TS or not TS? - ProQuest Search

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TS or not TS? Cyriac Athappily,1 Rickie Patani,1,2,3 Sanjiv Chawda,1 Elisabeth Rosser,4 Rajith de Silva1 1

Department of Neurology, Essex Centre for Neurological Sciences, Queen’s Hospital, Romford, Essex, UK 2 Anne Mclaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge, UK 3 Department of Clinical Neurosciences, Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, UK 4 Clinical Genetics Unit, Great Ormond Street Hospital for Children NHS Trust, London, UK Correspondence to Dr Rajith de Silva, Department of Neurology, Essex Centre for Neurological Sciences, Queen’s Hospital, Rom Valley Way, Romford,Essex RM7 0AG, UK; [email protected] CA and RP contributed equally to this paper and are joint first authors. Received 29 July 2012 Accepted 31 October 2012 Published Online First 13 March 2013

To cite: Athappily C, Patani R, Chawda S, et al. Pract Neurol 2013;13: 268–270.

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A 47-year-old woman had first presented in her late twenties with complex partial seizures and became seizure-free on carbamazepine. She re-presented 13 years later with migrainous headaches. MR scan of the brain showed several unusual, nonspecific high signal intensity, lesions in the deep and subcortical white matter of both cerebral hemispheres (figure 1). The lesions were typical of subcortical tubers and, as such, a diagnosis of tuberous sclerosis (TS) was queried, although she had no other ( peripheral) stigmata of TS.1 Question 1 What are the diagnostic criteria for TS? TS is an autosomal dominant, multisystem disorder, presenting with multiple harmatomous growths.1 It is usually caused by a mutation in either TSC1 or TSC2, coding for the proteins, hamartin and tuberin respectively.2 Although up to 90% of patients with TS experience seizures, epilepsy is not considered a diagnostic feature. There is no single pathognomonic clinical sign for this condition.3 Given the wide phenotypic variability in TS, Roach et al4 developed a set of diagnostic criteria in 1998 (see box 1 adapted from Hake1). They suggest several major and minor clinical features, but the cardinal signs for suspecting TS are the skin manifestations—in particular, periungual fibromas, adenoma sebaceum, Shagreen patches and ash-leaf macules (which may only be visualised after examination under Wood’s light). Despite careful examination of the skin in our patient, there were no peripheral stigmata of TS. There were no dental enamel pits or gingival fibromas. We did not request additional investigations for the presence of rectal polyps and bone cysts. On further questioning the patient disclosed that she was adopted at birth (with no subsequent contact with her biological parents). She had no children.

Box 1 Diagnostic criteria for tuberous sclerosis (adapted from Hake1) Major features: 1. Facial angiofibromas or forehead plaque 2. Nontraumatic ungual or periungual fibroma 3. Hypomelanotic macule (3 or more) 4. Shagreen patch (connective tissue naevus) 5. Multiple retinal nodular hamartomas 6. Cortical tuber 7. Subependymal nodule 8. Subependymal giant cell astrocytoma 9. Cardiac rhabdomyoma, single or multiple 10. Lymphangiomyomatosis 11. Renal angiomyolipoma Minor features: 1. Multiple randomly distributed pits in dental enamel 2. Hamartomatous rectal polyps 3. Bone cysts 4. Cerebral white matter radial migration lines 5. Gingival fibromas 6. Non-renal hamartomas 7. Retinal achromic patch Definite diagnosis – 2 major features Probable diagnosis – 1 major and 1 minor feature Suspected diagnosis – 1 major feature or 2 or more minor features.

Consequently, her family history was uninformative. Although she reported memory difficulties, a formal neuropsychological assessment was normal.

Question 2 What further imaging might help to support TS as the explanation for the MR findings at this point?

Athappily C, et al. Pract Neurol 2013;13:268–270. doi:10.1136/practneurol-2012-000371

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Figure 1 MRI T2 fluid attenuated inversion recovery (FLAIR) axial images showing cortical/subcortical tubers in the right occipital (A) and left frontal (B) lobes.

COMMENT Brain lesions in TS include cortical tubers, subependymal nodules (SENs) and subependymal giant cell astrocytomas (SEGAs). Cortical tubers are disorganised areas of cortex and are best identified using MRI.5 Only 3–4% of tubers show contrast enhancement.6 However, calcification is much better seen on CT, and, as approximately 50% of cortical tubers calcify, CT imaging is also useful. The amount of calcification increases with age and is rare in infants. SENs are more likely to calcify at an early age and are therefore best detected by CT or susceptibilityweighted imaging. SEGAs are rarer, are heterogeneous on MRI, often calcify and strongly enhance following contrast.5 Therefore both MR and CT images can help in patients with suspected TS.

Question 3 What further investigations are indicated? COMMENT CT scan of chest, abdomen and pelvis may be indicated, as the systemic features of TS can include lymphangiomyomatosis, cardiac rhabdomyomas and renal angiomyolipomas. CT chest was normal. CT abdomen, however, identified a renal mass, probably an angiomyolipoma (often found in TS, and ‘establishing’ the diagnosis). Ophthalmoscopy is also indicated, but in this case showed no retinal nodular harmartomas, or achromic patches.

Question 4 How would you confirm the diagnosis?


COMMENT We requested genetic testing with the patient’s informed consent. Screening for mutations and large scale deletions/duplications using fluorescent sequencing of the intron 8/exon 9 boundary of TSC1 identified a heterozygous base change (c.738-1G>A). This mutation predicts aberrant splicing of TSC1 mRNA, and was present at a low level on repeated sequence analysis. Post script

Later, a detailed ultrasound examination of the abdomen and pelvis showed that the suspected renal angiomyolipoma was, in fact, a prominent column of Bertin (a normal variant). Despite genetic “confirmation”, we now no longer had sufficient clinical criteria to diagnose TS. Renal ultrasound scan is recommended as a routine investigative tool in all cases of suspected TS. Question 5 How would you reconcile the genetic confirmation of TS in the absence of peripheral stigmata?

COMMENT This can be explained by mosaicism, which occurs when only a proportion of adult cells posses a mutation or chromosomal abnormality, and which occurs during development rather than being inherited. The heterozygous base change in TSC1 (c.738-1G>A) was consistently picked up at a low level when the sequence analysis was repeated. This supported the view that our patient was indeed a somatic mosaic for TS, thus explaining the lack of cutaneous stigmata and

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TEST YOURSELF other diagnostic features of this condition, and her mild phenotype. Interestingly, a second heterozygous nucleotide substitution was also detected in intron 17 of the TSC2 gene (c.1946+20C>T), which has not been previously reported. The result of both mutations co-existing, and any possible mechanistic interaction/direct phenotypic consequence(s) has yet to be determined. Mosaicism is fairly common in TS.2 7 Cases often manifest more than just one characteristic feature of TS8 but may not meet the “diagnostic” criteria. Up to 15% of definite TS patients lack a defined mutation; this prompted a search for additional genes. It now transpires, however, that these cases are more likely to be explained by mosaicism rather than by additional TSC genes. Limitations of the direct sequencing method in reliably detecting low level mutations (often seen in mosaicism) may possibly be overcome by newer and more sensitive methods such as ‘triple nested polymerase chain reaction-restriction fragment length polymorphism’ and ‘denaturing high performance liquid chromatography’.2 3 9 10 Individuals with mosaicism are often, but not always, mildly affected. However, they may pass the mutation on to a child or children, who may be more severely affected as they will not be mosaic. Identifying mosaic cases is therefore important for providing accurate genetic advice. Patients with a confirmed diagnosis of TS require routine monitoring to detect some common complications. Asymptomatic children should have a brain CT/ MRI every 1–3 years and asymptomatic adults should have this every 5 years. Regular renal ultrasonography (every 1–3 years) is also recommended for patients with no identified renal lesions. Electroencephalography or chest investigations may also be required, depending on the patients’ symptoms.11 There is no need for echocardiographic monitoring in older children and adults, as cardiac rhabdomyomas are congenital and regress with time.

Box 2

Learning points

▸ The tuberous sclerosis complex can present with a wide range of signs and symptoms. There is no single pathognomonic feature and at present the diagnosis depends on a set of clinical criteria outlined above. ▸ Both MRI and CT help to identify the various brain lesions which occur in TS. ▸ Mosaicism is common in tuberous sclerosis and therefore if the diagnosis is in doubt, genetic testing can lead to greater diagnostic clarity. ▸ Genetic testing using traditional methods has its limitations, and more advanced techniques may be required to detect low level mutations.

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This patient’s presentation with only a single diagnostic criterion of TS is highly unusual. A previous report described a patient with a solitary SEGA (another ‘major’ cerebral features in the diagnosis of TS), but no other manifestations.3 There are also cases of solitary cortical tubers that were not thought to be associated with TS. However, these patients did not undergo genetic testing and it is possible that they were indeed mosaics for TS.12 These cases (and indeed the present case) confirm a large degree of phenotypic heterogeneity in TS mosaics (see box 2). More generally, this case underlines the importance of clinical awareness of mosaicism in patients with suspected genetic conditions, where some—but not all—classical features are present. Acknowledgements We thank the referee for his helpful and insightful comments. Contributors CA and RP wrote the manuscript. SC performed and interpreted the neuroimaging. ER coordinated the genetic studies, and interpreted the findings. RdS is the patient’s consultant neurologist and was involved in all aspects of this case. Funding None. Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Finbar O’Callaghan, Bristol, UK.

REFERENCES 1 Hake S. Cutaneous manifestations of tuberous sclerosis. Ochsner J 2010;10:200–4. 2 Kwiatkowska J, Wigowska-Sowinska J, Napierala D, et al. Mosaicism in tuberous sclerosis as a potential cause of the failure of molecular diagnosis. N Engl J Med 1999;340:703–7. 3 Ichikawa T, Wakisaka A, Daido S, et al. A case of solitary subependymal giant cell astrocytoma: two somatic hits of TSC2 in the tumor, without evidence of somatic mosaicism. J Mol Diagn 2005;7:544–9. 4 Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 1998;13:624–8. 5 Radhakrishnan R, Verma S. Clinically relevant imaging in tuberous sclerosis. J Clin Imaging Sci 2011;1:39. 6 Grajkowska W, Kotulska K, Jurkiewicz E, et al. Brain lesions in tuberous sclerosis complex. Review. Folia Neuropathol 2010;48:139–49. 7 Roberts PS, Dabora S, Thiele EA, et al. Somatic mosaicism is rare in unaffected parents of patients with sporadic tuberous sclerosis. J Med Genet 2004;41:e69. 8 Verhoef S, Bakker L, Tempelaars AM, et al. High rate of mosaicism in tuberous sclerosis complex. Am J Hum Genet 1999;64:1632–7. 9 Jones AC, Sampson JR, Cheadle JP. Low level mosaicism detectable by DHPLC but not by direct sequencing. Hum Mutat United States; 2001;17:233–4. 10 Kwiatkowski D. TSC1, TSC2, TSC3? Or mosaicism? Eur J Hum Genet England; 2005;13:695–6. 11 Northrup H, Koenig MK, Au KS. Tuberous sclerosis complex. In: Pagon RA, Bird TD, Dolan CR, et al., eds. Gene reviews. Seattle, WA: University of Washington, 1993. 12 DiPaolo D, Zimmerman RA. Solitary cortical tubers. AJNR Am J Neuroradiol 1995;16:1360–4.
