Publications by authors named "Hanne Hove"

56 Publications

Non-aortic cardiovascular disease in Marfan syndrome: a nationwide epidemiological study.

Clin Res Cardiol 2021 Apr 22. Epub 2021 Apr 22.

Department of Endocrinology, Aarhus University Hospital, Palle Juul-Jensens Boulevard, 8200, Aarhus, Denmark.

Objectives: Studies indicate that other cardiovascular problems than aortic disease are a burden for patients with Marfan syndrome (MFS). The aim of the study was to assess the extent of this issue.

Methods: A registry-based population study of patients with a Ghent II verified MFS diagnosis. Each patient was matched with up to 100 controls on age and sex. From the Danish healthcare system, we identified 407 MFS patients (from 1977 to 2014) and their cardiovascular events and compared them with those in 40,700 controls. Total follow-up time was 16,439 person years.

Results: Mitral valve disease was significantly more common in MFS [HR: 58.9 (CI 38.1-91.1)] and happened earlier and more often in women than men with MFS [age at first registration: 22 vs. 38 years, HR: 2.1 (CI 1.0-4.4)]. Heart failure/cardiomyopathy was also more common in MFS [HR: 8.7 (CI 5.7-13.4)] and men were more affected than women, and at younger age [39 vs. 64 years, HR: 0.18 (CI 0.06-0.55)]. In all cases, atrioventricular block [HR: 4.9 (1.5-15.6)] was related to heart surgery. Supraventricular [HR: 9.7 (CI 7.5-12.7)] and ventricular tachycardia [HR: 7.7 (CI 4.2-14.3)] also occurred more often than in the control group. The risk of sudden cardiac death was increased [HR: 8.3 (CI 3.8-18.0)] but the etiology was unclear due to lack of autopsies.

Conclusion: Non-aortic cardiovascular disease in patients with MFS is exceptionally prevalent and the range of diseases varies between women and men. Physicians caring for MFS patients must be aware of this large spectrum of cardiovascular diseases.
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http://dx.doi.org/10.1007/s00392-021-01858-3DOI Listing
April 2021

Fracture Rates and Fracture Risk in Patients With Marfan Syndrome: A Nationwide Register-Based Cohort Study.

J Bone Miner Res 2021 Feb 10. Epub 2021 Feb 10.

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.

Marfan syndrome (MFS), a rare genetic disease, has a prevalence of 6.5 in 100,000. Studies show that patients with MFS have reduced areal bone mineral density (BMD) compared with non-MFS individuals. We have previously shown that patients with MFS have reduced volumetric BMD and compromised trabecular and cortical bone microarchitecture. The present study was a registry-based, nationwide, population-based, cohort study using register data, aimed to evaluate fracture risk and fracture rates in MFS. We included 406 (196 women) patients with MFS through the Danish National Patient Register and 40,724 (19,327 women) persons, randomly selected and matched from the Civil Registry System. A total of 21.9% of the MFS and 18.9% of the reference population had experienced at least one fracture from 1995 to 2018. The fracture incidence rate was 27.5 per 1000 person-years in the MFS cohort (highest in young men and old women with MFS), and 20.3 per 1000 person-years in the reference population. The overall incidence rate ratio between the MFS and the reference population was 1.35 (95% confidence interval [CI ] 1.18-1.55) for all fractures. When evaluating the risk of being registered with an osteoporosis diagnosis in the Danish National Patient Register, starting relevant treatment for osteoporosis or experiencing a hip or spine fracture, 10.3% of the MFS cohort and 3.3% of the reference population could be classified as being osteoporotic. The between-group subhazard ratio was 3.97 (95% CI 2.56-6.25). Patients with MFS started treatment with an antiosteoporotic drug at a younger age than the reference population (57 [interquartile range 55-67] versus 71 [63-73]) years. The life expectancy in MFS is increasing, resulting in more patients facing diseases that are related to old age, such as age-related bone loss and increased risk of fractures. Our data suggest that bone health and fracture prevention needs to be part of the standard care for patients with MFS. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4258DOI Listing
February 2021

Pregnancy outcomes in women with neurofibromatosis 1: a Danish population-based cohort study.

J Med Genet 2021 Jan 25. Epub 2021 Jan 25.

Childhood Cancer Research Group, Danish Cancer Society Research Center, Copenhagen, Denmark.

Background: The probability of a pregnancy, live birth, stillbirth and abortion has never been assessed in women with neurofibromatosis 1 (NF1) in a large population-based study.

Methods: We included 1006 women (15-49 years) registered with NF1 in the Danish National Patient Registry or followed in two national Centers for Rare Diseases and 10 020 women from the Danish population. Information on pregnancy outcomes was ascertained from health registries. Cumulative incidence, mean cumulative count, hazard ratios (HRs) and proportion ratios (PRs) with 95% CIs were calculated.

Results: The cumulative incidence of a first pregnancy at age 50 years was slightly lower in women with NF1 (74%; 95% CI 70 to 77) than in population comparisons (78%; 95% CI 77 to 79). When all pregnancies were included, two pregnancies were expected per woman at age of 50 years, irrespective of a NF1 diagnosis. The hazard of a pregnancy did not differ between women with NF1 (HR 1.03; 95% CI 0.95 to 1.11) and the comparisons after adjustment for somatic and psychiatric disease. The proportion of pregnancies that resulted in a live birth was 63% (783/1252) among women NF1 and 68% (8432/12 465) among the comparisons, yielding a PR of 0.95 (95% CI 0.90 to 1.00). The proportions of stillbirths (PR 2.83; 95% CI 1.63 to 4.93) and spontaneous abortions (PR 1.40; 95% CI 1.09 to 1.79) were increased in women with NF1.

Conclusions: A similar hazard for pregnancy was observed for women with NF1 and population comparisons after adjustment for potential medical consequences of NF1. However, women with NF1 experienced more spontaneous abortions and stillbirths.
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http://dx.doi.org/10.1136/jmedgenet-2020-107201DOI Listing
January 2021

Facial Asymmetry in Nonsyndromic and Muenke Syndrome-Associated Unicoronal Synostosis: A 3-Dimensional Study Based on Facial Surfaces Extracted From CT Scans.

Cleft Palate Craniofac J 2020 Sep 24:1055665620959983. Epub 2020 Sep 24.

3D Craniofacial Image Research Laboratory (School of Dentistry, University of Copenhagen, Center of Head and Orthopedics, Copenhagen University Hospital Rigshospitalet, and DTU Compute, Technical University of Denmark), Copenhagen, Denmark.

Objective: To quantify soft tissue facial asymmetry (FA) in children with nonsyndromic and Muenke syndrome-associated unicoronal synostosis (NS-UCS and MS-UCS), hypothesizing that MS-UCS presents with significantly larger FA than NS-UCS.

Design: Retrospective cohort study.

Patients And Methods: Twenty-one children (mean age: 0.6 years; range: 0.1-1.4 years) were included in the study (NS-UCS = 14; MS-UCS = 7). From presurgical computed tomography scans, facial surfaces were constructed for analysis. A landmark guided atlas was deformed to match each patient's surface, obtaining spatially detailed left-right point correspondence. Facial asymmetry was calculated in each surface point across the face, as the length (mm) of an asymmetry vector, with its Cartesian components providing 3 directions. Mean FA was calculated for the full face, and the forehead, eye, nose, cheek, mouth, and chin regions.

Results: For the full face, a significant difference of 2.4 mm ( = .001) was calculated between the 2 groups, predominately in the transverse direction (1.5 mm; < .001). The forehead and chin regions presented with the largest significant difference, 3.5 mm ( = .002) and 3.2 mm ( < .001), respectively; followed by the eye (2.4 mm; = .004), cheek (2.2 mm; = .004), nose (1.7 mm; = .001), and mouth (1.4 mm; = .009) regions. The transverse direction presented with the largest significant difference in the forehead, chin, mouth, and nose regions, the sagittal direction in the cheek region, and the vertical direction in the eye region.

Conclusions: Muenke syndrome-associated unicoronal synostosis presented with significantly larger FA in all regions compared to NS-UCS. The largest significant differences were found in the forehead and chin regions, predominantly in the transverse direction.
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http://dx.doi.org/10.1177/1055665620959983DOI Listing
September 2020

Bone Geometry, Density, and Microarchitecture in the Distal Radius and Tibia in Adults With Marfan Syndrome Assessed by HR-pQCT.

J Bone Miner Res 2020 12 22;35(12):2335-2344. Epub 2020 Sep 22.

Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark.

Marfan syndrome (MFS) is a hereditary disorder of connective tissue caused by mutations in the fibrillin-1 gene. Studies have shown that patients with MFS have lower bone mass, but little is known about the other constituents of bone strength. We hypothesize that patients with MFS will have larger bone area and compromised cortical microarchitecture compared with non-MFS individuals. A total of 74 adult patients with MFS and 145 age- and sex-matched non-MFS reference individuals were included in this study. High-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and distal tibia and dual-energy X-ray absorptiometry of total hip and the lumbar spine were performed, and bone turnover and sex hormones were measured. Patients with MFS had significantly lower areal bone mineral density (BMD) at the total spine (-13%) and total hip (-7%) when compared with the reference group. Patients with MFS had significantly larger total bone area at both the radius (+27%) and tibia (+34%). Volumetric BMD at both measured sites showed significantly reduced total, trabecular, and cortical volumetric BMD in patients with MFS compared with the reference group. The microarchitectural parameters at the radius and tibia were compromised in patients with MFS with significantly reduced trabecular number and thickness, leading to a higher trabecular separation and significantly reduced cortical thickness and increased cortical porosity compared with the reference group. The differences in bone density, geometry, or microarchitecture were not explained by increased bone turnover markers or circulating levels of sex hormones. We conclude patients with MFS have altered bone geometry, altered bone microstructure, and lower bone mass (lower areal BMD and volumetric BMD at all sites) compared with healthy reference individuals. Future studies should focus on fracture rates and fracture risk in adult and aging patients with MFS. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4138DOI Listing
December 2020

Novel Clinical and Radiological Findings in a Family with Autosomal Recessive Omodysplasia.

Mol Syndromol 2020 Jun 7;11(2):83-89. Epub 2020 Mar 7.

Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Autosomal recessive omodysplasia (-related) is a rare short-limb skeletal dysplasia caused by biallelic mutations in the gene. Affected individuals manifest with rhizomelic short stature, decreased mobility of elbow and knee joints as well as craniofacial anomalies. Both upper and lower limbs are severely affected. These manifestations contrast with normal height and limb shortening restricted to the arms in autosomal dominant omodysplasia (-related). Here, we report 2 affected brothers of Pakistani descent from Denmark with -related omodysplasia, aiming to highlight the clinical and radiological findings. A homozygous deletion of exon 6 in the gene was detected. The pathognomonic radiological findings were distally tapered humeri and femora as well as severe proximal radioulnar diastasis. On close observations, we identified a recurrent and not previously described type of abnormal patterning in all long bones.
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http://dx.doi.org/10.1159/000506384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325126PMC
June 2020

Validity of First-Time Diagnoses of Inherited Ichthyosis in the Danish National Patient Registry and the Danish Pathology Registry.

Clin Epidemiol 2020 19;12:651-657. Epub 2020 Jun 19.

Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark.

Purpose: Inherited ichthyosis is a monogenetic disease characterized by hyperkeratosis and scaling of the skin, with large interindividual variation in severity. It can affect quality of life for patients and their families. Population-based data on inherited ichthyosis are lacking, which hampers studies into its epidemiology.

Patients And Methods: Based on medical record review, we validated diagnoses of inherited ichthyosis in two nationwide population-based registries commonly used for epidemiological research: The Danish National Patient Registry and the Danish Pathology Registry. The study period was January 1, 1977, through December 31, 2015. Validation samples were taken from one regional hospital without a specialized dermatological department and two specialized dermatological departments. Positive predictive values (PPVs) were estimated overall and for each coding system (ICD-8, ICD-10 and SNOMED), including for specific ICD-10 codes.

Results: We identified 1772 first-time diagnoses of inherited ichthyosis; 363 patients were diagnosed at the departments selected for validation, and 307 of these patients (84.6%) had medical records enabling validation. We observed an overall PPV of 73.3% (95% CI: 68.1-77.9). For ICD-8, ICD-10, and SNOMED diagnoses, the PPVs were 73.2% (95% CI: 58.1-84.3), 74.7% (95% CI: 69.0-79.7), and 46.2% (95% CI: 22.1-71.7), respectively. In analyses for ICD-10 diagnoses, we observed much higher validity of diagnoses from the specialized departments (PPV 79.7%; 95% CI: 74.1-84.3) than the regional hospital (PPV 5.9%; 95% CI: 0.6-24.3). The PPVs for specific diagnoses were 80.1% for ichthyosis vulgaris and 96.6% for X-linked ichthyosis but below 45% for remaining, rarer, subtypes.

Conclusion: The PPV of first-time diagnosis of inherited ichthyosis made at specialized dermatological departments in the Danish National Patient Registry is approximately 80%. Diagnoses from the Danish Pathology Registry had low PPVs precluding their use for research.
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http://dx.doi.org/10.2147/CLEP.S232956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310968PMC
June 2020

Clinical characteristics and quality of life, depression, and anxiety in adults with neurofibromatosis type 1: A nationwide study.

Am J Med Genet A 2020 07 2;182(7):1704-1715. Epub 2020 Jun 2.

Psychological Aspects of Cancer, Danish Cancer Society Research Center, Copenhagen, Denmark.

Neurofibromatosis type 1 (NF1) is a genetic condition characterized by numerous somatic manifestations. The psychosocial burden in adults has rarely been studied. We examined the prevalence of self-reported impairment of quality of life (QoL), symptoms of anxiety and depression and need for support, associated with disease severity and visibility. We conducted a nationwide cross-sectional study of all 467 adults with NF1 diagnosed between 1977 and 2016 at one of the two national centers for rare diseases in Denmark. A total of 244 (56% response rate) completed a questionnaire that included standard measures of QoL, symptoms of depression and anxiety, indicators of disease-related severity, visibility, and need for professional support. Associations between disease severity and visibility and psychosocial burden were analyzed in descriptive and multivariate models. We observed impaired QoL (mean = 81.3; 95% CI, 76.2; 86.4); 19% reported symptoms of depression (mean = 5.7; SD = 5.4), and 15% reported anxiety (mean = 5.1; SD = 5.2) at a clinical level. Adults with NF1 also reported requiring professional support for physical, psychological, and work-related problems. Disease severity and (partly) visibility were significantly (p < .0001) associated with psychosocial well-being and a requirement for support. This study provides new understanding of the factors associated with impaired QoL, indicating that follow-up care should be optimized into adult life.
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http://dx.doi.org/10.1002/ajmg.a.61627DOI Listing
July 2020

Unique skeletal manifestations in patients with Primrose syndrome.

Eur J Med Genet 2020 Aug 27;63(8):103967. Epub 2020 May 27.

Institute of Medical Genetics and Genomics, New Delhi, India. Electronic address:

Primrose syndrome (OMIM 259050) is a rare disorder characterised by macrocephaly with developmental delay, a recognisable facial phenotype, altered glucose metabolism, and other features such as sensorineural hearing loss, short stature, and calcification of the ear cartilage. It is caused by heterozygous variants in ZBTB20, a member of the POK family of transcription repressors. Recently, this gene was shown to have a role in skeletal development through its action on chondrocyte differentiation by repression of SOX9. We describe five unrelated patients with Primrose syndrome and distinct skeletal features including multiple Wormian bones, platybasia, bitemporal bossing, bathrocephaly, slender bones, epiphyseal and spondylar dysplasia. The radiological abnormalities of the skull and the epiphyseal dysplasia were the most consistent findings. This novel constellation of skeletal features expands the phenotypic spectrum of the disorder.
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http://dx.doi.org/10.1016/j.ejmg.2020.103967DOI Listing
August 2020

Expanding the cerebrovascular phenotype of the p.R258H variant in ACTA2 related hereditary thoracic aortic disease (HTAD).

J Neurol Sci 2020 08 13;415:116897. Epub 2020 May 13.

Rigshospitalet, Copenhagen University Hospital, Center for Rare Diseases, Department of Pediatrics and Department of Clinical Genetics, Denmark.

Heterozygous variants in smooth muscle alpha-actin gene (ACTA2) are the most frequent cause of autosomal dominant hereditary thoracic aortic disease (HTAD). Several genotype-phenotype associations have been described, including a severe multisystemic smooth muscle disorder associated with de novo ACTA2 p.R179 variants, characterized by highly penetrant and early onset vascular disease, involvement of smooth muscle cell (SMC)-dependent organs and a distinct cerebrovascular phenotype. Missense variants at position 258 (p.R258C and p.R258H) have also been reported to have a more severe presentation including an increased risk for aortic dissection and a high risk of stroke. It has previously been suggested that the cerebrovascular phenotype of patients with p.R258 variants could represent a mild presentation of the cerebrovascular phenotype associated with p.R179 variants. Here we report on a five generation HTAD family with the p.R258H variant and describe the cerebrovascular findings seen in three family members, to expand on the previously reported phenotype associated with variants at this codon.
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http://dx.doi.org/10.1016/j.jns.2020.116897DOI Listing
August 2020

Forming and ending marital or cohabiting relationships in a Danish population-based cohort of individuals with neurofibromatosis 1.

Eur J Hum Genet 2020 08 18;28(8):1028-1033. Epub 2020 May 18.

Survivorship and Inequality in Cancer, Danish Cancer Society Research Center, Copenhagen, Denmark.

Individuals with neurofibromatosis 1 (NF1) may have problems in managing the transition between childhood and adulthood, such as forming a relationship or finding a partner. We aimed to determine the association between NF1 and forming and ending marital or cohabiting relationships by comparing a large Danish population of adults with NF1 with population comparisons. In this population-based cohort study, we compared a population of Danish adults who were hospitalized for or with complications to prior diagnosed NF1 (n = 787) with population comparisons matched on gender and birth year (n = 7787) through nationwide registries with annually updated information on marriage and cohabitation. Discrete-time survival models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the formation and termination of relationships, with adjustment for birth year, gender, and somatic and psychiatric comorbidities at entry. Individuals with NF1 were significantly less likely to form a relationship (HR = 0.65; 95% CI: 0.58-0.73), with the lowest association for individuals ≥33 years (HR 0.40; 95% CI: 0.25-0.63) and the highest for those aged 18-20 years (HR 0.82; 95% CI: 0.70-0.96). No significant difference was found for ending relationships (HR 1.00; 95% CI: 0.86-1.16). In conclusion, individuals who were hospitalized for NF1 are less likely to engage in marital or cohabiting relationships than population comparisons and are older when they form their first relationship. Once a relationship has been established, however, couples with a NF1-individual are not at greater risk of ending the relationship.
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http://dx.doi.org/10.1038/s41431-020-0645-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382505PMC
August 2020

Primrose syndrome: Characterization of the phenotype in 42 patients.

Clin Genet 2020 06 20;97(6):890-901. Epub 2020 Apr 20.

Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands.

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.
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http://dx.doi.org/10.1111/cge.13749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384157PMC
June 2020

Multisystem burden of neurofibromatosis 1 in Denmark: registry- and population-based rates of hospitalizations over the life span.

Genet Med 2020 06 28;22(6):1069-1078. Epub 2020 Feb 28.

Childhood Cancer Research Group, Danish Cancer Society Research Center, Copenhagen, Denmark.

Purpose: The aim was to assess lifetime risk for hospitalization in individuals with neurofibromatosis 1 (NF1).

Methods: The 2467 individuals discharged with a diagnosis indicating NF1 or followed in a clinical center for NF1 were matched to 20,132 general population comparisons. Based on diagnoses in 12 main diagnostic groups and 146 subcategories, we calculated rate ratios (RRs), absolute excess risks (AERs), and hazard ratios for hospitalizations.

Results: The RR for any first hospitalization among individuals with NF1 was 2.3 (95% confidence interval 2.2-2.5). A high AER was seen for all 12 main diagnostic groups, dominated by disorders of the nervous system (14.5% of all AERs), benign (13.6%) and malignant neoplasms (13.4%), and disorders of the digestive (10.5%) and respiratory systems (10.3%). Neoplasms, nerve and peripheral ganglia disease, pneumonia, epilepsy, bone and joint disorders, and intestinal infections were major contributors to the excess disease burden caused by NF1. Individuals with NF1 had more hospitalizations and spent more days in hospital than the comparisons. The increased risk for any hospitalization was observed for both children and adults, with or without an associated cancer.

Conclusion: NF1 causes an overall greater likelihood of hospitalization, with frequent and longer hospitalizations involving all organ systems throughout life.
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http://dx.doi.org/10.1038/s41436-020-0769-6DOI Listing
June 2020

Defining the clinical phenotype of Saul-Wilson syndrome.

Genet Med 2020 05 17;22(5):857-866. Epub 2020 Jan 17.

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Purpose: Four patients with Saul-Wilson syndrome were reported between 1982 and 1994, but no additional individuals were described until 2018, when the molecular etiology of the disease was elucidated. Hence, the clinical phenotype of the disease remains poorly defined. We address this shortcoming by providing a detailed characterization of its phenotype.

Methods: Retrospective chart reviews were performed and primary radiographs assessed for all 14 individuals. Four individuals underwent detailed ophthalmologic examination by the same physician. Two individuals underwent gynecologic evaluation. Z-scores for height, weight, head circumference and body mass index were calculated at different ages.

Results: All patients exhibited short stature, with sharp decline from the mean within the first months of life, and a final height Z-score between -4 and -8.5 standard deviations. The facial and radiographic features evolved over time. Intermittent neutropenia was frequently observed. Novel findings included elevation of liver transaminases, skeletal fragility, rod-cone dystrophy, and cystic macular changes.

Conclusions: Saul-Wilson syndrome presents a remarkably uniform phenotype, and the comprehensive description of our cohort allows for improved understanding of the long-term morbidity of the condition, establishment of follow-up recommendations for affected individuals, and documentation of the natural history into adulthood for comparison with treated patients, when therapeutics become available.
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http://dx.doi.org/10.1038/s41436-019-0737-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205587PMC
May 2020

Phenotypic variability in Muenke syndrome-observations from five Danish families.

Clin Dysmorphol 2020 Jan;29(1):1-9

Centre for Rare Diseases, Department of Paediatrics.

Muenke syndrome is a craniosynostosis syndrome associated with the p.Pro250Arg mutation in FGFR3. An increasing number of individuals with this mutation are reported to not have craniosynostosis. The purpose of this report is to increase awareness of the high phenotypic variability seen in Muenke syndrome. DNA testing for the p.Pro250Arg mutation is routinely performed in Denmark, in children presenting with isolated coronal synostosis. Verified diagnosis entails detailed family history, drawing of family pedigree, DNA testing of the parents, genetic counseling, skull radiographs, clinical photographs, and follow-up. Sixteen individuals from 5 Danish families with Muenke syndrome are presented. Large phenotypic variation was seen both within and across families. The most striking observations were that 6/16 (38%) cases did not have craniosynostosis and one individual presented with a normal phenotype. In addition, 3 unrelated cases had incomplete cleft palate, submucous cleft palate, and bifid uvula, respectively. There is strong evidence for reduced penetrance of the craniosynostosis trait in Muenke syndrome. We argue that many studies on Muenke syndrome have been influenced by ascertainment bias in regard to craniosynostosis. In addition, it is suggested that oral clefting might be part of the clinical spectrum seen in Muenke syndrome.
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http://dx.doi.org/10.1097/MCD.0000000000000300DOI Listing
January 2020

Multiple Fractures and Impaired Bone Fracture Healing in a Patient with Pycnodysostosis and Hypophosphatasia.

Calcif Tissue Int 2019 Dec 5;105(6):681-686. Epub 2019 Sep 5.

Department of Endocrinology, Hvidovre University Hospital Copenhagen, Kettegård Alle 30, 2650, Hvidovre, Denmark.

Pycnodysostosis (PYCD) is a rare recessive inherited skeletal disease, characterized by short stature, brittle bones, and recurrent fractures, caused by variants in the Cathepsin K encoding gene that leads to impaired osteoclast-mediated bone resorption. Hypophosphatasia (HPP) is a dominant or recessive inherited condition representing a heterogeneous phenotype with dental symptoms, recurrent fractures, and musculoskeletal problems. The disease results from mutation(s) in the tissue non-specific alkaline phosphate encoding gene with reduced activity of alkaline phosphatase and secondarily defective mineralization of bone and teeth. Here, we present the first report of a patient with the coexistence of PYCD and HPP. This patient presented typical clinical findings of PYCD, including short stature, maxillary hypoplasia, and sleep apnoea. However, the burden of disease was caused by over 30 fractures, whereupon most showed delayed healing and non-union. Biochemical analysis revealed suppressed bone resorption and low bone formation capacity. We suggest that the coexistence of impaired bone resorption and mineralization may explain the severe bone phenotype with poor fracture healing.
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http://dx.doi.org/10.1007/s00223-019-00605-1DOI Listing
December 2019

The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis.

Genet Med 2020 02 7;22(2):389-397. Epub 2019 Aug 7.

Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Purpose: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function.

Methods: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains.

Results: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains.

Conclusion: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
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http://dx.doi.org/10.1038/s41436-019-0612-0DOI Listing
February 2020

Phenotypic presentations of Hajdu-Cheney syndrome according to age - 5 distinct clinical presentations.

Eur J Med Genet 2020 Feb 11;63(2):103650. Epub 2019 Apr 11.

Department of Clinical Genetics, Aarhus University Hospital, Denmark; Pediatrics and Adolescent Medicine, Centre for Rare Diseases, Aarhus University Hospital, Denmark.

We present five Danish individuals with Hajdu-Cheney syndrome (HJCYS) (OMIM #102500), a rare multisystem skeletal disorder with distinctive facies, generalised osteoporosis and progressive focal bone destruction. In four cases positive genetic screening of exon 34 of NOTCH2 supported the clinical diagnosis; in one of these cases, mosaicism was demonstrated, which, to our knowledge, has not previously been reported. In one case no genetic testing was performed since the phenotype was definite, and the diagnosis in the mother was genetically confirmed. The age of the patients differs widely from ten to 57 years, allowing a natural history description of the phenotype associated with this ultra-rare condition. The evolution of the condition is most apparent in the incremental bone loss leading to osteoporosis and the acro-osteolysis, both of which contribute significantly to disease burden.
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http://dx.doi.org/10.1016/j.ejmg.2019.04.007DOI Listing
February 2020

Correction: Educational delay and attainment in persons with neurofibromatosis 1 in Denmark.

Eur J Hum Genet 2019 Jun;27(6):994-996

Survivorship Unit, Danish Cancer Society Research Center, Copenhagen, Denmark.

Since the publication of the article, the authors noticed that 'NFI cohort' and 'NFI-free cohort' columns in the 'Autism and the 'Autism/ADHD' rows had been erroneously interchanged in Table 3. This has now been updated in the HTML and PDF of the original article.
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http://dx.doi.org/10.1038/s41431-019-0378-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777544PMC
June 2019

Educational delay and attainment in persons with neurofibromatosis 1 in Denmark.

Eur J Hum Genet 2019 06 28;27(6):857-868. Epub 2019 Feb 28.

Survivorship Unit, Danish Cancer Society Research Center, Copenhagen, Denmark.

Most research on psychosocial consequences of neurofibromatosis type 1 (NF1) has focused on the relationship between disease factors and cognitive functioning. NF1 may impair domains of learning and attention, resulting in low academic performance. This study is the first nationwide population-based cohort study to investigate educational attainment and delay in completing mandatory school by persons with NF1. Educational information was collected from 550 persons at the age of 30 (born 1965-1984). They were diagnosed with NF1 in Denmark and compared to a cohort of NF1-free persons matched on gender and age (n = 4295). Multinomial logistic models were applied to estimate odds ratios (ORs) for obtaining short (≤9 years) or medium (10-12 years) education compared to long education (>12 years) by the age of 30 years. We calculated the probability of graduating 9 year of mandatory school at different ages in 932 persons with NF1 and 7962 NF1-free persons (born 1965-2000) using quantile regression. The OR of educational completion for short- and medium-term education was three fold (95% CI 2.55-3.99) and 1.29 fold (95% CI 0.99-1.69) higher, respectively, for persons with NF1 than NF1-free persons after adjusting for birth year, gender, psychiatric and somatic morbidity and mother's education. Persons with NF1 were significantly delayed in graduating mandatory school education compared to NF1-free persons. When 90% of persons have graduated, persons with NF1 were 1.2 times older than the NF1-free persons. Experiencing delays in mandatory school likely affect further educational achievements and may impair employment and entering work force.
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http://dx.doi.org/10.1038/s41431-019-0359-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777448PMC
June 2019

Spatially Detailed 3D Quantification of Improved Facial Symmetry After Surgery in Children With Unicoronal Synostosis.

Cleft Palate Craniofac J 2019 08 7;56(7):918-928. Epub 2019 Jan 7.

1 3D Craniofacial Image Research Laboratory (School of Dentistry, University of Copenhagen; Centre of Head and Orthopedics, Copenhagen University Hospital Rigshospitalet; and Department of Applied Mathematics and Computer Science, Technical University of Denmark), Copenhagen, Denmark.

Objective: To assess improvement of soft-tissue facial symmetry in children surgically treated for unicoronal synostosis (UCS) in infancy, to correlate pre- and postsurgical facial asymmetry and to evaluate whether the improvement was visually recognizable.

Design: Case-controlled follow-up.

Patients/settings: Eleven Danish children diagnosed with UCS were included, 3 of whom had tested positive for Muenke mutation. Preoperative computed tomography scans and postoperative 3dMD surfaces were available for measurements. A control group of healthy children matched for age and sex was employed.

Main Outcome Measures: Pre- and postsurgical facial asymmetry was analyzed using a computerized method capable of objective and spatially detailed quantification in 3-dimension (transverse, vertical, and sagittal directions). Asymmetry was evaluated in the facial region and 6 subregions (forehead, mouth, eyes, nose, cheek, and chin).

Results: The largest significant improvement was seen in the sagittal direction of the facial (1.9 mm), forehead (2.0 mm), and cheek (3.4 mm) regions. Small but significant improvements were also seen in the mouth, chin, and eye regions. No significant improvement was seen in the nose region. Significant correlations were found between the pre- and postsurgically calculated facial asymmetry and between calculated asymmetry and clinical validation scores.

Conclusions: All patients presented with improved facial symmetry after surgery and the improvements were visually recognizable. However, only 1 (9.1%) of the 11 patients reached a level of facial asymmetry as low as that seen in the control group. The best outcome was, in general, seen in cases with mild facial asymmetry presurgically.
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http://dx.doi.org/10.1177/1055665618821821DOI Listing
August 2019

A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation.

Am J Hum Genet 2018 10;103(4):553-567

Department of Clinical Genetics, Rigshospitalet, 2100 Copenhagen, Denmark.

The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.
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http://dx.doi.org/10.1016/j.ajhg.2018.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174323PMC
October 2018

Novel de novo mutation in ZBTB20 in primrose syndrome in boy with short stature.

Clin Dysmorphol 2019 Jan;28(1):41-45

3D Craniofacial Image Research Laboratory, School of Dentistry.

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http://dx.doi.org/10.1097/MCD.0000000000000244DOI Listing
January 2019

Causes of Mortality in the Marfan Syndrome(from a Nationwide Register Study).

Am J Cardiol 2018 10 21;122(7):1231-1235. Epub 2018 Jul 21.

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus,Denmark.

The Marfan syndrome (MFS) is strongly associated with aortic disease causing a high prevalence of prophylactic aortic surgery, aortic dissection, and sudden death. The aim of the present study was to evaluate mortality in a nationwide Danish MFS population diagnosed by the Ghent II criteria. In a register-based setting, we identified all Danish patients with MFS (n = 412, men n = 215) by assessment of their medical records. We established a gender and age matched control cohort based on 41,000 control patients (men n = 21,500). MFS cases risk time was 6,669 patient years. We applied Cox regression using each case and his/her control as one stratum, adjusting for age and calendar time. We found a significantly decreased lifespan of 50years compared with 60years among controls. The mortality hazard ratio among MFS compared with controls was significantly increased to3.6 (CI 2.8-4.7, p < 0.001); men 4.0 (CI 2.8-5.7, p < 0.001); women 3.2 (CI 2.1-4.8,p < 0.001). Aorta disease represented the main reason for the overall increased mortality with a hazard ratio of 194.6 (CI 67.4-561.7, p < 0.0001); men 208.7 (CI 53.8-809.1, p < 0.001); women 173.4 (CI 31.5-954.5, p < 0.001). In addition, an unexplained mortality due to respiratory illness was not attributed to pneumothorax. Excluding cardiovascular and respiratory causes of death, we found no indication that MFS is associated with increased mortality for other reasons.
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http://dx.doi.org/10.1016/j.amjcard.2018.06.034DOI Listing
October 2018

Aortic aneurysm: An underestimated serious finding in the EP300 mutation phenotypical spectrum.

Eur J Med Genet 2019 02 12;62(2):96. Epub 2018 Jun 12.

Cardiogenetics, Center for Medical Genetics, University of Antwerp/Antwerp University Hospital, Antwerp, Belgium. Electronic address:

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http://dx.doi.org/10.1016/j.ejmg.2018.06.008DOI Listing
February 2019

A study of familial Char syndrome involving the TFAP2B gene with a focus on facial shape characteristics.

Clin Dysmorphol 2018 Jul;27(3):71-77

Departments of Clinical Genetics.

In this case study, we investigate a child presenting with patent ductus arteriosus, short philtrum, duck-bill lips, strabismus, a flat nasal bridge, a broad forehead, low-set ears, hypertelorism, up-slanting palpebral fissures, almond-shaped eyes, and hypodontia, all leading to the clinical diagnosis of Char syndrome. Genetic analysis showed heterozygosity for the novel variant c.851T>C, p. Leu284Ser in the TFAP2B gene. Family analysis suggested that at least 20 members, extending six generations back, were affected. All 10 members available for genetic testing were heterozygous for the novel pathogenic variant. Qualitative analysis of the facial dysmorphology in the proband and three of the affected family members using three-dimensional surface scanning showed that the major deviations were observed in the forehead/eyebrow, nose, upper lip, and chin regions with, for example, a flattened nose and reduced height of the upper lip and the face. Furthermore, it is suggested that Char syndrome is associated with disturbances of tooth formation and eruption.
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http://dx.doi.org/10.1097/MCD.0000000000000222DOI Listing
July 2018

Biomechanical properties of the patellar tendon in children with heritable connective tissue disorders.

Eur J Appl Physiol 2018 Jul 5;118(7):1301-1307. Epub 2018 Apr 5.

Institute of Sports Medicine, Department of Orthopaedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Bispebjerg Bakke 23, 2400, Copenhagen, Denmark.

Purpose: Hereditary connective tissue disorders (HCTDs), such as classic Ehlers-Danlos syndrome (cEDS) and Marfan syndrome (MS) share overlapping features like hypermobility and tissue fragility. In clinical practice it remains a challenge to distinguish children and adolescents with HCTD from healthy children. The purpose of this study was to investigate the biomechanical properties of the patellar tendon and joint laxity (Beighton score) in children with HCTDs (n = 7) compared to healthy controls (n = 14).

Methods: The mechanical properties of the patellar tendon were assessed using simultaneous force and ultrasonographic measurements during isometric ramp contractions. Ultrasonography was also used to measure tendon dimensions. The HCTD children were matched with 2 healthy controls with regard to age, body mass index (BMI), sex and physical activity level.

Results: The HCTD children had a greater degree of joint laxity (P < 0.01). Although, the patellar tendon dimensions did not differ significantly between the two groups, the HCTD children showed a tendency toward a larger patellar tendon cross-sectional area (CSA) (35%, P = 0.19). Moreover, stiffness did not differ between the two groups, but secant modulus was 27% lower in children with a HCTD (P = 0.05) at common force and 34% lower at maximum force (P = 0.02).

Conclusions: The present study demonstrates for the first time that children with HCTDs have lower material properties (modulus) of their patellar tendon, which may be indicative of general impairment of connective tissue mechanics related to their increased joint laxity.
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http://dx.doi.org/10.1007/s00421-018-3862-7DOI Listing
July 2018

A complex phenotype in a family with a pathogenic SOX3 missense variant.

Eur J Med Genet 2018 Mar 24;61(3):168-172. Epub 2017 Nov 24.

Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.

Duplications and deletions of Xq26-27 including SOX3 (Xq27.1) have been associated with X-linked mental retardation and isolated growth hormone deficiency (OMIM 300123) or X-linked panhypopituitarism (OMIM 312000). Yet, pathogenic point mutations seem to be extremely rare. We report a family with three affected males with several clinical features including mild intellectual disability, microphthalmia, coloboma, hypopituitarism, facial dysmorphology and dental anomalies, including microcephaly, retrognathia and a solitary median maxillary central incisor amongst other features. Using Whole Exome Sequencing a missense variant in SOX3, NM_005634.2:c.449C>A; p.(Ser150Tyr) was identified. Segregation analysis in the family demonstrated that the variant was inherited through healthy females with its origin in the maternal grandmother showing germline mosaicism. Thus, we report one of the first cases of a pathogenic variant in SOX3 and germline mosaicism of this variant.
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http://dx.doi.org/10.1016/j.ejmg.2017.11.012DOI Listing
March 2018

Prenatal diagnosis of autosomal recessive Robinow syndrome using 3D ultrasound.

Clin Case Rep 2017 07 16;5(7):1072-1076. Epub 2017 May 16.

Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark.

This article hypothesizes that it is possible to detect and diagnose both the autosomal recessive and dominant forms prenatally using ultrasound. By focusing on the characteristic phenotypical presentation, the examinator is able to diagnose the syndrome prenatally, which is of clinical importance to the parents and counseling for the consideration of terminating the pregnancy.
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http://dx.doi.org/10.1002/ccr3.784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494388PMC
July 2017