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Short report
Paraspinal neurofibromas and hypertrophic neuropathy in Noonan syndrome with multiple lentigines
  1. Erin Conboy1,
  2. Radhika Dhamija2,
  3. Margaret Wang3,
  4. Jing Xie4,
  5. P James Dyck5,
  6. Alina G Bridges6,
  7. Robert J Spinner7,
  8. Amy C Clayton8,
  9. Robert E Watson9,
  10. Ludwine Messiaen4,
  11. Dusica Babovic-Vuksanovic1,8
  1. 1Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA
  2. 2Departments of Neurology and Pediatrics, University of Virginia, Charlottesville, Virginia, USA
  3. 3Department of Child Health, University of Missouri, Columbia, Missouri, USA
  4. 4Medical Genomics Laboratory, Department of Genetics, University of Alabama, Birmingham, Alabama, USA
  5. 5Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
  6. 6Department of Dermatology, Mayo Clinic, Rochester, Minnesota, USA
  7. 7Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, USA
  8. 8Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  9. 9Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Dusica Babovic-Vuksanovic, Department of Medical Genetics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; dbabovic{at}mayo.edu

Abstract

Background Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome, is an autosomal-dominant disorder characterised by lentigines, EKG abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, growth retardation and deafness. There is significant clinical overlap between NSML and other disorders that result from dysregulated rat sarcoma/mitogen-activated protein kinase pathway (RASopathies). Except for neurofibromatosis type 1, other RASopathies are not known to be typically associated with neurogenic tumours.

Methods and results We evaluated patients from three families with pigmentary skin lesions, progressive neuropathy, enlarged nerves, massive burden of paraspinal tumours (neurofibroma was confirmed in one patient) and a clinical diagnosis of NSML. All patients had a mutation in the protein tyrosine phosphatase catalytic domain of the PTPN11 gene; two unrelated patients had the p.Thr468Met mutation, while the family consisting of two affected individuals harboured the p.Thr279Cys mutation. Molecular analysis performed on hypertrophic nerve tissue did not disclose a second somatic hit in NF1, PTPN11, NF2 or SMARCB1 genes.

Conclusions Neurogenic tumours and hypertrophic neuropathy are unusual complications of NSML and may be an under-recognised manifestation that would warrant surveillance. Our observation may also have implications for other disorders caused by RAS-pathway dysregulation.

  • Genetics
  • Molecular genetics
  • Oncology
  • Other neurology
  • Peripheral nerve disease

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