JMed Genet 1998;35:943-947 943 Juvenile rheumatoid arthritis and del(22ql 1) J Med Genet: first published as 10.1136/jmg.35.11.943 on 1 November 1998. Downloaded from syndrome: a non-random association Alain Verloes, Cynthia Curry, Mauricette Jamar, Christian Herens, Patricia O'Lague, James Marks, Pierre Sarda, Patricia Blanchet Abstract mal part of the long arm of chromosome 22, Del(22qll) is a common microdeletion encompassing in its phenotype Shprintzen syndrome with an extremely variable phe- velocardiofacial syndrome,' Takao conotruncal notype. Besides classical manifestations, anomalies face syndrome, DiGeorge anomaly,2 such as velocardiofacial (Shprintzen) or some instances of Opitz GBBB syndrome type DiGeorge syndromes, del(22ql 1) syn- 2,' and isolated outflow tract defects (such as drome may be associated with unusual but truncus arteriosus, tetralogy of Fallot, or inter- probably causally related anomalies that rupted aortic arch). The incidence could be as expand its phenotype and complicate its high as 1/3500 births. recognition. We report here three children The spectrum of clinical anomalies associ- with the deletion and a chronic, erosive ated with 22ql 1 monosomy is remarkably vari- polyarthritis resembling idiopathic cases able. Recently, juvenile rheumatoid arthritis ofjuvenile rheumatoid arthritis (JRA). (TRA) has been reported in association with Patient 1, born in 1983, initially pre- del(22ql 1) in five children.4 We report here sented with developmental delay, facial three further cases of this association, indicat- dysmorphism, velopharyngeal insuffi- ing that the presence of a JRA-like disorder ciency, and severe gastro-oesophageal re- may not be fortuitous, but rather causally flux requiring G tube feeding. From the related to the presence of the deletion. age of 3 years, he developed JRA, which resulted in severe restrictive joint disease, osteopenia, and platyspondyly. Patient 2, Case reports born in 1976, had tetralogy of Fallot and PATIENT 1 peripheral pulmonary artery stenosis. This girl is the second child of unrelated She developed slowly, had mild dysmor- parents, born after an uneventful pregnancy. phic facial features, an abnormal voice, Clinical investigations at birth showed a tetra- and borderline intelligence. JRA was diag- logy of Fallot, which was partially surgically nosed at the age of 5 years. The disorder corrected at the age of 10 months, pulmonary followed a subacute course, with relatively valvular insufficiency, and peripheral pulmo- http://jmg.bmj.com/ mild inflammatory phenomena, but an nary stenosis. No other malformations were Wallonia Centre for extremely severe skeletal involvement present. Assessment of calcium metabolism Human Genetics, with major osteopenia, restrictive joint and immunodeficiency are not available from Liege University, CHU disease (bilateral hip replacement), and that time, but suspicion of DiGeorge syndrome Sart Tilman, B-4000 almost complete osteolysis of the carpal was never raised in her medical records. Liege, Belgium At the age of 4 years (fig 1A), she was admit- A Verloes and tarsal bones with phalangeal synos- ted for inflammatory swelling of the on October 2, 2021 by guest. Protected copyright. M Jamar toses, leading to major motor impairment painful C Herens and confinement to a wheelchair. Patient knees, for which she was treated with indometh- 3, born in 1990, has VSD, right embryo- acin and salicylates. Sedimentation ratio was Medical repeatedly high. There was no hepatosplenom- Genetics/Prenatal toxon, bifid uvula, and facial dysmor- at the of 1 egaly. Calcium homeostasis, serum parathor- Detection Unit, Valley phism. She developed JRA age mone and thyrocalcitonin, and lymphocyte Children's Hospital, year. She is not mentally retarded but has counts were normal. The clinical course was University of major speech delay secondary to congeni- California San notable for multiple relapses of the arthritis tal deafness inherited from her mother. the next 15 affecting all large and Francisco, Fresno, In the three a del(22qll) was during years, USA patients, small joints, usually with an important inflam- C Curry shown by FISH analysis. These observa- matory component but no fever ("subacute" P O'Lague tions, and five other recently published JRA). Therapy was initially limited to anti- J Marks cases, indicate that a JRA-like syndrome inflammatory drugs. Corticosteroids were used is a component of the del(22qll) spec- from 9 to 18 years and d-penicillamine from 12 Department of trum. The deletion may be overlooked in Medical Genetics, to 14 years. There were no ocular manifesta- University Hospital those children with severe, chronic in- tions of iridocyclitis or uveitis. At the age of 12, Arnaud de Villeneuve, flammatory disorder. transient non-viral hepatitis was noted. Progres- Montpellier, France (JMed Genet 1998;35:943-947) sive right ventricular insufficiency was treated P Sarda P Blanchet Keywords: juvenile rheumatoid arthritis; del(22ql 1) with digitalis. Despite corticoids, progressive syndrome destruction of the hips and knees led her to Correspondence to: become wheelchair bound. Because of progres- Dr Verloes. sive flexion deformity, she required tenotomies Del(22ql 1) syndrome is a newly recognised around the hips and knees at the age of 15. At Received 28 November 1997 Revised version accepted for contiguous gene syndrome resulting from a the age of 20, hip replacement was performed. publication 9 April 1998 (usually) submicroscopic deletion in the proxi- There was major involvement of the hands and 944 Verloes, Curry, _amar, et al A J Med Genet: first published as 10.1136/jmg.35.11.943 on 1 November 1998. Downloaded from Figure 1 Patient 1. (A) Front view in infancy. (B, C) Appearance at the age of22: note prominent nose with large tip and narrow palpebralfissures. wrists. Immune investigations repeatedly Del(22ql1) was shown on spread chromo- showed hypergammaglobulinaemia, circulating somes hybridised with the specific DNA probe IgA immune complexes, and absence of rheu- D22S75 and the control probe D22S39 matoid factor, anti-DNA antibodies, and anti- (Oncor), using standard FISH techniques, as nuclear antibodies. HLA typing was A3A9- recommended by the manufacturer. B35-DR1DR5. The mother suffered recurrent psychiatric When we saw her at the age of 22, she was problems and had abandoned her daughter non-ambulatory. Ankylosis of the elbows and during infancy. Features noted in family finger retraction severely restricted her ability photographs suggest that she probably also had in fine motor skills. She was of apparently low the deletion. None ofthe relatives had ankylos- normal intelligence. She had a large nose, nar- ing spondylitis, inflammatory bowel disease, row palpebral fissures, narrow mouth (fig 1B, uveitis, psoriasis, or psoriatic arthritis (and the C), and high palate. She had a high pitched, same is true for the other two cases). nasal voice. IQ testing was not performed. A skeletal survey showed kyphoscoliosis, general- PATIENT 2 ised arthropathy (including the sacroiliac This boy is the second child of healthy, joints), severe osteopenia, carpal osteolysis, and unrelated parents. His neonatal course was http://jmg.bmj.com/ secondary synostosis of the metacarpals and characterised by low birth weight, hypotonia, phalanges (fig 2). She had attended normal and poor feeding. Language development was school until the age of 10 and was switched delayed. Clinical examination at the age of thereafter to special schooling. Poor academic 2 years showed a coarse, expressionless achievement was attributed to her physical ("myopathic") face (fig 3A), brachycephaly problems. with normal OFC, flat nasal bridge, on October 2, 2021 by guest. Protected copyright. Figure 2 Patient 1. (A) Severe hand deformities. (B) X ray ofthe hand at the age of22 showing generalised osteolysis, osteoporosis, and secondary bonefusion. J7uvenile rheumatoid arthritis and del(22ql 1) syndrome 945 J Med Genet: first published as 10.1136/jmg.35.11.943 on 1 November 1998. Downloaded from Figure 3 Patient 2. (A) Front view in infancy. (B, C)Appearance at the age of 12: note prominent nose with large tip and narrow palpebral fissures. micrognathia, thick helices, short neck, tapering When first evaluated aged 7, several dysmor- fingers, and transverse palmar creases. X rays phic features were noted: ridged metopic showed delayed bone maturation, osteoporosis, suture, narrow, upward slanting palpebral and mild platyspondyly. Scans of the heart and fissures, large nose with bulbous tip, small head were normal. Later, velopharyngeal insuf- mouth, high vaulted palate with bifid uvula, ficiency (without cleft) failed to respond to crowded teeth, small ears, and right posterior intensive speech therapy. He had severe gastro- embryotoxon. She showed painful ankylosis of oesophageal reflux that necessitated gastros- the wrists, elbows, ankles, knees, fingers, and tomy feeding from the ages of 5 to 13. He suf- toes, with secondary retractions of the small fered from chronic constipation and was of joints. Calcium homeostasis, circulating vita- short stature (<3rd centile). His full scale IQ min A, and PTH were normal. X rays showed was estimated at 58 at the age of 14. Fig 3B and osteopenia (confirmed by osteodensitometry) C show his clinical appearance at the age of 12. and generalised JRA arthropathy. Immunologi- JRA was diagnosed at the age of 3. The cal investigations showed normal lymphocyte severe course of the disease required treatment count and the