Case report: Initial atypical skeletal symptoms and dental anomalies as first signs of Gardner syndrome: the importance of genetic analysis in the early diagnosis.

Background: Gardner syndrome is a rare genetic cancer predisposition disorder characterized by intestinal polyposis, multiple osteomas, and soft and hard tissue tumors. Dental anomalies are present in approximately 30%-70% of patients with Gardner syndrome and can be discovered during routine dental examinations. However, sometimes the diagnosis is challenging due to the high clinical variability and incomplete clinical picture. Herein, we report a family with various dental and bone anomalies, in which the definitive diagnosis was established with the help of a comprehensive genetic analysis based on state-of-the-art next-generation sequencing technology. Case presentation: A 17-year-old female index patient presented with dental (caries, impacted, retained and anteriorly located teeth) and atypical bone anomalies not resembling Gardner syndrome. She was first referred to our Genetic Counselling Unit at the age of 11 due to an atypical bone abnormality identified by a panoramic X-ray. Tooth 3.6 was surgically removed and the histopathology report revealed a Paget's disease-like bone metabolic disorder with mixed osteoblastic and osteoclastic activity of the mandible. A small lumbar subcutaneous tumor was discovered by physical examination. Ultrasound examination of the tumor raised the possibility of a soft tissue propagation of chondromatosis. Her sister, 2 years younger at the age of 14, had some benign tumors (multiple exostoses, odontomas, epidermoid cysts) and impacted teeth. Their mother had also skeletal symptoms. Her lower teeth did not develop, the 9th-10th ribs were fused, and she complained of intermittent jaw pain. A cranial CT scan showed fibrous dysplasia on the cranial bones. Whole exome sequencing identified a heterozygous pathogenic nonsense mutation (c.4700C>G; p.Ser1567*) in the APC gene in the index patient's DNA. Targeted sequencing revealed the same variant in the DNA of the other affected family members (the sister and the mother). Conclusion: Early diagnosis of this rare, genetically determined syndrome is very important, because of the potentially high malignant transformation of intestinal polyps. Dentists should be familiar with the typical maxillofacial features of this disorder, to be able to refer patients to genetic counseling. Dental anomalies often precede the intestinal polyposis and facilitate the early diagnosis, thereby increasing the patients' chances of survival. Genetic analysis may be necessary in patients with atypical phenotypic signs.

Importance and application of WES in fetal genetic diagnostics: Identification of novel ASPM mutation in a fetus with microcephaly.

Background: Prenatal whole exome sequencing (WES) approaches can provide genetic diagnosis with rapid turnaround time and high diagnostic rate when conventional tests are negative. Here we report a family with multiple pregnancy loss and with repeated occurrence of fetal microcephaly. Methods and results: Because of positive family history and recurrent structural abnormality during the pregnancies that may lead postnatal neurodevelopmental consequences, WES analysis was indicated. Umbilical cord blood sampling was carried out and WES was performed using Twist Human Core Exome Kit and Illumina sequencing technology. The presence of pathogenic variants was confirmed by Sanger sequencing. WES analysis revealed a known pathogenic c.8506_8507delCA (p.Gln2836Glufs*35, rs587783280) and a novel pathogenic c.3134_3135delTC (p.Leu1045Glnfs*17) ASPM mutations in the fetus in compound heterozygous state. The c.3134_3135delTC has never been reported in the literature. Conclusions: Our findings serve additional evidence that WES can be an efficient and relevant tool to diagnose certain genetic disorders with appropriate indication and to assess the recurrence risk of a disease. With the application of WES in combination with pre-implantation genetic tests, we can avoid the transmission of pathogenic mutations and we can achieve a decreased abortion rate in obstetric care.

Three-Year Follow-Up after Intrauterine mTOR Inhibitor Administration for Fetus with TSC-Associated Rhabdomyoma.

Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by seizures, neuropsychiatric disorders, and tumors of the heart, brain, skin, lungs, and kidneys. We present a three-year follow-up of a patient with TSC-associated rhabdomyoma detected in utero. Genetic examination of the fetus and the parents revealed a de novo variant in the TSC2 gene (c.3037delG, p.Asp1013IlefsTer3). Oral everolimus was initiated in the pregnant mother to regress the fetal tumor, which was successful. To the best of our knowledge, there is very little information regarding the use of everolimus therapy during pregnancy. West-syndrome was diagnosed when the proband was four months old. The symptoms were well-manageable, however temporarily. Therapy-resistant focal seizures were frequent. The patient had good vitals and was under regular cardiological control, showed a balanced circulation, and did not require any medication. Subependymal giant cell astrocytoma (SEGA) identified by regular neuroimaging examinations remained unchanged, which may be a consequence of early intrauterine treatment. Early detection of the pathogenic TSC2 variant, followed by in utero administration of everolimus and early vigabatrin therapy, allowed the detection of a milder developmental delay of the proband. Our study emphasizes how early genetic testing and management of epilepsy are pivotal for proper neurodevelopmental impacts and therapeutic strategies.

Observation of a Possible Successful Treatment of DEPDC5-Related Epilepsy with mTOR Inhibitor.

The mechanistic target of the rapamycin signaling pathway serves as a central regulator of cell metabolism, growth, proliferation, and survival. In its regulation, the GTPase-activating protein activity toward Rags1 complex has an inhibitory effect. Mutations in genes encoding this complex protein are among the most common abnormalities in focal epilepsies. Within these mutations, the mutations affecting the DEPDC5 gene have been associated with different autosomal dominantly inherited epilepsy types. Due to the limited data available on mTOR inhibitor therapy in nontuberous sclerosis complex epileptic patients, here we present the clinical management of a patient with intractable epilepsy, skin hypopigmentation, and a DEPDC5 variant. The patient's phenotype is compatible with a nonlesional DEPDC5-related epileptic encephalopathy. We initiated compassionate, off-label everolimus treatment as the patient's condition continuously deteriorated. Due to bilateral pneumonia occurring at the beginning of the treatment, it was temporarily discontinued, and resumed in half the dose. Follow-up examination after 18 months showed a 90% reduction in seizure frequency with moderate improvement in attention function and nutritional status. Our case report emphasizes the importance of early genetic testing in patients with epileptic encephalopathy. Clinical consequences of mammalian target of rapamycin complex 1 (mTORC1) upregulation may be amenable to tailored treatment with mTOR inhibitors. A clinical trial on an international scale would be needed to draw conclusions.

Overlapping Interstitial Deletions of the Region 9q22.33 to 9q33.3 of Three Patients Allow Pinpointing Candidate Genes for Epilepsy and Cleft Lip and Palate.

Introduction: Patients carrying interstitial deletions of the long arm of chromosome 9 show similar features. These phenotypes are often characterized by developmental delay, intellectual disability, short stature, and dysmorphism. Previously reported deletions differ in size and location spanning from 9q21 to 9q34 and were mostly detected by conventional cytogenetic techniques. Methods: Based on clinical features suggesting primarily chromosomal diseases, aCGH analysis was indicated. We report on de novo overlapping interstitial 9q deletions in 3 unrelated individuals presenting neurodevelopmental disorder and multiple congenital anomalies. Results: An 8.03-Mb (90 genes), a 15.71-Mb (193 genes), and a 15.81-Mb (203 genes) deletion were identified in 9q affecting 9q22.33q33.3. The overlapping region was 1.50 Mb, including 2 dosage-sensitive genes, namely EPB41L4B (OMIM #610340) and SVEP1 (OMIM #611691). These genes are thought to be involved in cellular adhesion, migration, and motility. The non-overlapping regions contain 24 dosage-sensitive genes. Conclusion: Besides the frequently described symptoms (developmental delay, intellectual disability, skeletal abnormalities, short stature, and dysmorphic facial features) shared by the patients with interstitial deletions of chromosome 9q reported thus far, two of our patients showed distinct forms of epilepsy, which were successfully treated, and one had a bilateral cleft lip and palate. Possible candidate genes for epilepsy and cleft lip and palate are discussed.

Cognitive functioning and clinical characteristics of children with non-syndromic orofacial clefts: A case-control study.

Introduction: The higher rate of neuropsychiatric disorders in individuals with non-syndromic orofacial clefts has been well documented by previous studies. Our goal was to identify children with non-syndromic orofacial clefts that are at risk for abnormal neurodevelopment by assessing their developmental history and present cognitive functioning. Materials and methods: A single-center, case-controlled study was carried out at the Department of Pediatrics of the University of Pécs in Hungary. The study consisted of three phases including questionnaires to collect retrospective clinical data and psychometric tools to assess IQ and executive functioning. Results: Forty children with non-syndromic oral clefts and 44 age-matched controls participated in the study. Apgar score at 5 min was lower for the cleft group, in addition to delays observed for potty-training and speech development. Psychiatric disorders were more common in the cleft group (15%) than in controls (4.5%), although not statistically significant with small effect size. The cleft group scored lower on the Continuous Performance Test. Subgroup analysis revealed significant associations between higher parental socio-economic status, academic, and cognitive performance in children with non-syndromic orofacial clefts. Analyzes additionally revealed significant associations between early speech and language interventions and higher scores on the Verbal Comprehension Index of the WISC-IV in these children. Discussion: Children with non-syndromic orofacial clefts seem to be at risk for deficits involving the attention domain of the executive system. These children additionally present with difficulties that affect cognitive and speech development. Children with non-syndromic orofacial clefts show significant skill development and present with similar cognitive strengths as their peers. Longitudinal studies with larger sample sizes are needed to provide more conclusive evidence on cognitive deficits in children with non-syndromic orofacial clefts at risk for neurodevelopmental difficulties.

[Neurofibromatosis-1 microdeletion syndrome.] / Neurofibromatosis-1 microdeletiós szindróma.

Neurofibromatosis type 1 is a clinically extremely heterogeneous neurocutaneous disorder, inherited in autosomal dominant manner. It is primarily caused by intragenic loss-of-function mutations in the NF1 gene, however, as a result of improvements in molecular diagnostics, copy number variants affecting the NF1 gene and its flanking regions are increasingly being detected. Based on genotype-phenotype analyses, two groups can be distinguished: neurofibromatosis type 1 caused by point mutations and the so-called 17q11.2 microdeletion syndrome caused by microdeletions. Microdeletions are observed in 5-10% of cases and can be divided into four different types (type 1, 2, 3 and atypical) according to the size of the deletion, the genomic location of the breakpoints and the affected gene content. Patients with microdeletions often have a more severe course of the disease, with an increased risk of malignancies. With this review, which summarizes the main characteristics and molecular genetic background of neurofibromatosis-1 microdeletion syndrome, we would like to emphasize the importance of early diagnosis of patients with microdeletion syndrome and draw attention to the importance of close follow-up. Orv Hetil. 2022; 163(51): 2041-2051.

Xp11.2 Duplication in Females: Unique Features of a Rare Copy Number Variation.

Among the diseases with X-linked inheritance and intellectual disability, duplication of the Xp11.23p11.22 region is indeed a rare phenomenon, with less than 90 cases known in the literature. Most of them have been recognized with the routine application of array techniques, as these copy number variations (CNVs) are highly variable in size, occurring in recurrent and non-recurrent forms. Its pathogenic role is not debated anymore, but the information available about the pathomechanism, especially in affected females, is still very limited. It has been observed that the phenotype in females varies from normal to severe, which does not correlate with the size of the duplication or the genes involved, and which makes it very difficult to give an individual prognosis. Among the patients studied by the authors because of intellectual disability, epilepsy, and minor anomalies, overlapping duplications affecting the Xp11.23p11.22 region were detected in three females. Based on our detailed phenotype analysis, we concluded that Xp11.23p11.22 duplication is a neurodevelopmental disorder.

Gene testing in Treacher Collins syndrome / Génvizsgálat Treacher Collins-szindrómában

Összefoglaló. A Treacher Collins-szindróma a mandibulofacialis dysostosisok csoportjába tartozó kórkép. Fobb jellegzetességei a maxillaris és mandibularis dysostosis, az antimongoloid szemrések, az alsó szemhéj colobomája, illetve a vezetéses halláscsökkenés. A szindrómával járó tünetek egyénenként és családon belül is nagyon eltéroek lehetnek; legenyhébb formái csaknem észrevehetetlenek, míg a súlyosabb esetekben az életet veszélyezteto légúti szövodmények léphetnek fel. Hátterében az esetek dönto többségében a TCOF1-gén eltérései játszanak szerepet, mely eltérések autoszomális domináns módon öröklodnek. Esetbemutatásunk célja, hogy felhívjuk a figyelmet a genetikai vizsgálat elvégzésének fontosságára olyan, klinikailag jól felismerheto tünetegyüttes, mint a Treacher Collins-szindróma esetén. Bár a betegség a klinikai kép alapján diagnosztizálható, az ismétlodés kockázatát csak úgy tudjuk pontosan meghatározni, ha ismerjük a családtagok genotípusát. A bemutatott család több tagjánál kimutatható volt a TCOF1-gén mutációja, annak ellenére, hogy klinikai tünetük nem volt. A jelenség magyarázata az inkomplett penetrancia, azaz a hibás gén fenotípusosan nem kerül kifejezodésre. Orv Hetil. 2020; 161(52): 2201-2205. Summary. Treacher Collins syndrome belongs to the group of mandibulofacial dysostoses. Its main features are maxillary and mandibular dysostosis, downward-slanting palpebral fissures, coloboma of the lower eyelid and conductive hearing loss. The symptoms associated with the syndrome can vary greatly from individual to individual and within the family. In its mildest form, the syndrome is almost imperceptible, and when severe, life-threatening respiratory complication can occur. TCOF1 is the major gene involved with an autosomal dominant mode of inheritance. The purpose of our case study is to draw attention to the importance of performing genetic testing in a clinically recognizable disorder such as Treacher Collins syndrome. Although the disease can be diagnosed based on the clinical symptoms, the risk of recurrence can only be accurately determined if the genotype of the family members is known. Several members of the presented family had a mutation in the TCOF1 gene despite having no clinical symptoms. The explanation for this phenomenon is incomplete penetrance, i.e., the defective gene is not expressed in the phenotype. Orv Hetil. 2020; 161(52): 2201-2205.

Maternal mosaicism underlies the inheritance of a rare germline AKT3 variant which is responsible for megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in two Roma half-siblings.

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a developmental brain disorder characterized by an enlarged brain size with bilateral perisylvian polymicrogyria and a variable degree of ventriculomegaly. MPPH syndrome is associated with oromotor dysfunction, epilepsy, intellectual disability and postaxial hexadactyly. The molecular diagnosis of this disorder is established by the identification of a pathogenic variant in either AKT3, CCND2 or PIK3R2. Previously reported AKT3 variants are associated with various brain abnormalities and may lead to megalencephaly. MPPH syndrome is usually due to germline pathogenic AKT3 variants. Somatic mosaic pathogenic variants associated with hemimegalencephaly, which is similar to MPPH, have also been observed. A Hungarian Roma family with two half-siblings, which present with intellectual disability, dysmorphic features, epilepsy, brain malformations, and megalencephaly was studied. Whole exome sequencing (WES) analysis was performed. WES analysis revealed a heterozygous c.1393C > T p.(Arg465Trp) pathogenic missense AKT3 variant in both affected half-siblings. The variant was verified via Sanger sequencing and was not present in the DNA sample from the healthy mother, which was derived from peripheral blood, suggesting maternal germline mosaicism. In conclusion, this is the first report in which maternal germline mosaicism of a rare pathogenic AKT3 variant leads to autosomal dominantly inherited MPPH syndrome.

Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type.

LGMD1D is an autosomal dominant limb girdle muscular dystrophy caused by variants in the DNAJB6 gene. This is typically an adult-onset disorder characterized by moderately progressive proximal muscle weakness without respiratory or bulbar involvement; however phenotypic variability is often observed with some individuals having earlier onset and more severe symptoms. Here, we present a family with a novel NM_005494.2:c.271T > G p.(Phe91Val) variant in DNAJB6 with a late-onset, mild and slowly progressive form of the disease, including one individual, who in her 7th decade of life has subclinical LGMD1D with only mild features on muscle biopsy and MRI. Unlike previously reported cases where missense variants affecting the Phe91 amino acid residue are associated with a more severe form of the disease, this family represents the mild end of the LGMD1D clinical spectrum. Therefore, this family adds further complexity to the genotype-phenotype correlation in DNAJB6-associated muscular dystrophies.

Mutation spectrum of the SCN1A gene in a Hungarian population with epilepsy.

PURPOSE: The vast majority of mutations responsible for epilepsy syndromes such as genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS) occur in the gene encoding the type 1 alpha subunit of neuronal voltage-gated sodium channel (SCN1A). METHODS: 63 individuals presenting with either DS or GEFS + syndrome phenotype were screened for SCN1A gene mutation using Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). RESULTS: Our research study identified 15 novel pathogen mutations in the SCN1A gene of which 12 appeared to be missense mutations with addition of two frameshift-deletions and one in-frame deletion. The distribution of clinical phenotypes in patients carrying SCN1A mutations was as follows: twelve patients had classical DS, three patients had GEFS + syndrome and two relatives of DS patients were suffering from febrile seizures. CONCLUSIONS: Our study highlights the phenotypic and genotypic heterogeneities of DS and GEFS + with the important aim of gaining a deeper understanding of SCN1A-related disorders. This study also represents the first genetic analysis of the SCN1A gene in a Hungarian cohort with the DS and GEFS + syndrome phenotype.

[MECP2 mutation in a male patient identified in the background of severe epileptic encephalopathy]. / Súlyos epilepsziás encephalopathia hátterében azonosított MECP2-gén-mutáció fiúbetegben.

Here we report on a severe, neonatal onset epileptic encephalopathy manifested in a currently 2-year-old boy with no family history of neurological disease. Extensive clinical investigations were unable to clarify the etiology of the infant's condition characterized by drug-resistant seizures and markedly delayed developmental skills. As in this class of disorders a genetic cause might be identified, a next-generation sequencing (NGS) epilepsy panel examination consisting of 128 genes was initiated for a correct diagnosis. The genetic analysis identified a previously undescribed hemizygous missense mutation in the MECP2 gene. Similarly to other, X-linked dominant disorders, Rett syndrome was originally hypothesized to be lethal in males. This theory, however, has been revised. The aim of this report is to review the wide spectrum of neurodevelopmental diseases observed in male patients carrying mutations in the MECP2 gene classically associated with Rett syndrome in girls. To the author's knowledge, this is the first report in Hungary to document MECP2 mutation of a male patient diagnosed by molecular genetic testing. Orv Hetil. 2019; 160(51): 2036-2039.

Possible Phenotypic Consequences of Structural Differences in Idic(15) in a Small Cohort of Patients.

Among human supernumerary marker chromosomes, the occurrence of isodicentric form of 15 origin is relatively well known due to its high frequency, both in terms of gene content and associated clinical symptoms. The associated epilepsy and autism are typically more severe than in cases with interstitial 15q duplication, despite copy number gain of approximately the same genomic region. Other mechanisms besides segmental aneuploidy and epigenetic changes may also cause this difference. Among the factors influencing the expression of members of the GABAA gene cluster, the imprinting effect and copy number differences has been debated. Limited numbers of studies investigate factors influencing the interaction of GABAA cluster homologues. Five isodicentric (15) patients are reported with heterogeneous symptoms, and structural differences of their isodicentric chromosomes based on array comparative genomic hybridization results. Relations between the structure and the heterogeneous clinical picture are discussed, raising the possibility that the structure of the isodicentric (15), which has an asymmetric breakpoint and consequently a lower copy number segment, would be the basis of the imbalance of the GABAA homologues. Studies of trans interaction and regulation of GABAA cluster homologues are needed to resolve this issue, considering copy number differences within the isodicentric chromosome 15.

[A rare form of ion channel gene mutation identified as underlying cause of generalized epilepsy]. / Generalizált epilepszia hátterében azonosított ioncsatorna-génmutáció ritka formája.

The advances in molecular genetic methods has lead to the discovery of the genetic alterations that underlie the etiology of most diseases previously held to be idiopathic. Targeted genetic examination of a pediatric male patient showing a normal intellect, an extended area of skin hypopigmentation, and suffering from generalized epilepsy displaying a switch in epilepsy syndrome during the course of the disease towards a neurocutaneous syndrome was unsuccessful. Whole-exome sequencing identified a heterozygous missense mutation in a potassium chloride cotransporter gene, which together with the phenotype underscores the diagnosis of an epilepsy syndrome known in the literature as idiopathic generalized epilepsy type 14. Orv Hetil. 2019; 160(21): 835-838.

Rubinstein-Taybi syndrome 2 with cerebellar abnormality and neural tube defect.

Rubinstein-Taybi syndrome (RSTS) is a rare dominant disorder with intellectual disability, postnatal growth deficiency, and multiple congenital anomalies. Approximately 50-70% of the patients have a mutation in the CREBBP gene (RSTS1) and 5-10% display an EP300 gene mutation (RSTS2). Craniospinal abnormalities such as microcranium, scoliosis, and lordosis are frequent findings in RSTS1, but malformations of the brain or spinal cord are seen only occasionally. Here, we report on a 3-year-old boy with facial abnormalities of RSTS, broad thumbs and halluces, developmental delay, autistic features, cerebellar underdevelopment, and a neural tube defect. Molecular diagnostic of the CREBBP and EP300 genes showed a heterozygous 17-bp deletion (c.5698_5714del AAGGCAGCAGGCCAGGT) in exon 31 of the EP300 gene. Findings underline that small (hypoplastic) cerebellum and neural tube defects belong to the phenotypic spectrum not only of RSTS1 but also of RSTS2. Based on the literature and this observation, we recommend that each individual with RSTS2 should be closely evaluated for neural axis and craniovertebral junction anomalies, and where appropriate, neuroimaging studies should be considered. Our frequency estimate of ~ 6% occult or overt neural tube defects in RSTS2 could represent an underestimate.

[A8344G mitochondrial DNA mutation observed in two generations]. / Két generációban megfigyelheto mitokondriális DNS A8344G mutáció.

This article presents the case of a 62-year-old mother and her 41-year-old daughter, who have had severe neurological symptoms for a few decades. After a long investigation period the definite diagnosis of MERRF syndrome was confirmed. After DNA isolation from our patient's blood sample we examined the mitochondrial DNA with direct sequencing. An adenine-guanine substitution was detected in the tRNA gene at position 8344, based on the sequence ferogram the heteroplasmy was over 90%. The clinical phenotype was not clearly characteristic for MERRF syndrome, adult-onset and lipomas are not typical in this disease. In our case report we would like to draw attention to the great phenotypic variation of the mitochondrial diseases and we emphasize that these disorders are underdiagnosed in Hungary even today. Orv. Hetil., 2017, 158(12), 468-471.

[Catch-22? Wide variety of phenotypes associated with the chromosome 22q11 deletion syndrome in two patients]. / A 22-es csapdája? A 22q11 kromoszóma deletiós szindróma változatos klinikai megjelenése két eset kapcsán.

The chromosome 22q11 deletion syndrome may present with a variety of phenotypes. Its symptoms generally include a characteristic facial dysmorphisms and multiplex developmental disorders. Fluorescence in situ hybridization is the current method of choice for the diagnosis if typical multiple defects and/or symptoms are present. The authors present the history of two patients who were followed-up for minor anomalies and various developmental disorders for several years in the genetic counseling office of the authors, but definitive diagnosis was not established. However, when DNA samples of the two patients were recently tested with array comparative genome hybridization, a diagnostic method which has already been used in their institute for several years, the results indicated deletion of the 11.2 region on the long arm of chromosome 22 in both patients. The authors draw attention to the incidence and wide phenotypic spectrum of the chromosome 22q11 deletion syndrome, and show that its identification can be aided with the novel molecular cytogenetic method available in their laboratory.

[Ganciclovir treatment of congenital cytomegalovirus infection]. / Ujszülöttkori cytomegalovirus-fertozés kezelése ganciclovirrel.

The authors present the cases of two infants with congenital cytomegalovirus infection, who to the best of the authors' knowledge were the first ones to receive ganciclovir treatment in Hungary. Both infants were treated for symptomatic congenital cytomegalovirus infection affecting the central nervous system. Ganciclovir was given intravenously in two phases, for a total of 4 and 6 weeks, in a daily dose of 5-10 mg/kg. Diagnosis of infection and follow-up of treatment efficacy was based on the quantitative assessment by PCR assay of viral nucleic acid in blood and urine samples. Treatment resulted in substantial reduction of viral copy numbers in both infants' blood and urine samples. Improvement in the biochemical markers of disease activity was accompanied with spectacular improvement of clinical symptoms in the infant with severe liver involvement. Following the treatment viral loads increased in both infant but clinical symptoms did not reoccur. In one patient a considerable improvement of hearing loss was observed. The authors' first results indicate that ganciclovir treatment of neonatal cytomegalovirus infection represents a promising approach in preventing the progression of the disease and in ameliorating the consequences.