American Journal of Medical Genetics 44:543-550 (1992)

Fragile X Family With Unusual Digital and Facial Abnormalities, Cleft Lip and Palate, and Epilepsy Danuta Z. Loesch, David A. Hay, and Leslie J. Sheffield Department of Psychology, La Dobe University (D.Z.L.,D.A.H.),and Murdoch Institute for Research into Birth Defects (L.J.S.),Melbourne, Australia

We present a fragile X family with unusual clinical manifestations.These findings,which often occur in the X-linked FG syndrome, include minor limb anomalies, cleft lip and palate, characteristic facial appearance, gastrointestinal problems and epilepsy, and intellectual disability. In a total sample of 54 fra(X) families, the frequency of minor limb anomalies was estimated to be 32%in the affected males and 19% in the female heterozygotes.These anomalies tend to occur in several members of the same family, where some craniofacial abnormalities reported as characteristic of the FG syndrome have also been encountered. Possible mechanisms for the occurrence of these unusual manifestations in the fra(X)families are discussed. o 1992 Wiley-Liss, Inc. KEY WORDS: Martin-Bell syndrome, FG syndrome, fragile X, limb malformations, facial anomalies ~

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INTRODUCTION Fragile X [fra(X)l,or Martin-Bell syndrome [MBSI, is a common X-linked, semidominant condition associated with mental retardation and some physical manifestations, such as narrow face, long jaw, large prominent ears, prominent forehead, highly arched and narrow palate, and joint laxity. Occasional minor limb anomalies, epilepsy, or other abnormalities have also been recorded [Hagerman et al., 1983;Sutherland and Hecht, 1985; k y n s , 19891. A fragility of the X chromosome at q27.3 can be demonstrated in -80% of the affected males and in one-third of female heterozygotes, who may be partially or fully affected with this condition

Received for publication November 13, 1989 revision received December 23, 1991. Address reprint requests to Dr. Danuta Z. Loesch, Department of Psychology, La “robe University, Bundoora, Victoria 3083, Australia.

0 1992 Wiley-Liss, Inc.

[Sherman et al., 19841. Despite recent discoveries of DNA probes diagnostic for fragile X [Vincent et al., 1991; Yu et al., 19911, the nature of the genetic defect and its relationship to the extremely variable clinical expression of this condition are not sufficiently understood. Importantly, it has been shown by Yu et al. [19921 that the inter- and intrafamilial variability also involves the fra(X) specific DNA segment. Therefore, recording a wide spectrum of clinical changes of MBS, including extreme or unusual manifestations, may be an important contribution to a better understanding of the mechanisms involved in the origin and effects of the genetic abnormality. Here we present a fragile X family with unusual clinical manifestations, some of them known to occur in the FG syndrome. In addition, we assess the occurrence of several abnormalities commonly observed in the FG syndrome in our total sample of 54 fra(X) pedigrees. The FG syndrome is a rare X-linked condition first described by Opitz and Kaveggia [1974]. The varying manifestations include mental retardation, relative microcephaly with broad prominent forehead and dolichocephalic skull, distinctive facial and hair appearance, simply structured ears, congenital abnormalities of the limbs (especially of fingers and toes), dermatoglyphic anomalies, congenital hypotonia with joint contractures, epilepsy, and chronic constipation with or without structural anal anomalies [Keller et al., 1976; Riccardi et al., 1977; Opitz et al., 1982; Dallapiccola et al., 1984;Neri et al., 1984;Thompson et al., 1985,19891. Such behavior traits as “affable, outgoing, sociable”personality are often reported, but major behavior abnormalities are absent in the affected subjects. Results of routine laboratory tests and chromosomal analysis are unremarkable, and to our knowledge no linkage study to determine the position of an abnormal locus on the X chromosome has so far been undertaken. The nature of the primary defect is unknown.

CLINICAL REPORTS The pedigree and physical characteristics of the family P are shown in Figures 1-6. The propositus (IV-2) was identified as fra(X) positive in a genetic counselling clinic in Perth (Western Australia), where he and his immediate family are still living and has not been ex-

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Fig. 1. Pedigree of Family P. The conventional categorisation of disability has been reduced to three categories: borderline (IQ 85-70), mild (70-551, and moderate and severe (below 55).

Fig. 2. (a, b) Patient 111-8.

amined by us. Most of the other relatives living in Victoria were tested subsequently at the Royal Children's Hospital in Melbourne, and several individuals were found to be fra(X) positive. Consequently, this family has been included in our large clinical and anthropometric study comprising 54 families with this disorder [Loesch et al., 1987, 1988, 19911. The clinical and cytogenetic findings and some psychometric and anthropometric measures in those available relatives of

family P who were found fra(X) positive or showed any physical defect are listed in Table I. See also Figures 2-6.

RESULTS AND COMMENTS In 7 out of 8 fra(X) positive individuals from family P examined by us, we find a combination ofphysical anomalies that do not fit with the clinical picture of the Martin-Bell syndrome. They include minor limb anomalies

Fragile X Family Abnormalities

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Fig. 3. Patient 111-9. The face (a,b) and detail of hands (c) and feet (d).

such as contractures, or terminal hypoplasia of fingers, generally limited mobility of finger and shoulder joints, and large and overlapping toes; facial appearance characterised by a prominent forehead and a high frontal hair line, frontal upsweep of hair with the strands often being brittle and scarce; prominent “thick” lips and mild micrognathia; simply structured ears; narrow andlor highly arched or asymmetrical palate, with cleft palate and hare lip in one male patient examined by us (IV-7) and in his aunt whom we have not seen. Other characteristics include epilepsy, underweight, and minor gastrointestinal complaints. In most of these individuals, we also find some degree of mental retardation from borderline to moderate, but hardly any physical findings typical of MBS. It is significant that most of the anomalies unusual for fragile X syndrome listed above are also present in one female individual (IV-5)who does not express either cytogenetic or physical or intellectual abnormalities of fra(X)syndrome and does not show the fragile X diagnostic DNA fragment. It may be of importance to note that this individual is not intellectually disabled and her lower verbal score is consistent with a

poor level of intellectual stimulation in the home. Her Block Design performance was very bizzare with consistent misorientations of her solutions by 90“ or 180”despite repeated reminding of the need for correct orientation. A pattern of very unusual errors on the Porteus Maze confirmed that she has some unusual spatial deficit that warrants full neuropsychological evaluation. The assessment of clinical findings in the most affected relative (111-91,who is fra(X)positive, as well as in her non-fra(X) daughter (IV-51,using the P.O.S.S.U.M. Syndrome Information System [Bankier, 19881yielded a possible (first choice) diagnosis of the FG syndrome. This was consistent with our clinical evaluation of the anomalies encountered in this family, as compared with descriptions in the literature referred to earlier in this study. There is extensive variability of the traits described as occurring in the FG syndrome in individual members of our family. Consistent with the reported variability in the clinical expression of this syndrome led some authors such as Thompson et al. [19851 to express the opinion that the “diagnosis of FG syndrome can be difficult in a single case. By observation of typical

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Fig. 4. Patient IV-5, daughter of 111-9. The face (a,b)and detail of hands (c) and feet (d).

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Fig. 6. Diagrammatic representation ofdermatoglyphic patterns in sibs 1V-5la)and IV-7(b).The unusual featuresare: distal displacement ofthe t-axial triradius. a presence of unusually situated and orientated loop pattern in IV-5, which could be defined as a variety of interdigital [ulnar), horizontally oriented loop I V [IV" in Loesch, 19831, and the horizontal orientation of interdigital loop IV in 1V-7.These features have not been encountered in their mother, 111-9. Fig. 5. The face of patient IV-7,son of III-9.

NT

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63 Sparse and brittle hair with frontal upsweep (cowlick)

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82 Brittle hair with distinct frontal upsweep (cowlick) (Fig. 4a,b)

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Marked facial Hare lip, narrow asymmetry, palate epicanthal folds, squint, simply structured ears (Fig. 5 ) Flared nostrils, thick Narrow palate lower lip, micrognatia, simply structured ears

Marked facial asymmetry including maxilla, thick lips (Fig. 4a,b)

Minor physical anomalies Face Palate and teeth Thick, prominent Moderately high lower lip, receding arched palate chin (Fig. 2) Receding chin, illHigh arched and shaped, sticking out narrow palate, ears irregular teeth Thick lips, flared High arched and nostrils, projectnarrow palate ing and simply structured ears, asymmetrical narrow face (Fig. 3a,b)

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Flexion joint contracture of f5 bilaterally and of left shoulder, broad hallux and 2nd toe on right Bilateral clinodactyly of fingers with flexion joint contracture on left, stiffness of other finger joints “marfanoid toe line on right

Small hands, short fingers, flexion joint 5 contracture of f bilaterally (Fig. 3 4 . Gap between hallux and IInd toe, “marfanoid toe line (Fig. 3d) Unusually large toes 3rd and 4th (operated), overlapping toes 1-11 on right (Fig. 4d). Unusual dermatoglyphic patterns (Fig. 6a) Gross hypotonia Un u su a1 dermatoglyphic patterns (Fig. 6b)

NAD

Limbs Terminal hypoplasia of fingers

TABLE I. Summary of Clinical and Cytogenetic Findings in 9 Affected Members of Family P ____~

PsychoCytogenetics logical % DNA testsb Ped Age in yrs. FRAXA+ sizea PPVT BD Head and hair no. 97 0 NT 63 Prominent forehead, 111-8 32 high frontal line, brittle hair (Fig. 2) 55 29 Prominent forehead 25 NT IV-3 10 with high frontal hairline 1 1.3 63 41 Prominent forehead 111-9 30 with high frontal line, brittle and sparse hair (Fig. 3a,b)

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NAD Speech impediment Blurred speech, epilepsy, abnormal spinal curvatures, chronic constipation. “Cyst in lower back” removed in childhood past hospital treatments for “stomach upset.” Speech impediment epilepsy NAD Stomach ulcer, chronic constipation. Clinical score of 15 on General Health Questionnaire (28 item version) [Goldberg, 19721 and abnormally high psychosis proneness scores [Chapman and Chapman, 19851 on dimensions of Social Anhedonia and Impulse Nonconformity NAD Psoriasis, enlarged thyroid gland, increased TBG level NT

Other clinical abnormalities

i60.0 141.0

41.0 10.0 64.0

63.5 40.0

NT

153.6 80.0 179.0

158.2 145.3

NT

NT

147.0 NT NT

Weight 60.0 34.0 42.5

Height 161.8 143.6 152.0

Arm span 167.0 140.0 156.0

NT

53.0 53.0

51.0 47.5 55.0

NT

12.3 12.2

11.1 NT 12.6

NT

5.6 5.6

5.6 NT 6.7

Not available for examination

Not available for further tests

Body measurements (in cms and kas) Head Face Upface circumf. length length“ .... Comments 54.0 11.8 6.4 Not available for further tests 52.7 As above 10.7 5.8 50.5 5.6 No previous hospital records 11.1 available

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Indicates size of PstI fragment (in kb) identified on a n abnormal chromosome by diagnostic probe pfxa3 [Yu et al., 19911,where the normal size of amplification (equivalent to 15-60 repeats) is within a 1.0 kb PstI fragment. Peabody Picture Vocabulary Test (PPVT) measures vocabulary knowledge using pointing response; the non-verbal Block Design Test (BD)measures mainly visuosopacial and visuornotor skills. These two aspects of cognitive skills were considered separately because visuo-spacial skills of the sort measured by the BD test are particularly affected in fragile X individuals (Theobald et a]. 1987, Loesch and Hay 1988, Crow and Hay 1990). NT = not tested. NAD = no abnormalities detected.

111-12

11-6 111-14

IV-5 IV-7 111-11

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Ped no. 111-8 IV-3 111-9

TABLE I. Summarv of Clinical and Cvtogenetic Findinns in 9 Affected Members of Familv P (continued)

Fragile X Family Abnormalities cases and sibling pairs, the spectrum of features of the FG syndrome is beginning to emerge.” The intuitive explanation for the clinical findings in family P is that the observed FG-like traits are simply an unusual manifestation of the fra(X) syndrome. However, it does not seem fully satisfactory considering that the anomalies similar to those found in the FG syndrome did not occur exclusively in individuals shown also to be affected with fra(X) by means of DNA tests, as in individual IV-5 in Table I. The same may be true also for 111-12 and 111-11, who clinically express some manifestations encountered in IV-5 and are not mentally retarded, but they have not been available for DNA analysis. Thus, a possibility to be considered is that these 2 conditions are independent and occurred by chance in one and the same family. However, this is contradicted by our observation that the unusual findings such as encountered in the Family P are also present in some proportion of individuals in the remaining 53 fragile X families of our pedigree data set, which includes 57 male and 107 female fra(X) subjects. For example, the observed frequency of minor anomalies of the upper limbs was 32%in the male and 20% in the female samples, and of the lower limbs, 19% and 13%in males and females, respectively. The observed upper limb anomalies included flexion contractures of fingers or limited mobility of shoulders, stiffness or enlargement of finger joints, clinodactyly,shortness of the Vth metacarpal bone, brachydactyly, and narrow fingertips. The lower limb abnormalities included, in particular, club foot, broad, very short or very long hallux or 2nd toe, a gap between the hallux and 2nd toe, webbing or irregularity of toes, clinodactyly, and narrow heels. The presence of the minor anomalies of the fingers in 19% of MBS female heterozygotes was pointed out in an earlier publication [Loesch and Hay, 19881. More importantly, we also find that these minor limb anomalies tend to occur in several MBS relatives of the same family; these anomalies were almost totally confined to 6 of our 54 families. Re-examining our data on these particular families in greater detail, we found that some individuals also manifest a number of facial characteristics observed in the FG syndrome, such as dolichocephalic skull with prominent forehead, high frontal hairline (with a frontal hair upsweep in 2 cases), apparent hypertelorism, upper prognathism with or without micrognathia, or gross facial asymmetry. Moreover, the abnormalities such as cleft palate, or epilepsy or congenital hypotonia are not uncommonly recorded in fragile X families (Loesch and Hay, 1988; Fryns, 1989; Loesch, unpublished). It is not impossible that some non-fra(X) relatives in those families may have also presented the above traits. Thus, it appears that some complex and consistent genetic mechanism may be involved in cosegregation of the fra(X) condition with another, less defined FG-like syndrome manifested by limb malformations, epilepsy, some intellectual disability, cleft lip, and palate and facial characteristics. The difficulty in the interpretation of this mechanism is aggravated by the fact that neither phenotypic or genotypic identity of the FG syndrome have yet been clearly established [Thompson et

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al., 19891. It is understood from the literature that this syndrome is an X-linked recessive. However, similar to the pattern of inheritance of fra(X), there have been some reports of affected females [Thompsonet al., 19891, and in our Family P the females express it as well as the males, which indicate sex-linked, semidominant inheritance. If this is true and this syndrome is not autosomal, the likely explanation, although requiring further studies in large and adequately clinically and cytogenetically (including DNA tests) examined families, is close linkage between fra(X) and the FG-like manifestations. Alternatively, there may be some common characteristic of a genotype that predisposes to genetic abnormality occurring in either of these conditions, with variable expression of the traits of FG syndrome in some cases, or some families. However, the possibility that IV-5 has been misdiagnosed as nonfragile X cannot be excluded, considering the latest findings of the tissuespecific mosaicism or an overlap between the “normal” and “fragile X specific” DNA result [Yu et al., 19921, in which case a hypothesis of cosegregation of 2 separate syndromes would not have enough support. The cause of the unusual manifestations encountered in our fra(X) family data can be clarified if clinical and molecular changes in the FG syndrome are specified and linkage studies performed in rare families of adequate size with manifestations of fra(X) and the FG-like condition. ACKNOWLEDGMENTS Our gratitude goes to all members of the families included in this analysis for their cooperation. We thank Professor David Danks and the Medical Staff from the Murdoch Institute, Royal Children’s Hospital in Melbourne, for access to the patients. Cytogenetic results were provided by Drs. Graham Webb and Margaret Leversha from the Murdoch Institute, and by Dr. Grant Sutherland. We especially thank Dr. Grant Sutherland and Dr. John Mulley from the Adelaide Children’s Hospital for performing DNA tests. This study was supported by the National Health and Medical Research Council of Australia. REFERENCES Bankier A (1988): Dysmorphology: Problems in nomenclature. Dysmorphology 224-30. Chapman U, Chapman JP (1985): Psychosis-proneness. In Alpert M (ed): “Controversies in Schizophrenia.” New York: Guildford, pp 157-172. Crowe SF,Hay DA (1989):Neuropsychological dimensions of the fragile X syndrome:Support for non-dominanthemisphere dysfunction hypothesis. Neuropsychologia 28:9-16. Dallapiccola B, Zelante L, Cristalli P (1984): Letter to the Editor: Diagnostic definition of the FG syndrome. Am J Med Genet 19379-381. Fryns J-P (1989):X-linked mental retardation and the fragile X syndrome: a clinical approach. In Davis KE (ed):”The Fragile X Syndrome.” OUP,Chapter 1. Goldberg DP (1972):The detection of psychiatric illness by questionnaire. In: “The Maudsley Monographs No. 21.”Oxford:Oxford University Press. Hagerman RT,Smith ACM, Mariner R (1983):Clinical features of the fragile X syndrome. In RJ Hagerman, PM McBogg (eds): ‘The Fragile X Syndrome.”Spectra, Chapter 2.

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