Paraspinal neurofibromas and hypertrophic neuropathy in Noonan syndrome with multiple lentigines.
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.


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.
Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA.
Erin
E
Conboy
Departments of Neurology and Pediatrics, University of Virginia, Charlottesville, Virginia, USA.
Radhika
R
Dhamija
Department of Child Health, University of Missouri, Columbia, Missouri, USA.
Margaret
M
Wang
Medical Genomics Laboratory, Department of Genetics, University of Alabama, Birmingham, Alabama, USA.
Jing
J
Xie
Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
P James
PJ
Dyck
Department of Dermatology, Mayo Clinic, Rochester, Minnesota, USA.
Alina G
AG
Bridges
Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, USA.
Robert J
RJ
Spinner
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Amy C
AC
Clayton
Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
Robert E
RE
Watson
Medical Genomics Laboratory, Department of Genetics, University of Alabama, Birmingham, Alabama, USA.
Ludwine
L
Messiaen
Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Dusica
D
Babovic-Vuksanovic
D000293:Adolescent; D000328:Adult; D005260:Female; D006801:Humans; D006984:Hypertrophy / Q000235:genetics; D044542:LEOPARD Syndrome / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009455:Neurofibroma / Q000209:etiology / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000209:etiology / Q000235:genetics; D009634:Noonan Syndrome / Q000209:etiology / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D013125:Spinal Neoplasms / Q000209:etiology / Q000235:genetics*
D020928:Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
Genetics; Molecular genetics; Oncology; Other neurology; Peripheral nerve disease