Monia Khemiri

Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels

BACKGROUND Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans. OBJECTIVE We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8. METHODS After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry. RESULTS Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation. CONCLUSION Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.

Screening for celiac disease in idiopathic pulmonary hemosiderosis

AIM The aim of this report was to screen for celiac disease (CD) in patients with idiopathic pulmonary hemosiderosis (IPH). PATIENTS AND METHODS Patients with IPH treated at the Childrens Hospital of Tunis between 1976 and 2006 were reviewed and investigated for CD, using serological and histological tests. RESULTS A total of 10 children (two boys and eight girls) had IPH. The mean age at diagnosis was 3.1 years. Three had digestive symptoms and positive CD serology, which was confirmed by histological data. Clinical and radiological findings improved markedly in all CD patients with corticosteroid treatment combined with a gluten-free diet. Symptoms of IPH and CD both returned in one patient who stopped the gluten-free diet. CONCLUSION Three of our 10 patients with IPH also had CD. These data illustrate the close etiopathogenic link between IPH and CD, and strongly suggest that CD be looked for in IPH patients, especially in those with symptoms suggestive of CD.

Bronchogenic cyst: an uncommon cause of congenital lobar emphysema.

We report a case of a 1-month-old boy who has developed respiratory distress. Chest X-ray and CT scan showed over distension of the left upper lobe and a mediastinal shift in favour of congenital lobar emphysema (CLE) of the left upper lobe. One month after uneventful lobectomy, he was readmitted at hospital for another episode of respiratory distress. Chest radiography revealed relapse of compressive emphysema in the remaining left lobe. Gastro oesophageal transit and MRI were performed, which have shown a mediastinal cystic mass. Accordingly, the patient underwent thoracotomy. Surgical examination found a subcarinal bronchogenic cyst which compressed the main left bronchus, causing the CLE of both upper and lower left lobes. Histological examination of removed cyst confirmed these data. Authors discuss causes of diagnostic delay.

A founder mutation underlies a severe form of phosphoglutamase 3 (PGM3) deficiency in Tunisian patients

Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Mutations in PGM3 gene have been recently shown to underlie a new congenital disorder of glycosylation often associated to elevated IgE. Herein, we report twelve PGM3 deficient patients. They belong to three highly consanguineous families, originating from a rural district in the west central Tunisia. The patients clinical phenotype is characterized by severe respiratory and cutaneous infections as well as developmental delay and severe mental retardation. Fourteen patients died in early infancy before diagnosis supporting the severity of the clinical phenotype. Laboratory findings revealed elevated IgE, CD4 lymphopenia and impaired T cell proliferation in most patients. Genetic analysis showed the presence, of a unique homozygous mutation (p.Glu340del) in PGM3 gene leading to reduced PGM3 abundance. Segregating analysis using fifteen polymorphic markers overlapping PGM3 gene showed that all patients inherited a common homozygous haplotype encompassing 10-Mb on chromosome 6. The founder mutational event was estimated to have occurred approximately 100 years ago. To date, (p.Glu340del) mutation represents the first founder mutation identified in PGM3 gene. These findings will facilitate the development of preventive approaches through genetic counselling and prenatal diagnosis in the affected families.

Tuberculous Meningitis in Bacille Calmette-Guerin–Vaccinated Children : Clinical Spectrum and Outcome

The Bacille Calmette-Guérin vaccination (BCG) contributed widely to reduce tuberculosis incidence in developing countries. The aim of this report was to assess the clinical “spectrum” and outcome of tuberculous meningitis in 16 Bacille Calmette-Guérin–vaccinated Tunisian children. They were 9 boys and 7 girls aged 2 to 168 months (median 72 months ± 65.88). Patients presented mainly with nonspecific symptoms. Neurologic severity was classified as grade I (n = 6) and grade II or III (n = 10). At short-term course, the majority of patients developed serious complications: hydrocephalus (n = 12), seizures (n = 8), tuberculoma (n = 6), and acute respiratory failure (n = 2). Three patients died. Among survivors, 4 patients showed a complete recovery while 9 developed permanent sequelae which were mild (n = 6) to severe (n = 3). Despite the Bacille Calmette-Guérin vaccination, tuberculous meningitis remains a life-threatening condition; vaccinated children have shown common presentation of tuberculous meningitis in terms of severity and poor outcome.

Pseudotumoral cutaneous aspergillosis in chronic granulomatous disease, report of a pediatric case.

Abstract:Invasive aspergillosis is a life-threatening condition in patients with chronic granulomatous disease (CGD). Skin invasion by Aspergillus occurs most commonly by contiguity to a neighboring cavity. We describe an unusual case of invasive cutaneous aspergillosis presented as a large burgeoning tumor in a 4-year-old girl with CGD who underwent surgical treatment for bifocal osteomyelitis of the left leg. The skin invasion occurred 4 months after a “successful” treatment of invasive pulmonary aspergillosis. Atypical presentation and diagnostic difficulties are discussed. Invasive cutaneous aspergillosis may be polymorphic. The diagnosis should be considered early in the etiological investigation of any suspicious skin lesions in CGD even in uncommon aspects such as burgeoning tumors.

Severe toxic methemoglobinemia mimicking septic shock in an infant.

Infants younger than six months of age are at an increased risk of methemoglobinemia (MTH) (Woolf and Wright, 2004). However, severe toxic MTH with a methemoglobin rate exceeding 60% has been rarely reported in the pediatric literature. The diagnosis may be unrecognized in infants, with a life-threatening condition due to multivisceral tissue hypoxia. We illustrate with the following case the occurrence of a central cyanosis associated to neurological distress and cardiovascular shock, due to a severe MTH in a young infant exposed to nitrites.

Hémorragie digestive révélant un corps étranger œsophagien chronique. À propos d’une observation pédiatrique

human hairless (HR) au niveau du chromosome 8p 12 a été rapportée initialement par Ahmad et al. [5]. Ultérieurement, plusieurs publications ont confirmé ce type de mutation et ont permis de mieux localiser le gène [1,6,7]. Des mutations, parfois multiples, au niveau du gène HR sont impliquées dans la pathogénie de ce syndrome [1]. L’hétérogénéité phénotypique des atrichies congénitales est causée par la variabilité du siège des mutations au niveau de ce gène [7].