telangiectasia

Rothmund-Thomson Syndrome

Clinical Characteristics
Ocular Features: 

Patients have been reported with juvenile and infantile cataracts.  Reported prevalence varies possibly because the diagnostic criteria have not been established and more than one disorder may be represented by the title.  Rothmund (an ophthalmologist) originally reported two families of 5 children in which lens opacities were found, but Thomson, who was a dermatologist, in a later report did not mention cataracts.  The lens opacities are usually nuclear or posterior cortical in location and may be evident in 50% of patients.  Iris stromal changes such as hypoplasia have also been reported.  Eyelashes and/or eyebrows may be sparse.  This is likely the same disorder as the previously described ‘mesodermal dysgenesis of the iris and skeletal dysplasia’ and formerly listed as 270240 in OMIM.

Systemic Features: 

This is a clinically heterogeneous disorder.  Skin atrophy with pigmentary changes, telangiectasia, short stature, premature aging, and skeletal abnormalities are characteristic.  There is an increased risk of malignancy, particularly osteosarcomas and skin cancer.  Saddle nose, sparse hair, hypogonadism, dysplastic nails, and teeth anomalies have also been described.

The skin is usually normal at birth but an erythematous rash typically appears in the first six months of life accompanied by swelling and blistering.  Eventually areas of hypo- and hyperpigmentation appear in a reticulated pattern with spots of punctate atrophy and telangiectasia.  Hyperkeratosis of the soles of the feet is common.  The skeletal abnormalities of dysplasia, radial ray defects, and missing bones are often evident at birth while osteopenia and delayed bone maturation are evident later.

Genetics

This is an autosomal recessive disorder in which most patients have mutations in the RECQL4 gene (8q24.3).

Mutations in the same gene cause Baller-Gerold syndrome (218600) suggesting that the two disorders are allelic but the phenotypes are considerably different.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the primary disorder but patients must be monitored for malignancies.  Visually significant cataracts should be removed.  It has been recommended that patients avoid excessive sun exposure to reduce the risk of skin cancers.

References
Article Title: 

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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