Clinical characterization of children and adolescents with NF1 microdeletions

Kehrer‐Sawatzki, Hildegard; Salamon, Johannes; Well, Lennart; Farschtschi, Said; Rosenbaum, Thorsten; Mautner, Victor‐Felix

doi:10.1007/s00381-020-04717-0

Cited by 20 publications

(24 citation statements)

References 101 publications

(195 reference statements)

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“…Cutaneous neurofibromas show age-related penetrance and they usually appear in adulthood, therefore this may contribute to the difference in frequency observed by us and by others. Nevertheless, a high frequency (60%) of cutaneous neurofibromas was observed among children by Kehrer-Sawatzki in a recent study (Kehrer-Sawatzki et al, 2020). The high prevalence of subcutaneous neurofibromas in type-1 NF1 patients is important to consider, since they are associated with mortality in NF1 disease (Tucker et al, 2005).…”

Section: Discussionmentioning

confidence: 96%

“…However, it is important to emphasize that the majority of our patients (13 out of 17) were less than 15 years old at the time of the examination. There are only few studies ( Kehrer-Sawatzki et al, 2020 ) that demonstrated pediatric clinical data, the majority of phenotypic data published previously originated mainly from adult patient populations.…”

Section: Discussionmentioning

confidence: 99%

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Genotype-Phenotype Associations in Patients With Type-1, Type-2, and Atypical NF1 Microdeletions

et al. 2021

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Neurofibromatosis type 1 is a tumor predisposition syndrome inherited in autosomal dominant manner. Besides the intragenic loss-of-function mutations in NF1 gene, large deletions encompassing the NF1 gene and its flanking regions are responsible for the development of the variable clinical phenotype. These large deletions titled as NF1 microdeletions lead to a more severe clinical phenotype than those observed in patients with intragenic NF1 mutations. Around 5-10% of the cases harbor large deletion and four major types of NF1 microdeletions (type 1, 2, 3 and atypical) have been identified so far. They are distinguishable in term of their size and the location of the breakpoints, by the frequency of somatic mosaicism with normal cells not harboring the deletion and by the number of the affected genes within the deleted region. In our study genotype-phenotype analyses have been performed in 17 mostly pediatric patients with NF1 microdeletion syndrome identified by multiplex ligation-dependent probe amplification after systematic sequencing of the NF1 gene. Confirmation and classification of the NF1 large deletions were performed using array comparative genomic hybridization, where it was feasible. In our patient cohort 70% of the patients possess type-1 deletion, one patient harbors type-2 deletion and 23% of our cases have atypical NF1 deletion. All the atypical deletions identified in this study proved to be novel. One patient with atypical deletion displayed mosaicism. In our study NF1 microdeletion patients presented dysmorphic facial features, macrocephaly, large hands and feet, delayed cognitive development and/or learning difficulties, speech difficulties, overgrowth more often than patients with intragenic NF1 mutations. Moreover, neurobehavior problems, macrocephaly and overgrowth were less frequent in atypical cases compared to type-1 deletion. Proper diagnosis is challenging in certain patients since several clinical manifestations show age-dependency. Large tumor load exhibited more frequently in this type of disorder, therefore better understanding of genotype-phenotype correlations and progress of the disease is essential for individuals suffering from neurofibromatosis to improve the quality of their life. Our study presented additional clinical data related to NF1 microdeletion patients especially for pediatric cases and it contributes to the better understanding of this type of disorder.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Genotype-Phenotype Associations in Patients With Type-1, Type-2, and Atypical NF1 Microdeletions

et al. 2021

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“…The developmental delay observed in patient 310221 was much less severe than the global developmental delay frequently observed in children with type 1 or very large atypical NF1 microdeletions (reviewed in [5]). Severe global developmental delay in language and motor skills has been observed in 28 (93%) of 30 children with NF1 microdeletions [51]. These delays were already apparent at a young age (1-3 years) and persisted during later childhood.…”

Section: Discussionmentioning

confidence: 99%

“…These patients frequently exhibit more severe clinical manifestations of NF1 as well as features that are not frequently seen in patients with intragenic NF1 mutations. The type 1 NF1 deletion-associated phenotype includes facial dysmorphic features, severe global developmental delay, significantly lower full-scale IQ scores, higher neurofibroma burden and an increased risk of malignant peripheral nerve sheath tumours (MPNSTs) as compared to patients with intragenic NF1 mutations [5,[51][52][53][54]. It has been postulated that some of the genes located within the type 1 NF1 microdeletion region and co-deleted with NF1 exert an influence on the clinical manifestation of the disease in NF1 deletion patients.…”

Section: Introductionmentioning

confidence: 99%

Atypical NF1 Microdeletions: Challenges and Opportunities for Genotype/Phenotype Correlations in Patients with Large NF1 Deletions

Kehrer‐Sawatzki

Wahlländer

Cooper

et al. 2021

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Patients with neurofibromatosis type 1 (NF1) and type 1 NF1 deletions often exhibit more severe clinical manifestations than patients with intragenic NF1 gene mutations, including facial dysmorphic features, overgrowth, severe global developmental delay, severe autistic symptoms and considerably reduced cognitive abilities, all of which are detectable from a very young age. Type 1 NF1 deletions encompass 1.4 Mb and are associated with the loss of 14 protein-coding genes, including NF1 and SUZ12. Atypical NF1 deletions, which do not encompass all 14 protein-coding genes located within the type 1 NF1 deletion region, have the potential to contribute to the delineation of the genotype/phenotype relationship in patients with NF1 microdeletions. Here, we review all atypical NF1 deletions reported to date as well as the clinical phenotype observed in the patients concerned. We compare these findings with those of a newly identified atypical NF1 deletion of 698 kb which, in addition to the NF1 gene, includes five genes located centromeric to NF1. The atypical NF1 deletion in this patient does not include the SUZ12 gene but does encompass CRLF3. Comparative analysis of such atypical NF1 deletions suggests that SUZ12 hemizygosity is likely to contribute significantly to the reduced cognitive abilities, severe global developmental delay and facial dysmorphisms observed in patients with type 1 NF1 deletions.

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“…4 Lower extremity alignment films, at age 13 years 10 months. The image demonstrates improvement in the leg length discrepancy to just over 2 cm syndrome is typically characterized by a more severe clinical presentation than that seen in the majority of NF1 patients, with more cutaneous, subcutaneous and externally visible plexiform neurofibromas than agematched patients with intragenic NF1 mutations, in addition to facial dysmorphic features, cognitive impairment, developmental delay, and an increased risk of malignant tumors [15][16][17]. This patient demonstrates developmental delay, is non-verbal but able to follow simple commands and has short stature, all of which can be found in NF1, but these features fit a wide variety of genetic disorders besides NF1 and acroscyphodysplasia.…”

Section: Discussionmentioning

confidence: 99%

Fourteen-year follow-up of a child with acroscyphodysplasia with emphasis on the need for multidisciplinary management: a case report

et al. 2020

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Background Acroscyphodysplasia has been described as a phenotypic variant of acrodysostosis type 2 and pseudohypoparathyroidism. In acrodysostosis, skeletal features can include brachydactyly, facial hypoplasia, cone-shaped epiphyses, short stature, and advanced bone age. To date, reports on this disorder have focused on phenotypic findings, endocrine changes, and genetic variation. We present a 14-year overview of a patient, from birth to skeletal maturity, with acroscyphodysplasia, noting the significant orthopaedic challenges and the need for a multidisciplinary team, including specialists in genetics, orthopaedics, endocrinology, and otolaryngology, to optimize long-term outcomes. Case presentation The patient presented as a newborn with dysmorphic facial features, including severe midface hypoplasia, malar flattening, nasal stenosis, and feeding difficulties. Radiologic findings were initially subtle, and a skeletal survey performed at age 7 months was initially considered normal. Genetic evaluation revealed a variant in PDE4D and subsequent pseudohypoparathyroidism. The patient presented to the department of orthopaedics, at age 2 years 9 months with a leg length discrepancy, right knee contracture, and severely crouched gait. Radiographs demonstrated cone-shaped epiphyses of the right distal femur and proximal tibia, but no evidence of growth plate changes in the left leg. The child developed early posterior epiphyseal arrest on the right side and required multiple surgical interventions to achieve neutral extension. Her left distal femur developed late posterior physeal arrest and secondary contracture without evidence of schypho deformity, which improved with anterior screw epiphysiodesis. The child required numerous orthopaedic surgical interventions to achieve full knee extension bilaterally. At age 13 years 11 months, she was an independent ambulator with erect posture. The child underwent numerous otolaryngology procedures and will require significant ongoing care. She has moderate intellectual disability. Discussion and conclusions Key challenges in the management of this case included the subtle changes on initial skeletal survey and the marked asymmetry of her deformity. While cone-shaped epiphyses are a hallmark of acrodysostosis, posterior tethering/growth arrest of the posterior distal femur has not been previously reported. Correction of the secondary knee contracture was essential to improve ambulation. Children with acroscyphodysplasia require a multidisciplinary approach, including radiology, genetics, orthopaedics, otolaryngology, and endocrinology specialties.

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Clinical characterization of children and adolescents with NF1 microdeletions

Cited by 20 publications

References 101 publications

Genotype-Phenotype Associations in Patients With Type-1, Type-2, and Atypical NF1 Microdeletions

Genotype-Phenotype Associations in Patients With Type-1, Type-2, and Atypical NF1 Microdeletions

Atypical NF1 Microdeletions: Challenges and Opportunities for Genotype/Phenotype Correlations in Patients with Large NF1 Deletions

Fourteen-year follow-up of a child with acroscyphodysplasia with emphasis on the need for multidisciplinary management: a case report

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