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 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.

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)

Children with acute rheumatic fever and acute poststreptococcal glomerulonephritis and their families in a subtropical zone: a three-year prospective comparative epidemiological study.

Over a period of three years (December 1980 through November 1983) the incidence and epidemiological features of acute rheumatic fever (ARF) and acute poststreptococcal glomerulonephritis (AGN) were studied prospectively in two regional hospitals in Kuwait serving a childhood population of 225,000. The study included 146 children with ARF and 256 family members and 125 children with AGN and 199 family members. The annual incidence of ARF and AGN were 19.6 and 17.8 respectively per 100,000 childhood population (7.3 and 6.7 respectively per 100,000 total population). Both diseases occurred sporadically throughout the year with a similar peak in winter. The clinical profile of ARF was essentially similar to that reported from temperate climates, and AGN followed mainly throat infections. Microscopic haematuria was detected in ten ARF family members (4%) and in 20 AGN family members (10%). Haematuria and low C3 were found in two (0.8%) and in seven (3.5%) ARF and AGN family members respectively. Of the nine family members with subclinical nephritis the group C streptococcus was isolated from three (33%). The geometric mean titre (GMT) of antistreptolysin O (ASO) and of antihyaluronidase (AH) in ARF and AGN patients were markedly elevated. Although the median age of ARF and AGN family members were 13 and 15 years respectively, yet the GMT of ASO and AH in the family members were slightly higher than those of the normal childhood population.

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 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.

Significance of endostreptosin antibody titers in poststreptococcal glomerulonephritis.

Endostreptosin (ESS) is an immunologically well defined cytoplasmic antigen of group A and some group C streptococci. ESS is probably the pathogenetic antigen of poststreptococcal glomerulonephritis (ASGN). Antibodies to ESS (ESS-Ab) were determined by microcomplement fixation in 1,102 patients and by ELISA in 105 patients. In 168 patients with ASGN (90 from the U.S.A. and 78 from Kuwait) the arithmetic mean titer was 45.2 (log10 1.40 +/- 0.606) and 50.2 (log10 1.51 +/- 0.394) respectively, both significantly elevated compared to 347 age matched children and adults from the U.S.A. whose arithmetic mean titer was 9.1 (log10 0.83 +/- 0.635) and 7.5 (log10 0.55 +/- 0.492) respectively and 139 children from Kuwait whose arithmetic mean titer was 15.7 (log10 0.92 +/- 0.495). In 51 patients with ASGN, the mean ELISA value was 67.5% higher than the values obtained from 54 normal age matched controls. Patients with streptococcal infections without renal involvement had only transiently and mildly elevated values. ESS-Abs in patients with other types of glomerulonephritides were in the range of normal. ESS-Ab titers do not parallel the titers of streptococcal exoenzymes. ESS-Ab titers are of importance for the differential diagnosis of renal diseases and of similar significance for the understanding of the pathogenetic mechanism of ASGN. They are possibly of significance for therapy in the form of an active vaccine.

Hypernatremic dehydration in infants with gastroenteritis.

Of 1045 children admitted with gastroenteritis over a 12-month period and studied retrospectively, serum sodium level was tested in 802. Sixty patients (7.5%) had hypernatremic dehydration (HD). The peak incidence of HD, the highest serum sodium levels, and the worst outcome were all encountered in infants under the age of 3 months. An association with pre-admission high solute feeding was less obvious. Pre-admission volume intake could not be evaluated. There was no association of HD with the etiological pathogen or climatic conditions. The weight-for-age was below the fifth percentile in 21 patients (35%). One patient (1.7%) died, another (1.7%) developed peripheral gangrene, and four (6.7%) were left with significant neurologic complications. All of these patients were under the age of 4 months. In this subtropical country, the most important risk factor for the development of hypernatremia in the course of gastroenteritis is the young age. Environmental risk factors do not seem to play a significant role.

Sporadic pharyngitis-associated acute poststreptococcal nephritis. A four-year prospective clinical study of the acute episode.

Between December 1980 and November 1984, the acute episode was studied prospectively in 187 children under 14 years presenting with acute poststreptococcal glomerulonephritis. The mean annual incidence was 19.5/10(5) children. The disease was mainly pharyngitis-associated and occurred throughout the year but peaked in the winter. The mean age was 5.4 years, and 71 percent of children were under the age of 8 years. Gross hematuria was the presenting feature in 93.6% of cases and was usually associated with edema. Hypertension was present in 45 percent, circulatory congestion in 27 percent, and heavy proteinuria in 22 percent of cases. The C3 level was low in 97 percent of the patients tested and returned to normal within 6-8 weeks. There were no deaths. Only one patient needed peritoneal dialysis. All except one patient were asymptomatic with normal creatinine within 8 weeks. The authors adopted a very optimistic attitude in the counseling of children with the disease and of their families.

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 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.

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.

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.

Familial Mediterranean fever (recurrent hereditary polyserositis) in children: analysis of 88 cases.

The clinical profile, course and complications of familial Mediterranean fever (recurrent hereditary polyserositis) seen in 88 children over a period of 11 years are presented. Forty eight children (55%) started their illness below the age of 5 years, and the mean age of onset was 4.9 years. Peritonitis occurred in 85% of children, arthritis in 50%, pleuritis in 33% and erysipelas-like lesions in 16%. Two children developed renal amyloidosis, and one third of the children were subjected to unnecessary operative surgery, reflecting the diagnostic difficulties. The arthritis was mono-articular in 80% and polyarticular in 20% of children with arthritis, and was seronegative (rheumatoid factor and antinuclear antibodies). Human leucocyte antigen (HLA) typing for the B-27 antigen carried out in ten children with arthritis was negative. The synovial attack showed a wide variation in the clinical presentation, course and duration of arthritis, causing diagnostic difficulties. The difficulties in the differentiation of recurrent hereditary polyserositis (familial Mediterranean fever) arthritis from the common causes of acute and chronic juvenile arthritis and the seronegative spondyloarthropathies are discussed. Of 45 children treated with colchicine, 42 children (93%) achieved a therapeutic response.

Evaluation of a two-minute strep A direct swab test (SADST) on patients with pharyngitis at a primary care clinic.

A two-minute strep A direct swab test (SADST) was used to detect the presence of Lancefield group A streptococci (GAS) from the throats of 207 patients with pharyngitis at a primary-care clinic. The results were compared with a standard culture method. Fifty-one specimens were positive and 156 specimens were negative for GAS by culture. The SADST had a sensitivity of 96% (49 of 51) and specificity of 98.7% (154 of 156). The predictive values of a positive and negative SADST, for GAS, were 96% and 98.7% respectively. The SADST showed negative reactions with five specimens containing beta-haemolytic streptococci other than GAS and 34 known stock cultures other than GAS. Our results indicate that SADST is a rapid, simple, convenient and reliable test to use for diagnosis of GAS pharyngitis at primary care clinics, physicians' offices and clinical laboratories.

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.