Novel KCNH1 Mutations Associated with Epilepsy: Broadening the Phenotypic Spectrum of KCNH1-Associated Diseases.

Here, we describe four patients suffering from a rather broad spectrum of epilepsy-related disorders, ranging from developmental and epileptic encephalopathy with intellectual disability (DEE) to genetic generalized epilepsy (GGE), which all harbor novel KCNH1 mutations. In one family, we found a weak association of a novel nonsense mutation with epilepsy, suggesting reduced penetrance, and which shows, in agreement with previous findings, that gain-of-function effects rather than haploinsufficiency are important for the pathogenicity of mutations. De novo missense variants in the pore region of the channel result in severe phenotypes presenting usually with DEE with various malformations. The potential pathogenicity of a novel KCNH1 germline mutation located outside of the critical pore domain observed in a GGE patient with a milder phenotype is supported by the fact that the very same amino acid exchange was detected as a somatic mutation in the resected brain tissue of a patient suffering from a focal cortical dysplasia type IIb. Thus, our case series broadens the phenotypic spectrum of KCNH1-associated diseases.

A novel 1p31.3p32.2 deletion involving the NFIA gene detected by array CGH in a patient with macrocephaly and hypoplasia of the corpus callosum.

Interstitial deletions or apparently balanced translocations involving bands 1p31 and 1p32 in the short arm of chromosome 1 are rarely described chromosomal imbalances. To our knowledge, there have been six cases documented to date. Five of these cases, where the NFIA gene is involved, show complex central nervous system malformations and in some cases urinary tract defects. We report another case of a microdeletion with involvement of the NFIA gene in the short arm of chromosome 1 (del(1)(p31.3p32.2)) with, amongst other features, hypoplasia of the corpus callosum, ventriculomegaly, and dysmorphic features. A microdeletion 1p31.3p32.2 which includes the NFIA gene is associated with hypoplasia of the corpus callosum, ventriculomegaly, and dysmorphic features.

Pedaudiologic findings after severe neonatal hyperbilirubinemia.

Neonatal hyperbilirubinemia (NHB) above 20 mg/dl (NHB20) has been shown to increase the risk of hearing impairments. Up to now, audiological findings based on behavioural audiometry (BA), otoacoustic emissions (TEOAE) and auditory brainstem responses (ABR) from children after being diagnosed with NHB20 have not been thoroughly compared to those with lower NHB-levels. We, therefore, aimed to assess the presence and characteristics of auditory dysfunction in children with NHB20. The audiological data of 15 children aged 11 months to 9 years with a NHB level between 22.6 and 45.6 mg/dl and/or MRI-confirmed bilirubin encephalopathy (NHBG) were compared retrospectively to 15 children with NHB levels between 12.5 and 19.4 mg/dl (CG). After matching by weeks of gestation at birth, BA, TEOAE and ABR were performed in all the children. Subsequently the groups were compared. Only two children of the NHBG had consistently normal audiologic findings. Hearing function disorders were detected in 87% (13/15) of the NHBG-children, ranging from total deafness to normal BA, including unilateral and bilateral deafness as well as cochlear hearing loss. Auditory neuropathy/dys-synchrony (AN) was found in a total of eight children (53%) of the NHBG. In addition, it was found that after the occurrence of NHB20, initially detected TEOAE can disappear in some cases. In the comparison group (CG) only two children demonstrated a hearing dysfunction, both of which were cochlear hearing impairments, whereas no child had AN. A bias towards hearing impairments has to be taken into account for both groups. Detailed pedaudiologic testing should be mandatory for all children after the occurrence of NHB20 including follow-up during the first 12 months. Audiological diagnostic work-up in the affected children requires objective investigations of hearing functions, while BA is recommended to evaluate the adequate therapeutic procedure.

Agenesis and dysgenesis of the corpus callosum: clinical, genetic and neuroimaging findings in a series of 41 patients.

Agenesis of the corpus callosum (ACC) is among the most frequent human brain malformations with an incidence of 0.5-70 in 10,000. It is a heterogeneous condition, for which several different genetic causes are known, for example, ACC as part of monogenic syndromes or complex chromosomal rearrangements. We systematically evaluated the data of 172 patients with documented corpus callosum abnormalities in the records, and 23 patients with chromosomal rearrangements known to be associated with corpus callosum changes. All available neuroimaging data, including CT and MRI, were re-evaluated following a standardized protocol. Whenever feasible chromosome and subtelomere analyses as well as molecular genetic testing were performed in patients with disorders of the corpus callosum in order to identify a genetic diagnosis. Our results showed that 41 patients with complete absence (agenesis of the corpus callosum-ACC) or partial absence (dysgenesis of the corpus callosum-DCC) were identified. Out of these 28 had ACC, 13 had DCC. In 11 of the 28 patients with ACC, the following diagnoses could be established: Mowat-Wilson syndrome (n = 2), Walker-Warburg syndrome (n = 1), oro-facial-digital syndrome type 1 (n = 1), and chromosomal rearrangements (n = 7), including a patient with an apparently balanced reciprocal translocation, which led to the disruption and a predicted loss of function in the FOXG1B gene. The cause of the ACC in 17 patients remained unclear. In 2 of the 13 patients with DCC, unbalanced chromosomal rearrangements could be detected (n = 2), while the cause of DCC in 11 patients remained unclear. In our series of cases a variety of genetic causes of disorders of the corpus callosum were identified with cytogenetic anomalies representing the most common underlying etiology.

Expanding the phenotype of alopecia-contractures-dwarfism mental retardation syndrome (ACD syndrome): description of an additional case and review of the literature.

Alopecia-contractures-dwarfism mental retardation syndrome (ACD syndrome; OMIM 203550) is a very rare genetic disorder with distinct features. To our knowledge, there have been four cases documented to date. In addition, another three patients, previously described as having IFAP syndrome (OMIM %308205), may also have ACD syndrome. We report on one patient with short stature, total alopecia, ichthyosis, photophobia, seizures, ectrodactyly, vertebral anomalies, scoliosis, multiple contractures, mental retardation, and striking facial and other features (e.g. microdolichocephaly, missing eyebrows and eyelashes, long nose, large ears) consistent with ACD syndrome. Results of laboratory testing in the literature case reports were normal, although in none of them, array-CGH (microarray-based comparative genomic hybridization) analysis was performed. In conclusion, the combination of specific features, including total alopecia, ichthyosis, mental retardation, and skeletal anomalies are suggestive of ACD syndrome. We propose that children with this syndrome undergo a certain social pediatric protocol including EEG diagnostics, ophthalmological investigation, psychological testing, management of dermatologic and orthopedic problems, and genetic counseling.

Conductive education for children with cerebral palsy: effects on hand motor functions relevant to activities of daily living.

OBJECTIVE: To study the effects of conductive education, a combined educational and therapeutic task-oriented approach for children with cerebral palsy (CP), on their hand motor functions and activities of daily living (ADLs). DESIGN: Individual cohort study (B-A-B design). SETTING: Ambulatory, referral center. PARTICIPANTS: Sixty-four children with CP, severity Gross Motor Function Classification System levels II through IV, ages 3 to 6 years. INTERVENTIONS: Phases B: a 4.5-month period of special education, including 2 hours of individual physiotherapy or occupational therapy per week (special education). Phase A: during a 9-month period, conductive education was administered in 3 blocks of 4 weeks (7 hours daily from Monday through Friday); between the blocks, special education was applied as in the B phases. MAIN OUTCOME MEASURES: Transformed sum scores (0.00-1.00) for coordinative (eg, force-movement synergy during object manipulation, aiming) and for elementary hand functions (eg, maximum grip force, tapping), based on kinetic and kinematic measures; standardized parent questionnaire to measure ADL competence scores from 0.00 (dependence) to 1.00 (independence). Outcome parameters were changes in these parameters during phase A (intervention) compared with average changes during the B phases (pre- and postintervention). Student t tests were used for dependent samples. RESULTS: Conductive education improved coordinative hand functions by 20% to 25% from baseline, compared with no improvement during special education; the preferred hand improved from .38 to .48 (mean, .10; 95% confidence interval [CI], .086-.114) and the nonpreferred hand improved from .39 to .47 (mean, .08; 95% CI, .034-.116). There were no changes in elementary hand motor functions. ADL competence improved by .11 (95% CI, .070-.149), from .50 to .61 ( approximately 20%), compared with no significant improvement under special education. CONCLUSIONS: Conductive education improved coordinative hand functions and ADLs in children with CP. There was no effect on elementary hand functions.

Gomez-Lopez-Hernandez syndrome (cerebello-trigeminal-dermal dysplasia): description of an additional case and review of the literature.

Gomez-Lopez-Hernandez syndrome is a very rare genetic disorder with a distinct phenotype (OMIM 601853). To our knowledge there have been seven cases documented to date. We report on an additional male patient now aged 15 8/12 years with synostosis of the lambdoid suture, partial scalp alopecia, corneal opacity, mental retardation and striking phenotypic features (e.g., brachyturricephaly, hypertelorism, midface hypoplasia and low-set ears) consistent with Gomez-Lopez-Hernandez syndrome. In early childhood the patient demonstrated aggressive behavior and raging periods. He also had seizures that were adequately controlled by medication. Magnetic resonance imaging (MRI) revealed rhombencephalosynapsis, i.e., a rare fusion of the cerebellar hemispheres, also consistent with Gomez-Lopez-Hernandez syndrome. In addition a lipoma of the quadrigeminal plate was observed, a feature not previously described in the seven patients reported in the literature. Cytogenetic and subtelomere analyses were inconspicuous. Microarray-based comparative genomic hybridization (array-CGH) testing revealed five aberrations (partial deletions of 1p21.1, 8q24.23, 10q11.2, Xq26.3 and partial duplication of 19p13.2), which, however, have been classified as normal variants. Array-CGH has not been published in the previously reported children. The combination of certain craniofacial features, including partial alopecia, and the presence of rhombencephalosynapsis in the MRI are suggestive of Gomez-Lopez-Hernandez syndrome. Children with this syndrome should undergo a certain social pediatric protocol including EEG diagnostics, ophthalmological investingation, psychological testing, management of behavioral problems and genetic counseling.

Feeding disorders in ex-prematures: causes--response to therapy--long term outcome.

Feeding disorders in ex-prematures do exist and may constitute a major challenge to their families' well being. A cases series of 86 ex-prematures with severe feeding disorders was analysed regarding co-morbidity, response to therapy and the long-term outcome after treatment. These children with a gestational age of <37 weeks had been referred for hospital rehabilitation because of severe feeding disorders, defined as tube feeding or average feeding times of more than 30 minutes. Behavioural therapy was the key element of the treatment. Ex-prematures accounted for 86/266 patients admitted for treatment of feeding disorders between 1995 and 2004. Whereas only 40.8% of these had cerebral palsy, 51.1% had a diagnosis of mental retardation and 87% had interaction problems. Response to treatment up to discharge was achieved in 61.6%. Univariat analyses showed that tube feeding at admission and swallowing difficulties were the best predictors of failure to respond to the intervention. Long-term follow-up data that were collected for 53 of the 86 children with similar initial response to therapy (64.2%) compared to children with no follow-up data (57.6%). Success of therapy after discharge was maintained in 94.1%; however, 25% of the children with normal BMI's at discharge and sustained success of therapy fell below the 3rd BMI percentile. Cerebral palsy, mental retardation and interaction problems appear to be important risk factors for severe feeding disorders in ex-prematures. A therapeutic intervention based on behavioural therapy achieved sustained success in almost two thirds of the children.

Association between life stress during pregnancy and infant crying in the first six months postpartum: a prospective longitudinal study.

OBJECTIVE: To examine prospectively the relationship between prenatal life stress and infant crying/fussing during the first 6 months of postnatal life, taking into account an array of confounders suggested in the literature. DESIGN: Prospective longitudinal study of a convenient sample, with data points in pregnancy and at about 6 weeks, 3, and 6 months postpartum. METHODS: The study included 86 pregnant women who completed a standardized, validated and widely used questionnaire on negative life changes experienced in the preceding 12 months. Women were grouped by median split on the impact score of negative life changes. Demographic, obstetric and lifestyle variables were obtained from pre- and postnatal interviews and from medical records in order to be taken into account as possible confounders. At all three postnatal data points, mothers kept a validated 5-day 24-h behavior diary to assess durations of infant crying/fussing. RESULTS: Infants of mothers with high scores of negative life changes exhibited more crying/fussing than infants born to mothers with low negative change scores, throughout the first half year postpartum, but particularly at ages 3 and 6 months. These results do not seem to be spurious due to the confounders considered in this report or to recording bias. CONCLUSION: Prenatal life stress is associated with infant crying/fussing in the first half year after delivery. To prevent or reduce infant crying and to foster a well-adapted parent-infant relationship, professionals attending expectant mothers should consider their emotional condition. If required, support should be provided already in pregnancy.

Screening of the hearing of newborns - Update.

INTRODUCTION: Permanent congenital bilateral hearing loss (CHL) of moderate or greater degree (≥40 dB HL) is a rare disease, with a prevalence of about 1 to 3 per 1000 births. However, it is one of the most frequent congenital diseases. Reliance on physician observation and parental recognition has not been successful in the past in detecting significant hearing loss in the first year of life. With this strategy significant hearing losses have been detected in the second year of life. With two objective technologies based on physiologic response to sound, otoacoustic emissions (OAE) and auditory brainstem response (ABR) hearing screening in the first days of life is made possible. OBJECTIVES: The objective of this health technology assessment report is to update the evaluation on clinical effectiveness and cost-effectiveness of newborn hearing screening programs. Universal newborn hearing screening (UHNS) (i), selective screening of high risk newborns (ii), and the absence of a systematic screening program are compared for age at identification and age at hearing aid fitting of children with hearing loss. Secondly the potential benefits of early intervention are analysed. Costs and cost-effectiveness of newborn hearing screening programs are determined. This report is intended to make a contribution to the decision making whether and under which conditions a newborn hearing screening program should be reimbursed by the statutory sickness funds in Germany. METHODS: This health technology assessment report updates a former health technology assessment (Kunze et al. 2004 [1]). A systematic review of the literature was conducted, based on a documented search and selection of the literature using predefined inclusion and exclusion criteria and a documented extraction and appraisal of the included studies. To assess the cost-effectiveness of the different screening strategies in Germany the decision analytic Markov state model which had been developed in our former health technology assessment report was updated. RESULTS: Universal newborn hearing screening programs are able to substantially reduce the age at identification and the age at intervention of children with CHL to six months of age in the German health care setting. High coverage rates, low fail rates and - if tracking systems are implemented - high follow-up-rates to diagnostic evaluation for test positives were achieved. New publications on potential benefits of early intervention could not be retrieved. For a final assessment of cost-effectiveness of newborn hearing screening evidence based long-term data are lacking. Decision analytic models with lifelong time horizon assuming that early detection results in improved language abilities and lower educational costs and higher life time productivity showed a potential of UNHS for long term cost savings compared to selective screening and no screening. For the short-term cost-effectiveness with a time horizon up to diagnostic evaluation more evidence based data are available. The average costs per case diagnosed range from 16,000 EURO to 33,600 EURO in Germany and hence are comparable to the cost of other implemented newborn screening programs. Empirical data for cost of selective screening in the German health care setting are lacking. Our decision analytic model shows that selective screening is more cost-effective but detects only 50% of all cases of congenital hearing loss. DISCUSSION: There is good evidence that UNHS-Programs with appropriate quality management can reduce the age at start of intervention below six months. Up to now there is no indication of considerable negative consequences of screening for children with false positive test results and their parents. However, it is more difficult to prove the efficacy of early intervention to improve long-term outcomes. Randomized clinical trials of the efficacy of early intervention for children with CHL hearing losses are inappropriate because of ethical reasons. Prospective cohort studies with long-term outcomes of rare diseases are costly, take a long time and simultaneously substantial benefits of early intervention for language development seem likely. CONCLUSIONS: A UNHS-Program should be implemented in Germany and be reimbursed by the statutory sickness funds. To achieve high coverage and because of better conditions for obtaining low false positive rates UNHS should be performed in hospital after birth. For outpatient deliveries additionally screening measures in an outpatient setting must be provided.

Haploinsufficiency of novel FOXG1B variants in a patient with severe mental retardation, brain malformations and microcephaly.

We have investigated the chromosome abnormalities in a female patient exhibiting a severe cognitive disability associated with complete agenesis of the corpus callosum and microcephaly. The patient carries a balanced de novo translocation t(2;14)(p22;q12), together with a neighbouring 720 kb inversion in chromosome 14q12. By combined fluorescence in situ hybridisation and Southern hybridisation, the distal inversion breakpoint on chromosome 14 was mapped to a region harbouring genes and ESTs derived predominantly from brain tissue. RT-PCR studies indicated that these transcripts comprise the 3' ends of novel splice variants of the winged helix transcription factor FOXG1B (also referred to in previous studies as FOXG1A and FOXG1C, as well as Brain Factor 1), the mouse orthologue of which is essential for normal development of the telencephalon. Analysis of these novel FOXG1B transcripts indicated that they are all disrupted by the breakpoint in the patient. Moreover, we have identified novel orthologous Foxg1 transcripts in the mouse and other vertebrates, which validates the functional importance of these variants and provides a direct genetic link between the patient phenotype and that of the heterozygous Foxg1 knockout mice. These results, together with previously published studies on patients with similar disorders and proximal 14q deletions, strongly suggest that several disorders associated with malformations of the human brain may be directly caused by mutations or alterations in the FOXG1B gene.

Economic evaluation of newborn hearing screening: modelling costs and outcomes.

OBJECTIVES: The prevalence of newborn hearing disorders is 1-3 per 1,000. Crucial for later outcome are correct diagnosis and effective treatment as soon as possible. With BERA and TEOAE low-risk techniques for early detection are available. Universal screening is recommended but not realised in most European health care systems. Aim of the study was to examine the scientific evidence of newborn hearing screening and a comparison of medical outcome and costs of different programmes, differentiated by type of strategy (risk screening, universal screening, no systematical screening). METHODS: In an interdisciplinary health technology assessment project all studies on newborn hearing screening detected in a standardized comprehensive literature search were identified and data on medical outcome, costs, and cost-effectiveness extracted. A Markov model was designed to calculate cost-effectiveness ratios. RESULTS: Economic data were extracted from 20 relevant publications out of 39 publications found. In the model total costs for screening of 100,000 newborns with a time horizon of ten years were calculated: 2.0 Mio.euro for universal screening (U), 1.0 Mio.euro for risk screening (R), and 0.6 Mio.euro for no screening (N). The costs per child detected: 13,395 euro (U) respectively 6,715 euro (R), and 4,125 euro (N). At 6 months of life the following percentages of cases are detected: U 72%, R 43%, N 13%. CONCLUSIONS: A remarkable small number of economic publications mainly of low methodological quality was found. In our own model we found reasonable cost-effectiveness ratios also for universal screening. Considering the outcome advantages of higher numbers of detected cases a universal newborn hearing screening is recommended.