Hum Genet (1985) 69:243-245
A distinct dysmorphic syndrome with spinocerebellar ataxia and probable autosomal recessive inheritance
J. S~inchez-Corona, D. Garcia-Cruz, A. Gonz~ilez-Angulo, M. C. Alvarez-Arratia, R. M. Rodriguez, and J. M. Cantu
Divisi6n de Gen6tica, Subjefatura de Investigacidn Cientffica, Unidad de Investigacfon Biomddica, Centro M6dico de Occidente, Instituto Mexicano del Seguro Social, Apartado Postal 1-3838, Guadalajara, Jalisco, Mexico
Summary. Two brothers and their sister aged 8, 13, and 7 years were found to have unusual facies (gross, rough and abundant hair, wide forehead, mild palpebral ptosis, small nose, anteverted nostrils, thick lips, and down-slanting corners of the mouth), dysarthria, delayed psychomotor development, scoliosis, feet deformities, and limb and gait ataxia. The characteristic clinical picture in the three sibs, once compared with other ataxic syndromes, allowed one to conclude that this could correspond to a distinct entity prob- ably inherited as an autosomal recessive disorder.
The hereditary ataxias constitute a heterogeneous group of about 50 degenerative disorders of the central nervous system, some of which have as common features limb and gait ataxia and dysarthria (Boyer et al. 1962; Konigsmark and Weiner 1970; McKusick 1983; Pedersen 1980; Pedersen et al. 1980). The purpose of this report is to delineate a probably "new" hereditary syndrome with ataxia observed in three sibs.
Clinical and family data
Case A. The 8-year-old propositus (III-12 in Fig. 1) was the product of the fifth full-term uncomplicated pregnancy and normal delivery. Birthweight was 4100 g. Delayed psycho- motor development was evident early, mainly in speech and walk (beginning at 18 and 24 months, respectively); reeling gait and scoliosis were noted at 3 years of age. Physical exami- nation at 8 years of age (Fig. 2) revealed a height of 111 cm (below the 3rd percentile), cephalic perimeter of 54 cm (be- tween the 90th-97th percentiles), dolichocephaly, mild macro- cephaly, gross, rough and abundant hair, wide forehead, mild palpebral ptosis, epicanthal folds, horizontal nystagmus, small nose, anteverted nostrils, thick lips, down-slanting corners of mouth, and slightly low-set ears. The neurologic evaluation revealed hypotonia, mild optic atrophy, dysarthria, limb and gait ataxia, diminished deep tendon reflexes, and Babinski's and Romberg's signs.
Offprint requests to: J. Sgmchez-Corona, Divisi6n de Gen6tica, Sub- jefatura de Investigaci6n Cientffica, Unidad de Investigaclon Bio- m6dica, Centro Mddico de Occidente, Instituto Mexicano del Seguro Social, Apartado Postal 1-3838, Guadalajara, Jalisco, Mexico
Case B. The propositus' sister (III-13 in Fig. 1 and Fig.2), aged 7 years, was the product of the sixth full-term uncompli- cated pregnancy and normal delivery. Birthweight was 3300 g. Her psychomotor development was also delayed. The clinical and neurologic findings were similar to those of her brother, except for the presence of plano-varus foot deformity in this case (Table 1).
Case C. The propositus' brother (III-11 in Fig. 1 and Fig. 3a,b), aged 13 years, was the product of the fourth full- term uncomplicated pregnancy and normal delivery, with a birthweight of 3100 g. He also had delayed psychomotor development of early onset. The physical examination was similar to Cases A and B except for normal height and normal ears (Table 1).
The cardiologic evaluation did not show any abnormality in the sibs. The laboratory examination in the three cases, in- cluding blood cell count, blood and urine chemistries, serum copper determination, screening tests for metabolic defects (Phenistix, glucose oxidase, Millon, ferric chloride, anthrone, DNPH, nitrosonaphthol, acid albumin turbidity, CTA, methylmalonic acid, Benedict, and cyanide nitroprusside), X chromatin, and karyotype (G-banding), yielded normal or negative results. The EEG studies showed a maturation defect in the propositus and a diffuse abnormality in his sister; cere- bellar atrophy with cortical and subcortical involvement was demonstrated by cranial tomography scan (CTS). The psycho- metric evaluation (Gesell's test) revealed mild mental retarda- tion in the propositus and his sister (IQs 60 and 65, respective- ly). On the other hand, the electromyographic studies reveal- ed a denervation pattern predominantly in distal limbs. The latter studies (EEG, CTS, Gesell's test, and electromyo- graphy) could not be carried out in Case C. The radiologic findings are shown on Table 2. Light microscopic hair analysis did not show any abnormality. However, in the propositus
I 2 3
I-7 8 9 10 11 / 12 13 16-31
Fig. 1. Pedigree
Fig.2. Left: the propositus; see short stature, peculiar facial character- istics, and feet deformities. Right: The propositus' sister (Case B); note similar facial characteristics and feet deformities
Table 1. Clinical and quantitative data
Case A Case B Case C
Age (years) 8 7 13
Height (cm) 11 la 108 a 145
Cephalic circumference (cm) 55 b 52.5 b 55
Inferior segment (cm) 53 53 72.5
Upper/lower segment ratio 1.09 1.03 1
IQ (Gesell's test) 60 65 ND
Peculiar face + + +
Thick, rough, and abundant hair + + +
Moderate exophthalmos + + +
Mild palpebral ptosis + + +
Small nose + + +
Anteverted nostrils + + +
Thick lips + + +
Down-slanting corners of the mouth + + +
Low-set ears + + -
Cubitus valgus + + +
Genu recurvatum + + +
Plano varus/valgus foot deformity + + +
1st hammertoe + + -
Unstable gait + + +
Upper and lower limb ataxia + + +
Dysarthria + + +
Diminished deep tendon reflexes + + +
Babinski's and Romberg 's signs + + +
Joint hypermobility + + +
Cutis laxa + + +
a Below the 3rd percentile b Above the 90th percentile ND: not determined
Fig.3. a The propositus' brother (Case C); see the facial appearance, the severe scoliosis, and the difficulty at bipedestation, b Facial close up of Case C. Note the characteristics of the hair and facial features
Table 2. Radiologic findings
Case A Case B Case C
Dolichocephaly + + +
Hypoplastic 12th rib + - +
Scoliosis + + +
Spina bifida occulta at L-5 - + +
Slender long bones + + +
Generalized osteopenia + + +
Delayed bone age + + +
1st hammertoe + + _+
Fig. 4. SEM of clinically abnormal hair. Notice the characteristic cuti- cular scales (original magnification x 640)
and his sister the scanning electron microscopic (SEM) studies revealed a peculiar hair configuration somewhat resembling rabbit hair (Fig. 4), which could not be included in human pat- terns (Stahl 1973). The nonconsanguineous parents, aged 46 (father) and 33 years at the propositus' birth, were clinically normal, as were three older brothers and two younger sisters.
The present cases showed an aggregate of clinical features consisting mainly in unusual facial appearance (rough hair, wide forehead, mild palpebral ptosis, horizontal nystagmus, small nose with anteverted nostrils, thick lips, down-slanting corners of mouth, and in two of them, low-set ears), dys- arthria, delayed psychomotor development, scoliosis, feet deformities, and ataxia. Among several inherited diseases in which ataxia is a common finding, either as the main feature or as an additional manifestation, the cerebellar ataxias were mainly considered for differential diagnosis. The association of ataxia of early onset, dysarthria, scoliosis, nystagmus, and feet deformities in patients of both sexes with normal parents resembles Friedreich's ataxia (one of the three predominantly spinal forms of ataxia) in which 10% of the cases occur with psychomotor impairment (Boyer et al. 1962). Nevertheless, the phenotypical appearance of the present cases, as well as the striking cerebellar atrophy showed by CTS, ruled out this entity (Friedreich's ataxia mainly occurs with degeneration of posterior funiculi, pyramidal, and spinocerebellar tracts of
spinal cord). The other two spinocerebellar ataxias (Sanger Brown and Becker) are autosomal dominant conditions with a relatively late onset (McKusick 1983) and thereby were easily discarded.
Since cerebellar atrophy is a common finding of the olivo- pontocerebellar atrophies (OPCA) (Konigsmark and Weiner 1970), they were also considered. One of them, the OPCA II, has an autosomal recessive pattern of inheritance but late onset, and presents with head-tremor and normal reflexes without any dysmorphy. The mild optic atrophy in the pro- positus and his sister is not a distinctive feature, since in several hereditary ataxias mild hyperpigmentation of the macular areas, optic atrophy, or pigmentary retinopathies have been observed (Stanescu-Segal and Michiels 1979). The ultrastructural hair findings found by SEM could be an addi- tional characteristic of this syndrome. The clinical and genetic heterogeneity in ataxias has been well documented and can be considered to be a result of the complexity in the organo- genesis, development, and function of the CNS, which seems to be a target for many mutant genes.
To conclude, the cases here described share a dysmorphic syndrome with mental retardation and ataxia, whose charac- teristic features permit one to distinguish a distinct probably autosomal recessive entity.
Acknowledgments. We should like to thank M. E. Gofii for her secre- tarial assistance, and A. Alcaraz for the art work.
Boyer SH IV, Chisholm AW, McKusick VA (1962) Cardiac aspect of Friedreich's ataxia. Circulation XXV: 493--505
Konigsmark BW, Weiner LP (1970) The olivopontocerebellar atro- phies: a review. Medicine 49 : 227-241
McKusick VA (1983) Mendelian inheritance in man, 6th edn. Johns Hopkins University Press, Baltimore
Pedersen L (1980) Hereditary ataxia in a large Danish pedigree. Clin Genet 17 : 385-393
Pedersen L, Platz P, Ryder LP, Lamm LU, Dissing J (1980) A linkage study of hereditary ataxias and related disorders. Evidence of heterogeneity of dominant cerebellar ataxia. Hum Genet 54:371- 383
Stahl CJ (1973) Identification of human remains. In: Spitz WU, Fisher RS (eds) Medicolegal investigation of death. Charles C Thomas, Springfield, pp 32-65
Stanescu-Segal B, Michiels J (1979) Heredoataxia (spinocerebellar degeneration), ERG alterations, temporal aspects. Ophthalmo- logica 178 : 267-272
Received October 18, 1984