Tuberous sclerosis - Europe PMC

*CL,INICAL

OBSERVATIONS

Tuberous sclerosis: case report and investigation of family members R. Douglas Wilson, MD, MSc, FRCSC Judith G. Hall, MD, MS, FAAP, FRCPC, FCCMG Barbara C. McGillivray, MD, BSc, FRCPC, FCCMG

Familial tuberous sclerosis probably occurs more often than is indicated by the literature: many family mem-bers show signs of being carriers of the gene for the disease when carefully examined. This article reports on a family with documented tuberous sclerosis in three generations and discusses the examination and investigation of at-risk family members, including the newborn, for signs of the disease. The potential teratogenic effects of anticonvulsants, used to control seizures in tuberous sclerosis, are also discussed. La transmission familiale de la sclerose tubereuse de Bourneville doit Wtre plus frequente que ne le suggere la litterature, car l'investigation approfondie revele souvent des indices d'un etat de porteur de gene dans la parente. On rapporte ici une famille montrant des cas confirmes de sclerose tubereuse sur trois generations. On decrit l'examen et l'exploration du sujet a risque y compris le nouveau-ne. On rappelle la possibilite d'un effet teratogene des anticonvulsivants utilises dans cette maladie. Tuberous sclerosis is an autosomal dominant disorder with wide variFrom the Department of Medical Genetics, University of British Columbia, Grace Hospital, Vancouver Reprint requests to: Dr. R. Douglas Wilson, University of British Columbia Clinical Genetics Unit, 4490 Oak St., Vancouver, BC V6H 3V5 -

For prescribing information see page 877

ability in expression. The classic triad of seizures, mental retardation and angiofibroma represents the severe end of the spectrum. Mildly affected carriers of the gene are difficult to detect. We report documented familial tuberous sclerosis in three generations of one family and discuss how examination and investigation of first-degree relatives (including the newborn) of affected individuals can help differentiate between familial and sporadic cases.

and her only child had died, the diagnosis being sudden infant death syndrome. Before the patient's last pregnancy her seizures had been controlled by phenobarbital and phenytoin. Pregnancy was diagnosed at 12 weeks, and at that time the patient

cy,

Case report

The patient was a 24-year-old white woman with one child and a history of two spontaneous abortions. At age 10 tuberous sclerosis had been diagnosed. She suffered from focal akinetic seizures and had low-normal intelligence. Physical examination revealed angiofibromas on her chin and lower lip, numerous phakomas (astrocytic hamartomas of the retina) in both eyes (Fig. 1) and many caf6-au-lait spots on her skin. X-ray films of her skull showed areas of calcification superimposed over the parietal region. A skeletal radiologic survey demonstrated cortical thickening of the lateral aspect of the proximal phalanx of the left index finger. There was a family history of tuberous sclerosis (Fig. 2), with mother and brother as well as a deceased older sister being affected. The maternal grandmother was possibly affected, as she had hypertension, late-onset diabetes mellitus and epilepsy. The clinically unaffected sister had not undergone computed tomography (CT) scanning; however, she and the brother showed evidence of the adrenogenital syndrome caused by 21-hydroxylase deficien-

Fig. 1 -Calcified astrocytic hamartoma of the retina.

C Tuberous Sclerosis Adrenogenital Syndrome Infant Death Syndrome Sudden *

(

Fig. 2-Pedigree of family with documented tuberous sclerosis in three generations. The numeral 2 indicates two spontaneous abortions, the outcome of matings with a partner other than the father of the affected child.

CAN MED ASSOC J, VOL. 132, APRIL 1, 1985

807

discontinued oral contraceptives and the phenytoin. She was admitted to hospital 8 weeks later because of an increasing frequency of seizures, as well as psychiatric problems related to disturbances of perception. Anticonvulsant medications, which included valproic acid (500 mg twice daily) and carbamazepine (200 mg twice daily), were prescribed, and phenobarbital administration (60 mg twice a day) was continued. In addition, 2 mg of fluspirilene was given intramuscularly once a week to control the psychiatric disturbance. She took the anticonvulsant medications irregularly, however, and discontinued them at 32 weeks of pregnancy. The patient underwent seven ultrasound examinations during the pregnancy. Fetal growth appeared normal until 37 weeks' gestation, when it was noted that, although the trunk and femur were the sizes expected, the head was the size expected at 32 weeks. No other abnormalities were detected. At 38 weeks of pregnancy the patient was admitted to hospital with hemorrhage due to marginal placental separation. Labour began spontaneously at 39 weeks, and a 3340-g boy with Apgar scores of 1 at 1 minute and 10 at 5 minutes was delivered vaginally. The patient then underwent tubal ligation. The infant had no dysmorphic features, but his head circumference was between the 10th and the 25th percentiles for his age. Wood's lamp examination revealed no depigmented areas or caf6-au-lait spots, and no angiofibromas were noted. However, an astrocytic hamartoma was observed in his right retina - a finding sufficient for a diagnosis of tuberous sclerosis. At 5 months of age CT scanning of the cranium showed widespread evidence of tuberous sclerosis involving the left parietal lobe and both frontal lobes, with multiple calcified subependymal nodules distorting the lateral ventricles (Fig. 3). The electroencephalogram (EEG) was dominated by high-voltage, generalized bursts of typical spike and spike/ slow-wave activity. This was a severe change from the pattern at age 4 days. Echocardiography showed a small, nonobstructing rhabdomyoma on the septal surface of the left 808

ventricle. Ultrasound images of the kidney were normal. Wood's lamp examination showed two small areas of depigmentation in the right scapular area. The ophthalmologic findings were similar to those at birth. Discussion The incidence of tuberous sclerosis is 1 in 30 000 births.' There is no known geographic, ethnic or gender predilection.2 The systems involved vary, depending on sex, with female patients more commonly exhibiting lung involvement,3 but because of selection biases in the studies done, the incidence of involvement of the various systems is not known. The recorded incidence reflects only patients with blatant signs and symptoms. If individuals who are mildly affected were considered the rate might be much higher.4 Tuberous sclerosis has been thought to be caused by a new mutation in 86% of cases.4,5 However, affected family members previously thought to be unaffected have been identified in 30% to 45% of families with this disease.6,7 Cassidy and colleagues7 recommended the following diagnostic examinations (in order of decreasing sensitivity) in cases of suspected tuberous sclerosis: 0 Detailed skin examination, including a search for facial angiofibromas, hypopigmented patches and a shagreen patch with the aid of a Wood's lamp.

Fig. 3A-Computed tomography (CT) scan showing distortion of lateral ventricles by multiple subependymal nodules, some of which are calcified.


* Examination of the nailbeds and digits, in a search for subungual and periungual fibromas causing altered nail shape. * Cranial CT scanning, in a search for intracranial calcifications, usually located periventricularly, and soft-tissue masses. * Radiologic examinations of the skull, hands and feet, in a search for intracranial calcification, visible interosseous densities of the cranium, and cortical cysts or bone formation along the shaft of the metatarsals or

metacarpals. * Ophthalmoscopic examination with the pupils dilated, in a search for retinal astrocytic hamartomas or hypopigmented choroidal defects. * Ultrasound examination or excretory urogram, in a search for multiple cysts of one or both kidneys or a hyperechogenic intrarenal mass

(angiomyolipoma). We feel that the examination of at-risk newborns should follow this protocol but should include echocardiography because rhabdomyomas (single or multiple), sometimes asymptomatic, often develop in infants with tuberous sclerosis and usually lead to death during the first year of life.8 Follow-up cardiac ultrasound scans when the child is 6 months and 1 year old are recommended. Hypopigmented patches occur in 15% to 85% of cases of tuberous sclerosis2 and may be present at birth. Angiofibromas, which are reddish-brown papules approximately 4

Fig. 3B-CT scan at a higher level, showing irregular brain tissue in the frontal lobes bilaterally and in the left posterior parietal lobe.

mm in diameter occurring in a butterfly distribution and occasionally on the chin, usually appear between ages 2 and 8 years but may be present at birth.2 They increase in size and number during pregnancy. A shagreen patch, which is a slightly raised, flesh-coloured, leathery plaque in the lumbosacral area, usually appears during childhood. It is present in 70% to 80% of adults with tuberous sclerosis and in 21% of children;9 it also may be noted at birth and perhaps has not been looked for enough in children. The child's skin should be re-examined at 6 months, 1 year and 2 years of age. By repeated Wood's lamp examination at age 5 months the infant in this report was shown to have two small depigmented areas not seen at birth. Cranial CT or ultrasound scanning may identify cerebral nodules, which have been shown by autopsy to be present as early as 28 weeks' gestation.10 Ultrasound examination of the newborn's cranium is easy because of the open fontanelle. Calcification increases with time, and, although cranial calcification has been found periventricularly in children, the cortical calcifications typical in adults have not been seen in children.2 Thus, repeat scans may be necessary at 6 months, 1 year and 2 years of age. At age 5 months the infant in this report showed calcified subependymal nodules. Unfortunately, CT scanning had not been done at birth. At birth, ocular abnormalities may be seen in as many as 52% of affected individuals.2 The characteristic lesion is a retinal astrocytic hamartoma at the posterior pole or in the juxtapapillary region;2 it is usually obvious at birth and has been reported as early as 3 months' gestation.9 Other ocular lesions have been described,2 but only retinal hamartomas are clearly a part of the syndrome.9 The finding of a retinal hamartoma in the newborn in this report confirmed the diagnosis of tuberous sclerosis. The renal lesions of tuberous sclerosis increase in size and number with age,2 but tumours or cysts have been noted in the kidneys of infants with tuberous sclerosis in the first week of life." No renal lesions were identified in the autopsy material of

a 28-week-old fetus'0 or by ultrasound scanning in the 5-month-old child in this report. The typical lesion is an angiolipoma, most frequently multiple and bilateral, and is found in 50% to 80% of patients with tuberous sclerosis. Tuberous sclerosis has been diagnosed prenatally through identification of cardiac tumours in the fetus of an affected father.'2 The tumours were obvious at 22 weeks' gestation, although an ultrasound scan at 18 weeks had shown no abnormalities. The pregnancy was terminated, and at autopsy the fetus was confirmed to have tuberous sclerosis. Rhabdomyomas have also been shown at autopsy in fetuses at 28 and 32 weeks' gestation and in newborns within the first week of life.'0"' In the case we have reported, ultrasound examinations were undertaken prenatally, but no cardiac rhabdomyoma was apparent until the child was 5 months old. Seizures are the most common initial complaint in children with tuberous sclerosis, and they occur in all affected patients who are mentally retarded, though not all patients with tuberous sclerosis and seizures are retarded.2 Mental retardation is common when tuberous sclerosis is diagnosed in childhood, occurring in 60% to 85% of the patients. In most cases the seizures begin early in life and become more frequent and severe, although occasionally there is a spontaneous remission. Many patients with tuberous sclerosis have a history of spasms in infancy. Monaghan and associates2 reported seizures in 81% of the 62 children with tuberous sclerosis in their study. Of the group experiencing seizures, 42% had a history of infantile spasms. Seizures among women with tuberous sclerosis greatly increase the risks to offspring. First, the risk of transmission of the gene for tuberous sclerosis is 50%, though the severity of expression is not predictable. Second, the teratogenic effects of anticonvulsant medications used during pregnancy have been documented;'3 they include craniofacial anomalies (cleft lip and palate), cardiac defects, limb defects and retarded growth. Ultrasound examination during the second trimester of pregnancy should show these abnor-

malities as well as those expected in a fetus with tuberous sclerosis. Amniocentesis to detect a-fetoprotein should be offered to patients using the anticonvulsant valproic acid because of the increased risk of a neural tube defect in the exposed fetus. 14 For women with tuberous sclerosis and seizures who are liable to become pregnant, physicians should consider anticonvulsant medications and dosages that minimize the risks of teratogenic effects. References 1. Lagos JC, Gomez MR: Tuberous sclerosis: reappraisal of a clinical entity. Mayo Clin Proc 1967; 42: 26-49 2. Monaghan HP, Krafchik BR, MacGregor DL et al: Tuberous sclerosis complex in children. Am J Dis Child 1981; 135: 912-917 3. Dwyer JM, Hickie JB, Garvan J: Pulmonary tuberous sclerosis: report of three patients and a review of the literature. Q J Med 1971; 40: 115-125 4. Rattan PK, Knuppel RA, Scerbo JC et al: Tuberous sclerosis in pregnancy. Obstet Gynecol 1983; 62 (suppl 3): 21s-22s 5. Bundey S, Evans K: Tuberous sclerosis: a genetic study. J Neurol Neurosurg Psychiatry 1969; 32: 591-603

6. Fleury P, de Groot WP, Delleman JW: Tuberous sclerosis: the incidence of sporadic cases versus familial cases. Brain Dev 1979; 2: 107-117 7. Cassidy SB, Pagon RA, Pepin M et al: Family studies in tuberous sclerosis: evaluation of apparently unaffected parents. JAMA 1983; 249: 1302-1304 8. Diamant S, Sharaz J, Holtzman M et al: Echocardiographic diagnosis of cardiac tumors in asymptomatic tuberous sclerosis patients. Clin Pediatr (Phila) 1983; 22: 297-299 9. Bender BL, Yunis EJ: The pathology of tuberous sclerosis. Pathol Annu 1982; 1: 339-382 10. Sharp D, Robertson DM: Tuberous sclerosis in an infant of 28 weeks' gestational age. Can J Neurol Sci 1983; 10: 59-62 11. Ostor AG, Fortune DW: Tuberous sclerosis initially seen as hydrops fetalis. Arch Pathol Lab Med 1978; 102; 34-39 12. Crawford DC, Garrett C, Tynan M et al: Cardiac rhabdomyomata as a marker for the antenatal detection of tuberous sclerosis. J Med Genet 1983; 20: 303-312 13. Dalessio DJ: Neurologic disease. In Burrows GN, Ferris TF (eds): Medical Complications During Pregnancy, 2nd ed, Saunders, Philadelphia, 1982: 438-439 14. Valproate and malformations [E]. Lancet 1982; 2: 1313-1314


809