Von Recklinghausen disease, also called neurofibromatosis 1 (NF1), is one of the world’s most common genetic disorders, and has a classical Mendelian transmission.
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Von Recklinghausen disease is autosomal dominant, but has very variable expressivity among affected individuals (i.e. there is a range of symptoms and signs that occur in different people with NF1). This disorder occurs in about 1 in 3500 births. The mutation is a loss-of-function mutation, and the gene is a tumor suppressor gene at 17q11.2.
Twin studies of expressivity
Most NF1 patients have café-au-lait (CAL) spots, axillary and groin freckles, neurofibromatous tumors and learning disabilities. This is a highly penetrant disorder in that every individual who carries the mutation in the NF1 gene will manifest the neurofibromatosis trait.
However, its expression varies in that there is a wide spectrum of clinical findings in those who carry the gene defect. This may be due to environmental events, which negatively impact the mutated gene to influence its expression, or epigenetic modifications, or the presence of somatic mosaicism.
One study on monozygotic twins who had NF1 showed that they had different phenotypes, which helped to distinguish the potential environmental and genetic influences on the trait expression. Non-transmissible influences could include second-hit events, such as infections, other mutations, epigenetic modifications and post-zygotic mutations.
In this study, the monozygotic twins showed a high degree of concordance in the number of CAL spots and of neurofibromas, as well as the IQ score, and cognitive disabilities together with speech problems. However, the contribution of second-hit events was underlined in tumor type, especially with respect to plexiform neurofibromas and malignant tumors arising from the sheaths of peripheral nerves.
On the other hand, one set of monozygotic twins showed concordant large paraspinal tumors, indicating the possibility of greater hereditary contribution in this tumor type. With regards to skeletal manifestations, pectus deformities showed high concordance, but not scoliosis.
Other studies have documented the extreme variability in clinical expressivity, both within and between affected families. This touches on not only the number of clinical features, but the complications of the disorder as well. Thus, the presence of CAL spots, axillary freckles, Lisch nodules and neurofibromas may vary from patient to patient very markedly.
What causes this variability?
Researchers have not yet understood the relative contribution of genetics, environment and epigenetic or other events to the expression of various traits in NF1. However, one explanation may be that so many mutations may cause NF1, and almost 50% are sporadic in occurrence.
Of the large number of suspected causative mutations, up to a tenth are large deletions of the entire 17q11.2 locus as well as involving adjacent gene regions. These are commonly found to be linked to the occurrence of more severe and uncommon clinical features, and this is termed the NF1 microdeletion syndrome.
Another set of patients comprises the majority, over 90%, in whom the mutation is confined within the 17q11.2 locus. Of these, one deletion (c.2970-2972 delAAT) in exon 17 has been found to concur with the absence of cutaneous tumors. This points the way to discovering other correlations between the genotype and phenotype of NF1, but nonetheless, it does not change the observation that different members of the same affected family often do show quite different phenotypes though carrying the same mutant allele of NF1.
This is possibly due to the modifying influence of other unlinked genes as well as to the activity of the normal NF1 gene. A study, which explored phenotypic correlations between near and distant relatives within large families, sought to determine the presence of such modifiers and their necessary influence.
The logic of such studies may be explained as follows: 50% of genes are common to first-degree relatives, such as parents, their offspring, and siblings, but only 25% between second-degree relatives, such as grandparents and uncles/aunts, and 12.5% by third-degree relatives, such as first cousins.
This means that if the impact of the gene on the phenotype is powerful, its impact should wane with each degree of succession in relationship as the shared genes continue to decline in percentage. On the other hand, twin studies will rule out the possibility that this increased correlation between phenotype and genotype among close relatives is due simply to more common environmental factors.
The above study analyzed both quantitative traits, such as the number of CAL spots and tumors, as well as binary traits, such as cognitive impairment. The researchers concluded that all of the clinical features studied had significant familial clustering, except for tumors.
Thus, small CAL spots, subcutaneous and plexiform tumors, and cognitive disabilities were most concordant in monozygotic twins, and reduced, but still significant, in parent-offspring and sibling-sibling pairs. It failed to reach significance between more distant degrees of kinship. This suggested that genetic traits unlinked to the causative NF1 mutation contributed to the phenotype.
Tumor number was almost identical for the twin pairs, but though the concordance decreased with other non-twin pairs, it was uniformly high and constant among first- , second- , and third-degree kinship pairs. This led to the conclusion that the primary NF1 mutation was the main influence in the production of cutaneous neurofibromas.
Large CAL spots, iris nodules and facial abnormalities were more concordant among siblings than parent-offspring pairs, and this suggests that these features owe more to an unlinked genetic contribution or to a common environment, but could also be due to the primary mutation.
In short, the primary NF1 mutation contributes only about 0.028 or less for the five quantitative traits, (number of CAL spots of small size and of large size, and number of cutaneous, subcutaneous and plexiform neurofibromas), but additive genetic variance (from unlinked genes) was significant for these five features.
However, more research is needed, because many severely affected individuals may probably have been excluded from the study due to having no offspring, and because of the racial composition of this study.