Severe Thoracic and Spinal Bone Abnormalities in neurofibromatosis type 1

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Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder that predisposes to the development of benign and malignant tumors. Classical skeletal abnormalities encompass sphenoid wing dysplasia, congenital bowing of the long bones and vertebral osteopathy associated with non-dystrophic or dystrophic scoliosis found in about 10% of NF1 patients. We report a 17-year-old boy affected by NF1 with extreme severe spinal and thoracic malformations affecting bone and lung tissues, including hypoplasia of the right lung, unilateral costal agenesis and severe dystrophic scoliosis characterized by association of hemivertebra, fusion of adjacent vertebral bodies and defective pedicles. At birth, he presented an acute respiratory distress requiring invasive ventilator support. The diagnosis of NF1 was confirmed at age 5 by the identification of a de novo heterozygous mutation c.4537C > T, p.Arg1513* in NF1. Trio-based Whole Exome Sequencing (WES) was performed to exclude coexistence of a second hit but no clearly other pathogenic variant has been identified. Until now, only one similar NF1 patient suffering from the same association of severe scoliosis and chest deformity leading to respiratory insufficiency was described. The severe prenatal NF1-related scoliosis could explain the lung abnormal development by absence of mechanical constraints. Severe Thoracic and Spinal Bone Abnormalities may be part of the NF1 bone phenotype and should be taken into account to allow adequate genetic counseling.

Introduction

Neurofibromatosis type 1 (NF1) is one of the most frequent autosomal dominant disorders, characterized by neurofibromas, “café-au-lait” spots, axillary or groin freckling, Lisch nodules, optic pathway glioma and skeletal lesions [Ferner, 2010]. Classical skeletal abnormalities encompass sphenoid wing dysplasia, congenital bowing of the long bones, respectively described in about 1% and 2% of NF1 patients and vertebral osteopathy associated with non-dystrophic or dystrophic scoliosis found in about 10% of NF1 patients [Ferner, 2010]. Characteristic features of dystrophic scoliosis include vertebral scalloping, rib penciling, vertebral wedging, absence or hypoplasia of the vertebral pedicles and intervertebral foraminal enlargement [Zhao et al., 2015]; [Alwan et al., 2005].

The defects in bone observed in NF1 patients are due to the loss of both copies of NF1 in osteoclasts and/or osteoblasts. Increased osteoclastic activity and impaired osteoblastic function have been demonstrated in several strains of Nf1 conditional knockout mice, used in particular to model dystrophic scoliosis [Wang et al., 2011]; [He et al., 2012]. In addition controversial theories explaining the determinism of dystrophic scoliosis include potential primary causes (i.e. primary mesodermal dysplasia, osteomalacia) and secondary causes related to intraspinal anomalies, responsible for mechanical stresses, like erosion of bone by localized neurofibromas and dural ectasia [Tsirikos et al., 2005]. We present here severe thoracic and spinal bone deformities observed in a patient affected by NF1.

Section snippets

Case report

The proband, a 17-year-old boy, was the second child from non-consanguineous healthy parents. Family history was uninformative. Pregnancy was uneventful, especially, all ultrasound exams were considered normal. Delivery at 40 weeks of gestation was marked by transitory moderate respiratory difficulties (APGAR 5/10) and the discovery of severe chest and spine deformations. During his early first hours of life, the patient presented with an acute respiratory distress requiring invasive

Discussion

The molecularly confirmed NF1 patient presented here had extreme severe spinal and thoracic malformations affecting bone and lung tissues, corroborating the single recently described similar NF1 patient suffering from the same association of severe scoliosis and chest deformity leading to respiratory insufficiency [Francis et al., 2015]. Moreover spine CT showed different types of abnormalities, including fusion of vertebral bodies, which are not typically associated with NF1 bony dysplasia.

References (9)

  • S. Alwan et al.

    Is osseous dysplasia a primary feature of neurofibromatosis 1 (NF1)?

    Clin. Genet.

    (2005)
  • R.M. Campbell et al.

    The characteristics of thoracic insufficiency syndrome associated with fused ribs and congenital scoliosis

    J Bone Jt. Surg Am

    (2003)
  • R.E. Ferner

    The neurofibromatoses

    Pract. Neurol.

    (2010)
  • L. Francis et al.

    Severe spinal and chest deformity secondary to neurofibromatosis

    Can. J. Anesth. Can. Anesth.

    (2015)
There are more references available in the full text version of this article.

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