malignancy

Dyskeratosis Congenita

Clinical Characteristics
Ocular Features: 

The conjunctiva and eyelids are prominently involved as part of the generalized mucocutaneous disease.  Keratinization of the lid margins, absent lacrimal puncta, trichiasis, cicatrizing conjunctivitis, entropion, ectropion, blepharitis, sparse eyelashes, and symblephara are important features.  The cornea is also involved with keratinization of the epithelial surface and vascularization.  The nasolacrimal duct is sometimes blocked.  At least one patient has been reported to have an exudative retinopathy. 

Systemic Features: 

Dyskeratosis congenita consists of a heterogeneous (genetic and clinical) group of inherited bone marrow failure and premature aging syndromes with the common feature of shortened telomeres.  There is considerable variability in the clinical features.  Prominent manifestations include nail dysplasia, oral leukoplakia, abnormal dentition, and reticulated skin pigmentation. Some patients have cognitive impairments.  Liver failure, testicular atrophy, pulmonary fibrosis, aplastic anemia, and osteoporosis along with features of aging such as premature grey hair and loss are typical.  There is an increased risk of malignancies, especially acute myelogenous leukemia.  Bone marrow failure is the major cause of early death.

Genetics

At least three autosomal dominant, three autosomal recessive, and one X-linked form of dyskeratosis congenita are recognized.  Mutations in at least 7 genes have been implicated.

Autosomal dominant disease can result from mutations in the TERC gene (DKCA1; 3q36.2; 127550), the TERT gene (DKCA2; 5p15.33; 613989), and the TINF2 gene (DKCA3; 14q12; 613990).  Mutations in the TINF2 gene are also responsible for Revesz syndrome (268130) with many features of DKC in addition to ocular findings of an exudative retinopathy resembling Coats disease.

Autosomal recessive disease is caused by mutations in the NOP10 (NOLA3) gene (DCKB1; 224230; 15q14-q15), the  NHP2 (NOLA2) gene (DKCB2; 5q35; 613987), and the WRAP53 gene (DKCB3; 17p13; 613988).  Mutations in the TERT gene may also cause autosomal recessive disease known as DKCB4 (613989).  

The X-linked disease (DKCX) (Zinsser-Engman-Cole syndrome) results from a mutation in the DKC1 gene (Xq28; 305000).  The same gene is mutated in Hoyeraal-Hreidarsson syndrome (300240) which some consider to be a more severe variant of dyskeratosis congenita with the added features of immunodeficiency, microcephaly, growth and mental retardation, and cerebellar hypoplasia. 

The majority of mutations occur in genes that provide instructions for making proteins involved in maintainence of telemeres located at the ends of chromosomes.  Shortened telomeres can result from maintainence deficiencies although the molecular mechanism(s) remain elusive.

Pedigree: 
Autosomal dominant
Autosomal recessive
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Treatment for DKC with hematopoietic stem cell transplantation can be curative but its long-term efficacy is poor.  Some advocate androgen therapy first.  Lifelong cancer surveillance and frequent ocular and dental evaluations are important with specific treatment as indicated.

References
Article Title: 

Retinoblastoma

Clinical Characteristics
Ocular Features: 

Retinoblastoma is the most common intraocular malignancy of childhood occurring in 1 in 18,000 to 1 in 30,000 live births worldwide. The majority of cases are diagnosed before the age of 3 years. The most common clinical feature at time of diagnosis is leukocoria (white pupillary reflex) followed by strabismus. Other presenting features include intraocular inflammation, spontaneous hyphema, hypopyon, heterochromia, proptosis, spontaneous globe perforation, retinal detachment, cataract, neovascularization of iris, glaucoma, nystagmus, tearing and anisocoria.

Retinoblastoma can usually be observed during fundus exam as a white subretinal or vitreous mass, occasionally with multifocal nodules, typically with calcification of the surface. The growth of the tumor can be endophytic, exophytic or diffuse. Endophytic growth of retinoblastoma occurs when the tumor penetrates the inner limiting membrane of the retina and can result in vitreous seeding and growth and can simulate iridocyclitis or endophthalmitis.  Exophytic growth occurs when the tumor grows into the subretinal space, which results in accumulation of subretinal fluid and retinal detachments. If the tumor infiltrates Bruchs membrane, there is an increased risk of invasion of choroidal vessels or ciliary nerves and vessels. Diffuse growth is rare and characterized by slow infiltration of retina with diffuse thickening.

Imaging studies such as ultrasound, computerized tomography, and MRI can show the extent of tumor and the presence of calcification.

Systemic Features: 

In heritable cases there is an increased risk of developing other malignant neoplasms throughout life such as osteosarcomas, cutaneous melanomas, pinealomas, and thyroid carcinomas. The risk for secondary malignancies is higher in areas treated with radiation, where osteogenic sarcoma, fibrosarcoma and soft tissue sarcomas may occur. Patients should be closely monitored for secondary tumors throughout life.

Genetics

Retinoblastoma is a malignant tumor of the developing retinal cells caused in most cases by mutations in both copies of the RB1 gene.  The RB1 gene is a tumor suppressor gene, located on chromosome 13q14 and is the first human cancer gene to be cloned. The gene codes for the tumor suppressor protein pRB, which by binding to the transcription factor E2F, inhibits the cell from entering the S-phase during mitosis.  Recent evidence suggests that post-mitotic cone precursors are uniquely sensitive to pRB depletion and may be the cells in which retinoblastoma originates.

However, more recent information suggests that the occurrence and viability of retinoblastic cells may be more complex than suggested by simple loss of function of the RB1 alleles.  There is increasing evidence for the role of epigenetic factors such as DNA methylation impacting the differential expression of more than 100 additional genes which may be influencing the retinoblastoma phenotype.  Among these is an upregulation of spleen tyrosine kinase (SYK) required for tumor cell survival which, if inhibited, leads to retinoblastoma cell death in vivo and in vitro.

Pedigrees of familial cases have an autosomal dominant pattern but the disease requires homozygosity of the RB1 mutation.  This complicates genetic counseling for retinoblastoma. One third of cases have a germline mutation with a mutation in only one of the two gene copies in every cell.  A somatic mutation in the second allele then leads to  homozygosity causing tumor development.  Since one of the parents contributed the germinal mutation, and there is high penetrance (as much as 85%), this leads to the autosomal dominant pattern in these families. In 6% of retinoblastoma cases with germline mutations the family history is positive. The risk for developing bilateral and multifocal retinoblastoma is high and the age of onset is around 14 months.  This is the case for virtually all bilateral tumors.  The mean number of tumors is about 5 in the two eyes.  The offspring of a parent with bilateral retinoblastoma have a 45% chance of developing a tumor (they have a 50% chance of inheriting the germline mutant allele).  Reduced penetrance of 10 to 15% lowers the expected occurrence of disease from 50% to 45%.

However, two thirds of cases are of non-germinal origin with both somatic mutations occurring in a single retinal progenitor cell.  Because this is a highly unlikely event, these cases are generally unilateral and unifocal with an average age of onset of 24 months. Sporadic cases constitute about 94% of all retinoblastomas, of which about 60% have unilateral disease with no germline mutations.  Individuals who acquire mutations in both alleles somatically (with single, unilateral tumors) do not have a mutation in their germ cells and therefore usually transfer no tumor risk to their offspring.  Laterality and number of tumors alone, however, cannot be used for accurate predictions in this case since about 15% of patients with unilateral and monofocal tumors actually have germline mutations.  This leaves a residual risk of transferring heritability of about 1-5% in unilateral patients without a family history.

To further complicate the story, recent evidence suggests that retinoblastoma is genetically heterogeneous.  About 6% of patients have no RB1 mutation.  In one study, about half of such individuals have up-regulation of the MYCN oncogene (2p24.3) suggesting a second mechanism leading to clinical retinoblastoma.  For unknown reasons, such tumors tend to  be larger, more aggressive, and discovered at an earlier age than unilateral non-familial RB1 tumors.  The MYCN gene product is a transcription factor important for organ development during embryogenesis.  Its amplification has been implicated in about 25% of neuroblastomas.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Enucleation may be necessary to eliminate the primary tumor, especially large ones, but other treatments can be used successfully to treat smaller tumors and spare vision. Intravenous chemotherapy is the most common treatment, which can be combined with subtenon chemotherapy, cryotherapy, thermotherapy, and plaque brachytherapy. External beam radiation can be used for refractive cases and recurrences. Another treatment alternative is localized ophthalmic artery intra-arterial chemotherapy.

It is necessary to follow all offspring of parents with bilateral tumors throughout the first decade because of the risk for new tumor development, as late as 5 to 7 years of age.   There are even a few case reports of retinoblastoma diagnosed in adults. However, since the retinal cells are generally mature by the age of 2.5 years, such events are very rare.  All parents of children with retinoblastoma should have complete fundus evaluations since rare tumors spontaneously regress leaving retinal scars, which in such a family pattern suggests that a germline mutation was inherited.

Survivors of hereditary retinoblastomas must be followed the rest of their lives, and especially so if radiation treatment was applied, because of the high risk of developing secondary neoplasms.  The risk rises with age.

References
Article Title: 

Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies

Rushlow DE, Mol BM, Kennett JY, Yee S, Pajovic S, Th?(c)riault BL, Prigoda-Lee NL, Spencer C, Dimaras H, Corson TW, Pang R, Massey C, Godbout R, Jiang Z, Zacksenhaus E, Paton K, Moll AC, Houdayer C, Raizis A, Halliday W, Lam WL, Boutros PC, Lohmann D, Dorsman JC, Gallie BL. Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol. 2013 Mar 12:327-34.

PubMed ID: 
23498719

A novel retinoblastoma therapy from genomic and epigenetic analyses

Zhang J, Benavente CA, McEvoy J, Flores-Otero J, Ding L, Chen X, Ulyanov A, Wu G, Wilson M, Wang J, Brennan R, Rusch M, Manning AL, Ma J, Easton J, Shurtleff S, Mullighan C, Pounds S, Mukatira S, Gupta P, Neale G, Zhao D, Lu C, Fulton RS, Fulton LL, Hong X, Dooling DJ, Ochoa K, Naeve C, Dyson NJ, Mardis ER, Bahrami A, Ellison D, Wilson RK, Downing JR, Dyer MA. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature. 2012 Jan 11;481(7381):329-34.

PubMed ID: 
22237022

Ataxia-Telangiectasia

Clinical Characteristics
Ocular Features: 

The ocular manifestations are striking although of little clinical consequence.  The conjunctivae have prominent telangiectases which usually develop between 3 and 5 years of age.  These apparently do not occur intraocularly.    Oculomotor apraxia is often an earlier sign consisting of difficulty in initiation of smooth pursuit movements which patients may modify by head motion in the direction of attempted gaze.  This aspect can be helpful in diagnosis of AT in young children with cerebellar ataxia. 

Systemic Features: 

Telangiectases are often found in the pinnae, on the cheeks, and on the forearms, usually after the onset of neurological signs.  However, this is also a disorder with multiple systemic signs, the most serious of which are unusual sensitivity to ionizing radiation, excessive chromosomal breakage, a deficiency in the immune system, mild cognitive impairment, and increased risk of malignancies.  Lymphomas, often of B-cell origin, and leukemia, usually of T-cell origin, are the most common malignancies but there is a significantly increased risk of breast cancer as well. Serum IgG2 and IgA levels are often reduced and sinopulmonary infections are common.  Serum alpha-fetoprotein levels are usually increased.  The ataxia is progressive and often begins as truncal unsteadiness with limbs involved later.  It is often accompanied by choreoathetosis and/or dystonia which may result in severe disability by the second decade.  Life span is shortened and many patients succumb to their disease by the 3rd and 4th decades. 

In some famiies with confirmed mutations in ATM the disorder presents with signs of primary torsion dystonia and myoclonus-dystonia.  These signs may resemble an apparent autosomal dominant pattern with parent-child transmission.  It is unclear whether these families represent a variant of AT or a unique disorder.  The latter is suggested by an earlier onset of signs, the lack of cerebellar atrophy,  and the absence of ataxia and ocular telangiectases on initial presentation.  The risk of malignancies in these famiies is high.

Some of these signs have been reported in milder form among heterozygous carriers as well.  The most serious is an increased risk of malignancy, perhaps as much as 6.1 times that of non-carriers.  This combined with the inherent sensitivity to ionizing radiation has led to the suggestion that X-rays should be used with caution, especially when considering mammograms among female relatives.

 

Genetics

This is an autosomal recessive disorder as a result of mutations in the ATM gene located at 11q22-q23.  Affected offspring of consanguineous matings are often homozygous for this mutation whereas those from unrelated parents are usually compound heterozygotes.  There is some evidence of genetic heterogeneity based on both clinical and DNA studies (AT variants).

Other conditions with oculomotor apraxia are: ataxia with oculomotor apraxia 1 (208920), ataxia with oculomotor apraxia 2 (602600), and Cogan type oculomotor apraxia (257550) which lacks other neurologic signs. Oculomotor apraxia may be the presenting sign in Gaucher disease (230800, 230900, 231000).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known for the neurologic manifestations.  However, patients and first degree relatives should be monitored for malignancies.  Childhood vaccinations may lead to widespread viral dissemination as a consequence of the immune defect.

References
Article Title: 

Ataxia telangiectasia: a review

Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet J Rare Dis. 2016 Nov 25;11(1):159. Review.

PubMed ID: 
27884168

Cognitive Phenotype in Ataxia-Telangiectasia

Hoche F, Frankenberg E, Rambow J, Theis M, Harding JA, Qirshi M, Seidel K, Barbosa-Sicard E, Porto L, Schmahmann JD, Kieslich M. Cognitive Phenotype in Ataxia-Telangiectasia. Pediatr Neurol. 2014 May 5.

PubMed ID: 
25037873

Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites

Saunders-Pullman R, Raymond D, Stoessl AJ, Hobson D, Nakamura T, Pullman S, Lefton D, Okun MS, Uitti R, Sachdev R, Stanley K, San Luciano M, Hagenah J, Gatti R, Ozelius LJ, Bressman SB. Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites. Neurology. 2012 Feb 15. [Epub ahead of print] PubMed PMID: 22345219.

PubMed ID: 
22345219
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