Novel biallelic PISD missense variants cause spondyloepimetaphyseal dysplasia with disproportionate short stature and fragmented mitochondrial morphology.

Biallelic variants in PISD cause a phenotypic spectrum ranging from short stature with spondyloepimetaphyseal dysplasia (SEMD) to a multisystem disorder affecting eyes, ears, bones, and brain. PISD encodes the mitochondrial-localized enzyme phosphatidylserine decarboxylase. The PISD precursor is self-cleaved to generate a heteromeric mature enzyme that converts phosphatidylserine to the phospholipid phosphatidylethanolamine. We describe a 17-year-old male patient, born to unrelated healthy parents, with disproportionate short stature and SEMD, featuring platyspondyly, prominent epiphyses, and metaphyseal dysplasia. Trio genome sequencing revealed compound heterozygous PISD variants c.569C>T; p.(Ser190Leu) and c.799C>T; p.(His267Tyr) in the patient. Investigation of fibroblasts showed similar levels of the PISD precursor protein in both patient and control cells. However, patient cells had a significantly higher proportion of fragmented mitochondria compared to control cells cultured under basal condition and after treatment with 2-deoxyglucose that represses glycolysis and stimulates respiration. Structural data from the PISD orthologue in Escherichia coli suggest that the amino acid substitutions Ser190Leu and His267Tyr likely impair PISD's autoprocessing activity and/or phosphatidylethanolamine biosynthesis. Based on the data, we propose that the novel PISD p.(Ser190Leu) and p.(His267Tyr) variants likely act as hypomorphs and underlie the pure skeletal phenotype in the patient.

Novel Alu insertion in the ZEB2 gene causing Mowat-Wilson syndrome.

Alu elements are short, interspersed elements located throughout the genome, playing a role in human diversity, and occasionally causing genetic diseases. Here, we report a novel Alu insertion causing Mowat-Wilson syndrome, a rare neurodevelopmental disorder, in an 8-year-old boy displaying the typical clinical features for Mowat-Wilson syndrome. The variant was not initially detected in genome sequencing data, but through deep phenotyping, which pointed to only one plausible candidate gene, manual inspection of genome sequencing alignment data enabled us to identify a de novo heterozygous Alu insertion in exon 8 of the ZEB2 gene. Nanopore long-read sequencing confirmed the Alu insertion, leading to the formation of a premature stop codon and likely haploinsufficiency of ZEB2. This underscores the importance of deep phenotyping and mobile element insertion analysis in uncovering genetic causes of monogenic disorders as these elements might be overlooked in standard next-generation sequencing protocols.

Prevalence and Patient Characteristics of Ectodermal Dysplasias in Denmark.

Importance: Ectodermal dysplasias constitute a group of rare genetic disorders of the skin and skin appendages with hypodontia, hypotrichosis, and hypohidrosis as cardinal features. There is a lack of population-based research into the epidemiology of ectodermal dysplasias. Objective: To establish a validated population-based cohort of patients with ectodermal dysplasia in Denmark and to assess the disease prevalence and patient characteristics. Design, Setting, and Participants: This nationwide cohort study used individual-level registry data recorded across the Danish universal health care system to identify patients with ectodermal dysplasias from January 1, 1995, to August 25, 2021. A 3-level search of the Danish National Patient Registry and the Danish National Child Odontology Registry was conducted to identify patients with diagnosis codes indicative of ectodermal dysplasias; patients registered in the Danish RAREDIS Database, the Danish Database of Genodermatoses, and local databases were also added. The search results underwent diagnosis validation and review of clinical data using medical records. Of 844 patient records suggestive of ectodermal dysplasias, 791 patients (93.7%) had medical records available for review. Positive predictive values of the diagnosis coding were computed, birth prevalence was estimated, and patient characteristics were identified. Data analysis was performed from May 4 to December 22, 2023. Results: The identified and validated study cohort included 396 patients (median [IQR] age at diagnosis, 13 [4-30] years, 246 females [62.1%]), of whom 319 had confirmed ectodermal dysplasias and 77 were likely cases. The combined positive predictive value (PPV) for ectodermal dysplasia-specific diagnosis codes was 67.0% (95% CI, 62.7%-71.0%). From 1995 to 2011, the estimated minimum birth prevalence per 100 000 live births was 14.5 (95% CI, 12.2-16.7) for all ectodermal dysplasias and 2.8 (95% CI, 1.8-3.8) for X-linked hypohidrotic ectodermal dysplasias. A molecular genetic diagnosis was available for 241 patients (61%), including EDA (n = 100), IKBKG (n = 55), WNT10A (n = 21), TRPS1 (n = 18), EDAR (n = 10), P63 (n = 9), GJB6 (n = 9), PORCN (n = 7), and other rare genetic variants. Conclusions and Relevance: The findings of this nationwide cohort study indicate that the prevalence of ectodermal dysplasias was lower than previously reported. Furthermore, PPVs of the search algorithms emphasized the importance of diagnosis validation. The establishment of a large nationwide cohort of patients with ectodermal dysplasias, including detailed clinical and molecular data, is a unique resource for future research in ectodermal dysplasias.

Employment, occupation, and income in adults with neurofibromatosis 1 in Denmark: a population- and register-based cohort study.

BACKGROUND: Little is known about employment status, occupation, and disposable income in adults with NF1. METHODS: From the Danish National Patient Registry and database of two national Centers for Rare Diseases, we identified 1469 adults with NF1, who were matched to 11,991 randomly selected population comparisons on sex and birth year and month. Annual information on employment, occupation and disposable income was ascertained from national registries in 1980-2019. RESULTS: Adults with NF1 had a lower odds ratio (OR) for employment [OR 0.71, 95% confidence interval (CI) 0.61-0.83] and higher OR for health-related unemployment (OR 2.94, 95% CI 2.16-3.96) at age 30 years than population comparisons, which persisted at age 40 and 50 years. Somatic diagnoses were associated with a higher OR for health-related unemployment in adults with NF1 than in the population comparisons. Adults with NF1 had a slightly lower disposable income, with a 14% (0.82-0.89) reduction observed among the youngest birth cohort. Furthermore, adults with NF1 were less likely to be in a high skilled occupation at ages 30, 40 and 50 years. CONCLUSION: Adults with NF1 have a lower employment rate, which was mainly due to health-related reasons and a slightly lower disposable income than adults without NF1. Thus, anticipation guidance for employment should be part of the management of NF1 families.

Endocrine morbidity in neurofibromatosis 1: a nationwide, register-based cohort study.

OBJECTIVE: Previous studies have found that neurofibromatosis 1 (NF1) is associated with an increased risk for endocrine disorders, but no comprehensive overview of the risk for specific endocrine disorders has been published. We assessed endocrine morbidity in individuals with NF1 from information on hospital admissions, surgery for endocrine disorders, and relevant medication. DESIGN: A nationwide population registry-based cohort study. METHODS: We identified 2467 individuals with NF1 diagnosed between 1977 and 2013 from the Danish National Patient Register and the RAREDIS database and 20 132 randomly sampled age- and sex-matched population comparisons. Information on endocrine diseases was identified using registrations of discharge diagnoses, surgery, and medication prescriptions. The rates of endocrine disorders in individuals with NF1 were compared with those in the comparison cohort in Cox proportional hazard models. RESULTS: Individuals with NF1 had a higher rate than the comparison group of any endocrine discharge diagnosis (hazard ratio [HR] 1.72, 95% confidence interval [CI]: 1.58-1.87), endocrine-related surgery (2.03, 1.39-2.96), and prescribed medications (1.32, 1.23-1.42). Increased HRs were observed for diseases and surgical operations of several glands, including pheochromocytoma, and for osteoporosis, and osteoporotic fractures. Decreased rates were observed with drugs for type 2 diabetes. Women with NF1 had higher HRs for surgery of the ovaries, uterus, and sterilization, but lower rates of surgeries of cervix and prescriptions for birth control pills. CONCLUSIONS: Neurofibromatosis 1 is associated with a variety of endocrine disorders, surgery, and medication related to endocrine disease. Awareness of endocrine morbidity is important in the clinical follow-up of individuals with NF1.

Cohort profile: life with neurofibromatosis 1 - the Danish NF1 cohort.

PURPOSE: The Danish neurofibromatosis 1 (NF1) cohort was initiated to study health-related, socioeconomic and psychological consequences of living with the monogenetic disorder NF1 using a nationwide and population-based approach. PARTICIPANTS: The cohort includes all 2467 individuals in Denmark who were hospitalised with or due to NF1 from 1977 to 2013 or registered in the RAREDIS Database (1995-2013), a national clinical database for rare diseases, or both. A comparison cohort matched to individuals with NF1 on sex and date of birth was identified in the Civil Registration System (n=20 132). FINDINGS TO DATE: All cohort members were linked to the unique Danish registries to obtain information on hospital contacts, birth outcomes, education and partnership. A questionnaire was completed by 244 of the 629 adult cohort members with NF1 registered in the RAREDIS Database to evaluate the psychosocial and emotional burden. Further, neuropsychological tests were performed on 103 adult cohort members with NF1 and 38 adult population comparisons. To date, six studies have been published. Individuals with NF1 had an increased risk for (1) hospitalisation for disorders affecting all organ systems of the body throughout all decades of life, (2) psychiatric disorders, (3) attaining a short or medium long education and (4) not forming a life partner. Women with NF1 had an increased risk for spontaneous abortions and stillbirths. Finally, adults with NF1 had an impaired quality of life and a high need for professional support for physical, psychological and work-related problems, which was partly associated with disease severity and visibility. FUTURE PLANS: The cohort will regularly be updated with newly diagnosed patients in the RAREDIS Database as well as with outcome information in the Danish registries. New studies are in progress to assess other medical and socioeconomic dimensions of living with NF1.

Early diagnosis enabling precision medicine treatment in a young boy with PIK3R1-related overgrowth.

Mosaic PIK3R1 variants have recently been demonstrated in patients with complex vascular malformations and overgrowth in a syndrome resembling PIK3CA-related overgrowth syndrome (PROS). The PIK3CA-inhibitor, alpelisib, seems to be a promising treatment option for PROS patients. We describe a young boy with overgrowth and a pathogenic mosaic variant in PIK3R1; c.1699A > G, p.(Lys567Glu). He was prenatally suspected of a syndrome on the presence of unusual transient fluctuating subcutaneous edemas and lymphedema of his left shoulder. The pathogenic variant, later found to be causative, was below detection threshold in whole-genome sequencing (WGS) analysis of amniotic fluid. Upon delivery a mosaic pathogenic PIK3R1 variant, was identified by whole-exome sequencing (WES) of a skin biopsy. With no proven treatment options available, and based on the theoretical disease mechanism, alpelisib therapy was initiated at nine months of age. In the first year of treatment growth normalized and the affected vascular and lymphatic tissue regressed. No side effects have been observed. This report underlines the importance of early variant detection in children suspected of having severe mosaic overgrowth, and proves that prenatal diagnosis is possible, enabling prompt treatment. Furthermore, it demonstrates the promising effects of alpelisib in this patient group.

School performance of children with neurofibromatosis 1: a nationwide population-based study.

Children with neurofibromatosis 1 (NF1) may have a high burden of somatic disease and cognitive impairments, which can lead to poor academic performance. We evaluated school grades from exams ending mandatory schooling (usually around age 15 or 16 years) of children with NF1 in a population-based registry study using a within-school matched design. The study included 285 children with NF1 and 12,000 NF1-free peers who graduated from the same school and year during 2002-2015. We estimated overall and gender-specific grades by subject and compared the grades of children with NF1 with those of NF1-free peers in linear regression models. We also examined the effect of social and socioeconomic factors (immigration status and parental education, income and civil status) on grades and age at finalizing ninth grade. School grades varied considerably by socioeconomic stratum for all children; however, children with NF1 had lower grades by an average of 11-12% points in all subjects. In the adjusted models, children with NF1 had significantly lower grades than their NF1-free peers, with largest negative differences in grades observed for girls with NF1. Finally, children with NF1 were 0.2 (CI 0.1-0.2) years older than their peers on graduating from ninth grade, but only maternal educational modified the age at graduating. In conclusion, students with NF1 perform more poorly than their peers in all major school subjects. Gender had a strong effect on the association between NF1 and school grades; however, socioeconomic factors had a similar effect on grades for children with NF1 and their peers.

Phenotypic spectrum of the recurrent TRPM3 p.(Val837Met) substitution in seven individuals with global developmental delay and hypotonia.

TRPM3 encodes a transient receptor potential cation channel of the melastatin family, expressed in the central nervous system and in peripheral sensory neurons of the dorsal root ganglia. The recurrent substitution in TRPM3: c.2509G>A, p.(Val837Met) has been associated with syndromic intellectual disability and seizures. In this report, we present the clinical and molecular features of seven previously unreported individuals, identified by exome sequencing, with the recurrent p.(Val837Met) variant and global developmental delay. Other shared clinical features included congenital hypotonia, dysmorphic facial features (broad forehead, deep-set eyes, and down turned mouth), exotropia, and musculoskeletal issues (hip dysplasia, hip dislocation, scoliosis). Seizures were observed in two of seven individuals (febrile seizure in one and generalized tonic-clonic seizures with atonic drops in another), and epileptiform activity was observed in an additional two individuals. This report extends the number of affected individuals to 16 who are heterozygous for the de novo recurrent substitution p.(Val837Met). In contrast with the initial report, epilepsy was not a mandatory feature observed in this series. TRPM3 pathogenic variation should be considered in individuals with global developmental delays, moderate-severe intellectual disability with, or without, childhood-onset epilepsy.

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

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.

Psychiatric disorders in individuals with neurofibromatosis 1 in Denmark: A nationwide register-based cohort study.

The aim of this study was to assess the risks of psychiatric disorders in a large cohort of 905 individuals with NF1 and 7614 population comparisons matched on sex and year of birth. The cohort was linked to the Danish Psychiatric Central Research Register to ascertain information on hospital contacts for psychiatric disorders based on the International Classification of Diseases version 8 and 10. The hazard ratio (HR) for a first psychiatric hospital contact was higher in girls (4.19, 95% confidence interval [CI] 1.81-9.69) and boys with NF1 (5.02, 95% CI 3.27-7.69) <7 years of age than in the population comparisons. Both sexes had increased HRs for developmental disorders, including attention deficit/hyperactivity disorders, autism spectrum disorders, and intellectual disabilities in childhood. Females with NF1 had also increased HRs for unipolar depression, other emotional and behavioral disorders, and severe stress reaction and adjustment disorders in early adulthood. The HRs for psychoses, schizophrenia, bipolar disorders, and substance abuse were similar in individuals with NF1 and the population comparisons. Finally, the cumulative incidence of a first hospital contact due to any psychiatric disorder by age 30 years was 35% (95% CI 29-41) in females and 28% (95% CI 19-37) in males with NF1. Thus, screening for psychiatric disorders may be important for early diagnosis and facilitation of appropriate and effective treatment in individuals with NF1.

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

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.

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

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).

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

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 (P = .001) was calculated between the 2 groups, predominately in the transverse direction (1.5 mm; P < .001). The forehead and chin regions presented with the largest significant difference, 3.5 mm (P = .002) and 3.2 mm (P < .001), respectively; followed by the eye (2.4 mm; P = .004), cheek (2.2 mm; P = .004), nose (1.7 mm; P = .001), and mouth (1.4 mm; P = .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.

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

Autosomal recessive omodysplasia (GPC6-related) is a rare short-limb skeletal dysplasia caused by biallelic mutations in the GPC6 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 (FZD2-related). Here, we report 2 affected brothers of Pakistani descent from Denmark with GPC6-related omodysplasia, aiming to highlight the clinical and radiological findings. A homozygous deletion of exon 6 in the GPC6 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.

Description of a family with X-linked oculo-auriculo-vertebral spectrum associated with polyalanine tract expansion in ZIC3.

Oculo-auriculo-vertebral spectrum (OAVS) [MIM:164210], or Goldenhar syndrome, is a developmental disorder associating defects of structures derived from the first and second branchial arches. The genetic origin of OAVS is supported by the description of rare deleterious variants in a few causative genes, and several chromosomal copy number variations. We describe here a large family with eight male members affected by a mild form of the spectrum, mostly auricular defects, harboring a hemizygous ZIC3 variant detected by familial exome sequencing: c.159_161dup p.(Ala55dup), resulting in an expansion of the normal 10 consecutive alanine residues to 11 alanines. Segregation analysis shows its presence in all the affected individuals, with a recessive X-linked transmission. Whole-genome sequencing performed in another affected male allowed to exclude linkage disequilibrium between this ZIC3 variant and another potential pathogenic variant in this family. Furthermore, by screening of a cohort of 274 OAVS patients, we found 1 male patient carrying an expansion of 10 to 12 alanines, a variant previously reported in patient presenting with VACTERL. Loss-of-function variants of ZIC3 are causing heterotaxy or cardiac malformations. These alanine expansion variants could have a different impact on the protein and thereby resulting in a different phenotype within the OAVS/VACTERL.

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

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).

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

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.

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

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.

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

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.