Katharina Schoner

Severe Facial Clefts in Acrofacial Dysostosis : A Consequence of Prenatal Exposure to Mycophenolate Mofetil?

BACKGROUND: Immunosuppressants are teratogenic in mice, rats, and rabbits and cause prenatal growth restriction in humans. As yet, there has been no proven teratogenicity in humans. CASE: We present a chromosomally normal fetus with severe acrofacial dysostosis and orofacial clefts. These were bilateral transverse and oblique clefts and defects of the midface. In addition, there were preaxial limb anomalies with digitalization of thumbs and internal cardiovascular, gastrointestinal, and urogenital malformations. The mother had been treated with high doses of the immunosuppressant mycophenolate mofetil in early pregnancy for systemic lupus erythematosus. CONCLUSION: Mycophenolate mofetil may have contributed to or even caused acrofacial dysostosis phenotype and extensive clefting.

Desbuquois dysplasia type I and fetal hydrops due to novel mutations in the CANT1 gene.

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.

Tetrasomy 12p (Pallister-Killian syndrome): difficulties in prenatal diagnosis

PurposeWe report a rare case of Pallister-Killian syndrome diagnosed prenatally with increased nuchal translucency during screening for trisomy 21.Materials and methodsEchografic and postmortem examination of the fetus, G-banded chromosome and FISH analysis on short- and long-term chorion villous sampling (CVS) culture.Results and discussionCytogenetic analysis revealed a supernumerary isochromosome 12p after long-term culture whereas a normal cell line was detected in short-term culture only. Sonografic examination in 17-weeks’ gestation showed further increase of the NT and the additional presence of brachymelia, diaphragmatic hernia and a marked dextroposition of the heart. Termination of the pregnancy was performed. The cases of PKS karyotypically confirmed on CVS are reviewed, and cytogenetic and sonographic aspects of the prenatal diagnosis of PKS are discussed.

Fetal Manifestation of the Fine-Lubinsky Syndrome

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.

Recurrent Johanson-Blizzard Syndrome in a Triplet Pregnancy Complicated by Urethral Obstruction Sequence: A Clinical, Molecular, and Immunohistochemical Approach

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.

Fetal Pathology of Neural Tube Defects – An Overview of 68 Cases

INTRODUCTION The prevalence of neural tube defects worldwide is 1 - 2 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.

Piepkorn type of osteochondrodysplasia: Defining the severe end of FLNB-related skeletal disorders in three fetuses and a 106-year-old exhibit

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.

Mutations in TGDS associated with additional malformations of the middle fingers and halluces: Atypical Catel–Manzke syndrome in a fetus

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.