Anna Latos-bielenska

Ciliopathies are rare congenital disorders, caused by defects in the cilium, that cover a broad clinical spectrum. A subgroup of ciliopathies showing significant phenotypic overlap are known as skeletal ciliopathies and include Jeune asphyxiating thoracic dysplasia (JATD), Mainzer-Saldino syndrome (MZSDS), cranioectodermal dysplasia (CED), and short-rib polydactyly (SRP). Ciliopathies are heterogeneous disorders with >187 associated genes, of which some genes are described to cause more than one ciliopathy phenotype. Both the clinical and molecular overlap make accurate diagnosing of these disorders challenging. We describe two unrelated Polish patients presenting with a skeletal ciliopathy who share the same compound heterozygous variants in IFT140 (NM_014,714.4) r.2765_2768del; p.(Tyr923Leufs*28) and exon 27–30 duplication; p.(Tyr1152_Thr1394dup). Apart from overlapping clinical symptoms the patients also show phenotypic differences; patient 1 showed more resemblance to a Mainz...

Fetal Valproate Syndrome (FVS) is caused by prenatal exposure to valproic acid (VPA). Clinical phenotype of FVS includes characteristic facial dysmorphism, various congenital defects, developmental delay/mental retardation, and other neurologic deficits. The risk of congenital malfomation in the developing fetus is 2 or 3-fold higher (4-6%) than that of background population. In this report, we describe clinical characteristics of 3 infants with the diagnosis of FVS. We summarize important issues in the management of VPA-treated women at childbearing age. Measures that include: informed planning of pregnancy, VPA treatment optimization to the lowest effective dose, folic acid supplementation, prenatal ultrasonographic monitoring, and maternal serum alpha-fetoprotein testing, should help to diminish the risk of adverse pregnancy outcomes. Embryopathy, is caused by prenatal exposure to valproic acid (VPA), one of the most common antiepileptic drugs. VPA and its derivatives are widely used in treatment of various seizure disorders and some psychiatric conditions. The majority of childbearing women exposed to VPA deliver healthy infants, however, the risk of congenital malfomation in the developing fetus is 2 or 3-fold higher (4-6%) than the risk in general po- pulation (2%) (1). First reports on possible teratogenic activity of VPA appeared in early 1980 s (2, 3). Currently, with great contributions from population-based registries of congenital malformations, the spectrum of defects observed in FVS is well described and established. Clinical phenotype of FVS encompasses structural con- genital defects, various neurologic deficits, as well as characte- ristic facial appearance. Congenital malfomations include limb defects (37%) (4), cardiac anomalies (26%), genitourinary ab- normalities (28%), oral clefts (4%), ocular and brain anomalies (10%), and spina bifida (3%) (5). Developmental deficits/mental retardation and hypotonia are found in 30-70% of affected indi- viduals (5, 6). Speech delay, hyperactivity, learning difficulties and autistic behaviour are also relatively frequent (7). Seizures are observed rarely (3%) (5). Facial dysmorphism include tri- gonocephaly with prominent metopic suture, bifrontal nar- rowing, micrognathia, broad, flat nasal bridge, anteverted nostrils, epicanthal folds, long and smooth philtrum, thin ver- million boarder, and mild changes of the external ears (5, 6). The aim of this report is twofold. First, by the clinical phenotype presentation of 3 infants with the diagnosis of FVS, we hope to draw attention of gynaecologists to the matter of pregnancy in epileptic mothers, second, we summarize the management issues in VPA-treated women of childbearing age, aiming at minimization of their risk of adverse pregnancy outcomes.

In 1997, the Polish Registry of Congenital Malformations (PRCM) was established, to fulfil epidemiological, prophylactic, socioeconomic and scientific functions. The PRCM is a population-based registry monitoring currently about 300 000 births a year in 13 provinces. Such a large area and population require a special organizational structure of the Registry. The PRCM Central Working Group and the computer database are located in the Department of Medical Genetics, University of Medical Sciences, Poznań. Here the data are collected, validated, encoded according to the ICD-10, and analysed. Provincial Working Groups are responsible for supervision of data collection in the given province. The PRCM staff has grown from about 250 members in 1997 to more than 400 members today. The PRCM collects information on structural defects diagnosed before the end of the second year of life. Minor anomalies are excluded from the registry. The main source of information is a registration form filled up by the physician diagnosing the anomaly. Since 2004 also electronic reporting has been possible. On 28 September 2005 there were 54 020 entries in the database concerning 33 729 children with at least one congenital malformation and 1261 control entries concerning children without malformations. The PRCM is also an important source of identification of families at genetic risk. Education of physicians and the community in the field of genetic counselling is also an important aim of the PRCM. Since 2001, the PRCM has been a member of the Eurocat. Detailed information on PRCM organization, electronic reporting, and results are available at the PRCM website (www.rejestrwad.pl).

By 2021, 10 cases of fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA, MIM #618278) syndrome have been reported, and five causative variants in the NHLRC2 gene (*618277) have been identified. First reported patients presented with recurrent respiratory distress, leading to death before the age of 3. In the recent publication by Rapp, Van Dijck, and Laugwitz et al., six more patients were described. The authors underlined the possibility of survival beyond infancy and neurodevelopmental delay occurrence.

BACKGROUND Using social media for research purposes is novel and challenging in terms of recruitment and ethical issues. This paper provides insight into the recruitment of European parents of children with specific congenital anomalies to engage in co-production research by using social media. A secret Facebook Page, providing optimal security, was set up for newly recruited Research Aware Parents (RAPs) to communicate privately and confidentially with each other and the research team to generate questions and to interpret findings. OBJECTIVE To use social media for recruitment and engagement of parents in research and to determine research priorities of parents who have children with Down syndrome, Cleft Lip with or without Cleft Palate, Congenital Heart Defects and Spina Bifida. METHODS The design was exploratory and descriptive with three phases. Phase 1, recruitment of RAPs and generation of research questions important to them, Phase 2, an online survey, designed using Qualtri...

Objective: Thirty years ago it was demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). Despite Public Health Initiatives across Europe recommending that women take 0.4 mg folic acid before becoming pregnant and during the first trimester, the prevalence of NTD pregnancies has not materially decreased in the EU since 1998, in contrast to the dramatic fall observed in the USA. This study aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in Europe from 1998 as it had been in the USA.Design and Setting: The number of NTD pregnancies from 1998 to 2017 that would have been prevented if folic acid fortification had been implemented in the 28 countries who were members of the European Union in 2019 was predicted was predicted using data on NTD prevalence from 35 EUROCAT congenital anomaly registries and literature searches for population serum folat...

Background: Ehlers-Danlos syndrome (EDS) is a common non-inflammatory, congenital connective tissue disorder. Classical type (cEDS) EDS is one of the more common forms, typically caused by mutations in the COL5A1 and COL5A2 genes, though causative mutations in the COL1A1 gene have also been described. Material and methods: The study group included 59 patients of Polish origin, diagnosed with cEDS. The analysis was performed on genomic DNA (gDNA) with NGS technology, using an Illumina sequencer. Thirty-five genes related to connective tissue were investigated. The pathogenicity of the detected variants was assessed by VarSome. Results: The NGS of 35 genes revealed variants within the COL5A1, COL5A2, COL1A1, and COL1A2 genes for 30 of the 59 patients investigated. Our panel detected no sequence variations for the remaining 29 patients. Discussion: Next-generation sequencing, with an appropriate multigene panel, showed great potential to assist in the diagnosis of EDS and other connect...

Background: The 22q11.2 microdeletion syndrome (22q11.2 deletion syndrome-22q11.2DS) refers to congenital abnormalities, including primarily heart defects and facial dysmorphy, thymic hypoplasia, cleft palate and hypocalcaemia. Microdeletion within chromosomal region 22q11.2 constitutes the molecular basis of this syndrome. The 22q11.2 microdeletion syndrome occurs in 1/4000 births. The aim of this study was to determine the frequency of 22q11.2 microdeletion in 87 children suffering from a congenital heart defect (conotruncal or non-conotruncal) coexisting with at least one additional 22q11.2DS feature and to carry out 22q11.2 microdeletion testing of the deleted children’s parents. We also attempted to identify the most frequent heart defects in both groups and phenotypic traits of patients with microdeletion to determine selection criteria for at risk patients. Methods: The analysis of microdeletions was conducted using fluorescence in situ hybridization (FISH) on metaphase chrom...

Data from the Polish Registry of Congenital Malformations (PRCM) suggest that the prevalence of limb reduction defects (LRDs) in some Polish regions is significantly higher in comparison to that reported in the European Surveillance of Congenital Anomalies (EUROCAT) registry, but specific risk factors are still unknown. The objectives of this study were two-fold: to detect risk factors linked to isolated LRDs among Polish natives and to search for geospatial clusters of isolated LRDs to identify high-risk areas across the country. Among the 2,939,001 births accounted for in the PRCM, we determined that there were 852 children with distinct LRDs. Our data demonstrate that lower birth weight, prematurity, and maternal smoking history are strongly associated with isolated LRDs. Furthermore, our investigation pointed to various additional risk factors for isolated LRDs, including paternal education, gestational hypertension, upper respiratory tract infections, and exposure to anti-infla...

EUROlinkCAT aims to investigate the health and educational outcomes of children with congenital anomalies for the first 10 years of their lives. We also aim to facilitate the development of a more reciprocal relationship between families with children with congenital anomalies, health and social care professionals, and researchers by conducting focus groups. The aim of the focus groups and parent interviews was to investigate parental experiences of having a child with a heart defect requiring surgery, cleft lip, spina bifida or Down Syndrome and to identify their research priorities. In total, seven interviews with 12 parents and eight focus groups with 58 parents and two caregivers were conducted in four European countries. We found that parents request more positive information with a focus on quality of life and what the children can achieve rather than solely on the negative aspects and limitations of the congenital anomaly. Some parents also highlighted discrepancies between t...

Background Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder. Currently, variants in any of six genes (IFT122, WDR35, IFT140, IFT43, IFT52 and WDR19) have been associated with this syndrome. All of these genes encode proteins essential for intraflagellar transport (IFT) a process that is required for cilium assembly, maintenance and function. Intra- and interfamilial clinical variability has been reported in CED, which is consistent with CED’s genetic heterogeneity and is indicative of genetic background effects. Results Two male CED patients from two unrelated Polish families were included in this study. Clinical assessment revealed...

To test previous signals of a risk of orofacial cleft (OC) and clubfoot with exposure to the antiepileptic lamotrigine, and to investigate risk of other congenital anomalies (CA). This was a population-based case-malformed control study based on 21 EUROCAT CA registries covering 10.1 million births (1995-2011), including births to 2005 in which the clubfoot signal was generated and a subsequent independent study population of 6.3 million births. A total of 226,806 babies with CA included livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. First-trimester lamotrigine monotherapy exposure in OC cases and clubfoot cases was compared to other nonchromosomal CA (controls). Odds ratios (OR) were adjusted for registry. An exploratory analysis compared the proportion of each standard EUROCAT CA subgroup among all babies with nonchromosomal CA exposed to lamotrigine monotherapy with non-AED exposed pregnancies. There were 147 lamotrigine monotherapy-exposed b...

The goal of this analysis is to identify risk factors for infantile hemangiomas (IH) to better delineate hemangioma predisposition. We analyzed live birth children with isolated cutaneous hemangioma that were reported to the Polish Registry of Congenital Malformations from across Poland between the years 1998 and 2016. Lower birthweight and gestational age were the most significant risk factors associated with IH. We also observed a trend for a higher risk of IH with a lower level of maternal and paternal education. Moreover, mothers with IH have a higher probability of having a child with IH compared to fathers. However, this association is only present when the child is female. Similarly, a higher risk of hemangioma in a female child is found among mothers having relatives of the first degree with IH, compared to fathers with a similar pedigree. Our results suggest the role of exogenous factors in the etiology of IH. The analysis of familial cases suggests a multifactorial model o...

9.25-9.40 (S 03) MR Krawczy ski and PRCM Working Group: A Materna-Kiryluk, J Mejnartowicz, A Balcar-Boro , M Czerwionka-Szaflarska, E Gajewska, M Krawczy ski, J Limon, J Sta czyk, E Szwałkiewicz-Warowicka, M Walczak, A Latos-Biele ska CONGENITAL MALFORMATIONS OF THE ORGAN OF VISION: EPIDEMIOLOGICAL DATA BASED ON POLISH REGISTRY OF CONGENITAL MALFORMATIONS 1997-2001, DIAGNOSTIC RECOMMENDATIONS AND GENETIC COUNSELLING. Chair and Department of Medical Genetics, University of Medical Sciences in Pozna ; Department of Paediatrics, Haematology and Oncology, Medical University of Bydgoszcz; Chair and Department of Pediatric Allergology and Gastroenterology, Collegium Medicum Bydgoszcz, University in Torun; Department of Neonatology, Medical University in Wrocław; Department of Gastroenterology and Metabolism, University of Medical Sciences, Poznan; Chair and Department of Biology and Genetics, Medical University of Gdansk; Institute of Paediatrics, Maria Konopnicka Memorial Teaching Hospit...

A new case of 9p- syndrome is presented in a 18 months old girl with typical clinical features of the syndrome: marked delay in psychomotor development, muscle hypotonia, trigonocephaly, up-slanting palpebral fissures, short nose with anteverted nostrils, long philtrum, low-set and hypoplastic auricles and others. Using G- and R- banding, the break point was found on the typical place of the chromosome 9-p22 band. The presented case confirms the earlier finding that clinical recognition of the syndrome is of great importance, since small deletions of the short arm of chromosome 9 can be easily overlooked.

Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy first described by Judith Sensenbrenner in 1975. CED is a complex disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. The clinical symptoms are variable and the CED phenotype may present intrafamilial and interfamilial differences. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disease. Mutations in six genes: IFT122, WDR35, IFT43, WDR19, IFT52, and IFT140 have been associated with this disorder. All known CED genes encode proteins that are part of the intraflagellar transport complex, which plays an important role in the assembly and maintenance of cilia.

Congenital anomalies (CA) are the paradigm example of rare diseases liable to primary prevention actions due to the multifactorial etiology of many of them, involving a number of environmental factors together with genetic predispositions. Yet despite the preventive potential, lack of attention to an integrated preventive strategy has led to the prevalence of CA remaining relatively stable in recent decades. The 2 European projects, EUROCAT and EUROPLAN, have joined efforts to provide the first science-based and comprehensive set of recommendations for the primary prevention of CA in the European Union. The resulting EUROCAT-EUROPLAN 'Recommendations on Policies to Be Considered for the Primary Prevention of Congenital Anomalies in National Plans and Strategies on Rare Diseases' were issued in 2012 and endorsed by EUCERD (European Union Committee of Experts on Rare Diseases) in 2013. The recommendations exploit interdisciplinary expertise encompassing drugs, diet, lifestyles, maternal health status, and the environment. The recommendations include evidence-based actions aimed at reducing risk factors and at increasing protective factors and behaviors at both individual and population level. Moreover, consideration is given to topics specifically related to CA (e.g. folate status, teratogens) as well as of broad public health impact (e.g. obesity, smoking) which call for specific attention to their relevance in the pre- and periconceptional period. The recommendations, reported entirely in this paper, are a comprehensive tool to implement primary prevention into national policies on rare diseases in Europe.

CLN8 is a ubiquitously expressed membrane-spanning protein that localizes primarily in the ER, with partial localization in the ER-Golgi intermediate compartment. Mutations in CLN8 cause late-infantile neuronal ceroid lipofuscinosis (LINCL). We describe a female pediatric patient with LINCL. She exhibited a typical phenotype associated with LINCL, except she did not present spontaneous myoclonus, her symptoms occurrence was slower and developed focal sensory visual seizures. In addition, whole-exome sequencing identified a novel homozygous variant in CLN8, c.531G>T, resulting in p.Trp177Cys. Ultrastructural examination featured abundant lipofuscin deposits within mucosal cells, macrophages, and monocytes. We report a novel CLN8 mutation as a cause for NCL8 in a girl with developmental delay and epilepsy, cerebellar syndrome, visual loss, and progressive cognitive and motor regression. This case, together with an analysis of the available literature, emphasizes the existence of a ...

Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy. Cranioectodermal dysplasia is characterized by craniofacial, skeletal, and ectodermal abnormalities. About 50 patients have been described to date. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disorder. Mutations in five genes: IFT122, WDR35, IFT43, WDR19, and IFT52 have been associated with CED. All known genes encode proteins that are part of the intraflagellar transport complex, which plays an important role in the assembly and maintenance of cilia. Here, we report a family with two children affected by Sensenbrenner syndrome, a 9-year-old girl and her older sister who died in infancy due to respiratory, liver, and renal insufficiency. Dysmorphic features included short stature with rhizomelic shortening of limbs, short fingers, preaxial polydactyly of left hand, narrow chest, craniosynostosis, dolichocephaly, high an...

Beckwith Wiedemann syndrome is a complex developmental disorder characterized by somatic overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycemia, and predisposition to embryonal tumors. We present epidemiological and clinical aspects of patients with Beckwith Wiedemann syndrome diagnosed prenatally or in the early years of life, using data from EUROCAT (European Surveillance of Congenital Anomalies) registries. The study population consisted of 371 cases identified between January 1990 and December 2015 in 34 registries from 16 European countries. There were 15 (4.0%) terminations of pregnancy after prenatal detection of severe anomaly/anomalies, 10 fetal deaths (2.7%), and 346 (93.3%) live-births. Twelve (3.6%) of the 330 live-births with available information on survival died in the first week of life, of those eleven (91.6%) were preterm. First-year survival rate was 90.9%. Prematurity was present in 40.6% of males and 33.9% of females. Macrosomia was found in 49....

Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional affected individual with RHD and a congenital heart defect, we found a homozygous loss-of-function (LOF) variant in SLIT3, recapitulating phenotypes reported with Slit3 inactivation in the mouse. To identify genes associated with RHD, we performed an exome-wide association study with 195 unresolved case subjects and 6,905 control subjects. The top signal resided in GREB1L, a gene implicated previously in Hoxb1 and Shha signaling in zebrafish. The significance of the association, which was p = 2.0 × 10(-5) for novel LOF, increased to p = 4.1 × 10(-6) for LOF and deleterious missense variants combined, and augmented further after accounting for segregation and de novo inhe...

Gastroschisis, a congenital anomaly of the abdomen, is associated with young maternal age and has increased in prevalence in many countries. Maternal illness and medication exposure are among environmental risk factors implicated in its aetiology. A population-based case-malformed control study was conducted using data from 18 European congenital anomaly registries, with information on first trimester medication use, covering 8 million births 1995-2012. 1577 gastroschisis cases (of which 4% stillbirths, 11% terminations of pregnancy) were compared to 153 357 non-chromosomal/monogenic controls. Literature review identified previous associations concerning maternal illness and medication exposure to be tested as signals. Logistic regression adjusted for maternal age group, registry, and time period was used to evaluate associations. Comparing gastroschisis to other congenital anomalies, the data supported signals concerning maternal depression (aOR 2.52, 95% CI 1.45, 4.39), antidepres...