Patient with rheumatoid arthritis and MCA/MR syndrome due to unbalanced der(18) transmission of a paternal translocation t(18;20)(p11.1;p11.1)

INTRODUCTION

Partial monosomy of the short arm of chromosome 18 is a well-described syndrome, with mental retardation and characteristic facial features being consistent findings. Patients have a round, flat face with almond-shaped eyes, upslanting palpebral fissures, and periorbital fullness. Long, flat philtrum and downturned corners of the mouth were also frequently observed. Moderate to severe mental retardation and speech delay are characteristic. In some patients, organ anomalies, especially holoprosencephaly, cleft palate, and cardiac defects, have also been reported [Telvi et al., 1995].

Partial or complete trisomy of the short arm of chromosome 20, a less-well-known chromosome aberration, has many facial features that overlap with the 18p deletion phenotype [Clark et al., 1993; LeChien et al., 1994]. The combination of 18p deletion/20p duplication has been reported twice [Cantú et al., 1992; Tumer et al., 1995]. We report on a patient with clinical and cytogenetic findings characteristic for both of these two chromosome aberrations in whom milk protein intolerance and juvenile rheumatoid arthritis (JRA) have also been diagnosed.

CLINICAL REPORT

The proposita was born at 41 weeks and 3 days of the first, uneventful pregnancy to a 23-year-old mother and 33-year-old father. The parents are healthy, and neither members with somatic or developmental abnormalities or fetal wastage has been documented in their families. The mother has had no further pregnancy, while a girl was born to the father from a second marriage. According to the father, she is healthy (examination has so far not been possible).

Birth measurements were normal for gestational age: weight 3,210 g, length 51 cm, head circumference 33 cm. At first examination at 18 months of age, growth parameters were within normal limits; she had an oval, flat face, upslanting palpebral fissures, periorbital fullness, hypoplastic midface with flat nose and downturned corners of the mouth. Cardiac examination, abdominal ultrasonography, radiologic skeletal survey, hearing test, and eye examinations showed normal results. Severe generalized muscular hypotonia was noticed. The patient was able to keep a sitting position only at age 3 years. Besides severe psychomotor retardation, she suffered from chronic diarrhea. At age 4 years, milk protein intolerance was diagnosed. She was started on a milk protein–free diet, and her gastrointestinal symptoms subsequently resolved. She was able to stand at 5 years of age. At age 6 years, she developed arthritis of the large joints followed by the involvement of the small finger joints. The results of immunologic studies supported the diagnosis of juvenile rheumatoid arthritis (elevated sedimentation rate, C-reactive protein (CRP), and complement levels with latex and Waaler-Rose test positive). Since initiation of steroid and Methotrexate treatment, the disease has been in remission. Currently, at 6.5 years of age (weight 21 kg, height 118 cm, both 25th–50th centile; Fig. 1), the patient has severe mental retardation. Her motor development corresponds to a 2-year-old child; she does not speak and understands only simple orders.

RESULTS

Conventional GTG-banded chromosome examination, performed on chromosome preparations from peripheral lymphocytes, suggested a slight enlargement of the short arm of chromosome 18. Examination of the parents showed a normal karyotype in the mother. The 18p + chromosome detected in the patient was also found in the healthy father. However, a second translocation chromosome could not be detected.

The nature of the aberration of the short arm of chromosome 18 was determined by FISH according to standard protocol [Pinkel and Gay, 1996]. Chromosome painting with a chromosome 18–specific library probe (Vysis, Downers Grove, IL) in the father demonstrated a translocation of the short arm of chromosome 18 to the centromeric region of chromosome 20. Studies with the chromosome 20–specific painting probe (Vysis) showed a balanced reciprocal translocation in the father (Fig. 2): an exchange between the short arms of chromosomes 18 and 20. FISH analysis with these two chromosome-specific libraries showed that our patient inherited from her father the normal chromosome 20 along with the der(18) chromosome containing the short arm of chromosome 20 and long arm of chromosome 18. Studies with the chromosome 18 alpha-satellite–specific fluorescence probe (Vysis) showed reduced signal intensity. Unfortunately, no analysis could be performed with a chromosome 20 alpha-satellite probe. From these findings, it was concluded that the proband had a deletion of the short arm of chromosome 18 and a duplication of the short arm of chromosome 20: 46,XX,der(18),t(18;20)(p11.1;p11.1)pat.

DISCUSSION

Although not highly distinct, the phenotypic anomalies found in the proposita are compatible with those found in the two other patients with monosomy of 18p combined with trisomy of 20p [Cantú et al., 1992; Tumer et al., 1995]. Among others, brachydactyly, short upslanting palpebral fissures, and wide mouth with downturned corners seem to be characteristic, along with developmental, mainly speech, delay. Mental retardation is both more consistent and more severe in dup(20p) as compared to del(18p) in which mental development can even be borderline normal, and it is not surprising that mental deficiency is unusually severe in our proband who has the combination of both aberrations. With respect to facial characteristics, the proposita more closely resembles the dup(20p) phenotype, especially the midface with short and upslanting palpebral fissures [Schinzel, 2001].

As additional findings, our patient also had immune system–mediated diseases. Although milk protein intolerance is a common pediatric disease, JRA seldom presents in early childhood. Immunologic disorders have not been reported in 35 cases with duplication of 20p [Schinzel, 2001]. The majority of some 150 case reports of 18p− concerned newborns and very young children who, possibly because of their age, did not show symptoms of JRA at the time of publication. However, JRA has already been described in a 5-year-old girl with 18p− [Finley et al., 1972], and arthritis of the small finger joints has been reported in another patient [Horsley et al., 1998]. In addition, autoimmune thyroid disease has been observed in at least 11 cases [Stoffer et al., 1981; Schinzel, 2001]. An immune mediator gene on the short arm of chromosome 18 had been postulated 30 years ago [Rudd et al., 1969], and low IgA levels are a common finding in 18p− patients [Schinzel, 2001]. Other potentially immunologic disorders found occasionally in 18p− patients include juvenile diabetes [van Dyke et al., 1964; Kistenmacher et al., 1974], Graves disease, eczema [Ruvalcaba and Thuline, 1969], nephritis [Sernia et al., 1982], and possibly also pernicious anemia [Goh, 1981] and alopecia [Schinzel, 2001]. All these observations considered, we conclude that the juvenile rheumatoid arthritis observed in our patient most likely is related to her chromosomal abnormalities, thus confirming the existence of a gene or genes controlling immunologic function on 18p.

Unbalanced whole arm translocations between nonacrocentric chromosomes are rare among liveborns, probably because of lethality due to gross gene imbalance. Interestingly, whole arm translocation involving the short arms of 18 and 20 as found in our patient was observed in at least two other cases [Cantú et al., 1992; Tumer et al., 1995]. Cantú et al. [1992] found that, in their patient, the chromosome 18 alpha-satellite DNA block was split, indicating a break at the centromeric region of this chromosome. We also found a reduced signal on chromosome 18 with the alpha-satellite probe. These findings suggest that whole arm translocations of nonacrocentric chromosomes involving the centromeres has no adverse effect per se (e.g., on cell division), and its biological consequences depend on the chromosomes involved and the resulting genetic imbalance.