromise the general functioning of the subjects and are often to some extent treatable. © 2017 Wiley Periodicals, Inc.

Complex craniosynostosis is associated with the 2p15p16.1 microdeletion syndrome.

In a screening project of patients with (complex) craniosynostosis using genomic arrays, we identified two patients with craniosynostosis and microcephaly with a deletion in the 2p15p16.1 chromosomal region. This region has been associated with a new microdeletion syndrome, for which patients have various features in common, including microcephaly and intellectual disability. Deletions were identified using Affymetrix 250K SNP array and further characterized by fluorescence in situ hybridization (FISH) analysis and qPCR. The deletions in our two patients overlapped within the 2p15p16.1 microdeletion syndrome area and were 6.8 and 6.9 Mb in size, respectively. FISH and qPCR confirmed the presence of only one copy in this region. Finemapping of the breakpoints indicated precise borders in our patients and were further finemapped in two other previously reported patients. Clinical features of patients with deletions in the 2p15p16.1 region vary. Including data from our patients, now eight out of nine reported patients have microcephaly, one of the major features, and all had intellectual disability. The current reported two patients add different forms of craniosynostosis to the clinical spectrum of this recently recognized microdeletion syndrome.

The East Flanders Prospective Twin Survey (EFPTS): an actual perception.

The East Flanders Prospective Twin Survey (EFPTS) is a prospective, population-based registry of multiple births in the province of East-Flanders, Belgium. EFPTS has several unique features: it is population-based and prospective, with the possibility of long-term follow-up; the twins (and higher order multiple births) are recruited at birth; basic perinatal data recorded; chorion type and zygosity established; and since 1969 placental biopsies have been taken and frozen at -20 °C for later determination of genetic markers. The EFPTS is the only large register that includes placental data and allows differentiation of three subtypes of monozygotic (MZ) twins based on the time of the initial zygotic division: the dichorionic-diamnionic pairs (early, with splitting before the fourth day after fertilization), the monochorionic-diamnionic pairs (intermediate, splitting between the fourth and the seventh day post-fertilization), and the monochorionic-monoamnionic pairs (late, splitting after the eighth day post-fertilization). Studies can be initiated taking into account primary biases, those originating 'in utero'. Such studies could throw new light on the controversy over the validity of the classic twin method, the consequences of early embryological events, and the gene-environment interactions as far as periconceptional and intrauterine environment are concerned.

Ring chromosome 20 syndrome: electroclinical description of six patients and review of the literature.

BACKGROUND: Ring chromosome 20 syndrome is a rare chromosomal disorder. METHODS: In six patients, we focused on the presenting epileptic phenotype, the behavioral and mental problems and the relationship between the ratio of mosaicism and the age at onset of the epilepsy. RESULTS: All patients presented with pharmacoresistant frontal lobe complex partial seizures. The earliest onset of epilepsy was seen in patients without mosaicism. There were three patients out of six with behavioral disturbances before the onset of seizures. All patients had mild to moderate cognitive impairment. Electroencephalogram recordings showed rhythmic theta waves with frontal predominance and non-convulsive status epilepticus (NCSE). CONCLUSIONS: The ring chromosome 20 syndrome is characterized by childhood-onset refractory epilepsy continuing throughout adult life, mental disability, and behavioral disturbances which can originate before seizure onset. Ictal EEG reveals a unique pattern. Our findings indicate a possible link between the percentage of affected cells and the age of epilepsy onset.

Genotype-phenotype relationships as prognosticators in Rett syndrome should be handled with care in clinical practice.

Rett syndrome (RTT; OMIM 312750) is an X-linked dominant neurodevelopmental disorder leading to cognitive and motor impairment, epilepsy, and autonomic dysfunction in females. Since the discovery that RTT is caused by mutations in MECP2, large retrospective genotype-phenotype correlation studies have been performed. A number of general genotype-phenotype relationships were confirmed and specific disorder profiles were described. Nevertheless, conflicting results are still under discussion, partly due to the variability in classification of mutations, assessment tools, and structure of the data sets. The aim of this study was to investigate relationships between genotype and specific clinical data collected by the same experienced physician in a well-documented RTT cohort, and evaluate its prognostic value in counseling young parents with a newly diagnosed RTT girl regarding her future outcome. The Maastricht-Leuven Rett Syndrome Database is a register of 137 molecularly confirmed clinical RTT cases, containing both molecular and clinical data on examination and follow up by the same experienced physician. Although the general genotype-phenotype relationships were confirmed, the clinical severity was still found to be very variable. We therefore recommend caution in using genotype-phenotype data in the prognosis of outcome for children in Rett syndrome. Early diagnosis, early intervention, and preventive management are imperative for better outcomes and better quality of daily life for RTT females and their families.

Time trends in the natural dizygotic twinning rate.

BACKGROUND: The natural dizygotic (DZ) twinning rate has been proposed as a reliable and useful measure of human fecundity, if adjusted for maternal age at twin birth. The aim of this study was to analyze age-adjusted trends in natural DZ twinning rates over the past 40 years using data from the 'East Flanders Prospective Twin Survey (EFPTS)'. METHODS: This study involved 4835 naturally conceived twin pregnancies between 1969 and 2009 from the population-based Belgian 'EFPTS'. Age-adjusted trends in the incidence of natural DZ twin pregnancies were calculated using a generalized linear model with Poisson distribution. RESULTS: Both the natural DZ twinning rates and maternal age at twin birth increased in a linear fashion from 1969 to 2009. When age-adjusted, we found that the trend in the natural DZ twinning rate was stable during the whole time period. CONCLUSIONS: According to our population-based data and after age-adjustment, a stable natural DZ twinning rate could be observed over the last four decades. Under the assumption that the spontaneous DZ twinning rate is a sensor of fecundity, this indicates a stable 'high' fecundity for this population.

Preimplantation genetic screening for aneuploidy of embryos after in vitro fertilization in women aged at least 35 years: a prospective randomized trial.

OBJECTIVE: To test the hypothesis that patients with advanced maternal age (AMA) have a higher implantation rate (IR) after embryo transfer of embryos with a normal chromosomal pattern for the chromosomes studied with preimplantation genetic screening (PGS) compared with patients who had an embryo transfer without PGS. DESIGN: Prospective randomized controlled trial (RCT). SETTING: Academic tertiary setting. PATIENT(S): Patients with AMA (> or =35 years). INTERVENTION(S): In an RCT, the clinical IR per embryo transferred was compared after embryo transfer on day 5 or 6 between the PGS group (analysis of chromosomes 13, 16, 18, 21, 22, X, and Y) and the Control group without PGS. MAIN OUTCOME MEASURE(S): No differences were observed between the PGS group and the Control group for the clinical IR (15.1%; 14.9%; rate ratio 1.01; exact confidence interval [CI], 0.25-5.27), the ongoing IR (at 12 weeks) (9.4%; 14.9%), and the live born rate per embryo transferred (9.4%; 14.9%; rate ratio 0.63; exact CI, 0.08-3.37). Fewer embryos were transferred in the PGS group (1.6 +/- 0.6) than in the Control group (2.0 +/- 0.6). A normal diploid status was observed in 30.3% of the embryos screened by PGS. CONCLUSION(S): In this RCT, the results did not confirm the hypothesis that PGS results in improved reproductive outcome in patients with AMA.

Another patient with a de novo deletion further delineates the 2q33.1 microdeletion syndrome.

A male patient, who had intra-uterine growth retardation, a low birth weight and hypotonia due to a chromosome 2q33.1 deletion, is described. At the age of 20 years, he displays short stature, microcephaly, a high forehead, microstomia, large teeth and is hypertonic. He is severely mentally retarded, has not developed speech, is hyperactive, anxious and at times aggressive. Full tiling array showed a de novo 14 Mb deletion at chromosome region 2q32.3q33.2, further delineating the 2q33.1 microdeletion syndrome.

Rett syndrome and long-term disorder profile.

In a cohort of 103 females clinically diagnosed with Rett syndrome (RTT), 91 had a detectable MECP2 mutation. Emphasis on details of natural history facilitated grouping of females with the same MECP2 mutation and the development of so-called disorder profiles. Some examples of disorder profiles of different recurrent MECP2 mutations are discussed. RTT females with the frequently recurrent R133C and R306C missense mutations and those with intragenic deletions in the C-terminus of MECP2 deserve more attention in larger studies as their development is different and milder in the long term. RTT females with the T158M missense mutation are often atypical with mainly behavioral characteristics in infancy and childhood but become classic RTT in adolescence after a slower, protracted course.

Testicular histology in boys with Prader-Willi syndrome: fertile or infertile?

PURPOSE: Prader-Willi syndrome is associated with hypogonadism. Cryptorchidism is found in 93% of cases and considered a phenotypic criterion. Men with Prader-Willi syndrome are thought to be infertile. To study the fertility probability in boys with Prader-Willi syndrome we analyzed testicular histology in 8 prepubertal boys and 1 man. MATERIALS AND METHODS: Eight boys 16 months to 14 years old with a proven molecular diagnosis of Prader-Willi syndrome, including 6 with a deletion on chromosome 15 and 2 with uniparental maternal disomy of chromosome 15, underwent orchiopexy and the man underwent unilateral orchiectomy. Prepubertal testes were classified into 4 Nistal categories according to mean tubular diameter, the tubular fertility index (average percent of tubules containing spermatogonia) and the Sertoli's cell index. RESULTS: Two of 8 prepubertal boys showed a favorable Nistal score of I, 1 showed a Nistal score of II and 5 showed a Nistal score of III. The testis in the man showed diffuse tubular atrophy with tubular hyalinization, a Sertoli's cell nodule, vacuolized Leydig cells, peritubular hyalinization and small tubuli. CONCLUSIONS: Prader-Willi syndrome appears to be a heterogenic disorder with respect to testicular histology. Although most boys showed absent spermatogonia, 2 of 8 had normal testicular histology. Therefore, it is suggested that it is uncertain what the fertility outcome is in boys with Prader-Willi syndrome.

Mutation analysis in Costello syndrome: functional and structural characterization of the HRAS p.Lys117Arg mutation.

Costello syndrome is a mental retardation syndrome characterized by high birth weight, postnatal growth retardation, coarse face, loose skin, cardiovascular problems, and tumor predisposition. De novo heterozygous missense mutations in HRAS codon 12 and 13 disturbing the intrinsic GTP hydrolysis cause Costello syndrome. We report a patient with typical Costello syndrome and a novel heterozygous missense mutation in codon 117 (c.350A>G, p.Lys117Arg) of the HRAS gene, resulting in constitutive activation of the RAS/MAPK pathway similar to the typical p.Gly12Ser and p.Gly12Ala mutations. Recombinant HRAS p.Lys117Arg demonstrates normal intrinsic GTP hydrolysis and responsiveness to GTPase-activating proteins, but the nucleotide dissociation rate is increased 80-fold. Consistent with the biochemical data, the crystal structure of the p.Lys117Arg mutant indicates an altered interaction pattern of the side chain that is associated with unfavorable nucleotide binding properties. Together, these data show that a RAS mutation that only perturbs guanine nucleotide binding has similar functional consequences as mutations that impair GTP hydrolysis and causes human disease.

Novel TBX5 mutations in patients with Holt-Oram syndrome.

Holt-Oram syndrome (MIM #142900) is an autosomal-dominant disorder characterized by radial ray deformities of the upper limb associated with cardiac septation and/or conduction defects. The disorder is caused by mutations in the transcription factor TBX5. Several studies report a rather low detection rate (range, 22-35%) of TBX5 mutations in patients with a clinical suspicion of Holt-Oram syndrome. The low detection rate is attributed to clinical misdiagnosis and genetic heterogeneity. However, a detection rate up to 74% has been reported when strict inclusion criteria for Holt-Oram syndrome are applied before genetic testing. We performed mutational analysis in a cohort of 27 unrelated patients referred with a clinical diagnosis of Holt-Oram syndrome. Seven TBX5 mutations were detected by direct sequencing. The detection rate of TBX5 mutations in this co hort of patients was 25.9% but increased to 54% when the strict phenotypical criteria were applied. No mutations were found in patients who did not meet these strict phenotypical criteria. Interestingly, we were unable to identify a TBX5 mutation in six of 13 patients who did meet the strict criteria. This study confirms TBX5 genetic testing should be reserved for patients who fulfill the strict phenotypic criteria for Holt-Oram syndrome.

MECP2 mutations are an infrequent cause of mental retardation associated with neurological problems in male patients.

Mutations in the methyl-CpG-binding protein 2 (MECP2) gene located on Xq28, cause Rett syndrome (RTT) in female patients. Meanwhile, nonmosaic MECP2 mutations unknown in girls have been found in an increasing number of male patients with a normal 46, XY karyotype. They can cause a broad spectrum of neurodevelopmental disorders which often show a combination of mental retardation (MR) with neurological symptoms. We present the results of MECP2 analysis in a group of 72 male patients with an unexplained combination of MR and neurological features, and review the mutational reports published on male patients since the discovery of the MECP2 gene. Analysis included sequencing of exon 1 which thus far was mostly omitted from DNA screening. One pathogenic mutation has been found in a patient with Rett variant, in addition to an unclassified variant and a series of nonpathogenic changes. No changes have been found in exon 1. Criteria for testing of male patients are classic RTT, severe neonatal encephalopathy, and RTT variant which may be clinically underrecognized. Testing can also be considered in males with a combination of unexplained MR and (progressive) neurological manifestations although the yield of MECP2 analysis is probably low in this situation. Based on the literature, MECP2 testing in males with MR only is debatable.

Congenital aural atresia in 18q deletion or de Grouchy syndrome.

OBJECTIVE: To study the occurrence of congenital aural atresia in patients with a deletion of the long arm of chromosome 18 (18q- deletion or de Grouchy syndrome). STUDY DESIGN AND PATIENTS: This retrospective study presents an overview of the otologic findings in 33 Dutch and Belgian patients with a deletion of 18q. MATERIALS AND METHODS: Detailed information on otorhinolaryngological findings was obtained from otorhinolaryngologists and audiologic centers. Data about medical and developmental history and phenotype were collected from physical examination by a clinical geneticist, by interviewing parents, and by reviewing medical and developmental records. Determination of deletion breakpoints was established by routine karyotyping, prometaphase studies, and/or fluorescence in-situ hybridization (FISH). RESULTS: Twenty out of 33 patients (61%) with a deletion 18q had congenital aural atresia (CAA) ranging from narrow external auditory canals to meatal atresia type IIB. Fifteen patients (45%) had conductive hearing impairment (range: 30 dB-70 dB). Twelve of these 15 patients (80%) received hearing aids, which resulted in improved hearing but not in speech development. CAA was found only in patients with a distal deletion of 18q (including band 18q22.3 or 18q23) and not in patients with more proximal 18q deletions. CONCLUSION: In patients with narrow ear canals or meatal atresia and unexplained mental retardation, chromosomal analysis is indicated. If de Grouchy syndrome is diagnosed in a young patient, auditory examination and surveillance are highly recommended.