Congenital malformations of the hand and fingers.

Congenital anomalies of the upper limb are in Denmark estimated to have an incidence of around 20 in 10,000 live births. This covers a wide array of conditions summarised in this review. At the time of referral, the patient is thoroughly examined, and a treatment plan is discussed with the family. In some cases, no treatment is needed, in others there might be a need for surgery, night splinting, or an upper limb prosthesis. In case an underlying syndromatic cause is suspected, the patient is referred for paediatric evaluation at specialized centre.

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.

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.

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.

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.

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.

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

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.

Unique skeletal manifestations in patients with Primrose syndrome.

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.

Primrose syndrome: Characterization of the phenotype in 42 patients.

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.

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

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.

Defining the clinical phenotype of Saul-Wilson syndrome.

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.