[DRESS syndrome and agranulocytosis, a rare combination]. / Syndrome d'hypersensibilité médicamenteuse et agranulocytose, une association rare.

INTRODUCTION: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe toxidermia that can lead to death from multivisceral failure. We report a case of DRESS associated with febrile agranulocytosis in a child. OBSERVATION: An 8-year-old child was hospitalized for diffuse maculopapular exanthema with edema of the extremities and face associated with cheilitis and febrile agranulocytosis. This symptomatology began 1month after the introduction of carbamazepine for partial epilepsy. The clinical picture was a multisystemic disease with colitis, interstitial pneumonitis, hepatic cytolysis, and hepatocellular insufficiency. HHV7 viral reactivation and increased eosinophils (20%) in the myelogram were demonstrated, providing the diagnosis of DRESS. The progression was favorable after carbamazepine therapy was stopped and systemic corticosteroids were administered. DISCUSSION: DRESS syndrome is a disorder that is unfamiliar to pediatricians. Its association with agranulocytosis is rare and the absence of hypereosinophilia contributed to diagnostic difficulties in this case. The multisystemic failure, the reactivation of HHV7, the increase of eosinophils in the myelogram, and the favorable progression under systemic corticosteroid therapy contributed greatly to the diagnosis. A cutaneous biopsy was not considered necessary for the diagnosis in the case reported herein. CONCLUSION: DRESS syndrome is rarely associated with agranulocytosis, but its diagnosis must be quickly raised so that the incriminated drug can be interrupted.

Management of pancreatic, gastrointestinal and liver complications in adult cystic fibrosis.

INTRODUCTION: The gastrointestinal tract is a major source of morbidity in adults with cystic fibrosis (CF), with a wide range of complications, some of them being specific to the underlying disease. STATE OF KNOWLEDGE: Abnormal CFTR function, with reduced bicarbonate and other ion transport levels through the apical surface of epithelial cells, affects the intestinal tract including the pancreas and the liver. Similarly to what is observed in the respiratory tract, gastrointestinal CFTR dysfunction leads to mucus accumulation, dysmotility, small bowel bacterial overgrowth and inflammation with alteration of innate immune responses, all of which being likely to be interrelated. In developed countries, almost half of patients with CF are adults followed in multidisciplinary CF care centres by pneumologists who often have to manage gastrointestinal complications. CONCLUSION: It therefore appears essential that adult gastroenterologists develop the expertise needed for managing CF gastrointestinal complications in close collaboration with multidisciplinary CF care centre teams to improve the quality of life of adults with CF.

[Do we need congenital adrenal hyperplasia screening for premature infants?]. / Faut-il maintenir un dépistage de l'hyperplasie congénitale des surrénales pour les prématurés ?

Congenital adrenal hyperplasia neonatal screening has been introduced in France since 1995. A recent survey has questioned its relevance in premature infants because of a high number of false positives and a low positive predictive value of 17-hydroxyprogesterone dosage. A workgroup at the French screening association (Association française de dépistage et de prévention des handicaps de l'enfant) collected all the epidemiological, clinical and biological data of premature children presenting with adrenal hyperplasia from the national cohort. Their results were compared with those of healthy premature children. All the data showed that the screening in children born before 32 weeks of gestational age is irrelevant, but that it is efficient after this term. A pilot study has been implemented in population to evaluate the opportunity to discontinue this screening in extreme preterm neonates.

[Genetic testing in asymptomatic minors: a survey among French geneticists]. / Les tests génétiques présymptomatiques chez le mineur: enquête auprès des généticiens français et position du groupe français de génétique prédictive.

Since their introduction, genetic tests have been carefully considered, with special attention to the release of information about the test and test results, the confidentiality of genetic information, the request and its motivation, and the psychological impact of the test. Careful consideration is needed when family members at risk are asymptomatic children or adolescents. Cautious reflection is warranted on whether and under which conditions genetic testing should be performed. Here, we report on the results of a survey conducted in France among 50 geneticists questioned on their opinions and practices concerning presymptomatic testing in three groups of diseases: those for which a medical benefit exists during childhood (e.g., retinoblastoma), diseases with onset during childhood for which there are no immediate medical consequences (e.g., type II/III spinal muscular atrophy), and those with onset during adulthood for which there is no medical benefit during childhood (e.g., Huntington disease). Guidelines are proposed: presymptomatic testing should not be performed in a minor without individual and direct information, all requests for presymptomatic genetic testing concerning a disease with onset in adulthood should be postponed, and all presymptomatic test requests for a minor should be addressed to a multidisciplinary team.

The pituitary stalk interruption syndrome: endocrine features and benefits of growth hormone therapy.

INTRODUCTION: Childhood anterior-pituitary insufficiency has many causes (malformative, genetic, traumatic, tumoral...). One particular entity can be clearly identified: pituitary stalk interruption syndrome (PSIS). The aim of our study was to analyse the long-term evolution of patients with PSIS. PATIENTS AND METHODS: The records of all the children followed at Dijon University Hospital between 1990 and 2008 who underwent brain magnetic resonance imaging (MRI) and endocrinological evaluation that revealed a growth hormone (GH) deficiency were analysed. We thus selected 14 children diagnosed with PSIS according to the results of MRI. We studied the perinatal characteristics of these patients, then the auxological and the endocrine evolutions, before the initiation of GH therapy and then after 1 and 3 years of treatment and during the last evaluation. RESULTS: Fourteen children were diagnosed with PSIS at a mean+/-sd age of 3.2+/-3.5 years, five of whom being diagnosed during the first 2 months of life. Growth, as well as other anterior-pituitary deficiencies, was systematically followed up two to four times a year depending on the clinical context. The results in terms of endocrinology were analysed in all 14 children, and with regard to auxology in the 10 children who received GH therapy for at least 12 months, with a mean of 8.3+/-4.2 years and at a mean maintenance posology of 0.22+/-0.02mg/kg per week. Among the 14 children, 12 had complete GH deficiency while two had a partial deficiency. Nine had multiple anterior pituitary deficiencies, diagnosed at the same time or later in five and four of them respectively. A clinical picture of panhypopituitarism was found in the infants who were diagnosed with PSIS in their first months of life. In the 10 children who were treated for at least 12 months, the height before treatment was -3.1+/-0.8 standard deviation score (SDS). At the last consultation, the total gain in height was +2.5+/-0.9 SDS compared to the distance to target height of +2.7+/-0.6 SDS. The height gain after 1 year of treatment corresponded to 60% of the total gain. CONCLUSION: In children with PSIS, the other anterior pituitary deficiencies are often associated with GH deficiency and sometimes during the first month of life. These functions therefore require to be carefully followed early, periodically and in the long term. Growth in these children responds particularly well to GH therapy, in particular during the first year.

Factors associated with mucoid transition of Pseudomonas aeruginosa in cystic fibrosis patients.

Although the mucoid form of Pseudomonas aeruginosa (Pa) is largely responsible for the progression of lung disease in cystic fibrosis (CF), the relationship between factors relating daily-care regimes to mucoidy acquisition are as yet poorly investigated. Fifty-two CF patients registered at the CF centre of Dijon, France, were retrospectively evaluated from the date of Pa colonization either to the first positive sputum culture for mucoid Pa (n = 26) or to the last culture in which the Pa remained non-mucoid (n = 26). All clinical, pathological and therapeutic events were recorded. The association between the parameters collected and mucoid transition of Pa was assessed in a Cox model with time-dependant covariables. The mean follow-up was 4.7 + or - 4.3 years. Three independent parameters were associated with the higher risk of mucoid transition of Pa: persistence of Pa in sputum (OR 7.89; p <0.01), use of inhaled bronchodilators (OR 3.40; p = 0.04), and the use of inhaled colimycin (OR 4.04; p = 0.02). Isolation of Staphylococcus aureus, Haemophilus influenzae or Streptococcus pneumoniae in sputum was associated with a lower risk (OR 0.24; p < 0.01). Mucoid transition of Pa was associated with variables that reflected the severity of both lung disease and Pa colonization. Although they do not lead to prophylactic measures, these results corroborate the need to avoid Pa persistence.

Renal insufficiency, a frequent complication with age in oral-facial-digital syndrome type I.

The oral-facial-digital syndrome type I (OFD I) is characterized by multiple congenital malformations of the face, oral cavity and digits. A polycystic kidney disease (PKD) is found in about one-third of patients but long-term outcome and complications are not well described in the international literature. Renal findings have been retrospectively collected in a cohort of 34 females all carrying a pathogenic mutation in the OFD1 gene with ages ranging from 1 to 65 years. Twelve patients presented with PKD - 11/16 (69%) if only adults were considered -with a median age at diagnosis of 29 years [IQR (interquartile range) = (23.5-38)]. Among them, 10 also presented with renal impairment and 6 were grafted (median age = 38 years [IQR = (25-48)]. One grafted patient under immunosuppressive treatment died from a tumor originated from a native kidney. The probability to develop renal failure was estimated to be more than 50% after the age of 36 years. Besides, neither genotype-phenotype correlation nor clinical predictive association with renal failure could be evidenced. These data reveal an unsuspected high incidence rate of the renal impairment outcome in OFD I syndrome. A systematic ultrasound (US) and renal function follow-up is therefore highly recommended for all OFD I patients.

The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening.

BACKGROUND: Cystic fibrosis (CF) is caused by compound heterozygosity or homozygosity of CF transmembrane conductance regulator gene (CFTR) mutations. Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice. METHODS: The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. The allelic prevalences of R117H (p(R117H)), on either intron 8 T5 or T7 background, and F508del (p(F508del)) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype. RESULTS: Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. The disease phenotype was predominantly mild; one child had classical CF, and three adults' severe pulmonary symptoms. In 5245 healthy adults, p(F508del) was 1.06%, p(R117H;T7) 0.27% and p(R117H;T5)<0.01%. The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%. CONCLUSIONS: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. The real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes.

Polymicrogyria in a child with inv dup del(9p) and 22q11.2 microduplication.

Polymicrogyria (PMG) is a relatively common malformation of the cortex for which the pathogenesis remains poorly understood. Both acquired and genetic causes are known, and to date more than 70 cases of PMG have been associated with chromosomal abnormalities. Here we report on a 12-year-old girl presenting with asymmetrical PMG predominantly affecting the right occipital lobe. She was the only child of consanguineous parents. At 7 years of age she was referred for mental retardation with speech delay and seizures. Cytogenetic studies of the patient revealed an inverted 9p duplication/deletion and bacterial artificial chromosomes (BACs)-array also showed a 22q11.2 microduplication confirmed by quantitative PCR. This case is of interest in the search for candidate genes and emphasizes the importance of the 22q11 region in PMG. It also highlights the efficiency of BACs-array in detecting complex rearrangements.

Tubulopathy and pancytopaenia with normal pancreatic function: a variant of Pearson syndrome.

Out of a series of 30 French patients with Pearson syndrome, we report on two patients with an atypical presentation, which include growth deficiency, pancytopaenia, tubulopathy and absence of exocrine pancreas dysfunction. Patient 1, a 4-year-old boy with a past history of pancytopaenia and transient metabolic acidosis at 13 months of age, presented at 2(1/2) years of age with severe tubulopathy of de Toni-Debré-Fanconi type, growth retardation, metabolic lactic acidosis and mild cytolysis. Despite normal exocrine pancreatic function, study of mitochondrial DNA revealed a 3.5 kb deletion. Patient 2 had a personal history of pancytopaenia requiring blood transfusions at 11 months of age and presented with severe intractable proximal and distal tubulopathy at 2 years of age. Exocrine pancreatic deficiency could not be evidenced and post-mortem studies revealed a 4.9 kb deletion of the mitochondrial DNA. A review of the literature revealed three patients presenting with Pearson syndrome and tubulopathy with normal pancreatic function and highlights delay in diagnosis in those three patients. The series of 30 French patients with Pearson syndrome also revealed that tubulopathy was present in 7/30 cases (23%), with variable outcome. In conclusion, Pearson syndrome should be screened for in children presenting with the association of growth retardation, anaemia/pancytopaenia, lactic acidosis and tubulopathy, even in the absence of exocrine pancreatic deficiency.

Array-CGH in a series of 30 patients with mental retardation, dysmorphic features, and congenital malformations detected an interstitial 1p22.2-p31.1 deletion in a patient with features overlapping the Goldenhar syndrome.

Genosensor Array 300 (Abbott) is a multiplex platform for array-based comparative genomic hybridization that detects unbalanced genomic aberrations including whole chromosome gains/losses, microdeletions, duplications and unbalanced subtelomeric rearrangements. A series of 30 patients with unexplained mental retardation, dysmorphic features, congenital abnormalities and normal high resolution karyotype and FISH subtelomeric studies were analyzed using Genosensor Array 300 array-CGH. We identified a chromosomal aberration in one patient with an interstitial 1p31.1 deletion. FISH analysis with BACs specific probes of the 1p region confirmed the interstitial 1p22.2-p31.1 deletion. The patient was a 20-year-old man with short stature, facial dysmorphism including asymmetry, scoliosis, severe psychomotor delay and an epibulbar dermoid cyst. The phenotype was compatible with Goldenhar syndrome despite the absence of asymmetric ears. This observation is of interest since it could be a clue in the search for the genes responsible for Goldenhar syndrome. This study demonstrates the utility of the array-CGH technology in detecting interstitial deletions.

Untreated growth hormone deficiency with extremely short stature, bone dysplasia, cleft lip--palate and severe mental retardation in a 26-year-old man with a de novo unbalanced translocation t(1;12)(q24;q24).

We report on a 26-year-old patient presenting with extremely short stature (height 72cm, weight 6.5kg, OFC 42.5cm), facial dysmorphism, cleft lip--palate, severe mental retardation and de novo 1q24.2--q25.2 and 12q24.31 interstitial deletion. He was the only child of non-consanguineous parents and his birth length was 43cm. He had severe feeding difficulties and required enteral nutrition until the age of 3 years. Standard cytogenetic analysis showed an apparently balanced de novo translocation t(1;12)(q24;q24). Endocrine studies at 11 years of age for severe growth retardation revealed multiple pituitary hormone deficiency with severe growth hormone deficiency, but the child was untreated because of associated mental retardation. At 26 years of age, he could not walk or speak and had no signs of puberty. Investigations revealed spondylo-epi-metaphyseal dysplasia with severe osteoporosis, enlarged aorta when compared to the patient's size and apparently normal pituitary development. High resolution karyotype showed a 1q24-q25 deletion, and comparative genomic hybridization studies confirmed the 1q interstitial deletion. FISH studies of both breakpoints using PACs and BACs enabled us to further characterize the 1q interstitial deletion (1q24.2-1q25.2) and also revealed a 12q24.31 interstitial microdeletion. This case is compared with previously reported patients with similar deletions, but the untreated pituitary deficiency could also be responsible in part for the severity of the growth deficiency. This observation is of interest for two reasons. First, these deletions could be a clue in the search for a gene responsible for growth hormone deficiency/midline defects. Second, it shows the importance of molecular cytogenetics in the study of de novo apparently balanced translocation with abnormal phenotype.

Low mannose-binding lectin concentration is associated with severe infection in patients with hematological cancer who are undergoing chemotherapy.

BACKGROUND: Mannose-binding lectin (MBL) is a serum lectin involved in innate immune response. Low serum MBL concentration may constitute a risk factor for infection in patients receiving myelosuppressive chemotherapy. METHODS: We conducted a prospective, observational study that assessed MBL concentration as a risk factor for infection in patients with hematological malignancy who were hospitalized to undergo at least 1 chemotherapy cycle. MBL deficiency was defined using an algorithm that considered the serum MBL concentration and the MBL genotype. The primary end point was the ratio of duration of febrile neutropenia to the duration of neutropenia. Secondary end points included the incidence of severe infection (e.g., sepsis, pneumonia, bacteremia, and invasive fungal infection). Logistic regression analysis was conducted, and Fisher's exact test was used to analyze binary outcomes, and Kaplan-Meier estimates and log rank tests were used for time-to-event variables. RESULTS: We analyzed 255 patients who received 569 cycles of chemotherapy. The median duration of neutropenia per cycle was 7 days (interquartile range, 0-13 days). Sixty-two patients (24%) were found to have MBL deficiency. Febrile neutropenia occurred at least once in 200 patients. No difference in the primary outcome was seen. The incidence of severe infection was higher among MBL-deficient patients than among non-MBL-deficient patients (1.96 vs. 1.34 cases per 100 days for analysis of all patients [P=.008] and 1.85 vs. 0.94 cases per 100 days excluding patients with acute leukemia [P<.001]). CONCLUSIONS: MBL deficiency does not predispose adults with hematological cancer to more-frequent or more-prolonged febrile episodes during myelosuppressive chemotherapy, but MBL-deficient patients have a greater number of severe infections and experience their first severe infection earlier, compared with nondeficient patients.

Colorectal cancer (CRC) screening using sigmoidoscopy followed by colonoscopy: a feasibility and efficacy study on a cancer institute based population.

BACKGROUND: Advanced distal neoplasia found at sigmoidoscopy could be the marker for more proximal lesions. PATIENTS AND METHODS: In the setting of a screening clinic, subjects underwent flexible sigmoidoscopy. If no significant lesion was found, sigmoidoscopy was planned after 5 years. If an advanced neoplasia was found, colonoscopy was performed just after the first sigmoidoscopy and at 1, 3 and 5 years. If a non-advanced neoplasia was found, sigmoidoscopy was performed at 1, 3 and 5 years and followed by colonoscopy if advanced lesion was found. RESULTS: At first screening 1704/1912 (88%) subjects had a negative sigmoidoscopy, 104 (5.4%) had an advanced neoplasia, 96 (6%) had a non-advanced neoplasia and eight (0.4%) had invasive colorectal cancer (CRC). At follow-up examinations at 1, 3 and 5 years, among 170 subjects with advanced and non-advanced neoplasia, one developed invasive CRC and 47 (31.6%), advanced neoplasia. At 5 years, among 718 first negative sigmoidoscopies, 572 (80%) were confirmed negative and 97 (14%) had advanced neoplasia. Colorectal cancer status at 5 years could be checked for interval cancers in 97% of subjects and no CRC was diagnosed in subjects who did not attend sigmoidoscopy at 5 years. Comparison of the incidence of invasive CRC to the data of registries of the Netherlands and Luxembourg suggested that the incidence of CRC was decreased by 36%-46%. Seven of the nine CRCs were Duke's A and the two others were Duke's B and C. CONCLUSIONS: Screening with sigmoidoscopy followed by colonoscopy in case of positive sigmoidoscopy leads to substantial decreases in the incidence of CRC. Most CRCs found are at an early, curable stage of their development.

Clinical, molecular, and genotype-phenotype correlation studies from 25 cases of oral-facial-digital syndrome type 1: a French and Belgian collaborative study.

Oral-facial-digital syndrome type 1 (OFD1) is characterised by an X linked dominant mode of inheritance with lethality in males. Clinical features include facial dysmorphism with oral, tooth, and distal abnormalities, polycystic kidney disease, and central nervous system malformations. Large interfamilial and intrafamilial clinical variability has been widely reported, and 18 distinct mutations have been previously reported within OFD1. A French and Belgian collaborative study collected 25 cases from 16 families. OFD1 was analysed using direct sequencing and phenotype-genotype correlation was performed using chi2 test. X inactivation studies were performed on blood lymphocytes. In 11 families, 11 novel mutations, including nine frameshift, one nonsense, and one missense mutation were identified, which spanned nine different exons. A combination of our results with previously reported cases showed that the majority of mutations (65.5%) was located in exons 3, 8, 9, 13, and 16. There was phenotype-genotype correlation between (a) polycystic kidney disease and splice mutations; (b) mental retardation and mutations located in exons 3, 8, 9, 13, and 16; and (c) tooth abnormalities and mutations located in coiled coil domains. Comparing the phenotype of the families with a pathogenic mutation to families with absence of OFD1 mutation, polycystic kidneys and short stature were significantly more frequent in the group with no OFD1 mutation, whereas lingual hamartomas were significantly more frequent in the group with OFD1 mutation. Finally, an X inactivation study showed non-random X inactivation in a third of the samples. Differential X inactivation between mothers and daughters in two families with high intrafamilial variability was of particular interest. Slight phenotype-genotype correlations were established, and X inactivation study showed that skewed X inactivation could be partially involved in the pathogenesis of intrafamilial clinical variability.

Gastric outlet obstruction by an antral mucosal diaphragm: a case of a congenital anomaly revealed by an acquired disease.

Congenital antral membrane may become symptomatic early in life or late in childhood. A gastric outlet obstruction was revealed in a 14-month-old girl, previously developing well until 3 days ago, by melaena and recurrent non-bilious vomiting, after administration of a non-steroidal anti-inflammatory drug for fever. Plain X-ray performed during the neonatal period was normal. Despite ultrasonography, contrast radiography and endoscopy, the correct diagnosis was made at surgery; the obstruction was due to an inflammatory, thickened membrane with mucosal oedema reducing the central aperture of the diaphragm. This case emphasizes that if antral membrane diaphragm is congenital, the onset of symptoms may result from an additional acquired lesion.