Volume 118 Clinical and laboratory observations 4 1 5 Number 3

intestinal chloride transport in cystic fibrosis. FASEB J 1988;2:2625-9.

7. Orlando RC, Powell DW, Croom TD, et al. Colonic and esophageal transepithelial potential difference in cystic fibro- sis. Gastroenterology 1989;96:1041-8.

8. Powell DW. Ion and water transport in the intestine. In: An- reoli TE, Hoffman DE, Fanestil DD, et al, eds. Physiology of membrane disorders. New York: Plenum Press, 1986;559-96.

9. Goldstein JL, Nash NT, AI-Bazzaz F, et al. Rectum has ab- normal ion transport but normal cAMP-binding proteins in cystic fibrosis. Am J Physiol 1988;254:C719-24.

10. Rask-Madsen J, Schiotz PO, Bartels U, et al. Electrical polar- ization of rectal mucosa and excretion of tetrahydroaldoster- one in patients with cystic fibrosis of pancreas and in normal subjects. Acta Paediatr Scand 1975;64:81-6.

11. Rechkemmer G, Halm D, Work J, et al. Independent reg- ulation of potassium transport and sodium absorption by aldosterone in guinea pig distal colon [Abstract]. Fed Proc 1987;46:635A.

Mental retardation in Turner syndrome

Daniel L. Van Dyke, PhD, Anne Wiktor, MT(ASCP), Jacque l yn R. Roberson, MD, and Lester Weiss, MD

From the Medical Genetics and Birth Defects Center, Henry Ford Hospital, Detroit, Michigan

In the late 1950s and early 1960s, patients with Turner syndrome were believed to have a higher incidence of men- tal retardation than the population at large. Today it is un- derstood that most patients with Turner syndrome have normal intelligence, 1 although many have specific learning

disabilities. 2 In reexamining the incidence of mental retar- dation in subjects with X-chromosome abnormalities, we found that those with a small ring X chromosome have an increased risk for mental retardation.

M E T H O D S

We identified all subjects who had karyotypes between January 1969 and March 1989 because of gonadal dysgen- esis or features of Turner syndrome, and those who had nu- meric or structural abnormalities of the X chromosome. By review of hospital and genetics clinic records, telephone communication with physicians, and direct follow-up ex- amination of the patients, we attempted to learn whether each of these patients had mental retardation. For the pur- pose of the study, we defined mental retardation as an in- telligence quotient <70 or full-time assignment to a special education program for the mentally impaired. If the physi- cian initially described the patient as having normal intel- ligence, we accepted this assessment. The intellectual func-

Submitted for publication July 26, 1990; accepted Oct. 1, 1990. Reprint requests: Daniel L. Van Dyke, PhD, Cytogenetics Labo- ratory, Henry Ford Hospital, Detroit, MI 48202. 9/22/25779

tion of all patients with an r(X), and of all who were reported to have subnormal intelligence by their physicians, was independently confirmed by examination of the patient or the complete medical records, or by direct contact with the physician.

Cytogenetic studies of the subjects with an r(X) included evaluation of 100 G-banded metaphase cells and C-banding to identify the size of the centromeric heterochromatin re- gion. In situ hybridization with centromere-specific probes was used to show that the rings had X centromeres. The

polymerase chain reaction with Y-chromosome probes was used to exclude the possibility that the Small ring was de- rived from a Y chromosome (details will be presented else-

where).

R E S U L T S

We identified 174 subjects with X abnormalities and go- nadal dysgenesis or features of Turner syndrome, 12 (7%) of whom had mental retardation (Table I). Among 15 with

] r(X) Ring X chromosome I

45,X/46,X,r(X) karyotype, six (40%) had more severe de- velopmental delay than is usually associated with Turner syndrome. The nine r(X) patients with normal intelligence had ring chromosomes that varied in size from nearly the same as a normal X to about the size of a chromosome 20, whereas all six r(X) patients with mental retardation had smaller rings. The phenotypic findings of the mentally re- tarded r(X) subjects are presented in Table II.

Of the 168 subjects who did not have a small r(X) six

4 1 6 Clinical and laboratory observations The Journal of Pediatrics March 1991

T a b l e I. Mental retardation among subjects with an X:chromosome abnormality

Subjects with mental

Total retardation subjects

Karyotype (No.) No. %

45,X 7O 1 1.0 45,X/46,XX 31 2 6.0 45,X/46,XY 6 1 17.0 lsochromosome Xq 34 2 6.0 Deletion X 12 0 Other X rearrangements 6 0 Medium or large r(X) 9 0 Small r(X) 6 6 100.0

Total 174 12 6.9 Total (excluding 168 6 3.6

small r[X])

(3.6%) had mental retardation. One with 45,X karyotype was normal until she was comatose for 3 weeks after cata- strophic bleeding into a crani0pharyngioma. A second pa- tient, with 45,X/46,XX mosaicism, had cardiac arrest af- ter surgery for jejunal atresia. She had hypoxic-ischemic and metabolic encephalopathy. A third patient with pri- mary amenorrhea had mental retardation and seizures. At 33 years of age her karyotype was 46,XX in 97 cells and 45,X in 3 cells. This is probably within normal limits, but she was not excluded because she had primary amenorrhea. A fourth patient, with 45.X/46,XY mosaicism, was se- verely mentally impaired, blind and deaf. and of short stat- ure. The final two patients had isochromosome X, typical Turner syndrome, and mild mental retardation. Excluding the two patients whose mental retardation was clearly as- sociated with postnatal catastrophes, 4 (2.4%) of 166 patients without a small r(X) had mental retardation.

All six patients with mental retardation and a small r(X) had 45,X/46,X,r(X) mosaicism. Three patients had a mi- nor population of cells with two copies of the r(X). No 46,XX cells were observed. In all cases the ring was smaller than chromosome 22. C-banding showed that the rings did not have the very small paracentromeric C-band that is characteristic of the Y chromosome. Molecular cytogenetic and polymerase chain reaction studies indicated that the ring originated from the X chromosome and not from the Y chromosome or from an autosome.

D I S C U S S I O N

The total frequency of mental retardation in the present series was 6.9%. Among those patients without a small r(X), the frequency of mental retardation was 3.6%. Excluding the two who had postnatal catastrophes, the frequency of

Table I I . Clinical features of subjects with small r(X) chromosomes

Present Total c a s e s " c a s e s t

Mental retardation or 6 17/19 developmental delay

Height <~ 50th percentile for 6 10/11 Turner syndrome

Head circumference _< 10th 3 6/10 percentile

Chronic otitis media 6 7/7 Strabismus or esotropia 4 8/11 Epicanthus 4 8/10 Simian crease 3 6/9 Seizures 2 7/11 Cubitus valgus 2 6/9 Residual lymphedema 3 5/9 Short fourth metacarpal 3 4/7 Sacral dimple 3 3/6 Pigmentary dysplasia 1 4/9 Heart malformation 3 4/10 Pigmented nevi 2 2/7 Neck web 0 1/11

*Numbers indicate cases among the six patients reported here who have the trait. 1"Numbers indicate cases where trait is present and total number of cases for which the trait was mentioned. Data include the present 6 subjects plus 13 others from references 3 (cases MR and CE), 4 (cases 610 and 1682), 5, 6, 7 (case 3), 8 (patients 1 and 2), 9, 10 (case 4), 11, 12, 13 (case 9), and case 23196 of Palmer (personal communication, 1989).

unexplained mental retardation was 2.4%, within the range of the 1% to 3% expected. The nine subjects with a medi- um-sized or larger r(X) had normal intelligence. In addition to the six patients with a small r(X) described here, we identified 13 others (Table II). At least 17 (89%) of these 19 patients had mental retardation; in two cases the intel- ligence level was unclear, v, 12 Thus the small r(X) appears

to be associated with a high risk of mental retardation and in this study accounted for half the mental retardation among patients with X-chromosome abnormalities.

The patients with a small r(X) appeared to be more growth retarded than is typical for Turner syndrome; 91% (10/11; Table II) had heights at or below the 50th percen- tile on the Turner syndrome growth chart. Of the 10 patients for whom head circumference data were available, all were below the 50th percentile, and six were at or below the 10th percentile. Of the 19 with a small ring, four had pigmentary dysplasia similar to hypomelanosis of Ito. This appears to be a general feature of chromosomal mosaicism. 14 Seizures (in 7/19) and simian creases (in 6/

19) appeared to be more common than expected for Turner syndrome. The phenotypic picture of patients with a small r(X) included menta ! retardation; growth retardation more severe than expected in Turner syndrome, and small head

Volume 118 Clinical and laboratory observations 41 7 Number 3

circumference, and it occasionally included seizures, simian

creases, and pigmentary dysplasia.

A structurally abnormal X chromosome is typically

inactivated in all or nearly all cells. The X-inactivation

center resides in the region Xq l 3-q21.1, and the long-arm

breakpoint in the very small rings was probably proximal to

this region. If the X-inactivation center were lost, then in-

activation probably never occurred and cells bearing the

ring would have two active copies of each gene on the ring.

As with autosomal duplication, this chromosomal imbal-

ance could result in mental retardation and birth defects.

We thank Drs. Charles Wolf, David Leach, Raymond Mellinger, Robert Van Sickle, Linda Bolton, Robert Lugg, Shoba Chandra, and Usha S. Ram for referring the r(X) patients. We also thank Deborah Anderson, Juanita Clark, Kathy Gasser, Deborah Kingery, Mark Terry, Jim Zabawski, and David Zieg for expert technical support, and Susan C. Olesen for editorial assistance.

R E F E R E N C E S

1. Garron DC. Intelligence among persons with Turner's syn- drome. Behav Genet 1977;7:105-27.

2. Money J, Alexander D. Turner's syndrome: further demon- stration of the presence of specific cognitional deficiencies. J Med Genet 1966;3:47-8.

3. Cohen MM, Sandberg AA, Takagi N, MaeGillivray MH. Autoradiographic investigations ofcentric fragments and rings in patients with stigmata of gonadal dysgenesis. Cytogenetics 1967;6:254-67.

4. Nielsen J, Fischer M, Friedrich U. Mental retardation in Turner's syndrome. J Ment Defic Res 1973;17:227-30.

5. de Grouchy J, Turleau C, Doussau de Bazignan M, Maroteaux P, Thibaue D. Incontinentia pigmenti (IP) and r(X), tentative

mapping of the IP locus to the X juxtacentromeric region. Ann Genet 1985;28:86-9.

6. Rott H-D, Ulmer R, Haneke E. Hypomelanosis of Ito and chromosomal mosaicism in fibroblasts [Letter]. Lancet 1986; 2:343.

7. Gemmill RM, Pearce-Birge L, Bixenman H, Hecht BK, Allanson JE. Y chromosome-specific DNA sequences in Tur- ner-syndrome mosaicism. Am J Hum Genet 1987;41:157-67.

8. Kushnick T, Irons TG, Wiley JE, Gettig EA, Rao KW, Bow- yer S. 45X/46X,r(X) with syndactyly and severe mental retardation. Am J Med Genet 1987;28:567-74.

9. Crolla JA, Llerena JC JR. A mosaic 45,X/46,X,r(?) karyo- type investigated with X and Y centromere-specific probes us- ing a non-autoradiographic in situ hybridization technique. Hum Genet 1988;81:81-4.

10. Crolla JA, Gilgenkrantz S, de Grouchy J, Kajii T, Bobrow M. Incontinentia pigmenti and X-autosome translocation: non-isotopic in situ hybridization with an X-centromere- specific probe (pSV2X5) reveals a possible X-centromeric breakpoint in one of five published cases. Hum Genet 1989; 81:269-72.

11. Sefiani A, Heuertz S, Turleau C, Thibaud D, de Grouchy J, Hors-Cayla M-C. Incontinentia pigmenti: Xp breakpoint is not the same in a case of r(X) and in X/autosome translocations. Ann Genet 1989;32:149-51.

12. Koch J, Kolvraa S, Hobolt N, et al. A case of 46,XX,r(X) (plql) diagnosed by in situ hybridization. Clin Genet 1990;37:216-20.

13. Sybert VP, Pagon RA, Donlan M, Bradley CM. Pigmentary abnormalities and mosaicism for chromosomal aberration: as- sociation with clinical features similar to hypomelanosis of Ito. J PEDIATR 1990;116:581-6.

14. Chitayat D, Friedman JM, Johnston MM. Hypomelanosis of Ito---a nonspecific marker of somatic mosaicism: report of case with trisomy 18 mosaicism. Am J Med Genet 1990;35:422-4.

Neonatal lupus erythematosus simulating transient myasthenia gravis at presentation

Lisa G. Rider, MD, David D. Sherry, MD, and Stephen T. Glass, MD

From the Division of Rheumatology, Children's Hospital and Medical Center, and the Depart- ments of Pediatrics and of Neurology and Neurosurgery, University of Washington, Seattle

Neonatal lupus erythematosus is a syndrome characterized

predominantly by congenital heart block and lupus der-

matitis. Less frequent systemic manifestations include he-

Submitted for publication Aug. 7, 1990; accepted Sept. 28, 1990.

Reprint requests: David D. Sherry, MD, Division of Rheumatolo- gy, Children's Hospital and Medical Center, 4800 Sand Point Way, NE, Seattle, WA 98105.

9/22/25720

ACh Acetylcholine NLE Neonatal lupus erythematosus RNP Ribonucleoprotein SLE Systemic lupus erythematosus

patosplenomegaly, cholestasis, lymphadenopathy, pneu-

monitis, and hematologic abnormalities.l3 The pathogene-

sis of this syndrome is presumably via transplacental pas-

sage of maternal antibodies with an almost universal obser-

vation of Ro or La antibodies in affected infants. 2, 4