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Depending on its location, size, and proximity to the cardiac structures, an intrapericardial teratoma may lead to severe circulatory disturbances and even fetal demise. A 34-year-old G2P1 presented at 20w5d with a solid cystic mass in the right thorax of the fetus, originating from the right atrium or lung, with signs of non-immune fetal hydrops, soon resulting in intrauterine fetal death. Detailed post-mortem autopsy revealed signs of hydrops fetalis universalis due to a spherical tumor mass originating from the aortic root. Histologic examination of the tumor showed the characteristic morphology of a teratoma. A 1.6-Mb microdeletion at 3q29 was identified by single nucleotide polymorphism array. This is the first report presenting the diagnosis of an intrapericardial teratoma in a fetus with a microdeletion of 3q29. Intrapericardial teratoma has a poor prognosis and the fetal outcome relies on the development of hydrops. A post-mortem examination is essential in order to make a definitive diagnosis, which underlines the status of the fetal pathologist and the need for interdisciplinary cooperation.
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BACKGROUND: In this study we aimed to describe the morphological and pathogenetic differences between tracheal agenesis and tracheal atresia, which are not clearly distinguished from each other in the literature, and to contribute thereby to the understanding and management of these conditions. Both tracheal agenesis and tracheal atresia represent rare disorders of still unknown aetiology that cannot be detected by prenatal ultrasound. If the affected foetuses survive until birth these conditions result in respiratory failure and in futile attempts to rescue the infant's life. RESULTS: Autopsies and genetic analyses, including singleton or trio exome sequencing, were performed on five neonates/foetuses with tracheal agenesis and three foetuses with tracheal atresia. Tracheal agenesis was characterized by absence of the sublaryngeal trachea and presence of a bronchooesophageal fistula and by pulmonary isomerism and occurred as an isolated malformation complex or as part of a VACTERL association. Special findings were an additional so-called 'pig bronchus' and a first case of tracheal agenesis with sirenomelia. Tracheal atresia presenting with partial obliteration of its lumen and persistence of a fibromuscular streak resulted in CHAOS. This condition was associated with normal lung lobulation and single, non-VACTERL type malformations. Trio ES revealed a novel variant of MAPK11 in one tracheal agenesis case. Its involvement in tracheooesophageal malformation is herein discussed, but remains hypothetical. CONCLUSION: Tracheal agenesis and tracheal atresia represent different disease entities in terms of morphology, pathogenesis and accompanying anomalies due to a primary developmental and secondary disruptive possibly vascular disturbance, respectively.
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Deformidades Congénitas de las Extremidades , Tráquea/anomalías , Recién Nacido , Embarazo , Femenino , Humanos , Constricción Patológica , Esófago/anomalíasRESUMEN
BACKGROUND: Diprosopus is a rare malformation of still unclear aetiology. It describes a laterally double faced monocephalic and single-trunk individual and has to be distinguished from the variant Janus type diprosopus. RESULTS: We examined seven double-faced foetuses, five showing true diprosopus, and one each presenting as monocephalic Janiceps and parasitic conjoined twins. Four of the foetuses presented with (cranio)rachischisis, and two had secondary hydrocephaly. Three foetuses showed cerebral duplication with concordant holoprosencephaly, Dandy-Walker cyst and/or intracranial anterior encephalocele. In the Janiceps twins, cerebral duplication was accompanied by cerebral di-symmetry. In the parasitic twins the cyclopic facial aspects were suggestive of concordant holoprosencephaly. In one of the true diprosopus cases, pregnancy was achieved after intracytoplasmic sperm injection. Whole-exome sequencing, perfomed in one case, did not reveal any possible causative variants.The comparison of our double-faced foetuses to corresponding artistic representations from the Tlatilco culture allowed retrospective assignment of hairstyles to brain malformations. CONCLUSION: Brain malformations in patients with diprosopus may not be regarded as an independent event but rather as a sequel closely related to the duplication of the notochord and neural plate and as a consequence of the cerebral and associated craniospinal structural instabilities.
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Holoprosencefalia , Gemelos Siameses , Embarazo , Femenino , Humanos , Masculino , Holoprosencefalia/genética , Museos , Estudios Retrospectivos , Semen , EncéfaloRESUMEN
Since the beginning of the pandemic, SARS-CoV-2 infection has dominated clinical practice. In the treatment of high-risk populations, there has long been uncertainty about the extent and consequences of infection. This high-risk population includes pregnant patients. The establishment of clinical registry studies was able to contribute an assessment of the pandemic situation for this collective within a very short time and with enormous effort. Based on a clinical case, the following report describes the association between SARS-CoV-2 infection of a pregnant patient with clinical signs of preeclampsia to the development of posterior reversible encephalopathy syndrome (PRES). Based on the case, the differential diagnostic workup between fulminant course of infection and preeclampsia is presented. The article presents the current data on the occurrence of PRES in pregnancy in the context of SARS-CoV-2 infection and addresses possible differential diagnoses. Interdisciplinary care of the patient allows an overview of aspects of each specialty to be presented.
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COVID-19 , Síndrome de Leucoencefalopatía Posterior , Humanos , COVID-19/diagnóstico , COVID-19/terapia , SARS-CoV-2RESUMEN
Biallelic PNKP variants cause heterogeneous disorders ranging from neurodevelopmental disorder with microcephaly/seizures to adult-onset Charcot-Marie-Tooth disease. To date, only postnatal descriptions exist. We present the first prenatal diagnosis of PNKP-related primary microcephaly. Pathological examination of a male fetus in the 18th gestational week revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities. Prenatal trio-exome sequencing identified compound heterozygosity for the PNKP variants c.498G>A, p.[(=),0?] and c.302C>T, p.(Pro101Leu). Segregation confirmed both variants in the sister fetus. Through RNA analyses, we characterized exon 4 skipping affecting the PNKP forkhead-associated (FHA) and phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the paternal c.498G>A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic PNKP-variants to compare prenatal/postnatal phenotypes. Both carry the splice donor variant c.1029+2T>C in trans with a variant in the FHA domain (c.311T>C, p.(Leu104Pro); c.151G>C, p.(Val51Leu)). RNA-seq showed complex splicing for c.1029+2T>C and c.151G>C. Structural modeling revealed significant clustering of missense variants in the FHA domain with variants generating structural damage. Our clinical description extends the PNKP-continuum to the prenatal stage. Investigating possible PNKP-variant effects using RNA and structural modeling, we highlight the mutational complexity and exemplify a PNKP-variant characterization framework.
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Enzimas Reparadoras del ADN/genética , Microcefalia/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Adulto , Enzimas Reparadoras del ADN/química , Femenino , Feto/anomalías , Humanos , Masculino , Microcefalia/diagnóstico , Mutación Missense , Fenotipo , Fosfotransferasas (Aceptor de Grupo Alcohol)/química , Diagnóstico Prenatal , Dominios Proteicos , Empalme del ARNRESUMEN
Multiple genes are known to be associated with osteogenesis imperfecta (OI), a phenotypically and genetically heterogenous bone disorder, marked predominantly by low bone mineral density and increased risk of fractures. Recently, mutations affecting MESD, which encodes for a chaperone required for trafficking of the low-density lipoprotein receptors LRP5 and LRP6 in the endoplasmic reticulum, were described to cause autosomal-recessive OI XX in homozygous children. In the present study, whole-exome sequencing of three stillbirths in one family was performed to evaluate the presence of a hereditary disorder. To further characterize the skeletal phenotype, fetal autopsy, bone histology, and quantitative backscattered electron imaging (qBEI) were performed, and the results were compared with those from an age-matched control with regular skeletal phenotype. In each of the affected individuals, compound heterozygous mutations in MESD exon 2 and exon 3 were detected. Based on the skeletal phenotype, which was characterized by multiple intrauterine fractures and severe skeletal deformity, OI XX was diagnosed in these individuals. Histological evaluation of MESD specimens revealed an impaired osseous development with an altered osteocyte morphology and reduced canalicular connectivity. Moreover, analysis of bone mineral density distribution by qBEI indicated an impaired and more heterogeneous matrix mineralization in individuals with MESD mutations than in controls. In contrast to the previously reported phenotypes of individuals with OI XX, the more severe phenotype in the present study is likely explained by a mutation in exon 2, located within the chaperone domain of MESD, that leads to a complete loss of function, which indicates the relevance of MESD in early skeletal development. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..
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Osteogénesis Imperfecta , Densidad Ósea/genética , Niño , Mutación del Sistema de Lectura , Homocigoto , Humanos , Chaperonas Moleculares , Mutación/genética , Osteogénesis Imperfecta/diagnóstico por imagen , Osteogénesis Imperfecta/genética , FenotipoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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PURPOSE: Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood. METHODS: In this study, 51 patients from 47 unrelated families were analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA). RESULTS: We have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease-gene associations for fetal akinesia: ADSSL1, ASAH1, ASPM, ATP2B3, EARS2, FBLN1, PRG4, PRICKLE1, ROR2, SETBP1, SCN5A, SCN8A, and ZEB2. Furthermore, a sibling pair harbored a homozygous copy-number variant in TNNT1, an ultrarare congenital myopathy gene that has been linked to arthrogryposis via Gene Ontology analysis. CONCLUSION: Our analysis indicates that genetic defects leading to primary skeletal muscle diseases might have been underdiagnosed, especially pathogenic variants in RYR1. We discuss three novel putative fetal akinesia genes: GCN1, IQSEC3 and RYR3. Of those, IQSEC3, and RYR3 had been proposed as neuromuscular disease-associated genes recently, and our findings endorse them as FA candidate genes. By combining NGS with deep clinical phenotyping, we achieved a 73% success rate of solved cases.
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Enfermedades Fetales/genética , Factores de Intercambio de Guanina Nucleótido/genética , Proteínas de Unión al ARN/genética , Canal Liberador de Calcio Receptor de Rianodina/genética , Transactivadores/genética , Adolescente , Adulto , Artrogriposis/genética , Artrogriposis/patología , Niño , Preescolar , Variaciones en el Número de Copia de ADN/genética , Femenino , Enfermedades Fetales/patología , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Masculino , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Adulto JovenRESUMEN
BACKGROUND: Autosomal-recessive SLOS is caused by mutations in the DHCR7 gene. It is defined as a highly variable complex of microcephaly with intellectual disability, characteristic facies, hypospadias, and polysyndactyly. Syndrome diagnosis is often missed at prenatal ultrasound and fetal autopsy METHODS: We performed autopsies and DHCR7 gene analyses in eight fetuses suspected of having SLOS and measured cholesterol values in long-term formalin-fixed tissues of an additional museum exhibit RESULTS: Five of the nine fetuses presented classical features of SLOS, including four cases with atrial/atrioventricular septal defects and renal anomalies, and one with additional bilateral renal agenesis and a Dandy-Walker cyst. These cases allowed for diagnosis at autopsy and subsequent SLOS diagnosis in two siblings. Two fetuses were mildly affected and two fetuses showed additional holoprosencephaly. These four cases and the exhibit had escaped diagnosis at autopsy. The case with bilateral renal agenesis presented a novel combination of a null allele and a putative C-terminus missense mutation in the DHCR7 gene CONCLUSIONS: In view of the discrepancy between the prevalence of SLOS among newborns and the carrier frequency of a heterozygous DHCR7 gene mutation, the syndrome-specific internal malformation pattern may be helpful not to miss SLOS diagnosis in fetuses at prenatal ultrasound and fetal autopsy.
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Síndrome de Smith-Lemli-Opitz/diagnóstico , Síndrome de Smith-Lemli-Opitz/fisiopatología , Anomalías Múltiples , Autopsia/métodos , Síndrome de Dandy-Walker , Femenino , Feto/metabolismo , Defectos de los Tabiques Cardíacos , Humanos , Mutación/genética , Mutación Missense/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Fenotipo , Embarazo , Síndrome de Smith-Lemli-Opitz/genéticaRESUMEN
Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development. Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the known null phenotype in humans. TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B. This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism. In spite of reduced abundance, residual GMAP variants maintain partial Golgi integrity, normal global protein secretion, and subcellular distribution of IFT20 in ODCD. These functions are lost when GMAP-210 is completely abrogated in ACG1A. However, a similar defect in chondrocyte maturation is observed in both disorders, which produces a cellular achondrogenesis phenotype of different severity, ensuing from aberrant glycan processing and impaired extracellular matrix proteoglycan secretion by the Golgi apparatus.
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The Piepkorn type of lethal osteochondrodysplasia (POCD) is a rare and lethal dwarfing condition. Four cases have been reported to date. The characteristic features are distinctly shortened "flipper-like" limbs, polysyndactyly, excessive underossification, especially of the limb bones and vertebrae, and large (giant) chondrocytes in the cartilaginous bone primordia. These characteristics allowed the diagnosis of Piepkorn type of osteochondrodysplasia in four new cases, three fetuses of 15 to 22 weeks and one 106-year-old museum exhibit. Piepkorn type of osteochondrodysplasia has been assigned to the giant cell chondrodysplasias such as atelosteogenesis type 1 (AO1) and boomerang dysplasia (BD). Analysis of the Filamin B gene in 3p14.3, which is associated with these disorders, allowed the identification of the first FLNB mutations in Piepkorn type of osteochondrodysplasia. The heterozygous missense mutations, found in the three fetuses, were located in exons 28 and 29, encoding the immunoglobulin-like repeat region R15, one of three mutational hot spots in dominant FLNB-related skeletal disorders. Direct preparations and alcian blue staining revealed single upper and lower arm and leg bone primordia, preaxial oligodactyly, and polysyndactyly with complete fusion and doubling of the middle and end phalanges II-V to produce eight distal finger rays. Considering the unique clinical features and the extent of underossification, Piepkorn type of osteochondrodysplasia can be regarded as a distinct entity within the AO1-BD-POCD continuum.
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Enfermedades Fetales/genética , Enfermedades Fetales/patología , Filaminas/genética , Mutación , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Adulto , Enanismo/genética , Enanismo/patología , Exposiciones como Asunto , Facies , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
INTRODUCTION: The prevalence of neural tube defects worldwide is 1â-â2 per 1000 neonates. Neural tube defects result from a disturbance of neurulation in the 3rd or 4th week of development and thus represent the earliest manifestation of organ malformation. Neural tube defects (NTD) are classified into cranial dysraphism leading to anencephaly or meningoencephalocele and spinal dysraphism with or without meningomyelocele. In isolated form they have multifactorial causes, and the empirical risk of recurrence in Central Europe is 2%. As associated malformations they tend to occur sporadically, and in monogenic syndromes they follow Mendelian inheritance patterns with a high risk of recurrence. PATIENTS: Autopsies were performed on 68 fetuses following a prenatal diagnosis of NTD and induced abortion. RESULTS: The incidence of NTDs in our autopsied fetuses was 8% and 11% in fetuses with malformations. The percentage of fetuses with anencephaly, encephalocele or spina bifida was 24, 18, and 60%*, respectively. Analysis of the sex distribution showed a female preponderance in cranial dysraphisms but the sex distribution of spina bifida cases was equal. The extent and localization of NTDs varied, with lumbosacral cases clearly predominating. The proportion of isolated, associated and syndromic neural tube defects was 56, 23.5 and 20.6% respectively. In the majority of syndromes, the neural tube defect represented a not previously observed syndromic feature. CONCLUSION: The high proportion of NTDs with monogenic background underlines the importance of a syndrome oriented fetal pathology. At the very least it requires a thourough photographic and radiographic documentation of the fetal phenotype to enable the genetic counsellor to identify a syndromic disorder. This is necessary to determine the risk of recurrence, arrange confirming mutation analyses and offer targeted prenatal diagnosis in subsequent pregnancies.
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Pierre-Robin sequence, radial deviation, and ulnar clinodactyly of the index fingers due to an additional phalangeal bone, as well as heart defects are the key features of Catel-Manzke syndrome. Although mutations in TGDS were identified as the cause of this disorder, the pathogenetic mechanism remains unknown. Here, we report on a fetus with severe heart defect, nuchal edema, talipes, Pierre-Robin sequence, and bilateral deviation and clinodactyly of the index and middle fingers. Pregnancy was terminated at the 22nd week of gestation. Postmortem radiographs showed hypoplasia and V-shaped displacement of the second and third proximal phalanges of both hands as well as hypoplasia of the first metatarsals and the phalangeal bones of the halluces. The suggested diagnosis Catel-Manzke syndrome was confirmed by the detection of two compound heterozygous mutations in TGDS: The known variant c.298G>T; p.(Ala100Ser) and the so far undescribed variant c.895G>A; p.(Asp299Asn), located in the predicted substrate binding site of TGDS. This is the first report on the association of mutations in TGDS with additional anomalies of the middle fingers and halluces. We provide a detailed phenotypic characterization of the only fetus with molecularly confirmed Catel-Manzke syndrome, which is relevant for prenatal diagnosis. Our findings widen the phenotype spectrum caused by TGDS mutations and underline the phenotypic overlap with Temtamy preaxial brachydactyly syndrome. This improves our understanding of the prenatal development and the pathogenetic mechanism of Catel-Manzke syndrome.
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Anomalías Múltiples/genética , Deformidades Congénitas de la Mano/genética , Cardiopatías Congénitas/genética , Hidroliasas/genética , Síndrome de Pierre Robin/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/fisiopatología , Braquidactilia/diagnóstico , Braquidactilia/genética , Braquidactilia/fisiopatología , Sordera/diagnóstico , Sordera/genética , Sordera/fisiopatología , Femenino , Feto/fisiopatología , Dedos/anomalías , Dedos/fisiopatología , Deformidades Congénitas de la Mano/diagnóstico , Deformidades Congénitas de la Mano/fisiopatología , Cardiopatías Congénitas/fisiopatología , Heterocigoto , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Anomalías de la Boca/diagnóstico , Anomalías de la Boca/genética , Anomalías de la Boca/fisiopatología , Mutación , Síndrome de Pierre Robin/diagnóstico , Síndrome de Pierre Robin/fisiopatología , Embarazo , Diagnóstico Prenatal , Anomalías Dentarias/diagnóstico , Anomalías Dentarias/genética , Anomalías Dentarias/fisiopatologíaRESUMEN
Rhabdomyomas are rare striated muscle-type tumors arising in the heart or in soft tissues. Using a monoclonal antibody specific for the cardiac isoform of α-actin (α-cardiac actin, α-CAA), differential expression patterns in striated muscle tissues were reported previously. The purpose of the present study was to determine whether the α-actin isoform specificity is maintained in rhabdomyomas according to their origin, comparing extracardiac to cardiac rhabdomyomas. We immunohistochemically investigated adult extracardiac (pharyngeal) rhabdomyomas (n = 4) and cardiac rhabdomyomas (n = 7) employing isoform-specific monoclonal antibodies. The extracardiac rhabdomyomas revealed only a few scattered α-CAA-positive tumor cells (antibody cAc1-20.42) while the cardiac rhabdomyomas exhibited abundant expression of α-CAA, indicating a close relatedness to cardiac muscle fibers. The α-skeletal actin (α-SKA) specific monoclonal antibody (3B3) produced the reverse results. General sarcomeric antibodies (HHF35 and Alpha Sr-1) displayed strong positivity in all rhabdomyomas studied. Alpha-smooth muscle actin (α-SMA) was negative or heterogeneously positive in extracardiac and cardiac rhabdomyomas. Our results suggest that despite similar morphology, the intrinsic differential alpha-actin isoform specificity of mature skeletal vs. cardiac muscle is maintained in extracardiac and cardiac rhabdomyomas. Thus, adult extracardiac rhabdomyomas differentiate towards mature skeletal muscle although they may exhibit centrally placed nuclei like cardiac muscle cells, while cardiac rhabdomyomas reflect true cardiac muscle differentiation. Our findings appear to indicate a different biological nature of cardiac and extracardiac rhabdomyomas, probably related to a different cell of origin. To our knowledge, this is the first report suggesting a derivation of extracardiac and cardiac rhabdomyomas from skeletal and cardiac muscle cells, respectively.
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Actinas/biosíntesis , Neoplasias Cardíacas/patología , Músculo Esquelético/patología , Miocardio/patología , Rabdomioma/patología , Neoplasias de los Tejidos Blandos/patología , Actinas/análisis , Anciano , Femenino , Humanos , Inmunohistoquímica , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Isoformas de Proteínas/análisisRESUMEN
OBJECTIVE: Fetal pathology aims to recognize syndromal patterns of anomalies for goal-directed mutation analyses, genetic counseling, and early prenatal diagnosis in consecutive pregnancies. Here, we report on five fetuses with Peters' plus syndrome (PPS) from two distinct families aborted after prenatal ultrasound diagnosis of hydrocephaly. METHOD: We performed fetal autopsies and molecular analyses. RESULTS: Among 44 fetuses with prenatally diagnosed hydrocephaly, four fetuses of 16 to 21 gestational weeks presented with additional cleft lip/palate and/or agenesis of the corpus callosum. Other features were growth retardation, hypertelorism, anomalies of the eyes, in part consistent with Peters' anterior chamber anomalies, mild brachymelia, brachydactyly, and also internal anomalies. Suspected PPS was confirmed by detection of B3GALTL mutation in these four fetuses and in one additional sib fetus, revealing homozygosity for the common c.660 + 1G > A donor splice site mutation in intron 8. CONCLUSIONS: Autosomal-recessive PPS has not yet been diagnosed prenatally. We want to alert ultrasonographers to the diagnosis of this disorder in growth-retarded fetuses with (recurrent) hydrocephaly, agenesis of the corpus callosum, and cleft lip/palate and stress the more severe fetal manifestation, describing a first such case with additional Dandy-Walker cyst and occult meningoencephalocele.
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Síndrome de Dandy-Walker/genética , Encefalocele/genética , Galactosiltransferasas/genética , Glucosiltransferasas/genética , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/genética , Deformidades Congénitas de las Extremidades/diagnóstico , Deformidades Congénitas de las Extremidades/genética , Diagnóstico Prenatal , Adulto , Agenesia del Cuerpo Calloso/diagnóstico por imagen , Agenesia del Cuerpo Calloso/genética , Labio Leporino/diagnóstico por imagen , Labio Leporino/genética , Fisura del Paladar/diagnóstico por imagen , Fisura del Paladar/genética , Córnea/anomalías , Análisis Mutacional de ADN , Síndrome de Dandy-Walker/diagnóstico , Encefalocele/diagnóstico , Femenino , Retardo del Crecimiento Fetal/diagnóstico por imagen , Asesoramiento Genético , Edad Gestacional , Humanos , Hidrocefalia/diagnóstico por imagen , Hidrocefalia/genética , Masculino , Mutación , Embarazo , Ultrasonografía PrenatalAsunto(s)
Anomalías Múltiples/diagnóstico por imagen , Apéndice Atrial/anomalías , Apéndice Atrial/diagnóstico por imagen , Ventrículos Cardíacos/anomalías , Ventrículos Cardíacos/diagnóstico por imagen , Síndrome de Heterotaxia/diagnóstico por imagen , Ultrasonografía Prenatal , Femenino , Humanos , EmbarazoRESUMEN
OBJECTIVE: A higher frequency of twin births in sibships of Klinefelter syndrome patients and also monozygotic or dizygotic twins, themselves being affected by Klinefelter syndrome have been noted repeatedly. To address this issue, we evaluated type and frequency of twinning among Klinefelter fetuses that we had received for autopsy within a 'Prenatal Diagnosis' program. METHOD: We performed fetal autopsies, and genetic analyses on DNA extracted from stained histological slides. RESULTS: Among 41 prenatal diagnoses of a 47, XXY karyotype we observed four twin pairs. One was dizygotic with discordant Klinefelter and Down syndrome. Three twin pairs were monozygotic as concluded from monochorial placentation. In two monozygotic pairs one twin partner was an acardiac monster and in one of these the acardiac twin showed a female gonadal sex and missing Y-chromosomal SRY-sequences as confirmed by polymerase chain reaction. CONCLUSIONS: There is a high rate of twinning and twin reversed arterial perfusion sequence among our Klinefelter fetuses. Forked umbilical cords at the placental insertion site in one case allowed classification as conjoined twins in the sense of a 'funiculopagus'. Anaphase lagging or semidizygosity by second polar body twinning are proposed as explanations for the gonadal sex discordance and the excessive developmental disadvantage in the one acardiac. Problems may arise with regard to non-invasive prenatal diagnosis of aneuploidies in twin pregnancies.
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Anomalías Múltiples/diagnóstico , Aneuploidia , Enfermedades en Gemelos/diagnóstico , Cardiopatías Congénitas/diagnóstico , Síndrome de Klinefelter/diagnóstico , Aberraciones Cromosómicas Sexuales , Cordón Umbilical/anomalías , Anomalías Múltiples/genética , Adulto , Amniocentesis/métodos , Diagnóstico Diferencial , Enfermedades en Gemelos/genética , Femenino , Genotipo , Cardiopatías Congénitas/genética , Humanos , Síndrome de Klinefelter/genética , Masculino , Gemelos , Gemelos Monocigóticos/genéticaRESUMEN
We report on a triplet pregnancy of consanguineous parents with one fetus being affected by recurrent Johanson-Blizzard syndrome (JBS). At autopsy in the 35th gestational week, the affected triplet presented with an especially severe and lethal manifestation of the disorder as compared to his elder affected brother and to cases in the literature, thus exemplifying great interfamilial and intrafamilial phenotypic variability. Arhinencephaly and cystic renal dysplasia associated with urethral obstruction sequence were features not described previously in the literature. In addition to the lack of exocrine acini as the characteristic feature of JBS, the pancreas revealed a resorptive inflammatory reaction with infiltration by eosinophilic granulocytes that focally dispersed onto islets of Langerhans, thus favoring a progressive destructive rather than primary dysplastic process and possibly explaining the occurrence of diabetes mellitus in later life. JBS maps to chromosome 15q15-q21.1 and is associated with mutations in the UBR1 gene. Testing the fetus and the affected sibling revealed a homozygous truncating mutation in UBR1. The resulting absence of the UBR1 protein was confirmed by Western blot. Immunohistochemical staining using a commercial anti-UBR1 antibody demonstrated staining, presumably artifactual. This finding suggests that, until an appropriately validated antibody has been identified, this modality should not be utilized for diagnosis or confirmation of this disorder.
Asunto(s)
Constricción Patológica/patología , Sordera/patología , Displasia Ectodérmica/patología , Hidronefrosis/patología , Hipotiroidismo/patología , Oligohidramnios/patología , Enfermedades Pancreáticas/patología , Enfermedades Vasculares Periféricas/patología , Síndrome del Abdomen en Ciruela Pasa/patología , Obstrucción Uretral/patología , Adulto , Ano Imperforado , Preescolar , Consanguinidad , Constricción Patológica/genética , Constricción Patológica/metabolismo , Sordera/genética , Sordera/metabolismo , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , Resultado Fatal , Femenino , Muerte Fetal , Edad Gestacional , Trastornos del Crecimiento , Pérdida Auditiva Sensorineural , Humanos , Hidronefrosis/genética , Hidronefrosis/metabolismo , Hipotiroidismo/genética , Hipotiroidismo/metabolismo , Discapacidad Intelectual , Masculino , Mutación , Mucosa Nasal/metabolismo , Nariz/anomalías , Nariz/patología , Oligohidramnios/genética , Oligohidramnios/metabolismo , Páncreas/patología , Enfermedades Pancreáticas/genética , Enfermedades Pancreáticas/metabolismo , Pancreatitis , Enfermedades Vasculares Periféricas/genética , Enfermedades Vasculares Periféricas/metabolismo , Embarazo , Embarazo Triple , Síndrome del Abdomen en Ciruela Pasa/genética , Síndrome del Abdomen en Ciruela Pasa/metabolismo , Recurrencia , Ubiquitina-Proteína Ligasas/deficiencia , Ubiquitina-Proteína Ligasas/genética , Obstrucción Uretral/genética , Obstrucción Uretral/metabolismoRESUMEN
We report on three hydropic fetuses of 17, 22 and 25 gestational weeks from three distinct families presenting with Desbuquois dysplasia type 1. All fetuses showed brachymelia and characteristic dysmorphic features. X-ray studies revealed δ-shaped extraphalangeal bones and disease-specific prominence of the lesser trochanter, varying in severity with fetal age. Early lethal manifestation of the disorder was reflected in lung hypoplasia and in early death of similarly affected siblings in cases 1 and 2. All families were German Caucasians by descent. Sequence analysis of the CANT1 gene revealed two frameshift mutations, c.228_229insC and c.277_278delCT, in homozygous and compound heterozygous configuration, respectively, and a homozygously novel missense mutation, c.336C>A (p.D112E), located within a highly conserved region of exon 2. Haplotype analyses by high-resolution single-nucleotide polymorphism array showed that the haplotype associated with c.228_229insC may be traced to a single founder in the German population.
Asunto(s)
Anomalías Craneofaciales/genética , Enanismo/genética , Hidropesía Fetal/genética , Inestabilidad de la Articulación/genética , Mutación , Nucleotidasas/genética , Osificación Heterotópica/genética , Polidactilia/genética , Adulto , Autopsia , Consanguinidad , Anomalías Craneofaciales/diagnóstico por imagen , Enanismo/diagnóstico por imagen , Síndrome de Ellis-Van Creveld/diagnóstico , Resultado Fatal , Femenino , Efecto Fundador , Haplotipos , Humanos , Hidropesía Fetal/diagnóstico por imagen , Lactante , Recién Nacido , Inestabilidad de la Articulación/diagnóstico por imagen , Masculino , Osificación Heterotópica/diagnóstico por imagen , Fenotipo , Polidactilia/diagnóstico por imagen , Polimorfismo de Nucleótido Simple , RadiografíaRESUMEN
OBJECTIVES: We report on a female fetus of 24 weeks gestational age with Fine-Lubinsky syndrome (FLS), representing the 7th case published so far. METHODS: Prenatal ultrasound was performed at 22+1 weeks of gestation and thorough postmortem examination was made after termination of pregnancy. RESULTS: The diagnosis of FLS in the fetus was based on characteristic features that were already apparent in early prenatal life, such as growth deficiency, brachycephaly, flat face with associated dysmorphic signs, microstomia and cataract, while deafness and mental retardation, which are syndrome-specific functional disorders and evident only postnatally, could not be taken into account. CONCLUSIONS: This case demonstrates the diagnostic problems in fetal syndromology if syndrome-specific features are not yet recognizable and additional complications occur that had not been observed in this disorder.