Hum. Genet. 36, 243--247 (1977)

© by Springer-Verlag 1977

Autosomal Recessive Microcephaly Associated with Chorioretinopathy

J. M. Cantd 1., J. A. Rojas 2, D. Garcia-Cruz 2, A. Hernindez 2, P. Pag~in 2, R. Fragoso 2, and C. Manzano 2

t Unidad de Investigaci6n Biom6dica de Oecidente del I.M.S.S., Apartado Postal 1--3838, Guadalajara, Jal., Mexico

2 Divisi6n de Gen6tica y Hematologia, Unidad de Investigaci6n Biom6dica de Occidente, Centro M6dico Oblatos del I.M.S.S., Guadalajara, Jal., Hospital de Pediatria del Centro M6dico Nacional del I.M.S.S. y Hospital Psiqui~itrico Infantil "Dr. Juan N. Navarro", S.S.A., M6xico, D. F., M6xico

Summary. Two sisters and their brother affected with microcephaly, micro- phthalmia, chorioretinal degeneration, and optic atrophy were studied. Be- sides the clinical features derived from the main abnormalities, nanosomy and cutis marmorata were found in the three patients. Both parents and three other sibs were normal. Possible intrauterine non-genetic etiologic factors (X- rays, toxoplasmosis, cytomegalovirus) which can lead to phenocopies were investigated with negative results. Based on these and previous observations, it seems clear that a distinct form of autosomal recessive microcephaly associated with chorioretinal degeneration can be separated from the hetero- geneous group of entities which presents microcephaly.

Introduction

Microcephaly is a heterogeneous state (Cowie, 1960), which can be caused by a variety of environmental and hereditary factors and can be present either as a single malformation or as a part of multiple malformation syndromes (Holmes et al., 1972). In 1966, McKusick et al. described 8 cases of microcephaly observed in two sibships of an inbreed group. In addition to the usual features of micro- cephaly they also found patchy, localized retinal pigmentations and choroidal atrophy in all affected individuals suggesting an entity different from simple autosomal recessive microcephaly.

The purposes of this report are to describe three siblings with microcephaly and chorioretinopathy and to discuss the etiology of this disorder in relation to other known microcephalic syndromes. The definite individualization of this auto- somal recessive disorder is concluded.

* To whom offprint requests should be sent.

244 J .M. Cantti et al.

| 2

i r-1 ©.

II

Fig. 1. Pedigree. Solid symbols: affected. Arrow: Proposita

Fig. 2 A - - C . General frontal view of the patients. (A) The proposita; (B) Brother 11-3; (C) Sister 11-7. Note the cutis marmorata in the three patients

C a s e R e p o r t s

The proposita (II-1 in Fig. 1, Fig. 2A) was the product of a full term pregnancy and un- complicated delivery. Birth weight and length were not recorded. Microcephaly and delayed growth and development were noted since early infancy. Progressive visual deficiency became evident during childhood. At 10 years of age, when she was first examined, she was found to be nanosomic and mentally deficient (Table 1). Cutis marmorata was present practically over the entire body.

Ophthalmologic Studies. Visual acuity could not be measured because of the mental retard- ation. The girl was able to follow big objects and her walking was insecure. The abnormal findings in the eye were: Horizontal nystagmus, microphthalmos, microcornea (9ram in diameter), pale and atrophic disks, thin veins and arteries, diffuse fine pigmentation of the fundus with scattered large clumps of pigment and large areas of retinal degeneration.

Microcephaly and Chorioretinopathy

Table 1. Clinical quantitative data

245

Case Proposita (II-1) Brother (II-3) Sister (I1-7)

Age (years) 10 6 4/12

Height (cm) 121.3 (2.4) a 100.9 (3.2) a 57.1 (2.3) a

Weight (kg) 18.0 (3.2) a 13.2 (3.6) a 3.3 (5.4) a

Cephalic circumference (cm) 43.0 (7.1) a 41.0 (7.1) a 35.0 (4.5) a

Upper/lower segment ratio 1.04 b 1.15 b 1.39 (61.9/59.4) (54.0/46.9) (33.2/23.9)

IQ 40 43

a SD below the normal mean b More than two SD below the normal mean for age, but within normality for height (accord- ing to data from Ramos Galv~in, 1975)

X-ray examination revealed all cranial diameters diminished and cranio-facial dispropor- tion. No calcifications were observed. Bone and chronological ages were concordant. The waking stage EEG showed very low voltage of the cortical and subcortical activities in all leads without focal signs. The IgM fluorescent antibody test for toxoplasmosis and the study of urine sediment for intranuclear inclusion bodies to discard congenital cytomegalovirus infection were negative.

Laboratory studies including blood cell count, blood and urine analysis, serum proteins by electrophoresis, screening tests for metabolic defects (Ferric chloride, DNPH, Benedicts, nitroprusside-cyanide, mucopolisaccharides by turbidometric method), urinary excretion 0fa- aminonitrogen, plasmatic aminogram (using a Beckman aminoacid analyzer model 120-C), thyroid function tests, X-chromatin and karyotype were normal or negative.

A brother (II-3 in Fig. 1, Fig. 2 B) and a sister (II-7 in Fig. 1, Fig. 2 C) were found to have the same clinical manifestations (Table 1), although less severe. Ophthalmologic, roentgenologic, and electroencephalographic findings were basically the same as those of the proposita. The tests performed to discard toxoplasmosis and cytomegalovirus infection were also negative. The hemaglutination inhibition test for rubella in II-7 and in the mother (I-2 in Fig. 1) were found to be positive, but no clinical manifestation of the infection was ever noted. Other laboratory examinations were normal or negative in both affected sibs.

The parents and three other sibs were normal and did not show curls marmorata. The mother has never been exposed to diagnostic X-rays. No antecedent of consanguinity could be definitely ascertained; however, both parents were born in the same village (population 500) and two of their grandparents had the same unusual last name. The family was Mexican Catholic and no evidence of interbreeding with Amish populations could be found. Other family data were irrelevant for this study.

Discussion

T h e c l in ica l a g g r e g a t e o b s e r v e d in these pa t ien ts m a i n l y consis ts o f m i c r o c e p h a l y ,

m i c r o p h t h a l m i a , r e t ina l p igmen ta t i ons , c h o r o i d a l and opt ic a t rophy . The mic ro - c epha ly a n d the a b n o r m a l E E G suggest e n c e p h a l o d y s p l a s i a wh ich cou ld e x p l a i n

the m e n t a l de f ic iency in the pa t ien ts . The v isua l def ic iency can be re la ted to the

o p h t h a l m o l o g i c a b n o r m a l i t i e s and the n y s t a g m u s to the encepha lodysp l a s i a . The

p r o p o r t i o n a t e n a n o s o m y , wh ich seems to be c o n g e n i t a l s ince the f o u r - m o n t h - o l d

pa t i en t was a l r e a d y t w o S D b e l o w the n o r m a l he igh t and we igh t means , does no t

246 J.M. Cantfi et al.

seem to be a specific feature of the syndrome since it is observed in other micro- cephalic conditions (Holmes et al., 1972). Cutis marmora ta is a consistent characteristic in these patients since the unaffected relatives did not show it, although its significance remains unestablished.

The presence of affected members of both sexes, the absence of the syndrome in other relatives, and the probable parental consanguinity suggest an autosomal recessive pattern of inheritance.

Some etiopathogenic considerations are pertinent to this study since pheno- copies related to intrauterine infection by cytomegalovirus and toxoplasmosis have seen observed (Holmes et al., 1972).

Although the antibody test for rubella was positive in case II-7 and in the mother, the finding is insignificant since the probability of being positive is 0.96 (Guti6rrez et al., 1970). Since the mother has never been exposed to X-rays, that etiology which has been associated with simple microcephaly (Wood et al., 1967) seems unlikely.

A similar disorder with microcephaly was described by McKusick et al. (1966) in 8 cases f rom two sibships, both with parental consanguinity. Their patients had microphthalmia, chorioretinal dysplasia, and somewhat small and pale optic disks. They also showed high-grade hyperopia, which could not be ascertained in our patients because of the mental deficiency, but could be probable because of the microphthalmia. Cutis marmora ta was not informed in their cases. The analysis of these patients together with those here reported permits the individu- alization of an autosomal recessive disorder characterized by microcephaly and chorioretinopathy.

Schmidt et al. (1967) have described a girl and her two brothers affected with microcephaly and atypical tapetoretinal degeneration. However, they also showed mongoloid palpebral slits and the proposita presented other multiple abnormalities including ichthyosis. Possibly the syndrome observed in that family could be the same as the one reported here. The associated anomalies observed in their proposita could be fortuitous phenomena, since they were not present in her two brothers.

It can be concluded f rom the present observations that a distinct autosomal recessive syndrome expressed by microcephaly, mental retardation, microphthal- mia, chorioretinal pigmentation, nanosomy, and probably cutis marmora ta can be separated from the heterogeneous group of entities showing microcephaly. It is advisable to keep this disorder in mind when studying newborns with micro- cephaly and chorioretinal degeneration, since recurrence risks could be either 1/4 or almost null in genetic or environmental circumstances respectively.

This work was partially supported by a grant from the Ford Foundation. We thank Dr. P. Alemgn, O. Angulo, A. Martucelli, F. Resano, J. Ruiz-G6mez, and C. Strecker for their help in the clinical and laboratory studies. The secretarial assistance of Mrs. Natalia Guill6n is gratefully acknowledged.

References

Cowie, V.: The genetics and sub-classification of microcephaly. J. Ment. Defic. Res. 4, 42--47 (1960)

Microcephaly and Chorioretinopathy 247

Guti6rrez, G., Ruiz-G6mez, J., Velasco-C~indano, L., Brtiggemann, C.: Investigaci6n de anti- cuerpos antirubeola en la poblaci6n infantil y en mujeres adultas en la ciudad de M6xico. Arch. Inv. Med. (Mex.) 1, 63--70 (1970)

Holmes, L. B., Mack, C., Moser, H. W., Pant, S. S., Halldorsson, S., Matzilevich, B.: Mental retardation. In: An atlas of diseases with associated physical abnormalities, pp. 117 143, 196. New York: Macmillan 1972

McKusick, V. A., Stauffer, M., Knox, D. L., Clark, D. B.: Chorioretinopathy with hereditary microcephaly. Arch. Ophthal. 75, 597 600 (1966)

Ramos-Galv~in, R.: Somatometrla pedi~itrica: Estudio semilongitudinal en nifios de la ciudad de M6xico. Arch. Inv. Med. (Mex.) 6 (Suppl. 1) 83--396 (1975)

Schmidt, B., Jaeger, W., Neubauer, H.: Eine Mikrozephalie mit atypischer tapetoretinaler De- generation bei 3 Geschwistern. Klin. Mbl. Augenheilk. 150, 188--196 (1967)

Wood, J. W., Johnson, K. G., Omori, Y.: In utero exposure to the Hiroshima atomic bomb. An evaluation of head size and mental retardation: Twenty years later. Pediatrics 39, 385--392 (1967)

Received December 16, 1976