American Journal of Medical Genetics 7:49 1-495 (1 980)

X-Linked Mental Retardation: Renpenning Revisited Patricia Fox, Dale Fox, and John W. Gerrard

Section of Medical Genetics of the Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada

Nine men with X-linked mental retardation (MR) belonging to the family originally described by Renpenning and his colleagues have been reexamined and restudied. None of these men have the fragile X chromosome, and none have macroorchidism; their testes range in size from small to average. All but one are severely retarded; one has an IQ of 70, the mean IQ of the re- mainder is 30 with a range of 18 to 45. They are short in stature, have small or normal-size ears and lower jaws, and a moderate degree of microcephaly, the mean skull circumference being just below two standard deviations from the normal.

Key words: mental retardation (MR), X-linked inheritance, Renpenning syndrome

I NTRO D UCT 10 N

In 1962 Renpenning et a1 [1962] described a Dutch Mennonite family living in Saskatchewan and Alberta, Canada, in which mental retardation (MR) was transmitted as an X-linked trait; the mothers were mentally normal and about one half of their sons were mentally retarded. At that time no associated chromosomal, biochemical, or structural abnormalities were identified. More recently Lubs [1968], Giraud et a1 [1976], and Harvey et al [ 19771 have all reported finding in the affected men of some families with X-linked MR a terminal constriction on the long arm of the X chromosome, here- after called the “fragile X chromosome,” Giraud et a1 [ 19761 found the same anomaly in a retarded woman. Turner et a1 [1978] subsequently found that the fragile X chromo- some was associated with macro-orchidism. This association has been confirmed by others [Ruvalcaba et al, 1977; Bowen et al, 19781. In view of the above we decided to review the families originally described by us [Renpenning et a], 1962; Dunn et al, 19621. This paper records our findings in the family originally reported by Renpenning et a1 [ 1962). As originally described (Fig. l), this family contained 20 retarded men of whom 14 were examined. On this occasion nine were reexamined. These nine differed in so many respects from the members of the family originally reported by Dunn et a1 [1962] that we think they form a distinct clinical entity.

Received for publication June 16, 1980; revision received July 30, 1980. Address reprint requests to Dr. John W. Gerrard, Department of Pediatrics, University Hospital, Saskatoon, Saskatchewan, Canada S7N 0x0.

0148-7299/80/0704-0491$01.40 @ 1980 Alan R. Liss, Inc.

492 Fox, Fox, and Gerrard

Fig. 1. Pedigree of Renpenning family.

MATERIALS AND METHODS

We measured height, weight, span, occipitofrontal head circumference (OFC), size of ears (height and width at the upper level of the external meatus), and size of testes. The length and breadth of the testes were measured using calipers; from these measurements the volume was calculated as follows: n/6 X length X width?. Photographs of the face, front and side views, were taken. Informed consent was obstained for all these procedures, from the patients, their parents, or their wards. Blood was then taken for chromosome studies. Five of the nine blood samples taken were studied in Saskatoon, Canada, and by P. Jacobs in Hawaii. The remaining four were studied in Saskatoon alone. The samples were cultured first in F-10 medium with 15% fetal calf serum for 72 hours for standard analyses, and then in medium 199 (GIBCO) or in “M’ medium (modified medium F-10 without folic acid, thymidine, or hypoxanthine - GIBCO) with 5% fetal calf serum for 96 hours to demonstrate the fragile X chromosome. One hundred cells in each case wete examined and scored; then G-band staining was carried out and 40 cells from each male were analyzed.

Renpenning Revisited 493

The data were then recorded and compared with information already at hand on six other families with X-linked mental retardation, all of whom had the fragile X chromo- some, and who have been fully described by Jacobs et a1 [ 19801. A standard t-test was used for evaluating the significance of the differences between the clinical features and findings in the two groups, those with and those without the fragile X chromosome.

RESULTS

Seven of the nine men reexamined were in institutions; two lived at home. One of the latter, #210, is only mildly retarded. He reached grade six at 17 years old, he has an IQ of 70, speaks intelligently, drives a car, and hopes to marry. He has a normal OFC. He is so much brighter than his affected relatives that he cannot be considered a representative example of this form of X-linked mental retardation. However, since no other cause of his MR is known, he may have the X-linked MR inherited in his family, and his anthropo- metric data are included in Table I.

functions and require help with simple procedures such as shaving. One has bilateral congenital colobomata, another has diabetes mellitus. With the exception of #210 all are relatively withdrawn. Detailed psychometric assessments were not carried out on this occasion, those carried out previously indicated that they had a mean IQ of 30 (range 18 to 45).

Cytogenetic Findings

none had the fragile X chromosome.

Measurements

Heights and spans were difficult to measure accurately as most subjects did not understand simple requests such as, ‘‘please stretch your arms out.” We did not encounter

Of the seven living in institutions, four are unable to look after their own bodily

All of the retarded men had an apparently normal 46,XY chromosome constitution;

TABLE I. Mean Measurements of Subjects With X-Linked Mental Retardation Without (Renpenning) and With the Fragile X Chromosome

Family Mean P value*

Height (cm)

Arm span (cm)

163.9 * 7*7 Renpenning Fragile X 173.4 f 6.9 Renpenning Fragile X 176.8 * 1.6

0.001 < P < 0.01

167.4 7.3 0.001 < P < 0.01

60.3 * 9.3 (kg) Fragile X 84.4 * 31.2 0.02 < P < 0.05 Weight Renpenning

Head circumference Renpenning 53.2 * 1.8 p < o.ool

Right testicular Renpenning 13.3 * 8.8 < o,ool

Left testicular Renpenning 12.3 * 7.4 p < o.ool

(cm) Fragile X 57.7 f 2.4

volume (ml) Fragile X 58.4 f 26.1

volume (ml) Fragile X 55.6 * 28.6 ~~~ ~~ ~

*Indicates the significance of the differences of the two groups of measurements. OFC = occipitofrontal circumference; R = right; L = left.

494 Fox, Fox, and Cerrard

analogous problems when studying subjects with the fragile X syndrome. The mean height, arm span, weight, OFC, and testicular volumes of this group as a whole were significantly less than the corresponding measurements of the men with the fragile X chromosome (Table I). Testicular volumes, 12.8 k 8.1 ml, were not only less than those with the fragile X chromosome, they were also on average, less than those of the normal adult population, namely 18.6 X 4.0 [Zachmann et al, 19741. However, their secondary sex characteristics were perfectly normal.

and their ears were not large. With regards to ear and face structure (Fig. 2), the mandible was not prominent

DISCUSS ION

When we originally tracked down the families reported by Renpenning et a1 [ 19621 and by Dunn et a1 [ 19621 we thought - even though the members of the former family were obviously more severely retarded and had some degree of microcephaly - the mean OFC being just two standard deviations below the normal [Nelhaus, 19681, that both were examples of so-called nonspecific X-linked MR. The renewed interest in this dis-

Fig. 2. Facial features of representative members of the Renpenning family.

Renpenning Revisited 495

order, due to the discovery of its association in some families with a fragile X chromo- some and macro-orchidism, spurred our review of the two families. The first family to be revisited was the kindred of Dunn et a1 [1962]. The retarded males in this family have the fragile X chromosome, macro-orchidism, normocephaly, prominent jaws, large ears, and often a characteristic, jocular, repetitive form of speech. Although mentally retarded, they are able to look after their own bodily functions, nearly all can speak meaningfully, and most can do simple tasks under supervision. The members of the kindred of Renpenning et a1 [1962], by contrast, are more severely retarded. Most are institutionalized, have OFCs two standard deviations below the normal, and lack fragile X, prominent jaws, large ears, and macro-orchidism. Testicular size varies, ranging from the very small to normal. We have not, so far, identified any associated biochemical abnormality. If the name Renpenning is to be attached to any condition it should be limited to the X-linked trait of severe retardation with reduced OFC and without fragile X.

ACKNOWLEDGMENTS

We are grateful to Dr. Patricia A. Jacobs for her help and encouragement and to

The study was supported by grant No. 6608-1 103-55 of the National Health Research Dr. Leonard K-T Tan for the statistical analyses.

and Development Program, Health and Welfare, Canada.

REFERENCES

Bowen P, Biederman B, Swallow K (1978): The X-linked syndrome of macro-orchidism and mental

Dunn HG, Renpenning H, Gerrard JW, Miller JK, Tabata T, Federoff S (1962): Mental retardation

Giraud F, Ayme S, Mattei JF, Mattei MG (1976): Constitutional chromosomal breakage. Hum Genet

Harvey J, Judge C, Wiener S (1977): Familial X-linked mental retardation with an X chromosome

Jacobs PA, Glover TW, Mayer M, Fox P, Gerrard JW, Dunn HG, Herbst DS (1980): X-linked mental

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Turner G, Gill R, Daniel A (1978): Marker X chromsome, mental retardation and macro-orchidism.

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Edited by John M. Opitz