Can the Diagnosis of NF1 Be Excluded Clinically?
This family had individuals affected across at least four generations, as shown in figure 1A. The proband, IV:5, presented aged 8 years in New Zealand, when a neurofibroma had been excised from his right arm. At the age of 20 years he developed difficulty in walking, pain in his right leg, and occasional paraesthesia in his hands. Peripheral subcutaneous neurofibromas, some of which were painful, a thoracolumbar scoliosis, and a neurological deficit in the lower limbs were identified on examination. Serial MRI showed progression of multiple peripheral nerve neurofibromas in his legs and bilaterally in his cervical spine. From the age of 21 he underwent excision of multiple symptomatic cervical spine neurofibromas. At 23, multiple subcutaneous lesions were excised from his right thigh, and were confirmed as benign neurofibromas with plexiform elements. Skin examination at age 25 confirmed just one CAL macule, six subcutaneous neurofibromas, and one cutaneous neurofibroma. Lisch nodules were noted, but neither axillary nor inguinal freckling were present.
(Enlarge Image)
Figure 1.
(A–E) Pedigrees of families 1–5.
IV:5's mother, III:5, was examined in the genetics department at the age of 50 years. She had no CAL, and skinfold changes were also absent apart from a few unilateral axillary freckles. Multiple painful subcutaneous neurofibromas, a plexiform neurofibroma, spinal neurofibromas, scoliosis, and Lisch nodules were all present.
III:2 was diagnosed with NF1 in her third decade, when a lump excised from her mouth was found to be a neurofibroma. In each of her three pregnancies (at 26–30 years of age), she developed new cutaneous neurofibromas. She was first reviewed in the genetics department at the age of 52, and painful cutaneous and subcutaneous neurofibromas were noted which were subsequently histologically confirmed. She had no skin pigmentary changes nor any symptomatic spinal tumours, and therefore MRI imaging was not performed at that time.
III:2's three sons, IV:2, IV:3, and IV:4, were each examined on account of their 50% risk of NF1. Two each had one CAL documented in childhood and one additionally had three subcutaneous nodules which subsequently disappeared. No other pigmentary changes, including Lisch nodules, were identified in any of these individuals. They have remained well with no signs of NF1, but this diagnosis could not be confidently excluded clinically until they were well into adulthood, given the minimal pigmentary findings of the condition in other family members, particularly their mother.
III:1 had a longstanding diagnosis of NF1 on the basis of subcutaneous neurofibromas, several of which had been removed and histologically analysed; his daughter (IV:1) also had CAL from early life. He developed deafness and had a brain scan at the age of 54 years. No cause for deafness was identified, but an asymptomatic cervical spinal neurofibroma with an intradural component was seen, with bilateral impingement on the C2 nerve roots. This required surgery, due to the risk of spinal cord compression. On examination at the age of 62, over 100 cutaneous and subcutaneous neurofibromas were present, as were axillary freckles and Lisch nodules. In contrast, only seven CAL (three of which required ultraviolet light for visualisation) were identified.
III:1's daughter, IV:1, was diagnosed in early childhood with NF1 on account of her family history and presence of CAL. At the age of 7 years, she had no learning difficulties and only four or five CAL patches, but she also had depigmented areas of skin over her back. By 22 years of age, she had six CAL, minimal axillary and inguinal freckling, and a small number of histologically proven neurofibromas.
II:2, III:5's late father, was reported as having a severe disfigurement due to skin lumps, and had died from what was highly likely to have been a malignant peripheral nerve sheath tumour (MPNST). His mother (I:1) was also thought by the family to have been affected with NF1, as her skin was covered in lumps. It was also reported that his late father (I:2, a first cousin of I:1) could have been similarly affected.
For all living affected individuals in this family, a diagnosis of NF1 could be made by application of the clinical consensus criteria. However, this was only possible for many of them well into adulthood, due to both the paucity of pigmentary manifestations, and the late onset of visible or symptomatic tumours in most individuals. What was not clinically straightforward was to exclude NF1 in at-risk individuals. This was a major source of anxiety for several family members, who were worried about risks to their offspring of this disabling condition. Pre-implantation genetic diagnosis was considered by IV:5 and his wife due to the burdensome nature of his own and his mother's (III:5) condition, but was not available when he and his wife were starting a family. After extensive consideration within the family, his two daughters were each tested at birth for the recently identified familial mutation, c.6364+2T>G, which had been found to result in exclusion of exon 33 and a subsequent frameshift resulting in a prematurely terminated protein. They were found to be unaffected.
Family 1
This family had individuals affected across at least four generations, as shown in figure 1A. The proband, IV:5, presented aged 8 years in New Zealand, when a neurofibroma had been excised from his right arm. At the age of 20 years he developed difficulty in walking, pain in his right leg, and occasional paraesthesia in his hands. Peripheral subcutaneous neurofibromas, some of which were painful, a thoracolumbar scoliosis, and a neurological deficit in the lower limbs were identified on examination. Serial MRI showed progression of multiple peripheral nerve neurofibromas in his legs and bilaterally in his cervical spine. From the age of 21 he underwent excision of multiple symptomatic cervical spine neurofibromas. At 23, multiple subcutaneous lesions were excised from his right thigh, and were confirmed as benign neurofibromas with plexiform elements. Skin examination at age 25 confirmed just one CAL macule, six subcutaneous neurofibromas, and one cutaneous neurofibroma. Lisch nodules were noted, but neither axillary nor inguinal freckling were present.
(Enlarge Image)
Figure 1.
(A–E) Pedigrees of families 1–5.
IV:5's mother, III:5, was examined in the genetics department at the age of 50 years. She had no CAL, and skinfold changes were also absent apart from a few unilateral axillary freckles. Multiple painful subcutaneous neurofibromas, a plexiform neurofibroma, spinal neurofibromas, scoliosis, and Lisch nodules were all present.
III:2 was diagnosed with NF1 in her third decade, when a lump excised from her mouth was found to be a neurofibroma. In each of her three pregnancies (at 26–30 years of age), she developed new cutaneous neurofibromas. She was first reviewed in the genetics department at the age of 52, and painful cutaneous and subcutaneous neurofibromas were noted which were subsequently histologically confirmed. She had no skin pigmentary changes nor any symptomatic spinal tumours, and therefore MRI imaging was not performed at that time.
III:2's three sons, IV:2, IV:3, and IV:4, were each examined on account of their 50% risk of NF1. Two each had one CAL documented in childhood and one additionally had three subcutaneous nodules which subsequently disappeared. No other pigmentary changes, including Lisch nodules, were identified in any of these individuals. They have remained well with no signs of NF1, but this diagnosis could not be confidently excluded clinically until they were well into adulthood, given the minimal pigmentary findings of the condition in other family members, particularly their mother.
III:1 had a longstanding diagnosis of NF1 on the basis of subcutaneous neurofibromas, several of which had been removed and histologically analysed; his daughter (IV:1) also had CAL from early life. He developed deafness and had a brain scan at the age of 54 years. No cause for deafness was identified, but an asymptomatic cervical spinal neurofibroma with an intradural component was seen, with bilateral impingement on the C2 nerve roots. This required surgery, due to the risk of spinal cord compression. On examination at the age of 62, over 100 cutaneous and subcutaneous neurofibromas were present, as were axillary freckles and Lisch nodules. In contrast, only seven CAL (three of which required ultraviolet light for visualisation) were identified.
III:1's daughter, IV:1, was diagnosed in early childhood with NF1 on account of her family history and presence of CAL. At the age of 7 years, she had no learning difficulties and only four or five CAL patches, but she also had depigmented areas of skin over her back. By 22 years of age, she had six CAL, minimal axillary and inguinal freckling, and a small number of histologically proven neurofibromas.
II:2, III:5's late father, was reported as having a severe disfigurement due to skin lumps, and had died from what was highly likely to have been a malignant peripheral nerve sheath tumour (MPNST). His mother (I:1) was also thought by the family to have been affected with NF1, as her skin was covered in lumps. It was also reported that his late father (I:2, a first cousin of I:1) could have been similarly affected.
For all living affected individuals in this family, a diagnosis of NF1 could be made by application of the clinical consensus criteria. However, this was only possible for many of them well into adulthood, due to both the paucity of pigmentary manifestations, and the late onset of visible or symptomatic tumours in most individuals. What was not clinically straightforward was to exclude NF1 in at-risk individuals. This was a major source of anxiety for several family members, who were worried about risks to their offspring of this disabling condition. Pre-implantation genetic diagnosis was considered by IV:5 and his wife due to the burdensome nature of his own and his mother's (III:5) condition, but was not available when he and his wife were starting a family. After extensive consideration within the family, his two daughters were each tested at birth for the recently identified familial mutation, c.6364+2T>G, which had been found to result in exclusion of exon 33 and a subsequent frameshift resulting in a prematurely terminated protein. They were found to be unaffected.
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