Compound heterozygous variants in MAPK8IP3 were detected in severe congenital hypotonia mimicking lethal spinal muscular atrophy.

Mitogen-activated protein kinase 8-interacting protein 3 gene (MAPK8IP3) encodes the c-Jun-amino-terminal kinase-interacting protein 3 (JIP3) and is involved in retrograde axonal transport. Heterozygous de novo pathogenic variants in MAPK8IP3 result in a neurodevelopmental disorder with or without brain abnormalities and possible axonal peripheral neuropathy. Whole-exome sequencing was performed on an individual presenting with severe congenital muscle hypotonia of neuronal origin mimicking lethal spinal muscular atrophy. Compound heterozygous rare variants (a splice and a missense) were detected in MAPK8IP3, inherited from the healthy parents. Western blot analysis in a muscle biopsy sample showed a more than 60% decrease in JIP3 expression. Here, we suggest a novel autosomal recessive phenotype of a lower motor neuron disease caused by JIP3 deficiency.

Missense MED12 variants in 22 males with intellectual disability: From nonspecific symptoms to complete syndromes.

We describe the phenotype of 22 male patients (20 probands) carrying a hemizygous missense variant in MED12. The phenotypic spectrum is very broad ranging from nonspecific intellectual disability (ID) to the three well-known syndromes: Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, or Ohdo syndrome. The identified variants were randomly distributed throughout the gene (p = 0.993, χ2 test), but mostly outside the functional domains (p = 0.004; χ2 test). Statistical analyses did not show a correlation between the MED12-related phenotypes and the locations of the variants (p = 0.295; Pearson correlation), nor the protein domain involved (p = 0.422; Pearson correlation). In conclusion, establishing a genotype-phenotype correlation in MED12-related diseases remains challenging. Therefore, we think that patients with a causative MED12 variant are currently underdiagnosed due to the broad patients' clinical presentations.

Clinical and genetic characteristics of craniosynostosis in Hungary.

Craniosynostosis, the premature closure of cranial sutures, is a common craniofacial disorder with heterogeneous etiology and appearance. The purpose of this study was to investigate the clinical and molecular characteristics of craniosynostoses in Hungary, including the classification of patients and the genetic analysis of the syndromic forms. Between 2006 and 2012, 200 patients with craniosynostosis were studied. Classification was based on the suture(s) involved and the associated clinical features. In syndromic cases, genetic analyses, including mutational screening of the hotspot regions of the FGFR1, FGFR2, FGFR3, and TWIST1 genes, karyotyping and FISH study of TWIST1, were performed. The majority (88%) of all patients with craniosynostosis were nonsyndromic. The sagittal suture was most commonly involved, followed by the coronal, metopic, and lambdoid sutures. Male, twin gestation, and very low birth weight were risk factors for craniosynostosis. Syndromic craniosynostosis was detected in 24 patients. In 17 of these patients, Apert, Crouzon, Pfeiffer, Muenke, or Saethre-Chotzen syndromes were identified. In one patient, multiple-suture craniosynostosis was associated with achondroplasia. Clinical signs were not typical for any particular syndrome in six patients. Genetic abnormalities were detected in 18 syndromic patients and in 8 relatives. In addition to 10 different, known mutations in FGFR1,FGFR2 or FGFR3, one novel missense mutation, c.528C>G(p.Ser176Arg), was detected in the TWIST1 gene of a patient with Saethre-Chotzen syndrome. Our results indicate that detailed clinical assessment is of paramount importance in the classification of patients and allows indication of targeted molecular testing with the highest possible diagnostic yield.

Variable expressivity of pfeiffer syndrome in a family with FGFR1 p.Pro252Arg mutation.

Pfeiffer syndrome is an autosomal dominant disorder classically characterized by craniosynostosis, facial dysmorphism and limb anomalies. The majority of cases are caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. A specific, rare mutation p.Pro252Arg, located between the second and third extracellular immunoglobulin-like domain of FGFR1, is associated with mild clinical signs. We report on a three-generation family with five members having a heterozygous FGFR1 p.Pro252Arg mutation. Phenotypic features within the family showed high variability from the apparently normal skull and limbs to the characteristic brachycephaly and digital anomalies. The typical features of Pfeiffer syndrome appeared only in the third generation allowing us to unveil the syndrome in several further family members in two previous generations. Variable expressivity can complicate the recognition of Pfeiffer syndrome, principally the mild type 1, requiring careful phenotyping and genetic counseling.

[Clinical and genetic characteristics of craniosynostosis]. / A craniosynostosis klinikai és genetikai jellemzoi.

Craniosynostosis is caused by premature fusion of one or more cranial sutures leading to deformity of the cranium. Depending on the type and number of the sutures involved and the order of their fusion, different forms of deformities may develop. Two main types of craniosynostosis can be distinguished: non-syndromic (isolated) and syndromic forms. In the latter group the cranial deformity is usually associated with dysmorphic features, limb anomalies and other symptoms while in non-syndromic form the cranial deformity can be seen only. The type and severity of associated anomalies in the syndromic form are different. Early fusion of sutures can be caused by both environmental and genetic factors. In the present paper the authors aim to review the clinical features and genetic background of craniosynostosis focusing on some common syndromes.

[Results of clinical and genetic diagnosis of rare diseases in the Eastern region of Hungary (2007-2013)]. / Ritka genetikai betegségek klinikai és genetikai diagnosztikájában szerzett tapasztalataink a kelet-magyarországi régióban (2007-2013).

INTRODUCTION: 80% of rare diseases have a genetic origin, and 50% manifest themselves as congenital anomalies. Their adequate health care includes early recognition of genetic anomalies and prevention of recurrence. AIM: The aims of the authors were to provide correct diagnoses to patients with multiple congenital anomalies with or without mental retardation attending to the outpatient clinic of the Clinical Genetics Center at the University of Debrecen in the time interval between August 1, 2007 and March 31, 2013, establish the possibility of prenatal diagnosis, assess the distribution of different genetic mechanisms in the background of rare genetic diseases, compare them with international data, and develop an algorithm for the diagnostic approach of rare genetic diseases applicable in Hungary. METHOD: Clinical data and genetic results of patients were evaluated, and patients were categorized into one of the ten proposed etiological groups, based on which the distribution of genetic causes was defined. RESULTS: Clinical diagnosis was achieved in 64.3% of patients, confirmed genetic diagnosis in 37.8%, while 35.7% of patients remained undiagnosed. Several dysmorphic syndromes and metabolic disorders were first diagnosed in Hungary, two of which unique in the literature. CONCLUSIONS: In the centre of the authors the diagnostic effectiveness of chromosome aberrations exceeds the international standards, that of known microdeletions and dysmorphic syndromes meets international data, and the genetic diagnosis of mendelian disorders and submicroscopic copy number changes remain below international figures.

Achondroplasia with multiple-suture craniosynostosis: a report of a new case of this rare association.

We report on a female patient with an exceedingly rare combination of achondroplasia and multiple-suture craniosynostosis. Besides the specific features of achondroplasia, synostosis of the metopic, coronal, lambdoid, and squamosal sutures was found. Series of neurosurgical interventions were carried out, principally for acrocephaly and posterior plagiocephaly. The most common achondroplasia mutation, a p.Gly380Arg in the fibroblast growth factor receptor 3 (FGFR3) gene, was detected. Cytogenetic and array CGH analyses, as well as molecular genetic testing of FGFR1, 2, 3 and TWIST1 genes failed to identify any additional genetic alteration. It is suggested that this unusual phenotype is a result of variable expressivity of the common achondroplasia mutation.

Cytogenetic Investigation of Infertile Patients in Hungary: A 10-Year Retrospective Study.

Chromosome abnormalities play a crucial role in reproductive failure. The presence of numerical or structural aberrations may induce recurrent pregnancy loss or primary infertility. The main purpose of our study was to determine the types and frequency of chromosomal aberrations in infertile patients and to compare the frequency of structural aberrations to a control group. Karyotyping was performed in 1489 men and 780 women diagnosed with reproductive failure between 2010 and 2020. The control group included 869 male and 1160 female patients having cytogenetic evaluations for reasons other than infertility. Sex chromosomal aberrations were detected in 33/1489 (2.22%) infertile men and 3/780 (0.38%) infertile women. Structural abnormalities (e.g., translocation, inversion) were observed in 89/1489 (5.98%) infertile men and 58/780 (7.44%) infertile women. The control population showed structural chromosomal abnormalities in 27/869 (3.11%) men and 39/1160 (3.36%) women. There were significant differences in the prevalence of single-cell translocations between infertile individuals (males: 3.5%; females: 3.46%) and control patients (males: 0.46%; females: 0.7%). In summary, this is the first report of cytogenetic alterations in infertile patients in Hungary. The types of chromosomal abnormalities were comparable to previously published data. The prevalence of less-studied single-cell translocations was significantly higher in infertile patients than in the control population, supporting an earlier suggestion that these aberrations may be causally related to infertility.

MED13L-related intellectual disability due to paternal germinal mosaicism.

The MED13L-related intellectual disability or MRFACD syndrome (Mental retardation and distinctive facial features with or without cardiac defects; MIM # 616789) is one of the most common forms of syndromic intellectual disability with about a hundred cases reported so far. Affected individuals share overlapping features comprising intellectual disability, hypotonia, motor delay, remarkable speech delay, and a recognizable facial gestalt. De novo disruption of the MED13L gene by deletions, duplications, or sequence variants has been identified as deleterious. Siblings affected by intragenic deletion transmitted from a mosaic parent have been reported once in the literature. We now present the first case of paternal germinal mosaicism for a missense MED13L variant causing MRFACD syndrome in one of the father's children and being the likely cause of intellectual disability and facial dysmorphism in the other. As part of the Mediator complex, the MED proteins have an essential role in regulating transcription. Thirty-two subunits of the Mediator complex genes have been linked to congenital malformations that are now acknowledged as transcriptomopathies. The MRFACD syndrome has been suggested to represent a recognizable phenotype.

[Genetic revision of the Hungarian Cystic Fibrosis Registry]. / A magyar Cystás Fibrosis Regiszter genetikai revíziója.

INTRODUCTION: Cystic fibrosis (CF) is one of the most common monogenic diseases. Genetic testing is becoming increasingly reasoned to establish or confirm the diagnosis by detecting abnormal mutations. OBJECTIVE: In order to develop a diagnostic strategy for cystic fibrosis and to facilitate mutation-specific treatments, the genetic revision of the Hungarian Cystic Fibrosis Registry was performed. METHOD: 582 patients' data and samples were used for the revision (528 originally included in the register and 54 received during the revision). First we reviewed the patients' existing genetic findings. Wherever necessary, a comprehensive three-level genetic analysis of the CFTR gene was done. RESULTS: According to our study, of the 528 patients present in the Registry, 395 (74.8%) had 2 pathogenic CFTR mutations. We completed and corrected 94 patients' previously incomplete genetic status. 73 different pathogenic variants were described, in which 1 aberration was not previously reported (c.3130G>A). The 5 most common mutations were: F508del (68.4%); CFTRdele2,3 (3.7%); G542X (3.2%); 2184insA (2.7%); W1282X (2.3%). Based on genotype and age, in Hungary 211 patients are eligible for the available lumacaftor-ivacaftor combination therapy, and 361 patients for the ivacaftor-tezacaftor-elexacaftor therapy. CONCLUSION: Due to the revision, we could identify the patients who can benefit from mutation-specific drugs instead of symptomatic therapy. In addition, the data obtained have been used to map the Hungarian distribution of mutations in the CFTR gene, which will help to develop a diagnostic strategy. Orv Hetil. 2022; 163(51): 2052-2059.

Helsmoortel-Van der Aa Syndrome-Cardiothoracic and Ectodermal Manifestations in Two Patients as Further Support of a Previous Observation on Phenotypic Overlap with RASopathies.

The ADNP-gene-related neurodevelopmental disorder Helsmoortel-Van der Aa syndrome is a rare syndromic-intellectual disability-an autism spectrum disorder first described by Helsmoortel and Van der Aa in 2014. Recently, a large cohort including 78 patients and their detailed phenotypes were presented by Van Dijck et al., 2019, who reported developmental delay, speech delay and autism spectrum disorder as nearly constant findings with or without variable cardiological, gastroenterological, urogenital, endocrine and neurological manifestations. Among cardiac malformations, atrial septal defect, patent ductus arteriosus, patent foramen ovale and mitral valve prolapse were the most common findings, but other unspecified defects, such as mild pulmonary valve stenosis, were also described. We present two patients with pathogenic ADNP variants and unusual cardiothoracic manifestations-Bland-White-Garland syndrome, pectus carinatum superiorly along the costochondral junctions and pectus excavatum inferiorly in one patient, and Kawasaki syndrome with pericardiac effusion, coronary artery dilatation and aneurysm in the other-who were successfully treated with intravenous immunoglobulin, corticosteroid and aspirin. Both patients had ectodermal and/or skeletal features overlapping those seen in RASopathies, supporting the observations of Alkhunaizi et al. 2018. on the clinical overlap between Helsmoortel-Van der Aa syndrome and Noonan syndrome. We observed a morphological overlap with the Noonan-like disorder with anagen hair in our patients.

New mutations in the ATM gene and clinical data of 25 AT patients.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, oculocutaneous telangiectasias, chromosomal instability, radiosensitivity, and cancer predisposition. The gene mutated in the patients, ATM, encodes a member of the phosphatidylinositol 3-kinase family proteins. The ATM protein has a key role in the cellular response to DNA damage. Truncating and splice site mutations in ATM have been found in most patients with the classical AT phenotype. Here we report of our extensive ATM mutation screening on 25 AT patients from 19 families of different ethnic origin. Previously unknown mutations were identified in six patients including a new homozygous missense mutation, c.8110T>C (p.Cys2704Arg), in a severely affected patient. Comprehensive clinical data are presented for all patients described here along with data on ATM function generated by analysis of cell lines established from a subset of the patients.

Blepharophimosis mental retardation syndrome Say-Barber/Biesecker/Young-Simpson type - new findings with neuroimaging.

We report on a female patient with blepharophimosis mental retardation syndrome of Say/Barber/Biesecker/Young-Simpson (SBBYS) type. Main findings in her were marked developmental delay, blepharophimosis, ptosis, cleft palate, external auditory canal stenosis, small and malformed teeth, hypothyroidism, hearing impairment, and joint limitations. We performed diffusion tensor magnetic resonance imaging (MRI) and tractography of the brain which showed inappropriate myelination and disturbed white matter integrity. Cytogenetic analysis, subtelomeric fluorescence in situ hybridization and comparative genomic hybridization failed to identify an abnormality. It remains uncertain whether the MRI findings are specific to the present patient or form part of the SBBYS syndrome.

[Detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation]. / Szubtelomerikus kromoszómaátrendezodések kimutatása idiopathiás mentális retardációban.

Subtelomeric regions of chromosomes are rich in genes; their rearrangements cannot be identified by traditional chromosome analysis. Since these subtelomeric aberrations are responsible for about 7% of cases with mental retardation, their detection is important both from the diagnostic point of view and to prevent recurrence in the family. Subtelomeric chromosomal alterations can be detected by fluorescence in situ hybridization. Based on international criteria, 35 out of 59 patients with mental retardation have been selected. Subtelomeric rearrangements were revealed in 6 patients (5 familial cases, 1 new onset) whereas the subtelomeric FISH result was normal in 29 cases. Deletion of 8pter and duplication of 12pter were detected in 2 patients, while a deletion of 21qter and duplication of the 10pter due to an unbalanced translocation were found in 3 other cases. Finally, a new onset deletion of 3qter was observed in 1 patient. In order to clarify the origin of chromosome aberrations, 12 healthy family members were also examined, 5 of them carried balanced translocations. We concluded that the phenotype is mostly influenced by the size of regions involved in deletion/duplication and - in case of translocations - by the associated chromosomal abnormalities.

22q13 Microduplication Syndrome in Siblings with Mild Clinical Phenotype: Broadening the Clinical and Behavioral Spectrum.

Distal duplication 22q (22q13.3qter) is a rare condition with only 24 cases described so far. Parental balanced reciprocal translocations and pericentric inversions involving chromosome 22 predispose to the conception of an unbalanced offspring and are more frequently reported than de novo events. The clinical phenotype of patients is highly variable and does not necessarily correlate with the extent of the duplicated segment. Short stature, microcephaly, hypertelorism, cleft lip or palate, low-set ears, and intellectual disability seem to be the most consistent features. Familial reoccurrence is extremely rarely reported. Here, we report 2 siblings with a 22q13.3qter duplication detected by array CGH; their mother is a carrier of a pericentric inversion in chromosome 22. Their relatively mild phenotype and identical chromosomal breakpoints as well as duplication size are unique. This is the first case described so far.

[Expression of ZEBRA protein of Epstein-Barr virus in Hungarian patients with Hodgkin lymphoma: latent or lytic cycle?]. / Az Epstein-Barr-vírus ZEBRA fehérjéjének expressziója magyarországi Hodgkin-lymphomás betegekben: latens vagy litikus ciklus?

INTRODUCTION: Epstein-Barr virus is a ubiquitous human herpes virus in the Hungarian population. The virus is associated with an increasing number of lymphoid malignancies, such as Hodgkin and non-Hodgkin lymphomas. The ability of the virus to establish life-long persistent infection and induce growth transformation is related to the viral proteins that are variously expressed in both normal and malignant cells. Although the presence of ZEBRA protein induces lytic cycle, some lymphoma cases show this protein expression. AIM: In our present study we investigated the frequency of expression of ZEBRA protein in Hungarian patients with Hodgkin lymphoma associated with Epstein-Barr virus infection. The authors wanted to clarify whether this expression is specific to latency type II or occurs in some non-Hodgkin lymphoma cases with latency type III as well. Does the expression of ZEBRA protein have any effect on therapeutic response and survival rate of the patients? METHOD: 109 HL and 59 NHL were studied for the presence of the virus in the tumor and for expression of the latency proteins and ZEBRA by immunohistochemistry. RESULTS: 25 samples were evaluated successfully for ZEBRA of the 47 LMP1 positive HL samples. We detected the weak expression of ZEBRA protein in 13 of the 25 LMP1 positive Hodgkin lymphoma cases and in 6 of the 18 LMP1 positive non-Hodgkin lymphoma samples. The authors could not find correlation between the expression of ZEBRA protein and the type of latency. During the followed 120 months the total survival of patients with ZEBRA positivity proved to be significantly shorter as compared to that of ZEBRA negative cases. The authors could not find significant difference in the uneventful survival of these two groups. CONCLUSION: In the examined group of patients the ZEBRA positivity associated with a poor prognosis of the disease. Besides this relatively small number of cases, additional extensive studies are needed to conclude our observation. Elucidation of the switching mechanisms by which Epstein-Barr virus induces lytic cycle may provide an efficacious therapeutic approach to the EBV-related malignancies.

[Association of Hodgkin lymphoma with Epstein-Barr virus in Hungary]. / Hodgkin-lymphomfás betegek Epstein-Barr-virus-asszociációjának vizsgálata.

INTRODUCTION: The occurrence of Epstein-Barr virus associated Hodgkin's lymphoma shows considerable variation from continent to continent and from country to country but in Hungary no such investigations have been performed so far. AIM: The authors analyse the presence of Epstein-Barr virus and the type of latency in histologic samples taken from Hodgkin's disease patients. METHOD: They have analyzed the presence of virus using PCR, in situ hybridisation and immunohistochemistry. RESULTS: Out of 109 cases, 61 patients (56%) showed virus positivity by PCR while latent membrane protein 1 positivity was found in 47 cases (43%). As regards to gender ratio, 53% female and 58% male patients were virus positive by PCR. Epstein-Barr virus association did not show any alteration in children (1-14 years) when compared to that of adults (out of the 10 children 6 were positive by PCR). As regards to the lifestyle of Epstein-Barr virus positive patients, the incidence of smoking and the ratio of poor social conditions were significantly higher. Mixed cell type was the most frequent (65%) in these patients and Epstein-Barr PCR virus positivity was highest in this type (60%), primarily in age groups 11-20 and over 51 years. Epstein-Barr virus PCR positivity was 52% in nodular sclerosis (negative cases cumulated in the age group 15-30 years), other histologic subtypes could not be evaluated due to the small number of cases. On examining Hodgkin's lymphoma and Epstein-Barr virus association disease models, they could not categorize their patients into any of them though characteristic patient groups could be more or less observed also in their material. This may be explained by the socioeconomic differences of the population living under different economic conditions. CONCLUSION: These results indicate that Epstein-Barr infection may play an important role in the development of Hodgkin's lymphoma in Hungary, too.

Lissencephaly and band heterotopia: LIS1, TUBA1A, and DCX mutations in Hungary.

The spectrum of lissencephaly ranges from absent (agyria) or decreased (pachygyria) convolutions to less severe malformation known as subcortical band heterotopia. Mutations involving LIS1 and TUBA1A result in the classic form of lissencephaly, whereas mutations of the DCX gene cause lissencephaly in males and subcortical band heterotopia in females. This report describes the clinical manifestations and imaging and genetic findings in 2 boys with lissencephaly and a girl with subcortical band heterotopia. An ovel mutation (c.83_84delAT, p.Tyr28Phefs*31) was identified in LIS1 in 1 of the boys with lissencephaly and another novel mutation (c.200delG, p.Ile68Leufs*87) was found in DCX in the girl with subcortical band heterotopia. The mutations appeared in the first half of the genes and are predicted to result in truncated proteins. A mutation was found in the TUBA1A gene (c.1205G>A, p.Arg402His) in the other boy. This mutation affects the folding of tubulin heterodimers, changing the interactions with proteins that bind microtubules.

Jumping translocation of chromosome 1q associated with good clinical outcome in a case of Burkitt leukemia.

Acquired jumping translocations (JTs) are rare secondary aberrations occurring in various hematological malignancies. In Burkitt lymphoma/leukemia (BL) chromosome 1q abnormalities such as partial or whole arm duplications/translocations are frequently associated with the disease-specific t(8;14)(q24;q32). JTs of 1q are considered to have a bad prognostic impact in BL. We report clinical, conventional and molecular cytogenetic findings of a 12-year-old boy who presented with BL. In addition to the primary aberration, t(8;14)(q24;q32), JT of 1q onto chromosomes 21 and der(14) as well as the formation of isochromosome 1q could be detected in his bone marrow sample. Despite the expected poor prognostic outcome of these aberrations, the patient has been experiencing an event free survival of 7.5 years at the time of the present report, reflecting the excellent clinical outcome of the disease.

Association between the Epstein-Barr virus and Hodgkin's lymphoma in the North-Eastern part of Hungary: effects on therapy and survival.

This retrospective study included 109 patients with Hodgkin's lymphoma (HL; 45 females, 64 males). In 47 of the 109 HL patients (43%), immunohistochemical analysis of their formalin-fixed, paraffin-embedded histologic samples revealed Epstein-Barr virus (EBV) by latent membrane protein (LMP) 1. The highest virus association (50%) was found with the mixed cellularity histologic subtype, especially in patients aged 11-20 and >50 years. Virus positivity in nodular sclerosis was 35% (negative cases accumulated in patients aged 15-30 years). Regarding clinical stages, histologic subtypes, general symptoms, treatments employed and response to treatment, the EBV-positive group was not significantly different from the virus-negative group. During the mean follow-up time of 83 months (9-300 months), the overall or event-free survival of EBV-negative patients was more favorable than that of EBV-positive patients, although the difference was not significant (p = 0.16 and p = 0.24, respectively). EBV infection may be involved in the pathogenesis of HL in our Hungarian study cohort, but it does not significantly affect clinical symptoms, therapeutic results or complete and event-free survival of HL patients.