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Incidence and odds ratios of major congenital anomalies, stratified by NF1 status of mother and child
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Background
Neurofibromatosis type 1 (NF1) is a dominantly inherited Rasopathy caused by mutations in the NF1 gene on chromosome 17. NF1 has been connected to congenital anomalies, e.g., in the skeletal and cardiovascular systems, but the overall incidence of anomalies is unknown. In this retrospective register-based total population study conducted...
Context in source publication
Context 1
... overall incidences and ORs of congenital anomal- ies among the children in this cohort, stratified by NF1 status of the child and the mother, are presented in Table 3. The overall incidence of congenital anomalies was significantly higher among children with NF1 than matched controls. ...
Similar publications
Background
Neurofibromatosis type 1 (NF1) is a cancer predisposing syndrome. Studies suggest that women < 50 years old (y.o.) with NF1 have an increased breast cancer (BC) incidence and BC associated mortality. However, this has not been widely recognized secondary to small study populations.
Methods
A systematic literature review was conducted th...
Purpose:
Neurofibromatosis 1 (NF1) is an autosomal dominant condition caused by pathogenic variants of the NF1 gene. A markedly increased risk of breast cancer is associated with NF1. We have determined the breast cancer survival and risk of contralateral breast cancer in NF1.
Methods:
We included 142 women with NF1 and breast cancer from five c...
Neurofibromatosis type I (NF1) is an autosomal dominant disease. Some NF1 patients experience atypical clinical manifestations, genetic testing is not widely available, and the types of mutations vary; thus, they are prone to misdiagnosis and missed diagnosis. Although headache is not included in the diagnostic criteria for NF1, the incidence of he...
Background
The hereditary predisposition to diabetes is only partially explained by genes identified so far. Neurofibromatosis type 1 (NF1) is a rare monogenic dominant syndrome caused by aberrations of the NF1 gene. Here, we used a cohort of 1410 patients with NF1 to study the association of the NF1 gene with type 1 (T1D) and type 2 diabetes (T2D)...
Citations
... Furthermore, NF1 children exhibited a significantly higher risk of congenital anomalies affecting the circulatory and musculoskeletal systems. Interestingly, non-NF1 children of mothers with NF1 did not exhibit a higher prevalence of anomalies compared to children from non-NF1 mothers [20]. ...
Neurofibromatosis is a genetic disorder arising de novo or with an autosomal dominant transmission that typically presents either at birth or in early childhood, manifesting through distinctive clinical features such as multiple café-au-lait spots, benign tumors in the skin, bone enlargement, and deformities. This literature review aims to resume the spectrum of maternal and fetal complications encountered in pregnant women with neurofibromatosis type 1 (NF1). Thorough research was conducted on databases such as Web of Science, PubMed, Science Direct, Google Scholar, and Wiley Online Library. This review includes 48 case reports, original studies, and reviews on NF1 in pregnancy. The research on the interlink between NF1 and fertility and its influence on human-assisted reproduction techniques is limited. Preimplantation testing (by in vitro fertilization) and prenatal diagnosis (by chorionic villus sampling or amniocentesis) are available to detect affected fetuses. However, genotype–phenotype correlation is difficult to predict. Preconceptional planning and targeted investigations are crucial in understanding the extent of maternal disease. Although in some cases lesions can evolve rapidly during pregnancy, most pregnancies and births in NF1 go well with careful planning. There is a higher incidence of pheochromocytomas and pre-eclampsia, vascular rupture, and cardio-respiratory issues. Anesthesia at birth is a challenge in most cases, and before offering spinal anesthesia, imaging tests should be performed to characterize spinal lesions. General anesthesia may also be challenging when the disease affects the face, neck, upper spine, or airways. Birth-related difficulties may arise because of large neurofibromas located at the level of skin incision or birth canal; uterine atony may be expected if there are uterine lesions. Some complications can develop in postpartum, and affected women should be carefully followed even after pregnancy. Fetal risks include preterm birth (spontaneous or iatrogenic), growth restriction and developmental issues, birth complications, cardiovascular risk, and fetal/neonatal demise. Pregnancies in women with NF1 should be regarded as high-risk and followed in a multidisciplinary fashion. Careful assessment of lesions is of utmost importance before and during pregnancy for anticipating potential maternal risks and before birth to plan anesthesia and delivery.
... Overgrowth syndromes (such as Beckwith-Wiedemann) also have well-established cancer risk [39]. Polydactyly has previously been described in all the aforementioned syndromes although as an uncommon part of the phenotype (Supplementary Table 1) [40][41][42]. When removing all individuals with neurofibromatosis and Down syndrome from our cohort, individuals with polydactyly+ had a slightly lower, although still increased, risk of cancer. ...
Background
Polydactyly is a feature of several cancer predisposition syndromes (CPS), however, cancer risk in individuals with polydactyly is largely unknown.
Methods
We performed a matched cohort study using data from Swedish national registers. We included 6694 individuals with polydactyly, born in Sweden between 1970–2017. Polydactyly was categorised as thumb polydactyly, finger polydactyly, polydactyly+ (additional birth defects and/or intellectual disability) or isolated polydactyly. Each exposed individual was matched to 50 comparisons by sex, birth year and birth county. Associations were estimated through Cox proportional hazard models.
Findings
An increased childhood cancer risk was found in males (HR 4.24, 95% CI 2.03–8.84) and females (HR 3.32, 95% CI 1.44–7.63) with polydactyly+. Isolated polydactyly was associated with cancer in childhood (HR 1.87, 95% CI 1.05–3.33) and young adulthood (HR 2.30, 95% CI 1.17–4.50) in males but not in females. The increased cancer risk remained after exclusion of two known CPS: Down syndrome and neurofibromatosis. The highest site-specific cancer risk was observed for kidney cancer and leukaemia.
Conclusions
An increased cancer risk was found in individuals with polydactyly, especially in males and in individuals with polydactyly+. We encourage future research about polydactyly and cancer associations and emphasise the importance of clinical phenotyping.
... Pulmonary vascular stenosis is more commonly seen accounting for a quarter of the cases. Other reported associated congenital heart defects have been coarctation of the aorta, unroofed coronary sinus, atrial septal defect, endocardial cushion defect, small left ventricular syndrome, aortic stenosis, ventricular septal defect, tricuspid atresia with d-Transposition of Great Arteries, vascular ring, and tetralogy of Fallot (Bender et al., 2013;Leppävirta et al., 2018;Lin et al., 2000;Neiman et al., 1974;Ramanjam et al., 2006;Tonsgard, 2006). Isolated ventricular septal defect is seldom reported among series of congenital heart defects associated with NF1. ...
... Subsequent reports in the United States, Finland and Turkey have each reported 1 case out of 35 (2.9%), 11 (9.1%), and 9 (11.1%) NF1 patients with CHD (Table 1) ( _ Incecik et al., 2015;Leppävirta et al., 2018;Neiman et al., 1974). Our index case had outlet (sub-pulmonic) VSD, a type of VSD which is more commonly seen in Southeast Asia (Lue, 1986). ...
Neurofibromatosis type 1 is an autosomal dominant multisystemic disease caused by mutation of the neurofibromin (NF1) gene located on chromosome 17q11. We report a case of Neurofibromatosis 1 with ambiguous genitalia, giant congenital melanocytic nevus, and associated subpulmonic outlet ventricular septal defect, hitherto unreported in sub-Saharan Africa. In addition, a literature review of congenital heart diseases associated with Neurofibromatosis 1 is presented.
... Cervicothoracic dislocation due to vertebral malformations can be developed due to dislocation in utero, in the first year of life or later, and it accompanied by compression/ hypoplasia/aplasia of the spinal cord at the level of paraparesis and lower limbs deformity. NF or bone dysplasia can lead to cervicothoracic dislocation in children [28] and can be caused by changes in the bone structure during life [21,28] or in utero [29,30]. In NF type I, the causes of abnormal vertebrae which can lead to the dislocation are increased by osteoclastic activity and impaired osteoblastic function [31], osteoporosis, osteopenia [32], dural ectasia [33], vasculopathy [34], and neurofibromas [35]. ...
PurposeTo evaluate the approaches to treatment of congenital and bone-dysplasia-related pediatric cervicothoracic dislocations and define the optimal treatment method.Methods
The publications available in PubMed and Google Scholar data bases were selected following such criteria as the disease in question, pediatric age, the treatment description, and follow-up results. The paper also includes the descriptions of our own six cases of the cervicothoracic dislocations detected in children with different vertebral malformations.ResultsOnly eight patients meeting the abovementioned selection criteria were found in the publications: three of them had the Klippel–Feil syndrome (KFS), two had one-level vertebral anomaly, one had neurofibromatosis (NF type 1), one had the Larsen syndrome, and one had a variation of VACTERL association. Their treatment was long term, multi stage, and complicated. Among six our own cases, four patients also had KFS, one had a variation of VACTERL association, and one had NF type 1. All the patients suffered from preoperative neurological disorders. Posterior instrumental fixation with posterior vertebral body resection was performed in four cases and one patient underwent a combined surgery. The parents of one of the patients refused the operation, so he was observed while receiving bracing treatment. Since the treatment was long term and complicated by reoperations, the average follow-up period comprised 5 years.Conclusion
Congenital cervicothoracic dislocations are an extremely rare pathology that manifests itself in early age and requires an early surgical treatment. Failure to provide the treatment leads to the patient’s disability. The surgical tactics for such patients is determined individually, but the published data and our own experience demonstrate that early multi-stage combined treatment has been the best option available so far. The cervicothoracic dislocations due to NF 1 manifest later and have a more favorable forecast.
... Although the association between FLIT and neurofibromatosis type 1 (NF1) has not been reported previously, the association between NF1 and major congenital anomalies is well recognized. [14] The genetic results in these 2 cases suggest that the role of DICER1 in the development of this type of congenital lung tumor is questionable and that a broader gene panel could be considered in the context of a diagnosis of FLIT. ...
Background: Fetal Lung Interstitial Tumor (FLIT) is a rare benign lung tumor. There have been 18 cases of FLIT described in the literature. FLIT is characterized by a region of arrested lung development and must be differentiated from other congenital lung lesions with poorer prognoses.
Case Presentation: We report the first two known cases of FLIT in Australia and New Zealand. In both cases, the patients developed respiratory distress at birth requiring intubation. Imaging revealed solid lesions and echocardiography demonstrated pulmonary hypertension. The patients underwent surgical resection without any complications or recurrence.
Conclusion: FLIT is a rare benign congenital lung tumor that can be adequately managed with surgical resection.
... 32 NF1 is a very large gene encoding a ubiquitous tumoursuppressor protein neurofibromin. 32 Hence, neurofibromatosis type 1 is characterized by various tumour and hamartomas developing mostly from neuro-cutaneous structures. The most important lesions include cutaneous neurofibroma and plexiform neurofibromas [ Figure 1], café au lait macules [ Figure 2], axillary freckling (Crowe sign), optic pathway glioma and Lisch nodules. ...
... The most important lesions include cutaneous neurofibroma and plexiform neurofibromas [ Figure 1], café au lait macules [ Figure 2], axillary freckling (Crowe sign), optic pathway glioma and Lisch nodules. 32 Various phenotypic features, systemic and malignant associations of neurofibromatosis type 1 are presented in Tables 2 and 3. 4,18,[32][33][34][35][36] Genotype-phenotype variations Genotype-phenotype variations in neurofibromatosis type 1 are mostly related to severity and results from deletions. A mild phenotype [ Figure 3] with café au lait macules but few or without cutaneous neurofibromas, plexiform neurofibromas and optic pathway glioma occur with 3-bp microdeletion (p.Met 99 2del,exon 17) of NF1. ...
... The most important lesions include cutaneous neurofibroma and plexiform neurofibromas [ Figure 1], café au lait macules [ Figure 2], axillary freckling (Crowe sign), optic pathway glioma and Lisch nodules. 32 Various phenotypic features, systemic and malignant associations of neurofibromatosis type 1 are presented in Tables 2 and 3. 4,18,[32][33][34][35][36] Genotype-phenotype variations Genotype-phenotype variations in neurofibromatosis type 1 are mostly related to severity and results from deletions. A mild phenotype [ Figure 3] with café au lait macules but few or without cutaneous neurofibromas, plexiform neurofibromas and optic pathway glioma occur with 3-bp microdeletion (p.Met 99 2del,exon 17) of NF1. ...
Ras/mitogen-activated protein kinase pathway dysregulation results in a group of disorders, collectively termed as RASopathies. Neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome/loose anagen hair, Legius syndrome, Costello syndrome, cardio-facio-cutaneous syndrome and capillary malformation-arteriovenous malformation are the well-recognized RASopathies. These are characterized by multi-organ tumours and hamartomas. Some other features in common are facial dysmorphism, skeletal abnormalities, congenital heart disease, neurocognitive abnormalities and risk of various solid-organ and haematological malignancies. Some of the RASopathies are heterogeneous, caused by several gene mutations resulting in variations in phenotypes and severity ranging from mild to fatal. Significant phenotypic overlaps among different disorders, often makes it difficult to pinpoint a clinical diagnosis. Specific cutaneous manifestations are present in some of the RASopathies and are often the earliest clinical signs/symptoms. Hence, dermatologists contribute significantly as primary care physicians by identifying disorder-specific cutaneous lesions. However, diagnostic work-up and management of these disorders are often multidisciplinary. Confirmation of diagnosis is possible only by genetic mapping in each case. Genetic counseling of the patients and the affected families is an important component of the management. The aim of this review is description of cutaneous manifestations of RASopathies in the background of multi-system involvement to enable dermatologists a comprehensive and logical approach to work up and diagnose such patients in the absence of facility for specific molecular testing.
... Antihypertensive medication, percutaneous transluminal angioplasty, or surgery can be used to treat hypertensive NF1 patients [31]. In a study on the congenital anomalies of NF1, hydronephrosis was detected in three and ureter duplication in one of 22 patients [32]. A horseshoe kidney [33,34], bladder involvement caused by neurofibromas accompanied by urinary incontinence [8], an autosomal-dominant polycystic kidney [35,36], anuric acute kidney injury caused by renal artery occlusion and a thromboembolism [20], and chronic renal disease attributable to bladder neurofibromas [21] have been (rarely) reported in NF1 patients, as have glomerulonephritis [19], focal segmental glomerular sclerosis [17,18], C1q nephropathy [37], and Joubert Syndrome with nephronophthisis [38]. ...
Neurofibromatosis type 1 (NF1) is an autosomal-dominant neurocutaneous syndrome affecting various parts of the body, including the renovascular and urinary systems. We evaluated the renovascular, urinary, glomerular, and tubular functions of children with NF1. We compared blood pressures, urinary findings, and renal glomerular and tubular functions in children with NF1 with those of a healthy age- and gender-matched control group. We evaluated 46 NF1 patients and 33 healthy controls. The mean ages of the NF1 group (female/male: 20/26) and the control group (female/male: 15/18) were 10.1 ± 4.6 and 10.6 ± 4.3 years respectively. Six NF1 patients were hypertensive. The mean blood pressures of the NF1 group were significantly higher than those of the control group. Renal artery stenosis was detected in one NF1 patient. Urinary tract anomalies were evident in 21.7% of NF1 but only 9% of control subjects. The mean estimated glomerular filtration rate (eGFR) of the NF1 group was significantly lower than that of the control group. Six NF1 patients evidenced eGFRs < 90 mL/min. In the NF1 group, tubular phosphorus reabsorption was significantly lower and uric acid excretion significantly higher than in the control group.Conclusion: Hypertension, urinary tract anomalies, and impaired renal function were more common in NF1 patients than healthy controls. Regular blood pressure measurements and evaluation of urinary tract and kidney function are essential for NF1 patients.
What is Known:
• NF1 is most commonly associated with systemic hypertension due to renal artery vasculopathy and the development of a pheochromocytoma.
• Hydronephrosis and bladder involvement have been documented in NF1.
What is New:
• Renal glomerular and tubular functions may be affected in NF1.
... Fetuses may also be affected by NF1 and may present higher incidence of malformations (Leppavirta et al 2018). 16 Our patient had two preterm deliveries, one due to abruptio placentae in the absence of hypertension and two out three children had clinical signs of NF1. Vaginal delivery was not contraindicated due to normal pelvic examination and undetectable viral load. ...
Although pregnant neurofibromatosis or HIV patient established a high-risk group, this report demonstrated that a careful planning and widespread valuations should be associated with a favorable prognosis for both mother and newborn.
... Few studies showed that patients with NF1 had a higher risk of cardiac malformations. Nevertheless, the repetition and mechanism of these manifestations are still unknown [8,9]. The condition is diagnosed based on the presence of two or more of the following conditions according to the National Institutes of Health diagnostic criteria: café au lait macules, neurofibromas, axillary/inguinal freckling, Lisch nodules, distinctive osseous lesions, glioma, and/or family history of NF [10]. ...
... PAH is an extremely rare complication of NF1. Children with fatal complications such as cerebral infarction, fatal brain tumors, and hemorrhage may die before diagnosis [9]. The association between NF1 and PAH remains unclear. ...
Neurofibromatosis type 1 (NF1), or von Recklinghausen disease, is a genetically transmitted autosomal dominant disease, with a prevalence of one per 4000 live births. Pulmonary arterial hypertension (PAH) is a rare but potentially life-threatening complication of NF1. There are no confirmatory data about the congenital association between PAH and NF1. However, in most cases, PAH is observed in late childhood or adulthood. Herein, we present a preterm baby with genetically confirmed NF1 who presented with PAH.
... Two studies on birth characteristics among children with NF1 performed in Denmark and Finland indicated that birth weight and gestational age in NF1 children differ from the general population, but were based on a limited number of children with NF1 (<500). [8][9][10][11] For children with TS there is one published study on birth weight available, based on 32 patients. 12 The aim of the current study was to determine whether birth characteristics in a large, population-based cohort of children in Sweden with NF1 and TS differ from that of the general population. ...
... Our results regarding NF1 agree with findings reported in a Finnish study [9][10][11] and with results on premature birth reported from Denmark. 8 Our risk estimates are considerably more precise as they are based on approximately 1800 NF1 patients, compared with <500 in each of the two other Nordic studies. No previous study has reported results for the child's condition at birth (Apgar score). ...
Objective
To evaluate whether children with neurofibromatosis type 1 (NF1) and tuberous sclerosis have different birth characteristics compared with the general population.
Study design
We identified all individuals born in Sweden between 1973 and 2014 from the nationwide Medical Birth Register, for whom information on both biological parents was available (n=4 242 122). NF1 and TS patients were identified using data from Swedish population-based health data registers. We assessed using logistic regression models the association between these neurocutaneous syndromes and birth characteristics in a cohort that included 1804 NF1 and 450 TS patients.
Results
Children with NF1 and TS were significantly more likely to be born preterm and via a caesarean section. In addition, children with NF1 were also more likely to be born with other birth characteristics, such as short length, a large head circumference, and a low Apgar score. Moreover, children with NF1 had an increased odds of being born with a high birth weight or large for gestational age (OR 1.61, 95% CI 1.42-1.82 and OR 1.82, 95% CI 1.60-2.06, respectively).
Conclusion
Children with NF1 1 and TS differ from the general population in regard to several birth characteristics, with the strongest associations observed for high birth weight and being large for gestational age in individuals with NF1.
