Dermatology MCQ - Genetic Disorders - Neurofibromatosis Type 1 (von Recklinghausen disease)

A 7-year-old boy presents with multiple, light brown, well-demarcated macules on his trunk, noted by his parents since infancy. On examination, he has axillary freckling and a few soft, flesh-colored papules on his skin. His mother reports he has had some difficulties with learning at school. An ophthalmologic exam is most likely to reveal which of the following, and what is the most common associated malignancy in children with this condition?

A. Angioid streaks; risk of malignant peripheral nerve sheath tumor (MPNST).
B. Lisch nodules (iris hamartomas); risk of optic pathway glioma.
C. Kayser-Fleischer rings; risk of pheochromocytoma.
D. Retinal detachment; risk of juvenile myelomonocytic leukemia (JMML).
E. Choroidal osteoma; risk of neuroblastoma.

Correct Answer: B. Lisch nodules (iris hamartomas); risk of optic pathway glioma.

Answer and Explanation

The correct answer is B. This question describes the classic presentation of Neurofibromatosis Type 1 (NF1). The patient meets the diagnostic criteria with multiple café-au-lait macules and axillary freckling. The soft papules are likely early cutaneous neurofibromas. The most common ocular finding in NF1 is Lisch nodules, which are benign melanocytic hamartomas of the iris present in >90% of adults with NF1. While learning disabilities are very common, the most common malignancy in children with NF1 is optic pathway glioma (a low-grade pilocytic astrocytoma of the optic nerve/chiasm). These often present in early childhood and can cause visual loss or precocious puberty.

Why the Other Options are Incorrect:

• A. Angioid streaks... MPNST: Angioid streaks are seen in pseudoxanthoma elasticum. While malignant peripheral nerve sheath tumor (MPNST) is a serious and classic malignancy in NF1, it typically arises in adolescents or adults from a pre-existing plexiform neurofibroma, not in childhood.

• C. Kayser-Fleischer rings... pheochromocytoma: Kayser-Fleischer rings are caused by copper deposition in Wilson's disease. Pheochromocytoma is associated with NF1, but it is less common than optic pathway glioma and typically presents in adults.

• D. Retinal detachment... JMML: Retinal detachment is not a typical feature of NF1. While there is an increased risk of juvenile myelomonocytic leukemia (JMML) in NF1, it is rare. Optic pathway glioma is the most common childhood cancer.

• E. Choroidal osteoma... neuroblastoma: Choroidal osteoma is a rare benign tumor not linked to NF1. Neuroblastoma risk is slightly increased in NF1 but, again, optic pathway glioma is far more common.

Additional High-Yield Information for Exams:

• Diagnostic Criteria (NIH, 2 or more required):

  1. ≥6 café-au-lait macules (>5 mm prepubertal, >15 mm postpubertal).

  2. Axillary or inguinal freckling.

  3. ≥2 Neurofibromas of any type or 1 plexiform neurofibroma.

  4. Optic pathway glioma.

  5. ≥2 Lisch nodules.

  6. A distinctive osseous lesion (e.g., sphenoid wing dysplasia, tibial pseudarthrosis).

  7. A first-degree relative with NF1 by the above criteria.

• Genetics: Autosomal dominant, but ~50% are de novo. Caused by mutations in the NF1 tumor suppressor gene on chromosome 17q11.2, encoding neurofibromin, a negative regulator of the RAS pathway.

• Clinical Features:

  • Cutaneous: Café-au-lait macules (often first sign), axillary freckling, cutaneous neurofibromas (increase at puberty).

  • Neurologic: Learning disabilities (most common complication), seizures, macrocephaly.

  • Orthopedic: Scoliosis, tibial pseudarthrosis.

  • Neoplastic: Optic pathway glioma (childhood), plexiform neurofibroma (can be disfiguring, risk of MPNST), pheochromocytoma (adult).

• Differential Diagnosis: Other conditions with café-au-lait macules: Legius syndrome (SPRED1 mutation, has freckling but no neurofibromas or Lisch nodules), McCune-Albright syndrome (unilateral, segmental café-au-lait with bony dysplasia and endocrine issues).

• Associated Conditions & Prognosis:

  • Prognosis: Highly variable. Most have a normal lifespan. Morbidity stems from learning difficulties, pain/discomfort from neurofibromas, and complications of specific tumors.

  • MPNST Risk: Lifetime risk ~8-13%. A plexiform neurofibroma that shows rapid growth, pain, or new neurological deficit raises suspicion.

• Management & Rationale:

  • Rationale: Management is multidisciplinary and surveillance-based, aiming for early detection and treatment of complications.

  • First-line/Obligatory Surveillance:

    • Annual physical exam with attention to skin, blood pressure (for pheo), and neurological/developmental assessment.

    • Annual ophthalmologic exam (until age 8, then less frequent) to screen for optic pathway glioma.

    • Education of patient/family about signs of complications (e.g., tumor growth, vision changes, bone pain).

  • Specific Treatments:

    • Optic Pathway Glioma: Often just monitored if asymptomatic. Chemotherapy (e.g., carboplatin/vincristine) for progressive/symptomatic tumors.

    • Plexiform Neurofibroma: Selumetinib (a MEK inhibitor) is FDA-approved for symptomatic, inoperable plexiform neurofibromas in children.

    • MPNST: Wide surgical excision, often with adjuvant radiotherapy/chemotherapy.

  • Genetic Counseling: Offered to patients and families.