Susan M. Huson

Guidelines for the diagnosis and management of individuals with neurofibromatosis 1

Neurofibromatosis 1 (NF1) is a common neurocutaneous condition with an autosomal dominant pattern of inheritance. The complications are diverse and disease expression varies, even within families. Progress in molecular biology and neuroimaging and the development of mouse models have helped to elucidate the aetiology of NF1 and its clinical manifestations. Furthermore, these advances have raised the prospect of therapeutic intervention for this complex and distressing disease. Members of the United Kingdom Neurofibromatosis Association Clinical Advisory Board collaborated to produce a consensus statement on the current guidelines for diagnosis and management of NF1. The proposals are based on published clinical studies and on the pooled knowledge of experts in neurofibromatosis with experience of providing multidisciplinary clinical and molecular services for NF1 patients. The consensus statement discusses the diagnostic criteria, major differential diagnoses, clinical manifestations and the present strategies for monitoring and management of NF1 complications.

A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity.

A population based study of von Recklinghausen neurofibromatosis in south east Wales (population 668,100) identified 69 families with 135 affected members (prevalence 1/4950 of the population). In these families penetrance of the NF-1 gene was 100% by the age of five years. The genetic fitness of NF-1 sufferers was found to be reduced to 0.47, the effect being more marked in males than females (f = 0.31 and 0.60, respectively). Forty-one of 135 cases were judged to represent new disease mutations and the mutation rate was estimated to lie between 3.1 x 10(-5) and 10.4 x 10(-5). A parental age effect for new mutations was not found, nor was a maternal effect on disease severity.

Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service.

Autosomal dominantly inherited tumor‐prone syndromes are a substantial health problem and are amenable to epidemiologic studies by combining cancer surveillance registries with a genetic register (GR)‐based approach. Knowledge of the frequency of the conditions provides a basis for appropriate health‐resources allocations. GRs for five tumor‐prone syndromes were established in the Manchester region of North West England in 1989 and 1990. Mapping birth dates of affected individuals from families onto regional birth rates has allowed an estimate of birth incidence, disease prevalence, and de novo mutation rates. Disease prevalence in order of frequency were for neurofibromatosis type 1 (NF1): 1 in 4,560; familial adenomatous polyposis (FAP): 1 in 18,976; nevoid basal cell carcinoma [Gorlin syndrome (GS)]: 1 in 30,827; neurofibromatosis type 2 (NF2) 1 in 56,161; and von Hippel Lindau (VHL) 1 in 91,111. Best estimates for birth incidence were: 1 in 2,699; 1 in 8,619; 1 in 14,963, 1 in 33,000; and 1 in 42,987, respectively. The proportions due to de novo mutation were: 42% (NF1); 16% (FAP); 26% (GS); 56% (NF2); and 21% (VHL). Estimates for NF1, NF2, FAP, and VHL are in line with previous estimates, and we provide the first estimates of birth incidence and de novo mutation rate for GS.

The clinical and diagnostic implications mosaicism in the neurofibromatoses

Neurofibromatosis type 1 and type 2 both occur in mosaic forms. Mosaicism results from somatic mutations. Early somatic mutations cause generalized disease, clinically indistinguishable from nonmosaic forms. Later somatic mutation gives rise to localized disease often described as segmental. In individuals with mosaic or localized manifestations of neurofibromatosis type 1 (segmental neurofibromatosis type 1), disease features are limited to the affected area, which varies from a narrow strip to one quadrant and occasionally to one half of the body. Distribution is usually unilateral but can be bilateral, either in a symmetric or asymmetrical arrangement. Patients with localized neurofibromatosis type 2 have disease-related tumors localized to one part of the nervous system; for example a unilateral vestibular schwannoma with ipsilateral meningiomas or multiple schwannomas in one part of the peripheral nervous system. The recognition of mosaic phenotypes is important. Individuals with the mosaic form, even with a generalized phenotype, are less likely to have severe disease. They also have lower offspring recurrence risk than individuals with the nonmosaic form. The mosaic forms of neurofibromatosis provide a good example of the effects of somatic mutation. It is increasingly recognized that mild and unusual forms of many dominantly inherited disorders are caused by the same mechanism.

An Absence of Cutaneous Neurofibromas Associated with a 3-bp Inframe Deletion in Exon 17 of the NF1 Gene (c.2970-2972 delAAT): Evidence of a Clinically Significant NF1 Genotype-Phenotype Correlation

Neurofibromatosis type 1 (NF1) is characterized by cafe-au-lait spots, skinfold freckling, and cutaneous neurofibromas. No obvious relationships between small mutations (<20 bp) of the NF1 gene and a specific phenotype have previously been demonstrated, which suggests that interaction with either unlinked modifying genes and/or the normal NF1 allele may be involved in the development of the particular clinical features associated with NF1. We identified 21 unrelated probands with NF1 (14 familial and 7 sporadic cases) who were all found to have the same c.2970-2972 delAAT (p.990delM) mutation but no cutaneous neurofibromas or clinically obvious plexiform neurofibromas. Molecular analysis identified the same 3-bp inframe deletion (c.2970-2972 delAAT) in exon 17 of the NF1 gene in all affected subjects. The Delta AAT mutation is predicted to result in the loss of one of two adjacent methionines (codon 991 or 992) ( Delta Met991), in conjunction with silent ACA-->ACG change of codon 990. These two methionine residues are located in a highly conserved region of neurofibromin and are expected, therefore, to have a functional role in the protein. Our data represent results from the first study to correlate a specific small mutation of the NF1 gene to the expression of a particular clinical phenotype. The biological mechanism that relates this specific mutation to the suppression of cutaneous neurofibroma development is unknown.

Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA

The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP3) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.

Management of the patient and family with neurofibromatosis 2: a consensus conference statement.

A consensus conference on neurofibromatosis 2 (NF2) was held in 2002 at the request of the United Kingdom (UK) Neurofibromatosis Association, with particular emphasis on vestibular schwannoma (VS) surgery. NF2 patients should be managed at specialty treatment centres, whose staff has extensive experience with the disease. All NF2 patients and their families should have access to genetic testing because presymptomatic diagnosis improves the clinical management of the disease. Some clinical manifestations of NF2, such as ocular abnormalities, can be detected in infancy; therefore, clinical screening for at-risk members of NF2 families can start at birth, with the first magnetic resonance (MRI) scan at 10 – 12 years of age. Minimal interference, maintenance of quality of life, and conservation of function or auditory rehabilitation are the cornerstones of NF2 management, and the decision points to achieve these goals for patients with different clinical presentations are discussed.

Analysis of limb reduction defects in babies exposed to chorionic villus sampling

In 1991 we reported a cluster of babies with limb abnormalities and suggested that chorionic villus sampling (CVS) was aetiologically associated with these defects. To address the issue more objectively, we have assessed reported limb reduction defects in 75 babies exposed to CVS in utero. 13 babies had an absent limb or a defect through the humerus or femur; 9 had defects through the radius or tibia; 22 defects of the carpus, tarsus, metacarpus, or metatarsus; 25 defects of the digits; and 6 defects of the terminal phalanx or nail only. There was a strong correlation between the severity of the defects and the duration of gestation when CVS was done. The median gestational age at CVS ranged from 56 (range 49-65) postmenstrual days for the most severe category to 72 (51-98) days for the least severe. The relation was seen for both isolated limb defects and for cases with oromandibular-limb hypogenesis syndromes. This relation is further evidence that CVS has an aetiological role in some limb reduction anomalies.

Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening

Background: Malignancy risks in patients with neurofibromatosis 1 (NF1) are increased, but those occurring outside of the nervous system have not been clearly defined. Aim: To evaluate the risk of breast cancer in women with NF1 in a population-based study. Methods: The risk of breast cancer in a cohort of 304 women with NF1 aged ⩾20 years was assessed and compared with population risks over the period 1975–2005 using a person-years-at-risk analysis. Results: There were 14 cases of breast cancers in the follow-up period, yielding a standardised incidence ratio (SIR) of 3.5 (95% CI 1.9 to 5.9). However, six breast cancers occurred in women in their 40s, and the SIR of breast cancer in women aged <50 years was 4.9 (95% CI 2.4 to 8.8). Interpretation: Women with NF1 aged <50 years have a fivefold risk of breast cancer, are in the moderate risk category and should be considered for mammography from 40 years of age.

Arthrogryposis multiplex congenita with maternal autoantibodies specific for a fetal antigen.

Fetal arthrogryposis multiplex congenita (AMC) is characterised by non-progressive multiple joint contractures, which may result in fetal death, and is heterogeneous in origin. It can associate with maternal myasthenia gravis and autoantibodies to muscle acetylcholine receptor (AChR). We found maternal antibodies that selectively inhibit the fetal form of the AChR in a mother who herself had no features of myasthenia gravis. Maternal autoantibodies specific for fetal antigens could be an unrecognised cause of other congenital disorders.