Develop. Med. Child Neurol. 1967, 9,493-505

Annotations

CHANGING CONCEPTS OF TUBEROUS SCLEROSIS TUBEROUS sclerosis has long been defined as a triad of epilepsy, adenoma sebaceum and mental retardation, but recent reports indicate that the disease encompasses a broader complex of symptoms. When seizures occur they are often atypical; infantile spasms with hypsarythmia are particularly common.ls* l3 The skin lesions include not only adenoma sebaceum but also depigmented or hyperpigmented patches, rough fibrous thickenings called ‘shagreen’ and characteristic periungual warts.2 As has been known for years, even the term adenoma sebaceum is itself a partial misnomer since typical nodules are composed of fibrous and vascular tissue as well as glandular structures. Finally LAGOS and G O M E Z ~ ~ have recently reported that 26 out of 71 patients with tuberous sclerosis who were seen at the Mayo Clinic from 1935 to 1964 were of ‘average’ intelligence.

The Mayo Clinic survey is unique not only because of its size but also because all earlier series, even the definitive article by CRITCHLEY and EARL’ in 1934, considered only institu- tionalized patients. Other cases of tuberous sclerosis with normal intelligence have been reported,6* lo, l7, but the possibility of a forme fruste in this diseasex2 has not been sufficiently appreciated. In the Mayo Clinic study the patients with normal intelligence were usually afflicted with seizures or intracranial calcification, indicating that average intelligence did not imply absence of brain damage.

LAGOS and GOMEZ also confirmed the lack of a relationship between von Reckinghausen’s disease and tuberous sclerosis. Despite the lack of any genetic overlap in the two syndromes’, it is still convenient to lump them both as ‘phakomatoses’. This term derived from the Greek phakos meaning ‘motherspot’ or ‘birth mark’,18 seems particularly suitable for disease that may be related to cell rests or defects in cellular migration.

Three crucial questions in tuberous sclerosis remain unanswered, (1) What is the incidence of mild forme fruste cases; and may these present as isolated conditions such as brain tumors, retinal driisen, chronic pulmonary disease, or visceral tumors ?; (2) What triggers or permits the growth of tumors in almost all visceral organs, tumors that apparently involve almost any type of ce1116?; (3) What is responsible for the variety of seizure patterns, and is there any direct association between the location or biochemistry of the brain lesions and the presence of seizures? Careful family studies provide one approach to the solution of these questions and may eventually permit the delineation of additional genetic hetero- geneity in the phakomatoses. Most authors currently subscribe to the view that the disease is inherited in a dominant pattern and that modifier genes act to alter expressivity.’. 4, ‘ 9

The possibility remains that two or more independent mutations may give rise to disorders which are as yet clinically indistinguishable. When two investigators can report 7 1 patients with tuberous sclerosis, and another author reports the urologic complications of 47 other cases6 there is ample clinical material for definitive genetic studies to be performed.

493

DEVELOPMENTAL M E D I C I N E AND CHILD NEUROLOGY. 1967, 9

In dealing with the classic manifestations of the disease the physician may have a respon- sibility that includes more than making a distressing diagnosis. The expanding brain tumors are characteristically located near the foramen of Monro,9 and often respond quite well to surgery.” I t is possible that the neuronal cortical nodules are more likely than other scars or brain tumors to lead to seizures. In some cases epileptogenic cortical foci have been successfully removed with a great reduction in the frequency of seizure^.'^ These developments increase the possibility of investigations being done on protein and nucleic acid synthesis, a s well a s cytogenetic studies, in one of the few disorders in which multiple tumors are available for biopsy and study.

Regardless of new directions in laboratory or clinical research, and despite the broader definition of the tuberous sclerosis complex, until genetic and biochemical insights are obtained, reviewers of the voluminous literature are sure to end up, like many of their predecessors, with only amazement at the variety of manifestations of tuberous sclerosis and puzzlement as to its pathogenesis.

3957 Lytham Court, GEORGE PAULSON Columbus, Ohio 73210, U.S.A.

REFERENCES I . Borberg, A. (1951) ‘Clinical and genetic investigations into tuberous sclerosis and Recklinghausen’s

neurofibromatosis: contribution to the elucidation of inter-relationship and eugenics of syndromes. Acttr ps~~chictt. scutrd., suppi. 7 1.

2. Butterworth, T., Wilson, M. (1941) ‘Dermatologic aspects of tuberous sclerosis.’ Arch. Dernz. Syph. (Chic.), 43, I .

3. Critchley, M., Earl, C. J . C . (1932) ‘Tuberose sclerosis and allied conditions.’ Brain, 55, 311. 4. Dickerson, W. W. (1951) ’Familial occurrence of tuberous sclerosis.’ Arch. Neirrol. Psychiut. (Chic.),

5. Duvoisin, R. C., Vinson, W. M. (1961) ‘Tuberous sclerosis: report of three cases without mental

6. Golji, H. (1961) ’Tuberous sclerosis and renal neoplasms.’ J . Urol., 85, 919. 7 . Gunther, M., Penrose, L. S. (1935) ‘Genetics of epiloia.’ J. Getref., 31,413. 8. Kapp, J . P., Paulson, G. W., Odom, G. L. (1967) ‘Brain tumors with tuberous sclerosis.’J. Neurosiirg.,

9. Kessel, F. K. ( 1949) ‘Some radiological and neurosurgical aspects of tuberous sclerosis.’ Acta psychiat.

10. Kofman, O., Hyland, H. H . (1959) ‘Tuberous sclerosis in adults with normal intelligence.’ Arch

11. Lagos, J . C., Gomez, M . R. (1967) ‘Tuberous sclerosis: reappraisal of a clinical entity.’ Proc.

12. Marshall, D., Saul, G. B., Sachs, E. (1959) ‘Tuberous sclerosis: a report of 16 cases in two family

13. Paulson, G. W., Lyle, C. B. (1966) ‘Tuberous sclerosis.’ Develop. Med. Child Neirrol., 8, 571. 14. Perot, P., Weir, B., Rasmussen, T. (1966) ‘Tuberous sclerosis. Surgical therapy for seizures.’ Arch.

15. Reed, W. B., Nickel, W. R., Campion, G. (1963) ‘Internal manifestations of tuberous sclerosis.’ Arch.

16. Rovere, M . della, Hoare, R . D., Pampiglione, G. (1964) ‘Tuberous sclerosis in children: an EEG study.’

17. Scheig, R. L., Bornstein, P. (1961) ‘Tuberous sclerosis in the adult. An unusual case without mental

18. Schnitzer, B. (1963) ‘Tuberous sclerosis complex. Report of a 62-year-old patient who died of renal

19. Van der Hoeve, J. (1932) ‘The Doyne memorial lecture: Eye symptoms in phakomatosis.’ Trans.

65, 683.

defect.’ J . Auier. merl. Ass., 175, 869.

26, 191.

scand., 24, 499.

Neitrol. Psychiat. (Chic.), 81, 43.

Mayo Clin., 42, 26.

trees revealing genetic dominance.’ New Engl. J . Melt., 261, 1102.

Neurol. (Chic.), 15, 498.

Derm. (Chic.), 87, 715.

Develop. Med. Child Neurol., 6, 149.

deficiency or epilepsy.’ Arch. intern. Med. (Chic.), 108, 789.

involvement.’ Arch. Path., 76, 626.

ophthal. SOC. U.K., 52, 380.

PARENTAL AWARENESS OF RETARDATION THE problem of acceptance by parents of a child’s mental subnormality has wide implica- tions. Great importance lies in the ability to realise the child’s handicap in terms of educa- bility and training. The acceptance of such limitations will avoid much frustration and

494