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Genetic diagnosis Counseling in MEN2 is on an autosomal dominant basis. About 5%
and counseling of cases of MEN2A and almost 50% of cases of MEN2B are the result of a new mutation in RET. Genetic testing should be performed in all cases and is available from diagnostic laboratories. Identification of a mutation in RET allows confirmation of diagnosis and enables predictive testing to be offered to at-risk family members. Because MTC can occur at an early age, predictive testing should be offered to at-risk individuals by the age of 5 years in MEN2A and FMTC families and before the age of 5 years in MEN2B families. Children and older individuals in whom a RET mutation is identified should be offered prophylactic total thyroidectomy. This should be carried out by 5 years of age in MEN2A and FMTC families and before the age of 5 years in MEN2B families (some experts recommend prophylactic thyroidectomy before 6 months of age). The presence of an unsuspected pheochromocytoma should always be ruled out in these patients prior to surgery as this tumor can cause sudden death as a result of an anesthesia-induced hypertensive crisis. Affected and at-risk individuals from MEN2A and FMTC families should be screened for pheochromocytoma and hyperparathyroidism by measuring catecholamine levels in a 24-hour urine sample and plasma calcium levels on an annual basis. At-risk individuals from MEN2 families (all types) who cannot be offered predictive testing should also be screened for MTC by an annual pentagastrin stimulation test until the age of 35 years.
Neurofibromatosis Type 1
(also known as: NF1; Von Recklinghausen’s disease)
MIM 162200
Clinical features Multiple café-au-lait (CAL) patches are the usual presenting feature. Affected children have six or more CAL patches greater than 5 mm in diameter (in postpubertal children these patches should be more than 15 mm in diameter). Other cutaneous manifestations of NF1 include axillary (see Figure 1) and inguinal freckling and cutaneous neurofibromas (see Figure 2). Other diagnostic features include plexiform neurofibromas, Lisch nodules (iris hamartomas), pseudoarthrosis of the tibia, sphenoid wing dysplasia, and optic nerve glioma. Affected children often have macrocephaly and short stature. Complications include learning difficulties, epilepsy, scoliosis, hypertension, and plexiform neurofibromas of the head and neck.
Figure 1. Axillary Figure 2. Multiple café-au-lait patches freckling. and cutaneous neurofibromas. Age of onset First year of life
Epidemiology The condition affects individuals of all races. It is one of the most common autosomal dominant disorders with a population prevalence of 1 in 3,000.
Inheritance Autosomal dominant
Chromosomal 17q11.2
location
Gene NF1
Mutational The NF1 gene is very large, spanning over 350 kb of genomic DNA with
spectrum 60 exons. Over 500 mutations have been identified. Most mutations are “private” (ie, restricted to a particular family). All types of mutations have been described (including nonsense, missense, frame-shift, and splice-site mutations) as well as small and large intragenic deletions and other rearrangements. Around 80% of mutations result in the production of a truncated protein and these mutations are evenly distributed over the entire coding sequence of the gene. The entire NF1 gene is deleted in about 5% of patients. These patients have a distinct phenotype with severe learning difficulties, facial dysmorphism, relatively large hands and feet, overgrowth, and numerous neurofibromas. Whole gene deletions can be detected by fluorescence in situ hybridization analysis.
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Molecular The NF1 gene encodes a protein called neurofibromin, which is
pathogenesis widely expressed in several tissues. Neurofibromin has a domain that demonstrates homology to GTPase-activating protein (GAP). The GAP-related domain down-regulates the activity of RAS, which is a major regulator of cellular growth and differentiation. The precise cellular functions of neurofibromin are unknown. There is evidence to suggest that NF1 is a tumor suppressor gene. NF1 is thought to result from haploinsufficiency.
Genetic diagnosis NF1 is a clinical diagnosis. Genetic testing is difficult because of the
and counseling large size of the gene, the vast number of mutations that have been identified, and the high proportion of “novel” mutations. Mutation testing is only available on a research basis at the present time. Counseling is on an autosomal dominant basis. About 50% of cases represent new mutations. NF1 shows a lot of variability in expression in affected members of the same family. Parents of such cases should be carefully examined clinically to look for the cutaneous features of NF1 and by slit-lamp examination to look for Lisch nodules. If neither parent fulfils the diagnostic criteria for NF1 there is a 1%–2% recurrence risk for this condition in their next pregnancy because of the possibility of gonadal mosaicism.
In large families with affected individuals in two or more generations, prenatal diagnosis can usually be offered by linkage analysis using intragenic and flanking markers. However, many families elect not to have a prenatal test as this does not provide any information about the severity or complications of NF1 in an affected child.
Retinoblastoma
MIM 180200
Clinical features The usual presenting features of retinoblastoma are leucocoria (white- eye or cat’s-eye reflex) or strabismus. Atypical presentations include glaucoma, uveitis, hyphema, and vitreous hemorrhage.
Age of onset Most retinoblastomas present before the age of 5 years. Bilateral disease presents earlier (mean age at diagnosis 12 months) than unilateral disease (mean age at diagnosis 24 months).
Epidemiology Retinoblastoma is the most common ocular tumor of childhood with a global incidence of about 1 in 15,000–20,000 live births.
Inheritance Autosomal dominant
Chromosomal 13q14.1–q14.2
location
Gene RB1 (retinoblastoma 1)
Mutational A small number of patients with retinoblastoma (2%–3%) have an
spectrum interstitial deletion or a translocation involving 13q14. Patients with an interstitial deletion of this region usually have other clinical features such as microcephaly, developmental delay, and dysmorphic features. Over 350 mutations have been identified in RB1. These include large rearrangements, small intragenic deletions and duplications, and point mutations. Point mutations include nonsense, missense, splice-site, and frame-shift mutations. Most mutations result in protein truncation.
Molecular RB1 is a tumor suppressor gene. It contains 27 exons and it encodes
pathogenesis a 724-amino-acid protein. Its protein product (Rb) is a nuclear
phosphoprotein that inhibits cellular proliferation by inhibiting progress of cells from the G1 to the S phase of the cell cycle. It does this by interacting with the E2F family of transcription factors. The Rb–E2F complex arrests cells in the G1 phase of the cell cycle by transcriptional repression of other genes such as TGFB and CDKN2A. Both alleles of RB1 have to be inactivated before uncontrolled cellular proliferation can occur.
Genetic diagnosis Only 10% of patients with retinoblastoma have a family history of
and counseling this tumor. These patients have an inherited germ line RB1 mutation and develop bilateral disease. About 30% of patients have bilateral disease but no family history of retinoblastoma. These patients also have germ line RB1 mutations, but these are assumed to be “new” mutations. The remaining patients have unilateral disease and no family history of retinoblastoma. Many patients with unilateral multifocal tumors are also likely to have a “new” germ line RB1 mutation, although somatic mosaicism for an RB1 mutation is also possible. Approximately 85% of patients with a unilateral unifocal tumor have sporadic disease as a result of chance inactivation of both alleles of RB1 in the tumor. About 10% of patients with a unilateral unifocal tumor have a “new” germ line
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Table 1. Family history, tumor-type, probability of germline mutation, and risks
to offspring and siblings.
All patients with retinoblastoma (familial and sporadic) should be offered genetic testing, which is available from a few specialized laboratories. In cases with unilateral disease both blood and fresh or archived tumor tissue will be needed for RB1 mutation analysis. Genetic counseling is guided by family history, the number and distribution of tumors, and the results of genetic testing (see Table 1). Siblings and offspring of patients should be offered regular screening for retinoblastoma by retinal examination (under anesthesia until the age of 3 years) from birth to the age of 11 years. This can be stopped if genetic testing shows that the individual being screened has not inherited the RB1 mutation identified in the affected proband. Long-term survivors of retinoblastoma with a germ line RB1 mutation are at increased risk of developing second non-ocular malignant tumors. These include osteosarcoma, soft tissue sarcomas (such as fibrosarcoma), malignant melanoma, and brain tumors. The risk of a second non-ocular tumor is much higher in patients who received radiotherapy for the treatment of their retinoblastoma.
Family Tumor type Probability Risk to offspring Risk to siblings
history of germline
mutation
Positive Bilateral 100% 50% – retinoblastoma
Negative Bilateral 95% Assumed to Around 3%–5% retinoblastoma be 50% (due to germline
mosaicism) Negative Multifocal, Uncertain Difficult to Difficult to
unilateral determine determine retinoblastoma
Negative Unifocal, 5%–10% 2%–5% 1% unilateral