Prenatal Diagnosis of Jeune Syndrome Caused by Compound Heterozygous Variants in DYNC2H1 Gene-Case Report with Rapid WES Procedure and Differential Diagnosis of Lethal Skeletal Dysplasias.

Skeletal dysplasias (SDs) are a large, heterogeneous group of mostly genetic disorders that affect the bones and cartilage, resulting in abnormal growth and development of skeletal structures. The high clinical and genetic diversity in SDs cause difficulties in prenatal diagnosis. To establish a correct prognosis and better management, it is very important to distinguish SDs with poor life-limiting prognosis or lethal SDs from other ones. Bad prognosis in foetuses is assessed on the basis of the size of the thorax, lung volumes, long bones' length, bones' echogenicity, bones' angulation or presented fractures, and the concomitant presence of non-immune hydrops or visceral abnormalities. To confirm SD diagnosis and perform family genetic consultation, rapid molecular diagnostics are needed; therefore, the NGS method using a panel of genes corresponding to SD or whole-exome sequencing (WES) is commonly used. We report a case of a foetus showing long bones' shortening and a narrow chest with short ribs, diagnosed prenatally with asphyxiating thoracic dystrophy, also known as Jeune syndrome (ATD; OMIM 208500), caused by compound heterozygous variants in the DYNC2H1 gene, identified by prenatally performed rapid-WES analysis. The missense variants in the DYNC2H1 gene were inherited from the mother (c.7289T>C; p.Ile2430Thr) and from the father (c.12716T>G; p.Leu4239Arg). The DYNC2H1 gene is one of at least 17 ATD-associated genes. This disorder belongs to the ninth group of SD, ciliopathies with major skeletal involvement. An extremely narrow, bell-shaped chest, and abnormalities of the kidneys, liver, and retinas were observed in most cases of ATD. Next to lethal and severe forms, clinically mild forms have also been reported. A diagnosis of ATD is important to establish the prognosis and management for the patient, as well as the recurrence risk for the family.

Severe Infantile Axonal Neuropathy with Respiratory Failure Caused by Novel Mutation in X-Linked LAS1L Gene.

LAS1L encodes a nucleolar ribosomal biogenesis protein and is also a component of the Five Friends of Methylated CHTOP (5FMC) complex. Mutations in the LAS1L gene can be associated with Wilson−Turner syndrome (WTS) and, much more rarely, severe infantile hypotonia with respiratory failure. Here, we present an eighteen-month old boy with a phenotype of spinal muscular atrophy with respiratory distress (SMARD). By applying WES, we identified a novel hemizygous synonymous variant in the LAS1L gene inherited from an unaffected mother (c.846G > C, p.Thr282=). We suggest that the identified variant impairs the RNA splicing process. Furthermore, we proved the absence of any coding regions by qPCR and sequencing cDNA using amplicon deep sequencing and Sanger sequencing methods. According to the SMARD phenotype, severe breathing problems causing respiratory insufficiency, hypotonia, and feeding difficulties were observed in our patient from the first days of life. Remarkably, our case is the second described patient with a SMARD-like phenotype due to a mutation in the LAS1L gene and the first with a variant impacting splicing.

Perinatalna opieka paliatywna realizowana w oddziale polozniczym i neonatologicznym we wspólpracy z hospicjum dla dzieci - doswiadczenia wlasne.

INTRODUCTION: Wady letalne prowadza do wewnatrzmacicznego zgonu plodu lub dziecka bezposrednio po urodzeniu lub we wczesnym okresie niemowlecym, bez wzgledu na zastosowane leczenie. W przypadku wad letalnych nie ma mozliwosci skutecznej pomocy dziecku, mimo postepu mi zeadsytcoysnoyw ania najnowoczesniejszej aparatury lub terapii. Rodzice, którzy decyduja sie na urodzenie dziecka z wada letalna moga byc objeci perinatalna opieka hospicyjna, która ma charakter kompleksowy. Polega ona na wsparciu ciezarnej w okresie przygotowania do porodu, w czasie porodu i po porodzie oraz na wsparciu jej rodziny oraz obejmuje udzielenie rodzicom pelnej informacji o chorobie ich dziecka. Opieka nad dzieckiem po urodzeniu jest nastawiona na ochrone przed uporczywa terapia i zapewnienie dziecku opieki paliatywnej. CEL: Wykazanie znaczenia perinatalnej opieki paliatywnej dla kobiet w ciazy, u których wyniki badan prenatalnych wskazywaly na ciezkie zaburzenie rozwojowe u plodu o potencjalnie letalnym rokowaniu oraz przedstawienie schematu postepowania wedlug modelu wewnatrzszpitalnego hospicjum perinatalnego. MATERIAL I METODY: Analiza retrospektywna objeto dokumentacje 67 pacjentek skierowanych do Programu RAZEM we Wroclawiu w latach 2014-2018 z powodu nieprawidlowych wyników badan prenatalnych (ultrasonograficznych lub/i genetycznych), które wskazywaly na ciezkie zaburzenie rozwojowe u plodu o potencjalnie letalnym rokowaniu. Dokonanoanalizy danych socjodemograficznych, danych klinicznych rozpoznania choroby u plodu, przebiegu ciazy i porodu, trybu postepowania w okresie prenatalnym, podczas porodu i po urodzeniu sie dziecka. WYNIKI: Do Programu zostalo skierowanych 67 kobiet w wieku 20-43 lat (srednio 31,2), które zglaszaly sie w okresie od 15 do 39 tygodnia ciazy (srednio w 25. tygodniu ciazy). Do opieki paliatywnej zakwalifikowano 57 kobiet, czyli 85% skierowanych do programu. Opieke paliatywna kontynuowano u 51 pacjentek, poniewaz 6 kobiet w trakcie procesu diagnostycznego zdecydowalo sie na zakonczenie ciazy (10,5%). Najczestszymi zaburzeniami u plodów byly aberracje chromosomowe, wady OUN i wady nerek. W 95% przypadków doszlo do obumarcia wewnatrzmacicznego plodu lub smierci noworodka. WNIOSKI: Perinatalna opieka paliatywna jest niezbedna forma opieki dla kobiet w ciazy, u których wyniki badan prenatalnych wskazuja na ciezkie zaburzenie rozwojowe u plodu o potencjalnie letalnym rokowaniu. Model wewnatrzszpitalny hospicjum perinatalnego jest korzystna forma opieki, zapewnia jej spójnosc i dobra komunikacje w zespole, co wplywa na dobra jakosc opieki. INTRODUCTION: Lethal defects lead to the intrauterine death of the fetus or the passing away of the child immediately after birth or in early infancy, regardless of the treatment used. In the case of lethal defects, it is not possible to effectively help the child, despite using the most modern equipment or medicines in the treatment or the progress made by medicine. Parents, who decide to continue the pregnancy, although the fetus has a lethal defect that cannot be cured, may be covered by perinatal hospice care, which is comprehensive and consists in supporting the pregnant woman during the prenatal time, during delivery and after delivery and support of her family, giving full information to the parents about their child's illness. Childcare after birth is focused on protecting the infant from persistent therapy and providing him with appropriate conditions. AIM: To demonstrate the role of perinatal palliative care for pregnant women in whom the results of prenatal tests pointed to a severe developmental disorder in the fetus with a potentially lethal prognosis, and to present a pattern of behavior for their hospitalization in the perinatal hospice. MATERIALS AND METHODS: The retrospective analysis included documentation of 67 patients referred to the RAZEM (TOGETHER) Program in Wroclaw in 2014-2018 due to abnormal results of (ultrasound and / or genetic) prenatal tests, which indicated a serious developmental disorder in the fetus with potentially lethal prognosis. Analysis was conducted of sociodemographic data, clinical data on fetal diagnosis, pregnancy and delivery, the procedure for prenatal delivery and postnatal birth. RESULTS: 67 women aged 20-43 years (mean 31.2) were referred to the RAZEM Program. Out of these, 57 women were enrolled for palliative care, which accounted for 85% of those referred to the program. Palliative care was continued in 51 patients, because 6 women decided to terminate their pregnancy during the diagnostic process (10.5%). The most common abnormalities in the fetuses were chromosomal aberrations, CNS defects and kidney defects. In 95% of the cases, intrauterine fetal death or neonatal death occurred. CONCLUSIONS: Perinatal palliative care is an indispensable form of care for pregnant women in whom the results of prenatal tests indicate a serious developmental disorder in the fetus with potentially lethal prognosis. The in-hospital model of a perinatal hospice is a beneficial form of care, as it ensures consistency and good communication in the team, which favourably affects its quality.

Prenatal Versus Postnatal Diagnosis of Meckel-Gruber and Joubert Syndrome in Patients with TMEM67 Mutations.

Renal cystic diseases are characterized by genetic and phenotypic heterogeneity. Congenital renal cysts can be classified as developmental disorders and are commonly diagnosed prenatally using ultrasonography and magnetic resonance imaging. Progress in molecular diagnostics and availability of exome sequencing procedures allows diagnosis of single-gene disorders in the prenatal period. Two patients with a prenatal diagnosis of polycystic kidney disease are presented in this article. TMEM67 mutations were identified in both fetuses using a whole-exome sequencing (WES) study. In one of them, the phenotypic syndrome diagnosed prenatally was different from that diagnosed in the postnatal period.

Lethal and life-limiting skeletal dysplasias: Selected prenatal issues.

Skeletal dysplasias are a heterogeneous group of congenital bone and cartilage disorders with a genetic etiology. The current classification of skeletal dysplasias distinguishes 461 diseases in 42 groups. The incidence of all skeletal dysplasias is more than 1 in every 5000 newborns. The type of dysplasia and associated abnormalities affect the lethality, survival and long-term prognosis of skeletal dysplasias. It is crucial to distinguish skeletal dysplasias and correctly diagnose the disease to establish the prognosis and achieve better management. It is possible to use prenatal ultrasonography to observe predictors of lethality, such as a bell-shaped thorax, short ribs, severe femoral shortening, and decreased lung volume. Individual lethal or life-limiting dysplasias may have more or less specific features on prenatal ultrasound. The prenatal features of the most common skeletal dysplasias, such as thanatophoric dysplasia, osteogenesis imperfecta type II, achondrogenesis, and campomelic dysplasia, are discussed in this article. Less frequent dysplasias, such as asphyxiating thoracic dystrophy, fibrochondrogenesis, atelosteogenesis, and homozygous achondroplasia, are also discussed.

Spectrum of Neurological Symptoms in Glycosylphosphatidylinositol Biosynthesis Defects: Systematic Review.

Background: Mutations of genes involved in the synthesis of glycosylphosphatidylinositol and glycosylphosphatidylinositol-anchored proteins lead to rare syndromes called glycosylphosphatidylinositol-anchored proteins biosynthesis defects. Alterations of their structure and function in these disorders impair often fundamental processes in cells, resulting in severe clinical image. This study aimed to provide a systematic review of GPIBD cases reports published in English-language literature. Methods: The browsing of open-access databases (PubMed, PubMed Central. and Medline) was conducted, followed by statistical analysis of gathered information concerning neurological symptomatology. The inclusion criteria were: studies on humans, age at onset (<18 y.o.), and report of GPIBD cases with adequate data on the genetic background and symptomatology. Exclusion criteria were: publication type (manuscripts, personal communication, review articles); reports of cases of GPI biosynthesis genes mutations in terms of other disorders; reports of GPIBD cases concentrating on non-neurological symptoms; or articles concentrating solely on the genetic issues of GPI biosynthesis. Risk of bias was assessed using Joanna Brigs Institute Critical Appraisal Checklists. Data synthesis was conducted using STATISTICA 13.3.721.1 (StatSoft Polska Sp. z.o.o.). Used tests were chi-square, Fisher's exact test (for differences in phenotype), and Mann-Whitney U test (for differences in onset of developmental delay). Results: Browsing returned a total of 973 articles which, after ruling out the repetitions and assessing the inclusion and exclusion criteria, led to final inclusion of 77 articles (337 GPIBD cases) in the analysis. The main outcomes were prevalence of neurological symptoms, onset and semiology of seizures and their response to treatment, and onset of developmental delay. Based on this data a synthesis of phenotypical differences between the groups of GPIBD cases and the general GPIBD cases population was made. Discussion: A synthetical analysis of neurological components in clinical image of GPIBD patients was presented. It highlights the main features of these disorders, which might be useful in clinical practice for consideration in differential diagnosis with children presenting with early-onset seizures and developmental delay. The limitation of this review is the scarcity of the specific data in some reports, concerning the semiology and onset of two main features of GPIBD.

Genetic testing in Poland and Ukraine: should comprehensive germline testing of BRCA1 and BRCA2 be recommended for women with breast and ovarian cancer?

PURPOSE: To characterize the spectrum of BRCA1 and BRCA2 pathogenic germline variants in women from south-west Poland and west Ukraine affected with breast or ovarian cancer. Testing in women at high risk of breast and ovarian cancer in these regions is currently mainly limited to founder mutations. METHODS: Unrelated women affected with breast and/or ovarian cancer from Poland (n = 337) and Ukraine (n = 123) were screened by targeted sequencing. Excluded from targeted sequencing were 34 Polish women who had previously been identified as carrying a founder mutation in BRCA1. No prior testing had been conducted among the Ukrainian women. Thus, this study screened BRCA1 and BRCA2 in the germline DNA of 426 women in total. RESULTS: We identified 31 and 18 women as carriers of pathogenic/likely pathogenic (P/LP) genetic variants in BRCA1 and BRCA2, respectively. We observed five BRCA1 and eight BRCA2 P/LP variants (13/337, 3.9%) in the Polish women. Combined with the 34/337 (10.1%) founder variants identified prior to this study, the overall P/LP variant frequency in the Polish women was thus 14% (47/337). Among the Ukrainian women, 16/123 (13%) women were identified as carrying a founder mutation and 20/123 (16.3%) were found to carry non-founder P/LP variants (10 in BRCA1 and 10 in BRCA2). CONCLUSIONS: These results indicate that genetic testing in women at high risk of breast and ovarian cancer in Poland and Ukraine should not be limited to founder mutations. Extended testing will enhance risk stratification and management for these women and their families.

Breakpoint Mapping of Symptomatic Balanced Translocations Links the EPHA6, KLF13 and UBR3 Genes to Novel Disease Phenotype.

De novo balanced chromosomal aberrations (BCAs), such as reciprocal translocations and inversions, are genomic aberrations that, in approximately 25% of cases, affect the human phenotype. Delineation of the exact structure of BCAs may provide a precise diagnosis and/or point to new disease loci. We report on six patients with de novo balanced chromosomal translocations (BCTs) and one patient with a de novo inversion, in whom we mapped breakpoints to a resolution of 1 bp, using shallow whole-genome mate pair sequencing. In all seven cases, a disruption of at least one gene was found. In two patients, the phenotypic impact of the disrupted genes is well known (NFIA, ATP7A). In five patients, the aberration damaged genes: PARD3, EPHA6, KLF13, STK24, UBR3, MLLT10 and TLE3, whose influence on the human phenotype is poorly understood. In particular, our results suggest novel candidate genes for retinal degeneration with anophthalmia (EPHA6), developmental delay with speech impairment (KLF13), and developmental delay with brain dysembryoplastic neuroepithelial tumor (UBR3). In conclusion, identification of the exact structure of symptomatic BCTs using next generation sequencing is a viable method for both diagnosis and finding novel disease candidate genes in humans.

Multiplex ligation-dependent probe amplification as a screening test in children with autism spectrum disorders.

BACKGROUND: Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders, characterized by the presence of various symptoms related to deficits in communication and social interactions as well as stereotyped and repetitive behavior. Increasing evidence indicates the contribution of genetic factors in the etiology of ASDs. Genetic diagnosis in ASDs is based on identifying chromosome aberrations, microaberrations and point mutations in specific genes. One of the diagnostic tools is multiplex ligase-dependent probe amplification (MLPA) with a set of probes dedicated to ASDs (SALSA MLPA P343 Autism-1; MRC-Holland BV, Amsterdam, the Netherlands) targeting the genes located in the regions 15q11-q13, 16p11 and the SHANK3 gene in the 22q13 region. OBJECTIVES: Our study included 240 patients referred to the clinical genetics unit because of ASDs and/or developmental delay and/or an intellectual disability. Before genetic testing, the patients underwent a comprehensive medical work-up. MATERIAL AND METHODS: Multiplex ligase-dependent probe amplification was performed in 256 DNA samples from 240 probands and 16 family members using the SALSA MLPA P343 Autism-1 probe mix (MRC-Holland BV) according to the manufacturer's protocol. RESULTS: We obtained 234 normal results and 22 abnormal results (15 probands and 7 abnormal results for probands' parents or siblings). We diagnosed 1 16p11 microdeletion syndrome and 1 16p11 microduplication syndrome. We also found 3 deletions and 1 duplication in 15q13 region including 2 or 3 genes and 9 single probe alterations in the regions examined (1 duplication and 7 deletions). CONCLUSIONS: Due to the low costs, MLPA test may be a good tool for the genetic screening of ASD patients.

In-silico analysis of Thr767Ile pathogenic variant in the MSH6 gene in family with endometrial cancer.

OBJECTIVE: To examine the mechanism of pathogenity of Thr767Ile variant on MSH6 protein. STUDY DESIGN: We describe a family diagnosed with endometrial cancer in two generations associated with variant in the MSH6 gene (p. Thr767Ile / c. 2300C>T) (rs587781462). MSH6 c. 2300C>T was associated with autosomal-dominant pattern of inheritance. MSH6 c. 2300C>T has pathogenic status in ClinVar and LOVD3 databases but it has never been described in context of hereditary endometrial cancer. We utilized a number of in-silico bioinformatic approaches using MSH6 protein sequence and structural information to assess influence of Thr767Ile on MSH6 properties. RESULTS: MSH6 Thr767 is highly conservative amino acid among various kingdoms of organisms. Thr767Ile was predicted deleterious and likely decreases affinity of MSH2-MSH6 complex to DNA but not affect interaction between MSH2 and MSH6. CONCLUSIONS: To the best of our knowledge, this is the first description of MSH6 T767I pathogenic variant that could be associated with a hereditary endometrial cancer. Bioinformatic analyses showed that T767I substitution most likely affects the MSH6 most important role, which is a DNA binding.

Clinical Observation of a Child with Prenatally Diagnosed De Novo Partial Trisomy of Chromosome 20.

BACKGROUND: Small supernumerary marker chromosomes (sSMCs) represent a group of structural chromosome rearrangements that cannot be characterized by conventional cytogenetic analysis, but can be identified by microarray studies. sSMCs are observed in approximately 0.075% of prenatal cytogenetic tests with clinical pathology in no more than 30% of sSMCS carriers. CASE: We present a boy who was diagnosed prenatally with a partial trisomy of chromosome 20. An increased nuchal translucency NT >99%tile, fetal neck cysts and abnormalities of the lumbosacral spine were observed in prenatal screening. After birth, facial dysmorphism, small male genitalia and defects of the vertebrae were observed. In the fourth year of life, dysmorphic features, brachydactyly, small male genitalia, short stature, psychomotor delay, hyperactivity as well as conductive hearing loss became apparent. CONCLUSION: Partial trisomy of chromosome 20, covering the region 20q21→20q23, results in serious clinical complications, including dysmorphic features and delay in psychomotor development.

Diagnosis and management in Pitt-Hopkins syndrome: First international consensus statement.

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, specific facial features, and marked autonomic nervous system dysfunction, especially with disturbances of regulating respiration and intestinal mobility. It is caused by variants in the transcription factor TCF4. Heterogeneity in the clinical and molecular diagnostic criteria and care practices has prompted a group of international experts to establish guidelines for diagnostics and care. For issues, for which there was limited information available in international literature, we collaborated with national support groups and the participants of a syndrome specific international conference to obtain further information. Here, we discuss the resultant consensus, including the clinical definition of PTHS and a molecular diagnostic pathway. Recommendations for managing particular health problems such as dysregulated respiration are provided. We emphasize the need for integration of care for physical and behavioral issues. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimization of diagnostics and care.

[Perinatal palliative care performed in obstetrics and neonatology wards and hospices for children - own experience].

OBJECTIVE: Lethal defects lead to the intrauterine death of the fetus or the passing away of the child immediately after birth or in early infancy, regardless of the treatment used. In the case of lethal defects, it is not possible to effectively help the child, despite using the most modern equipment or medicines in the treatment or the progress made by medicine. Parents, who decide to continue the pregnancy, although the fetus has a lethal defect that cannot be cured, may be covered by perinatal hospice care, which is comprehensive and consists in supporting the pregnant woman during the prenatal time, during delivery and after delivery and support of her family, giving full information to the parents about their child's illness. Childcare after birth is focused on protecting the infant from persistent therapy and providing him with appropriate conditions. Aim: To demonstrate the role of perinatal palliative care for pregnant women in whom the results of prenatal tests pointed to a severe developmental disorder in the fetus with a potentially lethal prognosis, and to present a pattern of behavior for their hospitalization in the perinatal hospice. PATIENTS AND METHODS: Materials and methods: The retrospective analysis included documentation of 67 patients referred to the RAZEM (TOGETHER) Program in Wroclaw in 2014-2018 due to abnormal results of (ultrasound and / or genetic) prenatal tests, which indicated a serious developmental disorder in the fetus with potentially lethal prognosis. Analysis was conducted of sociodemographic data, clinical data on fetal diagnosis, pregnancy and delivery, the procedure for prenatal delivery and postnatal birth. RESULTS: Results: 67 women aged 20-43 years (mean 31.2) were referred to the RAZEM Program. Out of these, 57 women were enrolled for palliative care, which accounted for 85% of those referred to the program. Palliative care was continued in 51 patients, because 6 women decided to terminate their pregnancy during the diagnostic process (10.5%). The most common abnormalities in the fetuses were chromosomal aberrations, CNS defects and kidney defects. In 95% of the cases, intrauterine fetal death or neonatal death occurred. CONCLUSION: Conclusions: Perinatal palliative care is an indispensable form of care for pregnant women in whom the results of prenatal tests indicate a serious developmental disorder in the fetus with potentially lethal prognosis. The in-hospital model of a perinatal hospice is a beneficial form of care, as it ensures consistency and good communication in the team, which favourably affects its quality.

Genetic variants in ATM, H2AFX and MRE11 genes and susceptibility to breast cancer in the polish population.

BACKGROUND: DNA damage repair is a complex process, which can trigger the development of cancer if disturbed. In this study, we hypothesize a role of variants in the ATM, H2AFX and MRE11 genes in determining breast cancer (BC) susceptibility. METHODS: We examined the whole sequence of the ATM kinase domain and estimated the frequency of founder mutations in the ATM gene (c.5932G > T, c.6095G > A, and c.7630-2A > C) and single nucleotide polymorphisms (SNPs) in H2AFX (rs643788, rs8551, rs7759, and rs2509049) and MRE11 (rs1061956 and rs2155209) among 315 breast cancer patients and 515 controls. The analysis was performed using high-resolution melting for new variants and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for recurrent ATM mutations. H2AFX and MRE11 polymorphisms were analyzed using TaqMan assays. The cumulative genetic risk scores (CGRS) were calculated using unweighted and weighted approaches. RESULTS: We identified four mutations (c.6067G > A, c.8314G > A, c.8187A > T, and c.6095G > A) in the ATM gene in three BC cases and two control subjects. We observed a statistically significant association of H2AFX variants with BC. Risk alleles (the G of rs7759 and the T of rs8551 and rs2509049) were observed more frequently in BC cases compared to the control group, with P values, odds ratios (OR) and 95% confidence intervals (CIs) of 0.0018, 1.47 (1.19 to 1.82); 0.018, 1.33 (1.09 to 1.64); and 0.024, 1.3 (1.06 to 1.59), respectively. Haplotype-based tests identified a significant association of the H2AFX CACT haplotype with BC (P <  0.0001, OR = 27.29, 95% CI 3.56 to 209.5). The risk of BC increased with the growing number of risk alleles. The OR (95% CI) for carriers of ≥ four risk alleles was 1.71 (1.11 to 2.62) for the CGRS. CONCLUSIONS: This study confirms that H2AFX variants are associated with an increased risk of BC. The above-reported sequence variants of MRE11 genes may not constitute a risk factor of breast cancer in the Polish population. The contribution of mutations detected in the ATM gene to the development of breast cancer needs further detailed study.

Short stature in genetic syndromes: Selected issues.

Short stature, which is defined as height below 2 standard deviations of the mean height for the age and sex, is one of the most frequent reasons for medical consultations in children. Short stature may occur due to a constitutional delay in growth, familial short stature or chronic diseases, including many genetic syndromes, metabolic and endocrine disorders. In this article the authors provide a mini-review of the most frequent genetic syndromes associated with short stature that should be taken into account in the differential diagnosis process. Syndromes caused by chromosomal aberrations and gene mutations were divided into 2 main groups: syndromes that are associated with intrauterine growth retardation (IUGR) and those in which IUGR does not occur in the natural history of the patient. The authors described the most important anomalies in each syndrome. Metabolic diseases and skeletal dysplasias were omitted, as they are major separate groups of diseases involving growth delay.

Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations.

Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc.

Fragile X syndrome in females - a familial case report and review of the literature.

BACKGROUND: Fragile X syndrome (FXS), one of the manifestations of FMR1-related disorders, is one of the most frequent genetic causes of intellectual disability. In over 99% of all cases it results from the expansion of CGG repeats in the 5'-untranslated region of the FMR1 gene and presents in males and in about 50% of the females with an FMR1 full mutation, usually with a milder phenotype. OBJECTIVE: Although the morphologic and behavioral phenotype in males is a well-recognized entity, the presentation in females is variable and not as specific. The objective of this paper is to present a family with quite a severe expression of the disorder in two sisters with a full mutation. METHODS: We report on a two-generation family where both males and females were found to be affected by FXS. We also present the diagnostic pathway and methods that led to the diagnosis of fragile X syndrome in the two sisters, as well as the method that explained the normal phenotype in their mother. RESULTS: The CGG repeats analysis in the FMR1 gene showed one normal allele and one allele with a full mutation in both sisters (probands) and their mother. A full mutation was also found in three male cousins of the probands. The analysis of the X-chromosome methylation status has shown a random X inactivation in proband 1 and 2 and a non-random one in the proband's mother, with the normal allele predominantly active. CONCLUSION: The reasons for different clinical presentations are discussed; moreover a review of the literature on females with FXS is presented. We hope that this paper will facilitate the future diagnosis of fragile X syndromes in females.

Coexistent chronic myelogenous leukemia with squamous cell carcinoma of the larynx associated with NOD2/CARD15 mutation in a young adult.

We report the case of a 37-year-old man with human papillomavirus-positive squamous cell carcinoma of the larynx coexisting with chronic myelogenous leukemia. The patient had no history of smoking or alcohol consumption. Within a few months, his rapidly growing tumor was classified as T4aN2cM0. It could be assumed that the rapid increase in the tumor mass, which did not respond positively to treatment, might have been associated with the coexistence of the chronic myelogenous leukemia, which had been found incidentally. Genetic testing revealed the presence of insertion mutation 3020insC within the NOD2 gene, which might be an important genetic predisposing factor, not only for a single tumor such as laryngeal cancer, but also for multiple primary neoplasms. The presence of an NOD2 mutation could significantly worsen the course of the cancer. Therefore, given the relatively high frequency of 3020insC mutations in the general population, it might be reasonable to perform genetic testing on a wider scale for patients with head or neck cancer, particularly in cases that follow an atypical course. It is also worth emphasizing the importance of thorough and periodically repeated laryngeal examinations in patients with chronic leukemia.

[Rapid diagnosis of the most common fetal aneuploidies with the QF-PCR method--a study of 100 cases]. / Szybka diagnostyka najczestszych aneuploidii u plodu meaoda QF-PCR--analiza 100 przypadków.

UNLABELLED: The aim of the study was to assess whether commercial kit QF-PCR can be used as the only method for rapic prenatal dia gnosis of chromosomes 13, 18, 21, X and Y aneuploidies, omitting cell culture and complete cyt6genetik analysis of fetal chromosomes. MATERIAL AND METHODS: DNA from amniocytes (94 cases) and trophoblast cells (6 cases) was analyzed witt QF-PCR according to the manufacturer's protocol. The obtained products were separated using ABI 310 Genetic Analyzer and the resulting data were analyzed using GeneMarker software. RESULTS: The results of QF-PCR were obtained in 95 out of 100 cases (95%). Abnormalities were found in 28 casea (29.5%). All these results were confirmed in subsequent cytogenetic analysis. Normal results were obtained in 62 patients (70.5%). However in that group, we found three chromosomal aberrations other than those analyzed b3 QF-PCR. Additionally two abnormal and three normal karyotypes were found in patients with inconclusive QF-POF results. CONCLUSIONS: QF-PCR is a fast and reliable tool for chromosomal aneuploidy analysis and can be used as the only method without a full analysis of the karyotype, but only in cases of suspected fetal 13, 18, 21 trisomy or numerica aberrations of X chromosome. In other cases, fetal karyotype analysis from cells obtained after cell culture should be offered to the patient.