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Temple syndrome (TS14, #616222) is a rare imprinting disorder characterised by phenotypic features including pre- and postnatal growth retardation, muscular hypotonia and feeding difficulties in infancy, early puberty and short stature with small hands and feet and often truncal obesity. It is caused by maternal uniparental disomies, paternal deletions and primary imprinting defects that affect the chromosomal region 14q32 and lead to a disturbed expression of imprinted genes in this region. Here, we present detailed clinical data of 8 patients with Temple syndrome, 4 with an imprinting defect, 2 with an imprinting defect in a mosaic state as well as 1 complete and 1 segmental maternal uniparental disomy of chromosome 14.

Background Mandibuloacral Dysplasia with type B lipodystrophy (MADB) is a rare premature aging disorder with an autosomal recessive inheritance pattern. MADB is characterized by brittle hair, mottled, atrophic skin, generalized lipodystrophy, insulin resistance, metabolic complications and skeletal features like stunted growth, mandibular and clavicular hypoplasia and acro-osteolysis of the distal phalanges. MADB is caused by reduced activity of the enzyme zinc metalloprotease ZMPSTE24 resulting from compound heterozygous or homozygous mutations in ZMPSTE24. Methods In 2012, and again in 2018, eight related patients from the remote tropical rainforest of inland Suriname were analysed for dysmorphic features. DNA analysis was performed and clinical features were documented. We also analysed all previously reported genetically confirmed MADB patients from literature (n = 12) for their clinical features. Based on the features of all cases (n = 20) we defined major criteria as those present in 85–100% of all MADB patients and minor criteria as those present in 70–84% of patients. Results All the Surinamese patients are of African descent and share the same homozygous c.1196A > G, p.(Tyr399Cys) missense variant in the ZMPSTE24 gene, confirming MADB. Major criteria were found to be: short stature, clavicular hypoplasia, delayed closure of cranial sutures, high palate, mandibular hypoplasia, dental crowding, acro-osteolysis of the distal phalanges, hypoplastic nails, brittle and/or sparse hair, mottled pigmentation, atrophic and sclerodermic skin, and calcified skin nodules. Minor criteria were (generalized or partial) lipoatrophy of the extremities, joint contractures and shortened phalanges. Based on our detailed clinical observations, and a review of previously described cases, we propose that the clinical diagnosis of MADB is highly likely if a patient exhibits ≥4 major clinical criteria OR ≥ 3 major clinical criteria and ≥ 2 minor clinical criteria. Conclusions We report on eight related Surinamese patients with MADB due to a homozygous founder mutation in ZMPSTE24. In low-income countries laboratory facilities for molecular genetic testing are scarce or lacking. However, because diagnosing MADB is essential for guiding clinical management and for family counselling, we defined clinical diagnostic criteria and suggest management guidelines.

Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is characterized by a variable degree of intellectual disability, impaired speech and language as well as social communicative skills and mild dysmorphic features. The SHANK3 gene is thought to be a major contributor to the phenotype. Apart from the syndrome-associated autistic features, symptoms from the bipolar spectrum can be discerned, in particular behavior instability and fluctuating mood culminating in a (hypo)manic state. In case of coincident major somatic events, a deteriorating course may occur. This study comprises seven adult patients (four females and three males; aged 21-44 years) with genetically proven PMS. Data from medical records were collected and extensive assessment of neuropsychological variables was performed to identify cognitive characteristics and their relation with psychopathology and treatment. All patients showed profound communication deficits and their developmental functioning ranged from 1.0 to 6.3 years. In addition, they had slow speed of information processing, impairment of attentional and executive functions and cognitive alexithymia. As to psychopathology, features from the affective and anxiety domains were prominent findings in these seven patients suggesting the presence of a bipolar spectrum disorder that could be effectively moderated with mood-stabilizing agents. Results are discussed in terms of the putative involvement of structural brain abnormalities, in particular cerebellar vermis hypoplasia and corpus callosum thinning and their cognitive and emotional sequelae. It is concluded that the treatment of 22q13.3-associated psychopathology should include prescription of mood-stabilizing agents in combination with individually tailored contextual neuropsychological measures.

BACKGROUND AND PURPOSE: We present the largest case series to date on basiocciput abnormalities in CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, and Ear abnormalities and/or deafness). We aimed to show that basiocciput abnormalities are common and may aid in diagnosis. We furthermore explored whether clivus size correlates with the type of chromodomain-helicase-DNA binding protein 7 gene (CHD7) mutation, which causes CHARGE syndrome, and with clinical criteria according to Blake et al and Verloes.MATERIALS AND METHODS: We retrospectively analyzed the clivus of 23 patients with CHARGE syndrome with CHD7 mutations on MR imaging or CT. We recorded the size of the clivus, the Welcher angle, basilar invagination, and Chiari I malformations. We compared the clival size and Welcher angle of patients with CHARGE syndrome with those of 72 age-matched controls. Additionally, we tested for correlations between clivus size and mutation type or clinical criteria.RESULTS: Eighty-seven percent of the patients with CHARGE syndrome had an abnormal clivus; 61% had a clivus >2.5 SD smaller than that of age-matched controls. An abnormally large Welcher angle was observed in 35%. Basiocciput hypoplasia was found in 70%, and basilar invagination, in 29%. None of the patients had a Chiari I malformation. At the group level, patients with CHARGE syndrome had a smaller clivus and larger Welcher angle than controls. No significant correlation between clivus size and mutation type or clinical criteria was found.CONCLUSIONS: Most patients with CHARGE syndrome have an abnormal clivus. This suggests that clivus abnormalities may be used as an additional diagnostic tool. Our results provide evidence that CHD7, which is expressed in the presomitic mesoderm during somitogenesis, plays an important role in the formation of the clivus.

Due to small numbers of reported patients with pathogenic variants in single genes, the phenotypic spectrum associated with genes causing neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorder is expanding. Among these genes is KLF7 (Kruppel-like factor 7), which is located at 2q33.3 and has been implicated in several developmental processes. KLF7 has been proposed to be a candidate gene for the phenotype of autism features seen in patients with a 2q33.3q34 deletion. Herein, we report 4 unrelated individuals with de novo KLF7 missense variants who share similar clinical features of developmental delay/ID, hypotonia, feeding/swallowing issues, psychiatric features and neuromuscular symptoms, and add to the knowledge about the phenotypic spectrum associated with KLF7 haploinsufficiency.

STUDY QUESTION: What is the prevalence of chromosomal abnormalities in azoospermic men and what are the clinical consequences in terms of increased risk for absent spermatogenesis, miscarriages and offspring with congenital malformations?SUMMARY ANSWER: The prevalence of chromosomal abnormalities in azoospermia was 14.4%, and the number of azoospermic men needed to be screened (NNS) to identify one man with a chromosomal abnormality with increased risk for absence of spermatogenesis was 72, to prevent one miscarriage 370-739 and to prevent one child with congenital malformations 4751-23 757.WHAT IS KNOWN ALREADY: Infertility guidelines worldwide advise screening of non-iatrogenic azoospermic men for chromosomal abnormalities, but only few data are available on the clinical consequences of this screening strategy.STUDY DESIGN, SIZE, DURATION: This retrospective multicentre cross-sectional study of non-iatrogenic azoospermic men was performed at the University Hospital Brussels, Belgium, and the University Medical Centre Groningen, The Netherlands, between January 2000 and July 2016.PARTICIPANTS/MATERIALS, SETTING, METHODS: Analysis of clinical registries retrospectively identified 1663 non-iatrogenic azoospermic men with available results of karyotyping and FSH serum levels. Iatrogenic azoospermia was an exclusion criterion, defined as azoospermia after spermatotoxic medical treatment, exogenous androgen suppletion or vasectomy and/or vasovasostomy. Also, men with a clinical diagnosis of anejaculation or hypogonadotropic hypo-androgenism and/or FSH values = 10 U/l) azoospermia. We estimated the NNS for chromosomal abnormalities to identify one man with absence of spermatogenesis and to prevent one miscarriage or one child with congenital malformations, and calculated the surgical sperm retrieval rates per chromosomal abnormality.MAIN RESULTS AND THE ROLE OF CHANCE: The overall prevalence of chromosomal abnormalities in azoospermia was 14.4% (95% CI 12.7-16.1%), its prevalence being higher in hypergonadotropic azoospermia (20.2%, 95% CI 17.8-22.7%) compared to normogonadotropic azoospermia (4.9%, 95% CI 3.2-6.6%, P LIMITATIONS, REASONS FOR CAUTION: The absolute number of chromosomal abnormalities associated with clinical consequences and adverse pregnancy outcomes in our study was limited, thereby increasing the role of chance. Further, as there are currently no large series on outcomes of pregnancies in men with chromosomal abnormalities, our conclusions are partly based on assumptions derived from the literature.WIDER IMPLICATIONS OF THE FINDINGS: The NNS found can be used in future cost-effectiveness studies and the evaluation of current guidelines on karyotyping in non-iatrogenic azoospermia.

Individuals with an extra X chromosome are at increased risk for autism symptoms. This study is the first to assess theory of mind and facial affect labeling in children with an extra X chromosome. Forty-six children with an extra X chromosome (29 boys with Klinefelter syndrome and 17 girls with Trisomy X), 56 children with autism spectrum disorder (ASD) and 88 non-clinical controls, aged 9-18 years, were included. Similar to children with ASD, children with an extra X chromosome showed significant impairments in social cognition. Regression analyses showed that different cognitive functions predicted social cognitive skills in the extra X and ASD groups. The social cognitive deficits were similar for boys and girls with an extra X chromosome, and not specific for a subgroup with high Autism Diagnostic Interview Revised autism scores. Thus, children with an extra X chromosome show social cognitive deficits, which may contribute to social dysfunction, not only in children showing a developmental pattern that is 'typical' for autism but also in those showing mild or late presenting autism symptoms. Our findings may also help explain variance in type of social deficit: children may show similar social difficulties, but these may arise as a consequence of different underlying information processing deficits.

Otocephaly-dysgnathia complex is characterized by mandibular hypo- or aplasia, ear abnormalities, microstomia, and microglossia. Mutations in the orthodenticle homeobox 2 (OTX2) and paired related homeobox 1 (PRRX1) genes have recently been identified in some cases. We screened 4 otocephalic cases for these 2 genes and identified OTX2 mutations in 2 of them, thus confirming OTX2 is implicated in otocephaly. No PRRX1 mutation was identified. Interestingly, ocular involvement is not a constant feature in otocephalic cases with an OTX2 mutation. In one case, the mutation was inherited from a microphthalmic mother. The mechanism underlying this intrafamilial phenotypic variability remains unclear, but other genetic factors are likely to be necessary for the manifestation of the otocephalic phenotype.

CHARGE (coloboma, heart defects, atresia of choanae, retardation of growth and development, genital hypoplasia, and ear abnormalities) and 22q11.2 deletion syndromes are variable, congenital malformation syndromes that show considerable phenotypic overlap. We further explored this clinical overlap and proposed recommendations for the genetic diagnosis of both syndromes. We described 2 patients clinically diagnosed with CHARGE syndrome, who were found to carry a 22q11.2 deletion, and searched the literature for more cases. In addition, we screened our cohort of CHD7 mutation carriers (n = 802) for typical 22q11.2 deletion features and studied CHD7 in 20 patients with phenotypically 22q11.2 deletion syndrome but without haploinsufficiency of TBX1. In total, we identified 5 patients with a clinical diagnosis of CHARGE syndrome and a proven 22q11.2 deletion. Typical 22q11.2 deletion features were found in 30 patients (30/802, 3.7%) of our CHD7 mutation-positive cohort. We found truncating CHD7 mutations in 5/20 patients with phenotypically 22q11.2 deletion syndrome. Differentiating between CHARGE and 22q11.2 deletion syndromes can be challenging. CHD7 and TBX1 probably share a molecular pathway or have common target genes in affected organs. We strongly recommend performing CHD7 analysis in patients with a 22q11.2 deletion phenotype without TBX1 haploinsufficiency and conversely, performing a genome-wide array in CHARGE syndrome patients without a CHD7 mutation.

How many infertile men who wish to conceive need to be screened for chromosomal abnormalities to prevent one miscarriage or the birth of one child with congenital anomalies (CAs)?In azoospermic men, the prevalence of chromosomal abnormalities is 15.2 and the number needed to be screened (NNS; minimummaximum estimate) for a miscarriage is 8088 and for a child with CAs is 7903951. The prevalence of chromosomal abnormalities in non-azoospermic men is 2.3 and the NNS are 315347 and 254312 723, respectively.Guidelines advise the screening of infertile men for chromosomal abnormalities to prevent miscarriages and children with congenital abnormalities, but no studies have been published on the effectiveness of this screening strategy.Retrospective cohort study of 1223 infertile men between 1994 and 2007.Men with azoospermia and men eligible for ICSI treatment visiting a university hospital fertility clinic in The Netherlands who underwent chromosomal analysis between 1994 and 2007 were identified retrospectively in a registry. Only cases of which at least one sperm analysis was available were included. Data were collected by chart review, with a follow-up of pregnancies and their outcomes until 2010. The chromosomal abnormalities were categorized according to their risk of unbalanced offspring, i.e. miscarriage and/or child with CAs. Multi-level analysis was used to estimate the impact of chromosomal abnormalities on the outcome of pregnancies in the different subgroups of our cohort. NNS for miscarriages and children with CAs were calculated based on data from our cohort and data published in the literature.A chromosomal abnormality was found in 12 of 79 men with azoospermia (15.2) and in 26 of 1144 non-azoospermic men (2.3). The chromosomal abnormalities were categorized based on the literature, into abnormalities with and abnormalities without increased risk for miscarriage and/or child with CAs. In our study group, there was no statistically significant difference between the subgroups with and without increased risk respectively, regarding the frequency of children born with CAs (1/20; 5.0 versus 1/14; 7.1), miscarriage (9/20; 45.0 versus 2/14; 14.3) or unaffected liveborn children (9/20; 45.0 versus 9/14; 64.3). The prevalence of chromosomal abnormalities with a theoretically increased risk of unbalanced progeny was 1.0 in non-azoospermic men and 3.8 in men with azoospermia. For the calculation of the NNS, the risk of an adverse pregnancy outcome in our cohort was compared with the incidence ranges of miscarriage and children with CAs in the general population. The number of azoospermic men that needs to be screened to prevent one miscarriage (8088) or one child with CAs (7903951) was considerably lower compared with the NNS in the non-azoospermic group (315347 and 254312 723, respectively).The prevalence of chromosomal abnormalities in infertile men is low, and although we included 1223 men, our conclusions are based on a small number (38) of abnormal karyotypes. As there are no large series on outcomes of pregnancies in infertile men with chromosomal abnormalities, our conclusions had to be partly based on assumptions derived from the literature.Based on the NNS calculated in our study, screening for chromosomal abnormalities is recommended in all azoospermic men. In non-azoospermic infertile men, screening might be limited to men with an additional risk factor (e.g. a history of recurrent miscarriage or a positive family history for recurrent miscarriage or children with CAs). The NNS can be used in future cost-effectiveness studies and the evaluation of current guidelines on karyotyping infertile men.Our institution has received research grants from Merck Sharpe Dohme BV, Ferring Pharmaceuticals and Merck Serono, The Netherlands. No competing interests declared.

Background CHARGE syndrome is a highly variable, multiple congenital anomaly syndrome, of which the complete phenotypic spectrum was only revealed after identification of the causative gene in 2004. CHARGE is an acronym for ocular coloboma, congenital heart defects, choanal atresia, retardation of growth and development, genital hypoplasia, and ear anomalies associated with deafness. This typical combination of clinical features is caused by autosomal dominant mutations in the CHD7 gene. Objective To explore the emerging phenotypic spectrum of CHD7 mutations, with a special focus on the mild end of the spectrum. Methods We evaluated the clinical characteristics in our own cohort of 280 CHD7 positive patients and in previously reported patients with CHD7 mutations and compared these with previously reported patients with CHARGE syndrome but an unknown CHD7 status. We then further explored the mild end of the phenotypic spectrum of CHD7 mutations. Results We discuss that CHARGE syndrome is primarily a clinical diagnosis. In addition, we propose guidelines for CHD7 analysis and indicate when evaluation of the semicircular canals is helpful in the diagnostic process. Finally, we give updated recommendations for clinical surveillance of patients with a CHD7 mutation, based on our exploration of the phenotypic spectrum and on our experience in a multidisciplinary outpatient clinic for CHARGE syndrome. Conclusion CHARGE syndrome is an extremely variable clinical syndrome. CHD7 analysis can be helpful in the diagnostic process, but the phenotype cannot be predicted from the genotype.

STUDY QUESTION: Do clinical characteristics of recurrent miscarriage couples with a chromosomal abnormality and who opt for PGD differ from couples that decline PGD after extensive genetic counselling?SUMMARY ANSWER: No differences in clinical characteristics are identified between recurrent miscarriage couples carrying a structural chromosomal abnormality who opt for PGD compared with those that decline PGD after extensive genetic counselling.WHAT IS KNOWN ALREADY: Couples who have experienced two or more miscarriages (recurrent miscarriage) are at increased recurrence risk if one of the partners carries a structural chromosomal abnormality. PGD can be offered to avoid (another) miscarriage or pregnancy termination when (invasive) prenatal diagnosis shows an abnormal result. To date, no reports are available that describe reproductive decision-making after genetic counselling on PGD in these specific couples.STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 294 couples carrying a structural chromosomal abnormality seeking genetic counselling on PGD between 1996 and 2012.PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were recurrent miscarriage couples carrying a structural chromosomal abnormality. They had been referred for genetic counselling to the only national licensed PGD centre. Clinical characteristics analysed included couple associated characteristics, characteristics concerning reproductive history and external characteristics such as type of physician that referred the couple for genetic counselling and the clinical geneticist performing the counselling on PGD.MAIN RESULTS AND THE ROLE OF CHANCE: Of 294 couples referred for counselling on PGD, 26 were not accepted because they did not meet the criteria for IVF-PGD. The remaining cohort of 268 couples consisted of two-thirds female and one-third male carriers. Main PGD indications were reciprocal translocations (83.9%) and Robertsonian translocations (16.7%). Following genetic counselling, 76.9% of included couples chose PGD as their reproductive option, the others declined PGD. Reproductive choice is not influenced by sex of the translocation carrier (P = 0.499), type of chromosomal abnormality (P = 0.346), number of previous miscarriages (P = 0.882), history of termination of pregnancy (TOP) because of an unbalanced fetal karyotype (P = 0.800), referring physician (P = 0.208) or geneticist who performed the counselling (P = 0.410).LIMITATIONS, REASONS FOR CAUTION: This study only included recurrent miscarriage couples carrying a structural chromosomal abnormality, who were actually referred to a PGD clinic for genetic counselling. We lack information on couples who were not referred for PGD. Some of these patients may not have been informed on PGD at all, while others were not referred for counselling because they did not opt for PGD to start with.WIDER IMPLICATIONS OF THE FINDINGS: This study shows that reproductive choices in couples with recurrent miscarriage on the basis of a structural chromosomal abnormality are not influenced by characteristics of the couple itself, nor by their obstetric history or external characteristics. These findings suggest that a couples' intrinsic attitude towards PGD treatment is a major factor influencing their reproductive choice. Future research will focus on these personal motives that seem to push reproductive decision-making following genetic counselling in a given direction.

Item does not contain fulltext In an institutionalised population of 471 mentally retarded adult residents (436 males and 35 females), 18 patients (16 males and 2 females) with dysmorphic features were selected to perform FISH studies by using subtelomeric probes to discover cryptic terminal deletions or duplications, undetectable with standard banding techniques. In the 13 investigated patients, no abnormalities were found with a selected battery of subtelomeric probes. The results of cryptic chromosomal rearrangement studies are variable but the frequency of positive diagnostic findings seems to be lower than previously expected.

Spinal muscular atrophies are a heterogeneous group of disorders. They differ in time of onset, clinical presentation, progression, severity and mode of inheritance. In 1985 a Dutch family was described with a dominant, non-progressive spinal muscular atrophy presenting at birth with arthrogryposis (MIM 600175). Linkage analysis was performed in this family. After having excluded the loci for Werdnig-Hoffmann's disease and for dominant distal spinal muscular atrophy with upper limb predominance, we were able to localise the gene to a 10 cM interval between the markers D12S78 and D12S1646 on chromosome 12q23-q24. Recently, dominant scapuloperoneal spinal muscular atrophy has been localised to an overlapping interval. However, the clinical appearances of scapuloperoneal spinal muscular atrophy and the present disorder make allelism unlikely. In 1994, a second Dutch family with a disorder similar to the present one was described. We excluded linkage to markers of the 12q23-q24 region in this family and thereby proved genetic heterogeneity of this type of dominant, congenital and nonprogressive spinal muscular atrophy.

False-negative trisomy 18 has been reported after chorionic villus sampling, but not after amniocentesis. We describe a double aneuploidy in cultured amniocytes that was initially misinterpreted as a pseudomosaicism. A patient was referred at 31 weeks of gestation because of fetal anomalies at ultrasound examination. Karyotyping of amniocytes showed a 47,XY, +3 karyotype in 61 clones and a 48,XXY, +18 karyotype in one clone. The latter was interpreted as a pseudomosaicism, the more since a second amniocentesis revealed only cells with a 47,XY, +3 karyotype. At 36 weeks gestational age, a boy was born with congenital anomalies suggestive of trisomy 18. A blood culture showed a 48,XXY, +18 karyotype, while in fibroblasts a 47,XY, + 3/48,XXY, +18 mosaicism was found. Umbilical cord and bladder epithelial tissue also revealed normal 46,XY cells, besides the aneuploid cells. Therefore, the child proper had a 46,XY/47,XY, +3/48,XXY, +18 mosaicism with the clinical symptoms of trisomy 18. To the best of our knowledge, this is the first report of a false-negative result of trisomy 18 together with three sex chromosomes after amniocentesis.

Interstitial deletions of chromosome 3p14p12 are a rare chromosome rearrangement. Twenty-six patients have been reported in the literature to date, however, a specific clinical phenotype has not yet been delineated. We describe three patients (two new) with overlapping chromosome 3p14p12 deletions and review the clinical and molecular data of 11 well-characterized, published cases. These patients had a number of features in common, such as short stature, failure to thrive, facial dysmorphism, congenital heart defects, urogenital abnormalities, neurological problems, hearing loss, and global developmental delay, suggesting that the interstitial chromosome 3p14p12 deletion gives rise to a multiple congenital anomaly syndrome. Some of the patients show clinical overlap with other complex syndromes such as CHARGE syndrome. Genotype-phenotype analysis revealed candidate genes for parts of the clinical features suggesting that the 3p14 deletion is a contiguous gene syndrome. (c) 2015 Wiley Periodicals, Inc.

Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature.

The influence of maturation, sleep state and respiration on heart rate variability was studied in 16 spontaneously breathing preterm infants (< 33 weeks). ECG, respiratory impedance curve and movements were recorded four times a day, during the first three days of life. The power content of selected frequency bands of the R-R interval power spectrum, as well as respiratory frequency and breath amplitude oscillation frequency, were calculated for 3-min periods. An increase in low-frequency heart rate variability with gestational age was found. High-frequency variability increased during early postnatal life. Sleep state influenced very low-frequency heart rate variability. The amount of respiratory sinus arrhythmia and breath amplitude sinus arrhythmia was determined mainly by respiratory rate and breath amplitude oscillation frequency, respectively. The influences of gestational and postnatal age on heart rate variability might be due to an increase in sympathetic tone before birth and a change in parasympathetic-sympathetic balance after birth. Respiration has an important influence on heart rate variability, even in very preterm infants.

CHARGE syndrome is a multiple congenital anomaly syndrome that can be life-threatening in the neonatal period. Complex heart defects, bilateral choanal atresia, esophageal atresia, severe T-cell deficiency, and brain anomalies can cause neonatal death. As little is known about the causes of death in childhood and adolescence, we studied post-neonatal death in patients with CHARGE syndrome. We collected medical data on three deceased children from a follow-up cohort of 48 CHARGE patients and retrospectively on an additional four deceased patients (age at death 11 months to 22 years). We analyzed the factors that had contributed to their death. In five patients respiratory aspiration had most likely contributed to premature death, one died of post-operative complications, and another choked during eating. From our findings and a literature review, we suggest that swallowing problems, gastro-esophageal reflux disease, respiratory aspiration and post-operative airway events are important contributors to post-neonatal death in CHARGE syndrome. Cranial nerve dysfunction is proposed as the underlying pathogenic mechanism. We recommend every CHARGE patient with feeding difficulties to be assessed by a multidisciplinary team to evaluate cranial nerve function and swallowing. Timely treatment of swallowing problems and gastro-esophageal reflux disease is important. Surgical procedures on these patients should be combined whenever possible because of their increased risk of post-operative complications and intubation problems. Finally, we recommend performing autopsy in deceased CHARGE patients in order to gain more insight into causes of death.

Contains fulltext : 80605.pdf (Publisher’s version ) (Closed access) Kallmann syndrome (KS) is the combination of hypogonadotropic hypogonadism and anosmia or hyposmia, two features that are also frequently present in CHARGE syndrome. CHARGE syndrome is caused by mutations in the CHD7 gene. We performed analysis of CHD7 in 36 patients with KS and 20 patients with normosmic idiopathic hypogonadotropic hypogonadism (nIHH) in whom mutations in KAL1, FGFR1, PROK2 and PROKR2 genes were excluded. Three of 56 KS/nIHH patients had de novo mutations in CHD7. In retrospect, these three CHD7-positive patients showed additional features that are seen in CHARGE syndrome. CHD7 mutations can be present in KS patients who have additional features that are part of the CHARGE syndrome phenotype. We did not find mutations in patients with isolated KS. These findings imply that patients diagnosed with hypogonadotropic hypogonadism and anosmia should be screened for clinical features consistent with CHARGE syndrome. If such features are present, particularly deafness, dysmorphic ears and/or hypoplasia or aplasia of the semicircular canals, CHD7 sequencing is recommended.

Objective The GRIN2A gene has been associated with both benign childhood epilepsies and severe epileptic encephalopathies. This study evaluates the genotype–phenotype correlations in patients with GRIN2A variants. Methods A systematic literature search was performed, identifying all patients reported before May 2014 with GRIN2A variants. Patients were classified in two groups based on their GRIN2A genotype. Group I genotypes had an expected detrimental effect on protein expression: nonsense, frameshift, splice site, or initiation codon sequence variants, translocations with breakpoints within GRIN2A, or deletions comprising GRIN2A. Group II genotypes were expected to result in an altered protein structure or function: missense or in-frame sequence variants. Results Of 136 patients, 74 were included in group I and 62 in group II. Epilepsy was diagnosed in 86% of patients in both groups, with focal seizures being most common (82%). Benign epilepsy with centrotemporal spikes (BECTS) was significantly more often diagnosed in group II than in group I (51% versus 27%, p=0.03). Continuous spikes and waves during slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS) occurred more often in group I than in group II (50% versus 37%), although not statistically significant (p=0.29). Mild to severe developmental problems related to speech and language (80%), cognition (66%), and motor skills (48%), and behavioural problems (61%) were present in both groups. Speech and language problems were significantly more often reported in group I than in group II (90% versus 69%, p=0.02), also in patients with no LKS/CSWS (94% versus 50%, p=0.01). Conclusion GRIN2A variants are associated with a spectrum of epilepsies, mainly accompanied by language developmental problems. This epilepsy-aphasia syndrome spectrum ranges from relatively mild BECTS to more severe LKS/CSWS. This study shows that GRIN2A genotypes with an expected milder effect on protein function are associated with a relatively more benign phenotype including BECTS without language problems.

Introduction With microarray analysis, several novel microdeletion syndromes have been ascertained that are often accompanied by a specific behavioural phenotype requiring specific treatment modalities. Objectives Investigating the neuropsychiatric phenotype of Phelan-McDermid syndrome. Aims Diagnostic evaluation of an adult female with mild intellectual disability. Methods Detailed genetic, neuropsychiatric and neuropsychological examination. Results The patient is a 22-years-old female. Aged 4, conventional karyotyping demonstrated a translocation 11;22. Her history is characterized by neonatal hypotonia accompanied by feeding problems, global intellectual disability, sleep disturbances, delayed development of speech, and ritualistic/compulsive behaviours. Since about two years recurrent mood changes paralleled by an increase of pre-existent autistic behaviours became prominent. Psychotropics induced severe extrapyramidal symptoms without, however, any reduction of problematic behaviours. At examination, no dysmorphic features were observed. Her behaviour showed autistic-like elements and mood alterations. Neuropsychological assessment revealed mild intellectual disability (SON-R IQ: 61) and a developmental age of 6;3 years with marked attentional deficits. Visuomotor, speech, and memory functioning were in line with her developmental age. Fluctuation in mood and affect was substantiated. MRI-brain disclosed no abnormalities. Microarray analysis confirmed the de novo t(11;22) that had resulted in a 11qter duplication of 8,77Mb and a 515kb 22qter deletion, encompassing the SHANK3 gene, in agreement with a diagnosis of Phelan-McDermid syndrome. Conclusion Here a never reported unbalanced translocation leading to Phelan-McDermid syndrome with its characteristic neuropsychiatric phenotype is demonstrated. Apart from the implementation of systematic environmental measures, a plasma-concentration controlled treatment with valproic acid for mood stabilisation was advised.

Item does not contain fulltext We report four patients with an interstitial deletion of chromosome 2q32-->2q33. They presented similar clinical findings including pre- and postnatal growth retardation, distinct facial dysmorphism, thin and sparse hair and fair built, micrognathia, cleft or high palate, relative macroglossia, dacrocystitis, persisting feeding difficulties, inguinal hernia and broad based gait. All were severely mentally retarded. Three patients had a specific behavioral phenotype with hyperactivity and motor restlessness, chaotic behavior, happy-personality but with periods of aggression and anxiety, sleeping problems and self-mutilation. (head-banging). Array CGH and fluorescence in situ hybridization (FISH) allowed us to delineate the deletion size and showed that the four patients share a 8.1 Mb minimal deleted region. Reviewing additional nine case reports of patients with similar deletions showed striking phenotypic similarities which enabled the delineation of the 2q32.2q33 syndrome. Deletion of 2q32 has been also associated with the wrinkly skin syndrome (WWS) and isolated cleft palate. Although the patients presented here shared many aspects of WWS, they did not had the wrinkly skin. All patients had a cleft or high palate, most likely as a result of hemizygosity for SATB2. A potential commonly deleted interval of the three patients with behavioral problems, excluding the deletion in the patient without behavioral problems, is at most 0.5 Mb in size harboring only two genes.

To study the influence of artificial ventilation rate on neonatal heart rate variability (HRV), ECG and respiratory impedance curves were recorded four times a day in 20 preterm infants (< 3 3 wk) during the first 3 d after birth while the infants were ventilated at a wide range of ventilator rates. The contents o f selected frequency bands within the R-R interval power spectrum were calculated for 3-min periods. Respiratory distress syndrome severity was assessed at each measurement. Respiratory sinus arrhythmia (RSA) induced by the ventilator appeared to mimic spontaneous RSA. As in spontaneous respiration, the amount of RSA (power in a frequency band around the respiratory rate) increases as the ventilation rate decreases. This phenomenon is most probably due to entrainment with baroreflex-related fluctu­ ations in the heart rate. Although the artificial ventilation rate influences RSA and thus high-frequency HRV ? an increase in respiratory distress syndrome severity results in a decrease in low-frequency HRV. Thus, the attenuation of low-frequency HRV by respiratory distress syndrome is not likely to be due to artificial ventilation. (Pediatr Res 37: 124-130, 1995)

The instantaneous heart rate shows a variation around the mean heart rate caused by cardioregulatory mechanisms which are mediated through the sympathetic and vagal autonomic nervous system. To gain more insight into the influence of physiological parameters on neonatal heart rate variability a study was performed in four healthy preterm newborns during the first five days of life. Instantaneous heart rate, respiration rate, transcutaneous pO2, blood pressure and behaviour were recorded during 40 minutes four times a day. Long term heart rate variability was calculated as the difference between p95 and p5 of instantaneous heart rate values sampled during three minutes. A clear relationship between long term variability and age (maturity of the autonomic nervous system), respiration rate (respiratory sinus arrhythmia or a tidal volume mediated effect) and behaviour (increase of sympathetic tone during REM sleep) was found. No influence of blood pressure, heart rate, and transcutaneous pO2 within physiological ranges could be detected. The relative influence of the different physiological parameters on heart rate variability has to be established before the value of heart rate variability as a monitoring tool in neonatal intensive care can be investigated.