Case Report: Clinical and molecular genetic analysis of a patient with coexisting complete androgen insensitivity syndrome and neurofibromatosis type 1 and 15pstk + polymorphism
Aug 2026· Frontiers in Pediatrics· 0 citations· 22 references
TL;DR
This is the first report of concurrent CAIS and NF1, which enriches and expands the genotypic and phenotypic spectra of both disorders.
Abstract
To report a pediatric patient with coexisting complete androgen insensitivity syndrome (CAIS), neurofibromatosis type 1 (NF1), and 15pstk + polymorphism, and to analyze its clinical phenotypes and molecular genetic characteristics.
Clinical data of a 7-year-and-11-month-old patient with female social gender were retrospectively analyzed. Pathogenic gene variants were identified by whole-exome sequencing (WES), pedigree verification was performed by Sanger sequencing, and variant pathogenicity was evaluated using bioinformatics tools.
The patient exhibited typical phenotypes of both diseases, accompanied by unique features, including epicanthal folds, webbed neck, broad great toes and thumbs. WES identified a maternally inherited hemizygous missense variant in the
AR
gene (c.2599G > A, p.Val867Met) and a
de novo
heterozygous missense variant in the
NF1
gene (c.5488C > T, p.Arg1830Cys).
This is the first report of concurrent CAIS and NF1, which enriches and expands the genotypic and phenotypic spectra of both disorders.
Background.
neurofibromatosis type 1 is a common hereditary autosomal dominant disorder caused by pathogenic genetic variants in the NF1 gene located on chromosome 17q11.2. the disease is characterized by high allelic heterogeneity and the absence of clear genotypic correlations, with the exception of large deletions associated with a more severe phenotype. Clinically, neurofibromatosis is characterized by the presence of multiple (>6) "café-au-lait” spots, neurofibromas of any type or plexiform neurofibromas, freckles in the axillary or inguinal areas, hamartomatous Lisch nodules of the iris, optic glioma, and bone dysplasia. therefore, the description of each new genetic variant is essential for expanding the spectrum of known variants and improving molecular diagnostics.
Case Report
. the article describes a clinical and molecular genetic study of a 10-year-old boy. since early childhood, the patient has had multiple “café-au-lait” spots, speech impairment, grade 1 hypotrophy, rickets, sequelae of perinatal CNs damage, myotonic syndrome, and a delay in motor development. Magnetic resonance imaging of the brain revealed signs of focal damage to both hemispheres, the cerebellar vermis, and the left subcortical nuclei, and a glioma of the right optic nerve was detected. Neurofibromatosis type 1 was diagnosed based on clinical criteria. Whole-genome DNA sequencing was performed, followed by bioinformatics analysis and confirmation of the results by direct sanger sequencing. A previously undescribed complex, likely pathogenic variant NM_001042492.3:c.40 60_4068delinsC of the NF1 gene was identified in the heterozygous state. this variant leads to a reading frameshift and premature translation termination after the synthesis of 23 amino acids (p.ser1354Leufs*23). this variant is not present in available population genetic variant databases.
Conclusion.
thus, wholegenome sequencing identified a new pathogenic variant in the NF1 gene associated with the development of neurofibromatosis type 1. the obtained data expand the range of variants for this pathology and can be used in medical genetic counseling, as well as in algorithms for molecular genetic diagnostics of patients with suspected neurofibromatosis type 1.
I. Z. Zhalsanova, E. Fonova, D. N. Erburova et al.· Siberian journal of oncology· 0 citations
INTRODUCTION
The Wnt ligand secretion mediator is encoded by WLS, and biallelic variants in this gene have been associated with an ultra-rare syndrome known as Zaki syndrome (ZKS). This study presents the fourteenth documented case of ZKS globally and reviews the clinical and genetic information of previously identified ZKS patients.
METHODS
A 17-year-old female from Iran underwent whole-exome sequencing due to a range of phenotypic symptoms suggestive of a unique syndrome. Sanger sequencing was employed to validate the candidate variant and to investigate its segregation among family members.
RESULTS
The patient was found to be homozygous for NM_024911.7: c.1433A>G, p.(Tyr478Cys) located in exon 11 of WLS. She represents the fifth ZKS patient identified with this variant, indicating a possible mutational hotspot. Furthermore, our patient exhibited distinct clinical characteristics compared to previously reported cases, including hyperphagia, congenital blindness, clinodactyly, and early pubertal development. A comparison of all reported ZKS patients suggests that this syndrome displays a recognizable pattern of developmental delay, intellectual disability, postnatal microcephaly, facial dysmorphism, skeletal and ocular anomalies, and short stature. Nevertheless, challenges persist in diagnosing ZKS due to poorly defined genotype-phenotype correlations.
CONCLUSION
The clinical characteristics observed in our patient expand the phenotypic spectrum of ZKS. Additionally, the p.(Tyr478Cys) variant may represent a potential mutational hotspot within WLS.
Naeim Ehtesham, M. Mazaheri, Zahra Sadr et al.· European Journal of Medical...· 0 citations
Background.
Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor syndrome characterized by marked polymorphism of clinical manifestations. There is evidence of genotypic correlations in NF1 with more pronounced manifestations of the disease with certain mutations in the
NF1
gene. therefore, it is important to describe patients with a specific mutation and a severe NF1 phenotype.
Purpose of the study
: to describe the genetic and clinical features of NF1 and its treatment tactics in the patient with severe manifestations of the disease and a unique mutation in the
NF1
gene.
Material and Methods.
A ten-year-old girl with a sporadic case of NF1 was examined, X-ray examination was performed, a blood sample was taken with DNA extraction and sanger sequencing of the
NF1
gene.
Results.
The patient was identified to have a unique pathogenic variant c.240_241del(p.Y80fs) in the NF1 gene, and the following clinical manifestations of NF1: retrocerebellar brain cyst, femur plexiform neurofibroma, grade 3 scoliosis, and femur fibrous dysplasia. successful surgical correction of the scoliosis was performed. targeted therapy with selumetinib was prescribed for femur plexiform neurofibroma treatment.
Conclusion.
the identified NF1 variant: c.240_241del(p.Y80fs) has not previously been described in the scientific literature and is not included in the ClinVar database. the clinical manifestations of NF1, characterized by severe combined lesions, have been described. treatment of such cases of NF1 requires a combination of targeted therapy and high-tech surgery.
R. Mustafin· Siberian journal of oncology· 0 citations
A Chinese patient presenting with classic hallmarks of MGORS7 alongside atypical clinical features, including hearing and visual impairments is reported, suggesting that growth hormone therapy may be beneficial for growth retardation in patients with MGORS7.
Ying Zhao, Yiyang Fu, Shuying Zhang et al.· Frontiers in Genetics· 0 citations
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant multisystem disorder caused by
NF1
gene variants. Although NF1 shows marked clinical and genetic heterogeneity, large Chinese cohorts integrating clinical features,
NF1
variant spectrum, and external variant contextualization remain limited.
We conducted a cross-sectional study of 847 clinically confirmed Chinese patients with NF1 to characterize demographic features, clinical manifestations, DNB-defined severity, and
NF1
variant spectrum. Whole-exome sequencing was performed in 211 patients. Transcript-level variant distribution was assessed using a 500-bp sliding-window approach and further contextualized using ClinVar-derived
NF1
variant data.
Among 847 patients, the median age was 23 years, 27.5% had a family history of NF1, and more than 90% were younger than 40 years. Café-au-lait macules, neurofibromas, and plexiform neurofibromas were observed in 98.3%, 70.7%, and 20.9% of patients, respectively. Younger age, lower neurofibroma burden, and absence of learning difficulties were associated with DNB-defined mild classification. Among 211 genetically tested patients, pathogenic/likely pathogenic
NF1
variants were identified in 182 patients, 11 carried
NF1
variants of uncertain significance, and 18 had no reportable
NF1
variant. In total, 152 distinct
NF1
variants were identified, including 45 novel sites. Transcript-level analysis showed regional variation in reportable nucleotide-level
NF1
variants, with relatively higher variant density around exons 10–15 and 44–49. Comparison with ClinVar pathogenic/likely pathogenic
NF1
variants showed no significant window-level difference after multiple-testing correction.
This cross-sectional study summarizes the clinical and genetic features of Chinese patients with NF1 and expands the known
NF1
variant spectrum in this population. Transcript-level analysis showed regional variation in reportable
NF1
variants, broadly paralleling the ClinVar pathogenic/likely pathogenic
NF1
variant distribution. These findings provide a basis for future longitudinal studies to validate clinically meaningful genotype–phenotype relationships in NF1.
Ya-Xin Guo, Xin-De Liu, Yi-Qiu Yan et al.· Orphanet Journal of Rare Dis...· 0 citations
The discovery of variants in PTEN, SRCAP, PQBP1, and NOG identifies novel candidate genes and uncovers potential disease mechanisms in craniosynostosis.
Yufeng Huang, Lingyue Huang, L. Hu et al.· Frontiers in Genetics· 0 citations
