daniela2

 
 

 

Tuberous Sclerosis Complex (TSC) & gluten intolerance?

 

 My mother was told she has this by an urologist yesterday. She's had benign fatty tissue growth all her life in several lumps on her arms, had surgery to get a breast lump removed a few years ago, and recently had to get surgery to remove lumps on her kidneys which were causing her severe pain. The lumps themselves are benign, but they can cause pain depending on where they are. TSC is a genetic condition for which the cause is unknown and for which there is no real cure (other than removal, but they could just grow back I suppose). I have some of these same lumps on my inner thighs.   So I guess that means I have it too.

I'm wondering if this is related to gluten intolerance. My mother, who is now 50 years old, is a lifelong vegatarian, and being Indian, we typically rely heavily on grains in our diet anyway. The kidney lumps developed after my mom quit rice for wheat instead-- this is what Indians typically do in order to lose weight, but my mom actually gained 20 lbs instead. She's also in the early stages of arthritis of the knee--I'm not sure if it's rheumatoid or osteo though, she herself doesn't know very well all her ailments. I know gluten can cause all sorts of weird autoimmune reactions in the body, so I wouldn't be surprised if it contributes to TSC. Thoughts?


P.S. My mom has been listening to my rants! She apparently asked the doctor (75 yrs old) if TSC could be related to gluten intolerance, to which he replied that "gluten only causes stomach problems" and "you're doing too much research." That's great medical care, right there.   But thankfully it seems like she will at least try to avoid gluten... I think she's secretly happy that she will no longer have to eat disgusting things like cracked wheat rice to "be healthy." Or at least that's how I would feel!

 

Neurologic Presentation of Celiac Disease
KHALAFALLA O. BUSHARA
Neurology Department, Minneapolis VA Medical Center and University of Minnesota, Minneapolis, Minnesota

 

 

 

 

Celiac disease (CD) long has been associated with neurologic and psychiatric disorders, notably cere- bellar ataxia, peripheral neuropathy, epilepsy, dementia, and depression. A wider spectrum of neurologic syn- dromes increasingly are recognized both as complications of prediagnosed CD and as initial manifestation of CD.1,2
Cerebellar Ataxia
Cooke and Smith3 first reported a group of 16 patients with biopsy examination–proven CD who had gait ataxia and peripheral neuropathy. Cerebellar in-
volvement was reported in some of these patients and in subsequent multiple case reports.4 – 8 Although some pa- tients had low vitamin E levels,9–11 others had normal vitamin levels and the cerebellar syndrome was attrib- uted to CD mechanisms, rather than malabsorption.12,13 Studies also have shown that cerebellar and other neuro- logic syndromes may be the presenting manifestation of CD.1,13,14 In one study, 10 of 144 (7%) CD patients presented with neurologic symptoms.1 In patients with cerebellar ataxia of unknown cause, biopsy examination– proven CD was found in 16% (4 of 25),14 16.7% (4 of 24),1 12.5% (3 of 24),15 and 1.9% (2 of 104).16 It is accepted widely that patients with ataxia of unknown cause should be screened for CD. However, it remains controversial whether gluten sensitivity (defined as “a state of heightened immunologic responsiveness to in- gested gluten in genetically predisposed individuals”17) without intestinal involvement should be considered the cause of cerebellar degeneration in ataxia of otherwise unknown cause.18 The diagnosis of gluten sensitivity is made by showing high antigliadin antibodies even in the absence of intestinal pathology and the antibodies that correlate with mucosal damage (antiendomysium and anti–tissue transglutaminase antibodies) and that are considered highly specific for CD.19 The prevalence of positive antigliadin antibodies in ataxia of unknown cause has varied between 0% and 41% in different studies.14 –16,20 –23 On average, antigliadin antibodies seem to be more prevalent in ataxia than in the general population (30%; 89 of 209 in ataxic patients compared with 8%–12% in controls), suggesting an association between cerebellar degeneration and gluten sensitiv- ity.14 –16,20 –22 However, there also is evidence of a high prevalence of antigliadin antibody positivity in genetic neurodegenerative disorders such as hereditary spinocer- ebellar ataxia and Huntington’s disease.21,24 It remains unclear whether gluten sensitivity contributes to the pathogenesis of these disorders or whether it represents an epiphenomenon. It also is controversial whether an-

tigliadin antibodies directly interact with the nervous system.25,26
The effect of gluten-free diet on ataxia has been vari- able.27–30 There are rare reports showing efficacy of im- munomodulation with intravenous immunoglobu- lins.31,32
Neuropathy
Evidence for peripheral neuropathy has been found in up to 49% of CD patients.33 In a recent series of 20 patients with neuropathy and biopsy examination– confirmed CD, 9 patients presented with neuropathic symptoms before the diagnosis of CD was made.34 Chronic distal, symmetric, predominantly sensory neu- ropathy is described most commonly in patients with CD; however, pure motor neuropathy, mononeuritis multiplex, Guillain–Barré–like syndrome and autonomic neuropathy also have been reported.3,34–38 The most common electrophysiologic diagnosis is that of mixed sensorimotor axonal peripheral neuropathy.35–37 How- ever, electrophysiologic studies can be normal or only mildly abnormal in many CD patients with neuropa- thy.34 Indeed, CD was found in 8% of 400 patients with neuropathy and normal electrophysiologic studies.34 In one study, antiganglioside antibodies were found (by using rapid ganglioside agglutination immunoassay39) in 13 (65%) of 20 patients with CD and neuropathy.34 These autoantibodies bind to the Schwann cell surface, nodes of Ranvier, and axons in peripheral nerves. Anti- ganglioside antibodies commonly are associated with autoimmune peripheral neuropathies with some specific- ity (eg, immunoglobulin [Ig]G antibodies to GM1 and GD1b in Guillain–Barré syndrome variants with axonal degeneration, anti-GQ1b and GT1b in Miller–Fisher’s syndrome, and IgM antibodies to GM1 in multifocal motor neuropathy). Alaedini et al40 reported 6 patients with CD who were positive for 1 or more IgG antibodies to GM1, GM2, GD1a, and GD1b (4 patients had anti- GM1 antibodies and none had GQ1b or GT1b).
There are few case reports documenting the co-occur- rence of CD with less common neuromuscular syndromes such as polymyositis, dermatomyositis, inclusion body myositis, and neuromyotonia.37,41,42
The effect of gluten-free diet on peripheral neuropathy and other neuromuscular disorders associated with CD is unclear. In only a few reports was a gluten-free diet said to be effective.36,43 Other reports indicated the persis- tence and progression of neuropathy despite an adequate gluten-free diet.44 – 46 Although autoimmune mecha- nisms likely are responsible for the peripheral neuropathy and other neuromuscular disorders described with CD,
published trials of immunomodulation using corticoste- roids and/or intravenous immunoglobulins are lacking.

Cerebellar Ataxia
Cooke and Smith3 first reported a group of 16 patients with biopsy examination–proven CD who had gait ataxia and peripheral neuropathy. Cerebellar in-
volvement was reported in some of these patients and in subsequent multiple case reports.4 – 8 Although some pa- tients had low vitamin E levels,9–11 others had normal vitamin levels and the cerebellar syndrome was attrib- uted to CD mechanisms, rather than malabsorption.12,13 Studies also have shown that cerebellar and other neuro- logic syndromes may be the presenting manifestation of CD.1,13,14 In one study, 10 of 144 (7%) CD patients presented with neurologic symptoms.1 In patients with cerebellar ataxia of unknown cause, biopsy examination– proven CD was found in 16% (4 of 25),14 16.7% (4 of 24),1 12.5% (3 of 24),15 and 1.9% (2 of 104).16 It is accepted widely that patients with ataxia of unknown cause should be screened for CD. However, it remains controversial whether gluten sensitivity (defined as “a state of heightened immunologic responsiveness to in- gested gluten in genetically predisposed individuals”17) without intestinal involvement should be considered the cause of cerebellar degeneration in ataxia of otherwise unknown cause.18 The diagnosis of gluten sensitivity is made by showing high antigliadin antibodies even in the absence of intestinal pathology and the antibodies that correlate with mucosal damage (antiendomysium and anti–tissue transglutaminase antibodies) and that are considered highly specific for CD.19 The prevalence of positive antigliadin antibodies in ataxia of unknown cause has varied between 0% and 41% in different studies.14 –16,20 –23 On average, antigliadin antibodies seem to be more prevalent in ataxia than in the general population (30%; 89 of 209 in ataxic patients compared with 8%–12% in controls), suggesting an association between cerebellar degeneration and gluten sensitiv- ity.14 –16,20 –22 However, there also is evidence of a high prevalence of antigliadin antibody positivity in genetic neurodegenerative disorders such as hereditary spinocer- ebellar ataxia and Huntington’s disease.21,24 It remains unclear whether gluten sensitivity contributes to the pathogenesis of these disorders or whether it represents an epiphenomenon. It also is controversial whether an- tigliadin antibodies directly interact with the nervous system.25,26

The effect of gluten-free diet on ataxia has been vari- able.27–30 There are rare reports showing efficacy of im- munomodulation with intravenous immunoglobu- lins.31,32

 

Epilepsy
Several studies have suggested an association be- tween CD and epilepsy.47–50 A high prevalence of epi- lepsy (3.5%–5.5%) has been reported in patients with CD compared with controls.47,48 On the other hand, a higher CD prevalence (.8%–2.5%) was found in epilepsy patients compared with the general population.49 –52
A more specific syndrome of bilateral occipital cerebral calcification and seizures has been associated with CD. This association first was described by Visakorpi et al53 in 1970 and subsequently was confirmed by several stud- ies.54 –58 However, the syndrome seems to be rare. Fois et al49 screened 783 children presenting with seizures and found CD in 9 patients with partial and/or grand mal seizures. Of these only 3 (.3%) had cerebral calcification (2 had occipital calcification and occipital seizures with epi- sodes of transient blindness). Luostarinen et al51 examined brain scans of 130 patients with epilepsy and found 11 patients with intracerebral calcifications (3 had posterior calcifications) but none had CD. Magaudda et al59 found CD in only about half of epileptic patients with bilateral occipital calcification who underwent duodenal biopsy examination. The majority of the patients reported had complex partial seizures referable to the occipital or temporal lobes; however, secondarily generalized sei- zures, other seizure types, and episodic headaches also were described.60,61 The syndrome can be distinguished clinically from Sturge–Weber syndrome by the absence of facial angioma (port wine stain or nevus flammeus), bilaterality of the occipital calcification, and their exten- sion into the subcortical region on computed tomogra- phy scan. The calcified lesions described in CD also lack contrast enhancement on magnetic resonance imaging and, unlike Sturge–Weber syndrome, are not associated with cerebral atrophy or vascular anomalies.59 The his- tology of the calcified lesions in CD is similar but not identical to Sturge–Weber syndrome and consists of patchy pial angiomas, fibrosed veins, and large jagged microcalcifications.62 Interestingly, by using radiograph spectroscopy, Toti et al63 found that calcium (43%) and silica (57%) were present in the calcified lesions. It has been suggested that the calcification in CD is related to low folic acid levels; however, this is controversial.54,59 In Sturge–Weber syndrome, the calcification has been at- tributed to blood stasis in the angiomas, chronic isch- emia, and altered metabolism.
The effect of gluten-free diet on epilepsy control in CD has been variable. In most patients the beneficial effects of the diet have been reported as better seizure control and a decrease in antiepileptic medications but not the resolution of seizures.58,64,65 Surgical resection has been recommended for intractable seizures localizable to the occipital or temporal lobes.62,66


Autism
Autism is a common (1 in 1000) developmental disorder of early childhood characterized by impairment in social interaction and communication with absence of speech in about 50% of cases.84 Autistic children also display various behaviors that typically include stereo- typed motor behaviors (hand flapping, body rocking), insistence on sameness, and resistance to change. The underlying cause of autism remains unclear; however, it is believed to be a genetic disorder based on studies showing high concordance in monozygotic twins.85 Au- tism can be a manifestation of genetic disorders such as fragile X syndrome and tuberous sclerosis; however, the majority of cases are idiopathic. The available data sug- gest involvement of multiple interacting genes and en- vironmental modifiers in the pathogenesis of autism.86 Similar to schizophrenia, the implication of gluten sen- sitivity in autism was based mostly on the leaky-gut hypothesis: that abnormal intestinal mucosa permits ab- sorption of digestion products of dietary proteins such as gluten and casein.87 This results in excessive intake of short peptides that provoke an immune reaction or act as exorphins that directly affect the nervous system. Excess peptides in autism from abnormal intestinal mucosa and/or a defective peptidase activity is also the basis for the opioid excess hypothesis.88,89 However, there is little evidence to support these hypotheses. Whether urinary peptides and activity of certain peptidases are altered in autism continues to be a controversial issue.89 –93 It also is controversial whether the intestinal mucosa in autism is abnormal. D’Eufemia et al94 reported abnormal intes- tinal permeability in 9 of 21 autistic children but none of 40 controls. Horvath et al95 found a high prevalence of reflux esophagitis, gastritis, chronic duodenitis, low in- testinal disaccharidase activity, and higher pancreatobili- ary response to intravenous secretin, suggesting up-reg- ulation of hepatic and pancreatic secretin receptors. The same group reported improvement of autistic symptoms for weeks after a single intravenous secretin injection; however, subsequent randomized trials showed no differ- ence between secretin and placebo.96,97
Wakefield et al98 reported chronic colitis and reactive ileal lymphoid hyperplasia in 12 children with develop- mental regression (9 with autism) and suggested a cor- relation with measles, mumps, and rubella vaccine.

 

These findings have not been replicated by other groups and their interpretation remains highly controversial. Other studies showed evidence for immunopathologic changes in the intestinal mucosa of autistic children.99 Although similar nonspecific mucosal changes (including ileal lymphoid hyperplasia and increased intraepithelial lymphocytes) have been shown in CD, a direct associa- tion between CD and autism is lacking.100 None of 11 autistic children screened by Pavone et al101 had CD and none of 120 children with CD had autistic features. Only a few studies addressed the effect of dietary intervention in autism.102 McCarthy and Coleman103 reported no change in gastrointestinal symptoms in autistic children after gluten challenge. Behavioral improvement in autis- tic children on a gluten-free and casein-free diet has been reported by some groups.104–106 Others showed no sig- nificant effect of gluten-free and casein-free diets.107

 

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La sclerosi tuberosa è conosciuta anche come sindrome di Bourneville-Pringle ed è una facomatosi che si trasmette con carattere autosomico dominante.

caratterizzata da una iperplasia geneticamente determinata delle cellule ectodermiche e mesodermiche, con formazione di lesioni amartomatose a livello della cute, del sistema nervoso centrale, e di altri organi come il cuore e i reni[2]. Nella sua forma più classica si manifesta con le seguenti caratteristiche:

Le manifestazioni cliniche della patologia sono però estremamente variabili perfino tra i membri affetti della stessa famiglia: alcuni soggetti possono addirittura essere asintomatici e trascorrere tutta la vita senza sapere di essere malati o venirne a conoscenza solo quando la diagnosi viene posta ai loro figli. L'incidenza è di 1 su 6.000-7.000 nati, ma la frequenza potrebbe essere maggiore, considerata l'alta variabilità di sintomi che impedisce una diagnosi precisa e tempestiva: al mondo si calcolano oggi circa un milione di individui affetti.

Le crisi epilettiche sono il primo sintomo in circa l'80% dei casi e si manifestano di solito nella prima infanzia, ma in alcuni casi l'esordio non si verifica prima del secondo o terzo decennio di vita. Nel 40-50% dei pazienti è presente un grave ritardo mentale, mentre il 60-90% dei neonati affetti da questa sindrome presenta alla nascita macchie cutanee biancorosacee (ipocromiche); ciò è dovuto a formazioni amartomatose dell'epidermide, e queste ipopigmentazioni prendono il nome di macchie di Fitzpatrick. Le crisi epilettiche sono causate dai tuberi che si formano a livello del sistema nervoso centrale e che fungono da focolai epilettogeni. Tra le manifestazioni cutanee più precoci ricordiamo le chiazze acromiche a forma di tubero, di solito presenti alla nascita.

Il segno anatomico tipico della malattia è l'amartomatumore benigno che si presenta sotto forma di focolai multipli di cellule lentamente proliferanti, appartenenti a tipi istologici diversi, a seconda dell'organo interessato. Benché possa essere colpito qualunque organo, le sedi più frequentemente coinvolte sono rappresentate dal sistema nervoso centrale, dal cuore, dai reni, dalla cute, dagli occhi e dai polmoni. Quando ad essere colpito è il sistema nervoso centrale, possono insorgere lesioni di varia entità a carico del cervello. Sono queste ultime all'origine di ritardo mentale, ritardo del linguaggio e dello sviluppo motorio, crisi epilettiche e, talvolta, disturbi comportamentali e autismo. Non mancano casi, seppur rari, in cui si sviluppano tumori maligni.

La manifestazione cutanea più caratteristica della patologia è l'adenoma sebaceo, recentemente rinominato con un termine più specifico:angiofibromi facciali. Essi compaiono fra i tre e i cinque anni e si accrescono di numero durante la pubertà. Si dispongono "a macchia di farfalla" sul naso, sulle guance, tra le pieghe labiali e, spesso, sul mento. L'accumulo sottocutaneo di collagene, localizzato sul fondo della schiena e sul retro del collo, si manifesta con macchie leggermente rilevate, di colore bruno-giallastro, con aspetto di buccia d'arancia. Le placche sono soffici e rossastre.

A 3 anni di vita, il 92% dei malati presente della macchie biancastre sulla pelle, l'87% ha già varie crisi epilettiche, il 71% presenta crisi convulsive con più di un episodio al mese, il 47% è ritardato mentalmente (nel 70% lieve o moderato e nel restante 30% grave o gravissimo), il 33% ha una placca zigrinata con papule ocra in rilievo localizzata sul retro del collo e, ancora più frequentemente, sul fondo della schiena, il 72% presenta già tutti i sintomi tipici dell'angiofibroma, con ghiandole tumorali benigne di colore rosso acceso, rossobrunastro o aranciorosaceo, disposte "a macchia di farfalla" sulla cartilagine nasale, sulla parte alta delle guance (creando una sorta di strisce che si irradiano fino ai bordi della faccia), sotto la bocca, attorno alle pieghe nasali, labiali e nel cuore delle guance; amartomi retinici, segno tipico della malattia, sono raramente apprezzabili nei primi anni di vita del malato, mentre divengono uno dei sintomi caratteristici dell'iperplasia tuberosa a partire dalla prima età adulta, risultando addirittura nel 97% dei malati ultraquarantenni; ritornando ai minori di 36 mesi, una discreta percentuale tra i malati (circa il 20%) presenta un insolito accumulo di grasso e collagene sulla fronte, rendendola più o meno ingrossata e flaccida, a seconda della gravità dell'accumulo. 

Un tumore molto frequente, tra i più classici della sclerosi tuberosa, è l'angiomiolipoma renale: è un tumore in teoria benigno, ad evoluzione lenta ma inarrestabile, che interessa le ghiandole surrenali e può comparire a qualunque età, e di norma, dalla sua comparsa, è rara la sopravvivenza oltre i 15 anni di vita dall'origine delle cellule tumorali. Nel corso della sua vita, un malato di sclerosi tuberosa presenterà questa forma tumorale in almeno ottanta casi su cento. Non è da meno, infine, l'astrocitoma a cellule giganti:frequentissimo focolaio di epilessia e portatore di ipertensione intracranica, questo tumore prolifera in modo graduale e continuo, non essendo vulnerabile ad alcuna terapia. 

È un tumore tipico della sclerosi tuberosa, infatti il 60% circa dei malati di astrocitoma a cellule giganti è affetto da sclerosi tuberosa. La precocità dell'insorgenza di questo tumore, inoltre, influenza immancabilmente l'aspettativa di vita dei soggetti che ne sono affetti, svantaggiandoli rispetto a quelli che non lo presentano. L'astrocitoma a cellule giganti si presenta nel 53% dei malati di sclerosi tuberosa, nell'arco della loro vita. Dalle due percentuali si deduce che questo tumore è meno frequente, in generale, della sclerosi tuberosa generica, perciò va posta molta attenzione diagnostico-eziologica in caso di qualunque astrocitoma cerebrale, nell'età evolutiva specificatamente.

In circa la metà dei pazienti, prima di nascere si forma, a livello cardiaco, un rabdomioma, un tumore sicuramente benigno e non cronico, che può essere facilmente diagnosticato con una semplice ecografia del feto durante la gestazione. Esso regredisce spontaneamente dopo al massimo un anno di vita del paziente, e nel 93% dei casi non lascia strascichi sulla salute, ma nel rimanente 7% è la causa delle più svariate aritmie cardiache, in particolare una forma di bradicardia irregolare e la tachicardia ventricolare polimorfa catecolaminergica. Queste aritmie, comunque, sono autorisolventesi entro i 20 anni di età del soggetto.

Sono frequenti anche le anomalie gengivali negli sclerotici tuberosi, in quanto i due quinti dei malati accusano diversi ristagni di liquidi e di materiale semisolido in particolari "sacche" a livello della gengiva, superiore più tipicamente, definiti "pozzi gengivali"; questi, nella maggioranza dei casi, sono praticamente congeniti ed appaiono biancastri, molto rigonfi e doloranti al tatto. Essi si presentano sopra i denti, gli incisivi in particolare, che spesso sono influenzati nel loro sviluppo, essendo causa di difetti a carico della crescita completa della parte esterna del dente.

In ultima analisi, sembra esistere un importante correlazione tra la fibrosi cistica polmonare e la sclerosi tuberosa, fatto sta che le cisti alveolari, generalmente asintomatiche o con segni aspecifici relegati agli stadi più avanzati di esse, sono considerate un criterio diagnostico di consistente utilità laddove non si riscontri una causa organica ad esse, che nel caso della sclerosi tuberosa sarebbe imputabile ad una o più particolari e singolari mutazioni genetiche (non in molti casi, infatti, i responsabili sono i due geni di funzione proteica e connettiva trattati nel paragrafo relativo all'eziologia).

Certezze diagnosticheModifica

Un sintomo certo, ma solo a partire dagli otto anni di vita, è rappresentato dalla presenza di uno o più noduli subependimali: questo non significa che chi presenta noduli di questo genere sia necessariamente malato di sclerosi tuberosa; nella grande maggioranza dei casi, infatti, non è così: la certezza, al contrario, sta ad indicare che, passata l'età infantile, nessun individuo malato di sclerosi tuberosa è privo di noduli subependimali nel proprio organismo, quindi li possiede nel 100% dei casi se è malato;se questi sono totalmente assenti in un ragazzino, si ha la certezza diagnostica opposta, ovvero che il soggetto sicuramente è immune dalla sclerosi tuberosa.

EziologiaModifica

Dal punto di vista eziologico, due sono i geni coinvolti nell'insorgenza della malattia: il TSC1 - la cui probabile localizzazione è il braccio lungo del cromosoma 9 - e il TSC2[5], localizzato sul braccio corto del cromosoma 16. Il 68% dei casi di insorgenza della patologia è dovuto a una nuova e, quasi sempre, sporadica mutazione del DNA.

Signs and symptoms

Findings in TSC include the following:

  • Neurologic findings: Abnormal neurologic findings result from the location, size, and growth of tubers and the presence of subependymal nodules (SENs) and subependymal giant cell astrocytomas (SEGAs)
  • Cutaneous findings: The best-known cutaneous manifestation of TSC is adenoma sebaceum, which often does not appear until late childhood or early adolescence
  • Cardiac findings: Cardiac involvement is usually maximal at birth or early in life; it may be the presenting sign of TSC, particularly in early infancy; 50-60% of individuals with TSC have evidence of cardiac disease, mostly rhabdomyomas.
  • Ophthalmic findings: At least 50% of patients have ocular abnormalities; some studies have reported a prevalence as high as 80%; these lesions are actually retinal astrocytomas that tend to become calcified over time
  • Pulmonary findings: Prospective and retrospective studies have found cystic pulmonary abnormalities in as many as 40% of women with TSC
  • Renal findings: Renal manifestations of TSC are the second most common clinical feature; 4 types of lesions can occur: autosomal dominant polycystic kidney disease lesions, isolated renal cyst(s), angiomyolipomas (AMLs), and renal cell carcinomas
  • Dental findings: Pitting of the dental enamel is invariably present in the permanent teeth of patients with TSC [] ; gingival fibromas occur in 70% of adults with TSC, in 50% of children with mixed dentition (primary and permanent teeth), and in 3% of children with only primary teeth
  • Gastrointestinal findings: Hamartomas and polyposis of the stomach, intestine, and colon may occur
  • Hepatic findings: Hepatic cysts and hepatic AMLs, typically asymptomatic and nonprogressive, have been reported in as many as 24% of patients with TSC, with a marked female predominance (female-to-male ratio 5:1)
  • Skeletal findings: Sclerotic and hypertrophic lesions of bone may be found incidentally on radiography performed for other indications
  • History

    As with all of medical practice, recognizing a disease, let alone managing it appropriately, is impossible unless its diagnosis is first considered in a particular patient. While this may seem self-evident, in fact most physicians are only dimly, if at all, aware of TSC. This awareness usually extends only to the Vogt triad or to individuals with severe neurological morbidity. As many as 50% of people with TSC have normal intelligence, and increasingly the diagnosis is being newly made in adults with renal, cutaneous, or pulmonary manifestations.

    History should focus upon identification of specific signs and symptoms suggestive of or consistent with TSC. Particular symptoms occur at various points in the life span, and this serves as a framework for history taking.

    • Cardiac involvement is maximal in prenatal life or infancy.
    • Seizures, autism, and developmental delays present in infancy or childhood. Seizures are often not intractable, and many adult patients may no longer suffer from them or require anticonvulsants. Many will have been told that they had febrile convulsions or an age-related epilepsy syndrome.
    • Cutaneous manifestations such as ash leaf macules are often present from birth but frequently are unrecognized. More obvious lesions such as angiofibromas or shagreen patches usually appear in childhood to early adolescence.
    • Renal lesions can present as hypertension and renal failure in the case of polycystic kidney disease, usually in infancy or early childhood. AMLs manifest as flank pain, hematuria/retroperitoneal hemorrhage, or abdominal masses from childhood throughout adult life.
    • Pulmonary involvement typically occurs in the second or third decade, with dyspnea, pneumothorax, or chylothorax. It often is misdiagnosed as emphysema, particularly in those with a history of smoking.
    • Persons with dental involvement may have had their teeth sealed or bonded for pitting, or a gingival fibroma resected.

    Family history should center on identification of one or more of these manifestations in first- or second-degree relatives. Specific questioning is often necessary, as TSC lesions often are ascribed to other causes, eg, pulmonary involvement as emphysema, renal lesions as "atypical Wilms tumors," etc.

     

    Comprehensive diagnostic criteria were set out first by Dr. Manuel R. Gomez; they now exist in revised form as set forth in a consensus statement from the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association (USA). [] 

    Major features of TSC include the following:

    • Facial angiofibromas or forehead plaque
    • Nontraumatic ungual or periungual fibroma
    • Hypomelanotic macules (>3)
    • Shagreen patch (connective tissue nevus)
    • Multiple retinal nodular hamartoma
    • Cortical tuber: When cerebellar cortical dysplasia and cerebral white matter migration tracts occur together, they should be counted as one rather than two features of tuberous sclerosis.
    • Subependymal nodule
    • Subependymal giant cell astrocytoma
    • Cardiac rhabdomyoma, single or multiple
    • Lymphangioleiomyomatosis: When both lymphangioleiomyomatosis (LAM) and renal AMLs are present, other features of tuberous sclerosis should be present before a definite diagnosis is assigned. As many as 60% of women with sporadic LAM (and not TSC) may have a renal or other AMLs.
    • Renal AML: When both LAM and renal AMLs are present, other features of tuberous sclerosis should be present before a definite diagnosis is assigned (see previous remarks).

    Minor features of TSC include the following:

    • Multiple randomly distributed pits in dental enamel [] 
    • Hamartomatous rectal polyps: Histologic confirmation is suggested.
    • Bone cysts: Radiographic confirmation is sufficient.
    • Cerebral white matter radial migration lines: Radiographic confirmation is sufficient. One panel member felt strongly that 3 or more radial migration lines should constitute a major sign.
    • Gingival fibromas
    • Nonrenal hamartoma: Histologic confirmation is suggested.
    • Retinal achromic patch
    • "Confetti" skin lesions
    • Multiple renal cysts

    The following are the diagnostic criteria for TSC:

    • Definite TSC - Two major features or one major feature plus two or more minor features
    • Possible TSC - Either one major feature or two or more minor features

    Molecular genetic testing is now commercially available in the United States through several companies, including Athena Diagnostics. Testing through Athena was extended to include screening for large deletions and other types of mutations, to improve their diagnostic yield.

    • Under optimal circumstances, genetic testing identifies mutations in up to 75-80% of affected individuals. Therefore, a negative genetic diagnostic test result does not exclude a diagnosis of tuberous sclerosis.
    • Diagnosis should be possible in most cases using established clinical criteria. Molecular genetic testing is useful in uncertain or questionable cases, for prenatal diagnosis, and for screening family members of an affected individual. The utility of molecular diagnostic testing is limited by the cost (approximate self-pay costs of $3300 to provide deletion analysis and DNA sequencing for TSC1 and TSC2 index cases, and $450 for confirmatory testing in family members). Costs are frequently not covered by private insurance carriers. Patient assistance programs may be available through various laboratories.
     
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