Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome).

BACKGROUND: Majeed syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. The objectives of this study were to map, identify, and characterise the Majeed syndrome causal gene and to speculate on its function and role in skin and bone inflammation. METHODS: Six individuals with Majeed syndrome from two unrelated families were identified for this study. Homozygosity mapping and parametric linkage analysis were employed for the localisation of the gene responsible for Majeed syndrome. Direct sequencing was utilised for the identification of mutations within the genes contained in the region of linkage. Expression studies and in silico characterisation of the identified causal gene and its protein were carried out. RESULTS: The phenotype of Majeed syndrome includes inflammation of the bone and skin, recurrent fevers, and dyserythropoietic anaemia. The clinical picture of the six affected individuals is briefly reviewed. The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families. LPIN2 was found to be expressed in almost all tissues. The function of LPIN2 and its role in inflammation remains unknown. CONCLUSIONS: We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. Understanding the aberrant immune response in this condition will shed light on the aetiology of other inflammatory disorders of multifactorial aetiology including isolated chronic recurrent multifocal osteomyelitis, Sweet syndrome, and psoriasis.

The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review.

UNLABELLED: A new autosomal recessive syndrome of chronic recurrent multifocal osteomyelitis (CRMO) and congenital dyserythropoietic anaemia (CDA) with microcytosis has recently been described in four children (two sibships) of one consangineous Arab family. In this report, we describe the clinical features and course of the syndrome of CRMO and CDA in two additional patients (one sibship) from another consanguineous Arab family and review the literature. The two patients (brother and sister), the products of a consanguineous marriage, developed the syndrome at an early age of 3 weeks and 2 months respectively. The diagnosis of CRMO was confirmed by radiological and technetium isotope bone scans. Bone marrow studies confirmed the diagnosis of CDA. Peripheral blood films showed hypochromia and microcytosis. The sites involved by CRMO were periarticular, mainly around the elbow, knee, wrist and small joints of the hand. The brother is now 21 years old and the sister 3.5 years old and CRMO is still active with frequent relapses. The brother developed flexion deformities at the age of 13 years. Both patients failed to thrive; weight and height were below the 5th percentile. CONCLUSION: This is the second report of the syndrome of chronic recurrent multifocal osteomyelitis and microcytic congenital dyserythropoietic anaemia, confirming it as a clinical entity, inherited as an autosomal recessive trait. The disease is characterised by an early onset, long clinical course of remissions and relapses, and seems to be different from the sporadic form of chronic recurrent multifocal osteomyelitis.

The clinical patterns of myalgia in children with familial Mediterranean fever.

OBJECTIVES: To study the frequency and clinical patterns of myalgia in a defined group of children with familial Mediterranean fever (FMF). METHODS: A prospective 4-year (September 1995-September 1999) study of children with FMF seen in the pediatric FMF clinic of Jordan University teaching hospital. Diagnosis of FMF was made according to published criteria. Once the diagnosis of FMF and myalgia was made, details about myalgia were collected by interview with the child and his/her parents and entered into a special study form. RESULTS: Of 264 children with FMF seen over the study period, 65 (25%) developed myalgia. Three clinical patterns of myalgia were identified: the spontaneous pattern, the exercise-induced pattern, and the protracted febrile myalgia syndrome (PFMS), seen in 8%, 81%, and 11% of patients, respectively. The three patterns differed in the severity of pain, height of fever, and duration of the episode. In 33 children with the exercise-induced myalgia, in which response to colchicine could be reliably assessed, a favorable response was achieved in 97%. Three children with the PFMS had a dramatic response to corticosteroids. CONCLUSIONS: Myalgia in children with FMF is common and can follow three different clinical patterns.

Differential diagnosis of fever of unknown origin in children.

Fever of unknown origin in children follows two main clinical patterns, namely fever of unknown origin and chronic episodic fever of unknown origin. Fever of unknown origin is characterized by daily fever persisting for more than 3 weeks. The main causes are infectious, rheumatologic disorders, and malignancy. Chronic episodic fever of unknown origin is characterized by fever lasting for a few days to a few weeks, followed by a fever-free interval and a sense of well-being. The main causes are familial Mediterranean fever, the hyper-immunoglobulin D syndrome, familial Hibernian fever, Behcet disease, the syndrome of periodic fever, aphthous stomatitis, pharyngitis and adenitis, and cyclic neutropenia.

Poststreptococcal reactive arthritis.

The occurrence of an entity designated poststreptococcal reactive arthritis (PSReA) has been highlighted in recent reports. The syndrome was considered part of the spectrum of acute rheumatic fever by some, whereas others stressed the differences between the two diseases. As distinct from acute rheumatic fever, PSReA is characterized by a shorter latency period between the inciting streptococcal infection and the onset of arthritis, a higher frequency of involvement of the small joints and axial skeleton, poor response to aspirin and other nonsteroidal anti-inflammatory drugs, a protracted course of arthritis, a low incidence of carditis, and absence of other major manifestations of acute rheumatic fever. Recent studies have demonstrated an increased frequency of DRB1*01 in patients with PSReA, which contrasts with the increased frequency of DRB1*16 in rheumatic fever. Because 6% of patients with PSReA have been reported to have late onset carditis, it is judicious to recommend that patients with PSReA receive prophylactic antimicrobials for a minimum period of 5 years or until the age of 21 years, whichever is longer.

The acute scrotum in Arab children with familial Mediterranean fever.

Over a period of 7 years, among 175 boys under the age of 16 years with familial Mediterranean fever (FMF), 16 (9%) developed 28 episodes of scrotal swelling that was unilateral in 26 (93%) and bilateral in 2 (7%). Fever and pain were present in 15 (94%) children; fever was characterized by a gradual onset and pain was moderate in intensity. The episodes were self-limiting and lasted from 8 h to 5 days. Scrotal swelling was the presenting feature of FMF in 4 (25%) patients. Six (38%) children underwent surgery; the operative findings, available in 3, showed a normal testis and epididymis and inflammation of the tunica vaginalis. The self-limiting nature of the episodes lasting for a few days was similar to the clinical course of serositis seen in FMF. This strongly suggests that inflammation of the tunica vaginalis, resulting in scrotal swelling, is another feature of FMF serositis. The gradual onset of fever, pain, swelling, and recurrence in a boy of Mediterranean origin, especially in the presence of a relevant family history, strongly points toward the diagnosis of FMF and conservative management. Early diagnosis and prophylactic colchicine therapy are expected to avert recurrences, which may result in ischemic testicular necrosis and FMF nephropathy.

Familial Mediterranean fever in children: the expanded clinical profile.

The clinical picture of familial Mediterranean fever (FMF) has been appreciably expanded in the last 10 years. Over 8 years, we studied the expanded clinical profile of FMF in 476 children. Of these, 81% had abdominal pain, 41% chest pain, 42% arthritis, 12% severe myalgia, 12% skin manifestations, 4% scrotal swelling, 3% recurrent episodic fever, and one child (0.2%) developed recurrent hyperbilirubinaemia. Two (0.4%) children developed renal complications which were reversed by colchicine; however of 19 probands, 36 family members suffered from chronic renal failure. Our study indicates a familial predisposition to nephropathy in certain families with FMF. This study is the first to report the expanded clinical profile of FMF in a large group of Arab children, giving an opportunity to compare the findings with those in children with FMF in other ethnic groups, and to help in the study of genotype-phenotype correlation.

Recurrent episodic fever. A presenting feature of familial Mediterranean fever.

OBJECTIVES: To study the natural course and outcome of recurrent episodic fever without serositis as a presenting feature of familial Mediterranean fever (FMF). PATIENTS: Of 309 children with FMF seen over a period of 5 years, 8 presented with recurrent episodes of fever without serositis, imposing a difficult diagnostic problem. RESULTS: The age at onset of fever ranged between 5 months and 8 years with a mean of 2.5 years. Five patients eventually developed serositis. The duration between onset of fever and onset of serositis ranged between 1.5-3 years with a mean of 2 years. Of the 3 patients who did not develop serositis, 2 had a family history of FMF. Therapeutic response to colchicine was dramatic in 7 children (one refused colchicine prophylaxis). CONCLUSION: Episodic fever alone without serositis is a presenting feature of FMF. In patients from Mediterranean ancestors and/or the presence of family history of FMF, a therapeutic diagnostic test with colchicine could be rewarding.

Recurrent hyperbilirubinaemia, a feature of familial Mediterranean fever: report of a child and review of the literature.

Recurrent hyperbilirubinaemia was described as a feature of familial Mediterranean fever in the 1950s and early 1960s. However, over the last 33 years only one case has been published. We present a 12-year-old Arab boy who developed recurrent hyperbilirubinaemia in the course of familial Mediterranean fever. His response to colchicine was excellent. Review of the literature reveals that hyperbilirubinaemia of familial Mediterranean fever has a distinct clinical picture characterized by concurrent peritonitis, minimal jaundice and short duration. Factors contributing to the paucity of reports in recent literature are discussed.

Renocolic fistula as a complication to xanthogranulomatous pyelonephritis.

Four patients with xanthogranulomatous pyelonephritis were found to have renocolic fistulae. Coincidentally, the left kidney was involved in all four cases. All patients presented with renal mass. Two cases have had coexistent renal stones, one of them presented with massive upper gastrointestinal bleeding as a result of portal hypertension. Another patient had a history of Schistosomiasis. In none of the patients was the renal condition confidently diagnosed preoperatively, nor was the colonic fistula suspected. In all four patients, nephrectomy was performed together with resection of the involved colon followed by a satisfactory recovery. The possibility of a colonic fistula should be kept in mind as a complication to this rare renal condition in spite of the absence of colonic symptoms and normal finding in barium enema studies.

The clinical patterns of arthritis in children with familial Mediterranean fever.

We studied the clinical patterns of arthritis in 133 children with familial Mediterranean fever (FMF) over 5.5 years. Six clinical patterns were noted. The commonest was recurrent monoarticular arthritis as seen in 95 children (71%), mainly affecting the knee and ankle joints. This type followed two different courses: acute (< 1 month) and chronic (> 1 month). In 18 (14%) children, both knee or ankle joints were simultaneously and symmetrically involved: here too the course was either acute or chronic. Five (4%) children developed symmetric polyarthritis similar to juvenile rheumatoid arthritis (JRA). Six (4%) children developed asymmetric oligoarticular arthritis similar to acute rheumatic fever (ARF). The small joints of the hands (SJH) were involved in seven (5%) children, and the small joints of the feet in one. One child developed sacroiliitis similar to ankylosing spondylitis (AS). Between attacks, the joints were normal. Overall, outcome was good: residual damage of the hip joint occurred in one patient and of the shoulder in another. Although the clinical presentation and course of FMF arthritis are diverse, delineating these clinical patterns may help with earlier recognition and treatment. The low incidence of residual articular damage in this study may be related to the use of colchicine prophylaxis.

Familial Mediterranean fever in Arab children: the high prevalence and gene frequency.

UNLABELLED: Over a period of 3 years, 192 children with familial Mediterranean fever were prospectively studied. Of these, 106 (55%) were girls and 86 (45%) were boys. The prevalence was 1:2600 children with a gene frequency of 1:50. The age at onset ranged between 4 months and 16 years. Of these patients 24% started their illness below the age of 2 years and 88% were symptomatic before the age of 10 years: 82% had recurrent abdominal pain, 43% had pleurisy, 37% had arthritis, 15% had cutaneous manifestations, 12% had splenomegaly and 4% had hepatomegaly. The presenting symptoms were abdominal pain in 51%, unilateral chest pain in 23% and arthritis in 26%. The family history was positive in 62%. Of 12 affected families 19 members had/have renal failure and amyloidosis was confirmed in 7 patients. CONCLUSIONS: Our data show a high prevalence of familial Mediterranean fever and a high gene frequency in Arab children similar to that reported in Jews and Americans.

The group specific polysaccharide antibody in children with non-suppurative sequelae of group A streptococcal infection.

The kinetics of the group A specific polysaccharide antibody were studied in children with acute rheumatic fever who had no carditis, children with acute rheumatic fever who had carditis and developed rheumatic heard disease and in children with acute poststreptococcal glomerulonephritis. The children with rheumatic fever who had carditis and those who did not, were kept on continuous antistreptococcal prophylaxis. In the group of children who developed rheumatic heart disease the titer of the antibody at onset was significantly higher than those who had rheumatic fever but no carditis (P = 0.01). After a mean follow-up period of three years, a high titer was maintained in children who developed rheumatic heart disease only and was significantly higher than that found in children with rheumatic fever who had no carditis (P = 0.001) and in children with poststerptococcal nephritis (P = 0.001).

Acute rheumatic fever in Kuwait: The declining incidence.

The incidence of acute rheumatic fever in children aged 5-14 years in Kuwait was studied prospectively over a period of five years (1984 through 1988). The mean annual incidence in the study period was 2.9/100,000 children. There was a decline in the incidence from 3.7/100,000 in 1984 to 2.5/100,000 in 1988. Twenty-seven percent of children with acute rheumatic fever presented as recurrences in 1985; this also declined to 11% in 1988.

Office diagnosis and management of group A streptococcal pharyngitis employing the rapid antigen detecting test. A 1-year prospective study of reliability and cost in primary care centres.

The impact of introducing the rapid antigen detecting test for the diagnosis of group A streptococcal pharyngitis in primary care centres and the direct and comprehensive cost-effectiveness of four alternative strategies for the management of group A streptococcal pharyngitis and the prevention of rheumatic fever were assessed in a 1-year prospective randomized study, carried out in children between the ages of 5 and 14 years. Data from the study showed that the test was easy to perform and reliable when introduced as a service in primary care. The strategy of using the rapid antigen detecting test and a 10-day oral penicillin course for diagnosis and treatment proved to be the safest and most cost-effective. If compliance with a 10-day course of oral penicillin is unlikely to be achieved, the strategy of introducing the test and treatment by intramuscular benzathin penicillin G proved to be the second best cost-effective alternative. In developing countries, where acute rheumatic fever is still common and the cost of the test and a 10-day course of penicillin may prove to be formidable, a strategy of treating all children with pharyngitis with intramuscular benzathin penicillin G seems to be the most cost-effective. The strategy of diagnosing group A streptococcal pharyngitis on clinical grounds proved to be the worst.

Acute rheumatic fever and the evolution of rheumatic heart disease: a prospective 12 year follow-up report.

Sixty four children who presented with the initial attack of acute rheumatic fever and maintained continuous regular secondary prophylaxis, were followed up prospectively for 12.3 years (an observation period of 775 patient-years). The prevalence rate of rheumatic heart disease in the 29 children who had carditis in the initial attack and in the 35 children who had no carditis initially was 49 vs 0%, respectively. The overall prevalence rate of rheumatic heart disease was 20%. Mitral incompetence developed in 11 patients (17%), aortic incompetence in 2 (3%) and mitral stenosis in 2 (3%). None of the patients developed aortic stenosis. Two recurrences developed with a recurrence rate of 0.003 per patient per year. One patient needed cardiac surgery and there was no mortality. These data strongly suggest that continuous regular secondary prophylaxis can prevent or significantly reduce the development of mitral and aortic valve stenosis, the prevalence rate of rheumatic heart disease and mortality.

Group A streptococcal strains in Kuwait: a nine-year prospective study of prevalence and associations.

During a period of 9 years (December, 1980, through November, 1989), 407 Group A streptococcal strains were isolated from 294 children with acute rheumatic fever and 303 of their family contacts, 234 children with acute post-streptococcal glomerulonephritis and 242 of their family contacts and 219 children with uncomplicated Group A streptococcal pharyngitis. Of the 407 strains 216 (53%) were M and/or serum opacity factor typable, 143 (35%) were only T typable and 48 (12%) were nontypable. Throughout the period of study the M12 and M1 were the most prevalent strains; however, important changes among the prevalent strains were observed. Although the study started in 1980 the serotypes M18, M81, M3, M15 and M58 made their first appearance 7 to 9 years later. These findings show the value of long term studies in detecting the changes in the prevalence of streptococcal strains in the community. M18 was isolated from three children with nephritis but not from children with rheumatic fever; this association has not been reported before. M12 was isolated from 26% of the nephritic children and their families vs. 7% from the rheumatic children and their families (P less than 0.05) vs. 17% from children with uncomplicated streptococcal pharyngitis. M49 was isolated from 7% of the nephritic children and their families vs. none from rheumatic children and their families vs. 1.4% from children with uncomplicated streptococcal pharyngitis. These findings support the concept of nephritogenicity of some streptococcal strains.(ABSTRACT TRUNCATED AT 250 WORDS)

Human heart sarcolemmal sheath antibodies in children with non-suppurative sequelae of group A streptococcal infections: a follow up study.

The kinetics of the human heart sarcolemmal sheath antibody were studied in children with acute rheumatic fever who had no carditis, children with acute rheumatic fever who had carditis and developed rheumatic heart disease, and in children with acute poststreptococcal glomerulonephritis. The children with rheumatic fever and those who developed valvular heart disease were given continuous secondary antistreptococcal prophylaxis. The titre of antibody at onset was significantly higher than that of the controls in children with acute rheumatic fever and carditis and in children with acute poststreptococcal nephritis. The difference in the antibody titre between children with rheumatic fever who had no carditis and controls was not statistically significant. After a mean follow up of three years, however, a high titre was only maintained in children with rheumatic fever who developed valvular heart disease.