Changes in the structure of chromosome 18 are implicated in a number of conditions affecting health and development. 18p- and distal 18q- syndrome has been estimated to occur in 1/50,000 and 1/40,000 live births, respectively. The characteristics of 18p- syndrome are wide ranging and include speech delay, holoprosencephaly spectrum, micrognathia, ptosis, flat nasal bridge, wide mouth with short upper lip, excessive dental caries, large protruding ears, and skeletal abnormalities. 18q- syndrome also presents with a wide variety of clinical features that commonly includes foot anomalies, carp like mouth, midface hypoplasia, cleft palate, cleft lip, inner epicanthal folds, slanted palpebral fissures, narrow or atretic external auditory canals and low set ears. Features common to both syndromes include intellectual disability, short stature, microcephaly, tone abnormalities, seizures, hearing loss and cardiac defects. The phenotypic severity of either condition appears to be correlated with the amount of genetic material affected ¹ .

Ring chromosome 18, or r(18), is a rarer condition that most commonly forms when there is breakage in both chromosome arms, fusion of those breakpoints and the subsequent loss of the distal fragments ² . Ring chromosomes can also result from terminal deletions as well as contiguous duplication, with some of these cases demonstrating inversion of these duplications and thus an inv dup del rearrangement mechanism. As a result of the inconsistent amount of duplication and hemizygosity of the distal ends, the r(18) phenotype is extremely variable. Clinical characteristics are typically a combination of 18p- and distal 18q- syndrome ³ .

IgA deficiency and immunological diseases such as type 1 diabetes mellitus (T1DM), juvenile rheumatoid arthritis (JRA), Grave’s disease, hypothyroidism, and vitiligo have been reported in a number of individuals with 18p-, 18q-, and to a lesser extent r(18) ^{3– 8} . These numerous reports may represent chance relationships or suggest true genetic linkages. To the best of our knowledge, there have been seven reported cases of chromosome 18 abnormalities and JRA (see Table 1). Here we report the first case of late onset rheumatoid arthritis (RA) associated with mosaic 18p-, distal 18q-, and r(18) in a 32 year old Dominican woman with intellectual disability, hypothyroidism, vitiligo, IgA deficiency, interstitial lung disease (ILD), cystic bronchiectasis, and features consistent with both 18p- and distal 18q- syndrome.

The described chromosomal abnormalities are most likely de novo, since maternal analysis was normal and her father was normal in appearance and health . Furthermore, ring chromosomes usually arise de novo, with only 1% inherited ⁹ . Of the inherited cases, 90% are maternal since the presence of a ring blocks spermatogenesis and induces infertility in males.

Consistent with previously reported cases of r(18) (see Table 1), our patient had many of the characteristics associated with both 18p- and distal 18q- syndrome. The features shared between the two conditions include intellectual disability, short stature, microcephaly, IgA deficiency, autoimmune disorders (RA, vitiligo, hypothyroidism), and likely conductive hearing loss. Features specific to 18p- include excessive dental caries, while those specific to distal 18q- include cleft palate, carp shaped mouth, and clubfoot. Duplication did not appear to cause any distinguishing Edwards syndrome manifestations such as clenched fist, rocker bottom feet, severe organ involvement, and failure to thrive.

The unique feature of our patient was her late onset of RA compared to the early JRA previously reported ^{4– 8, 10} . Our patient was RF positive, anti-CCP negative and met 9/10 of the 2010 American College of Rhematology (ACR) Clinical Classification Criteria for RA ⁶ . To the best of our knowledge there have been seven reported, and six published, cases of RA associated with chromosome 18 abnormalities ( Table 1). Daentl first mentioned an unpublished case of JRA in a patient with 18p- and IgA deficiency ⁷ . In the first published case, Finley et al. reported a 9-month-old female with 18p-, swelling and contractures in many joints, fever, rash, and hepatosplenomegaly, consistent with JRA ⁶ . JRA has subsequently been associated with cases of 18q- as well ^{5, 7, 9} .

The exact genes involved with RA and autoimmune disease development in chromosome 18 abnormalities are still not well defined. There is a suggested link between PTPN2 (protein tyrosine phosphatase non-receptor type 2), located at 18p11.2-11.3, and RA and T1DM ^{11, 12} . Genome wide studies have shown evidence for the association of the PTPN2 locus with RA susceptibility in both Japanese and European populations ^{11, 13} . A case similar to ours was reported by Jain et al. with de novo r(18), del(18q23-18qter) and del(18p11.3-18pter) associated with hyperthyroidism, T1DM, vitiligo, and IgA deficiency, but not RA ³ . Their case had a more distal deletion that likely spared PTPN2. Another autoimmune critical region was proposed on 18p, with molecular breakpoints at 12,316,423-1,231,7830; interestingly, PTPN2 is not in this region ¹² . The genetic basis of autoimmune disease is not as well established in 18q- compared to 18p-. On the long arm, Merriman et al. proposed a locus at 18q12-21 that influences development of autoimmune diseases ¹⁴ . Another gene of interest is NFATc1 (nuclear factor of activated T cells) at 18q23, implicated in maintaining the programmed death receptor (PD-1) and ligand (PD-L) pathway that is essential for regulatory T cells to terminate immune responses and protect against autoimmunity ^{15, 16} . It is difficult to establish a definitive genotype-phenotype association, but it appears plausible that this proposed autoimmune critical region and PTPN2 on the short arm, as well as NFATc1 on the long arm may play a part in the autoimmune diseases seen in our patient.

Overall, adult RA has a poorer outcome compared to JRA ¹⁷ . Mortality rates in RA patients are increased due to medication related infections, gastrointestinal bleeding as well as extra-articular pulmonary, renal disease, and cardiovascular manifestations ¹⁷ . Our patient was also found to have ILD, bronchiectasis, and pulmonary hypertension. To the best of our knowledge, there is no known connection between interstitial lung pathologies and chromosome 18 abnormalities. However, ILD and bronchiectasis are known extra-articular manifestations of RA. In a population study, the lifetime risk of developing ILD was 7.7% for RA patients and 0.9% for non-RA subjects ¹⁸ . The classic presentation is a reticular, reticulonodular or honeycomb pattern in the lung bases.

The patient was also on several medications known to cause drug-induced interstitial lung disease (DI-ILD) including: methotrexate, adalimumab, sulfasalazine, and diclofenac ¹⁹ . The predominantly bilateral patchy ground-glass opacities with upper lobe predominance in our patient do suggest a hypersensitivity pneumonitis picture. Unfortunately, ground-glass opacities are non-specific and pattern of involvement on HRCT does not always correspond to histological findings. Medications known to cause DI-ILD were discontinued in our patient, with further management focusing on better characterizing the extent and etiology of ILD and continuation of steroid therapy.

Our report describes the first case of late onset RA associated with mosaic 18p-, 18q- and dicentric r(18). The complex rearrangements were detected by aCGH, karyotype and FISH. Her syndrome has features of both 18q- and 18p-, including multiple autoimmune disorders that support the idea of genetic loci on chromosome 18 playing a role in disease expression. Additionally, the finding of ILD - whether caused by RA, drug exposure, or an unexplored linkage - is an important condition to be aware of in patients with chromosome 18 abnormalities and autoimmune diseases. Ultimately, further studies are required to better define the genotype-phenotype associations that will further the clinical management of these patients.

Written and informed consent was obtained from the mother, who was the designated health care proxy prior to publishing this case report, for publication of any potentially identifiable clinical data that may be associated.