Dominique Bremond-Gignac

Familial CHARGE syndrome because of CHD7 mutation: Clinical intra- and interfamilial variability

CHARGE syndrome (OMIM #214800) is a multiple malformation syndrome with distinctive diagnostic criteria, usually because of CHD7 (chromodomain helicase DNA binding 7) haploinsufficiency. Familial occurrence of CHARGE syndrome is rare. We report six patients from two Caucasian families (both with one parent and two children) affected by mild to severe CHARGE syndrome. Direct sequencing of the CHD7 gene was performed in these two unrelated families. A mutation in exon 8 (c.2501C>T – p.S834F) in first chromodomain was found in family A and a nonsense mutation in exon 2 (c.469C>T – p.R157X) in family B. Both mutations are de novo in the parents. In family A, the elder son had bilateral cleft lip and palate, esophageal atresia with fistula, complex heart defect and vertebral abnormalities, while the younger had a posterior coloboma. Their mother had asymptomatic vestibular dysfunction and retinal coloboma, identified after the molecular diagnosis of her children. In family B, both affected children had severe expression of CHARGE syndrome. The father carrying the mutation only had asymmetric anomaly of the pinnae. These familial reports describe the intrafamilial variability of CHARGE syndrome, and underline the presence of CHD7 mutations in patients who do not fit the ‘classical clinical criteria’ for CHARGE syndrome.

Blepharophimosis-mental retardation (BMR) syndromes: A proposed clinical classification of the so-called Ohdo syndrome, and delineation of two new BMR syndromes, one X-linked and one autosomal recessive.

We report on 11 patients from 8 families with a blepharophimosis and mental retardation syndrome (BMRS) phenotype. Using current nosology, five sporadic patients have Ohdo syndrome, associated with congenital hypothyroidism in two of them (thus also compatible with a diagnosis of Young‐Simpson syndrome). In two affected sibs with milder phenotype, compensated hypothyroidism was demonstrated. In another family, an affected boy was born to the unaffected sister of a previously reported patient. Finally, in the last sibship, two affected boys in addition had severe microcephaly and neurological anomalies. A definitive clinical and etiologic classification of BMRS is lacking, but closer phenotypic analysis should lead to a more useful appraisal of the BMRS phenotype. We suggest discontinuing the systematic use of the term “Ohdo syndrome” when referring to patients with BMRS. We propose a classification of BMRS into five groups: (1) del(3p) syndrome, (possibly overlooked in older reports); (2) BMRS, Ohdo type, limited to the original patients of Ohdo; (3) BMRS SBBYS (Say‐Barber/Biesecker/Young‐Simpson) type, with distinctive dysmorphic features and inconstant anomalies including heart defect, optic atrophy, deafness, hypoplastic teeth, cleft palate, joint limitations, and hypothyroidism. BMRS type SBBYS is probably an etiologically heterogeneous phenotype, as AD and apparently AR forms exist; (4) BMRS, MKB (Maat–Kievit–Brunner) type, with coarse, triangular face, which is probably sex‐linked; (5) BMRS V (Verloes) type, a probable new type with severe microcephaly, hypsarrhythmia, adducted thumbs, cleft palate, and abnormal genitalia, which is likely autosomal recessive. Types MKB and V are newly described here.

Vertigo is an underestimated symptom of ocular disorders: dizzy children do not always need mri

Vertigo, instability, dizziness, or equilibrium disorders are not usually considered as consequences of ophthalmologic problems. We present data indicating that ocular disorders can be responsible for these symptoms in children. In a population of 523 pediatric patients with vertigo or disequilibrium and referred for vestibular testing in our otolaryngology department during a 5-year period, 27 children presented with normal vestibular and somatic neurologic examinations but with ophthalmologic disorders (vergence insufficiency or latent strabismus with binocular vision in 70% and anisometropia in 41%). These patients represented 24% of all vergence insufficiencies detected and 4% of all orthoptic examinations performed in the pediatric ophthalmology department. These ocular abnormalities were considered to be the initial cause of the problems. In two thirds of these patients the symptoms were completely resolved by simple ophthalmologic treatment. No other additional tests, such as magnetic resonance imaging, were required. Therefore we propose that every child complaining of vertigo or dizziness but with normal clinical somatic neurologic and vestibular examinations should have a complete ophthalmologic examination before additional, more costly, investigations. This should lead to better screening and more appropriate care of ocular disorders in children and avoid unnecessary magnetic resonance imaging.

Early lipid supply and neurological development at one year in very low birth weight (VLBW) preterm infants

BACKGROUND The rapid growth of the developing brain during early post-natal life makes it particularly vulnerable to a nutritional deficit. The neurological development of the very low birth weight preterm infant could be related to early lipid supply. AIMS To evaluate in preterm infants of gestational age ≤ 28 weeks of amenorrhea (WA) the relations between the neurological development determined at a corrected age of one year using the test of Brunet-Lézine and 1) the cumulative intakes of proteins, carbohydrates, lipids and energy during the first 28 days of life and 2) the weight gain in the first 28 days of life. MATERIALS AND METHODS Study of a mono-centric cohort of 48 premature infants of gestational age ≤ 28 WA consecutively hospitalized and followed longitudinally up to a corrected age of one year. RESULTS In simple univariate analysis, there was a significant correlation between the developmental quotient (DQ) at a corrected age of one year and the cumulative intake of energy and lipids at 14 days of life (p=0.02, p=0.01, respectively), the number of days to reach the minimum weight (p=0.02) and the weight gain from birth to D28 of life (p=0.04). There was no correlation between the DQ and early intake of proteins or carbohydrates. In multivariate analysis, only the association between the DQ at one year of corrected age and the cumulative lipid intake at 14 days of life remained statistically significant (p=0.04). CONCLUSION Our study demonstrates the importance of early lipid supply during the first two weeks of life for the neurological development at a corrected age of one year of very low birth weight preterm infants.

Prevalence of Vernal Keratoconjunctivitis: a Rare Disease?

Objective: To determine the prevalence of vernal keratoconjuntivitis (VKC) in Europe. Methods: A cross-sectional survey was mailed to 3003 ophthalmologists from six countries (Finland, France, Italy, The Netherlands, Norway and Sweden) representing 151.9 million inhabitants. Results were analysed per country, and VKC prevalence for the 15 European member states in 2002 was extrapolated. Six hypotheses were used: disease duration (4 or 8 years) combined with three prevalence hypotheses for non-responding ophthalmologists. Results: The response rate to the survey was 29.5%. The estimates of VKC prevalence in Western Europe (per 10 000 inhabitants) ranged from 1.16 to 10.55. The prevalence of VKC with corneal complications ranged from 0.30 to 2.26. The VKC prevalences per country were in the following ranges: Italy 2.4–27.8, Finland, 0.7–8.4, Sweden 1.2–8.7, The Netherlands 0.6–4.6, France 0.7–3.3 and Norway 0.3–1.9. VKC with corneal complications were: Italy 0.4–4.8, Sweden 0.3–2.4, Finland 0.2–2.8, The Netherlands 0.2–1.6, France 0.3–1.4 and Norway 0.1–1.0. Conclusions: Based on the most likely hypotheses concerning disease duration and non-responding ophthalmologists’ VKC case rate, the best estimate of VKC prevalence in Western Europe is 3.2/10 000 inhabitants. The prevalence of VKC with corneal complications is 0.8/10 000 inhabitants.

Abnormality of vergence latency in children with vertigo.

Abstract.It is well known that vergence movements are important for distance appreciation, depth vision and stereopsis. Moreover, vergence movements are very probably used by the CNS during head and body motion to adjust the gain of the vestibulo-ocular reflex (VOR) according to the viewing distance. A recent clinical study of Anoh-Tanon et al. suggested that vertigo in children with normal vestibular function could be associated with abnormal vergence clinically assessed. The purpose of this study was to test this hypothesis with objective vergence eye movement recordings. We examined the latency of vergence, saccades and combined movements in twelve children with the complaint of vertigo but without vestibular abnormality. Convergence and saccades combined with convergence or with divergence had abnormally long latencies (relative to normal children of matched age). In contrast, divergence and isolated saccades showed only mild latency increase relative to normals. Lengthening of latency could be due to impaired cortical control. Orthoptic vergence training reduced all latencies; however, even the reduced latency of vergence and of combined movements was still abnormal. The improvement after orthoptic vergence training could be due to increased visual attention, although such mechanism cannot eliminate completely the initiation deficit of vergence movements. Objective eye movement recordings are thus useful for a diagnosis and treatment of children with vertigo.

Speed-accuracy of saccades, vergence and combined eye movements in children with vertigo

Vergence abnormalities could lead to inappropriate vestibulo-ocular reflex (VOR), causing vertigo and imbalance (Brandt 1999). Indeed, a recent study by Anoh-Tanon et al. (2000) reported the existence of a population of children with symptoms of vertigo in the absence of vestibular dysfunction but with abnormal vergence findings in orthoptic tests. The purpose of this study was to examine in such children the accuracy, duration and mean velocity of vergence and saccades; additionally, for a few subjects, the effect of orthoptic vergence training on these parameters was also investigated. LEDs were used to stimulate saccades, pure vergence along the median plane and combined saccade-vergence movements. Movements from both eyes were recorded with a photoelectric device (Bouis). The results show that children with vertigo perform saccades as normal subjects of comparable age. In contrast, vergence, particularly convergence, shows abnormalities: poor accuracy, long duration and low speed. During combined movements, the well known reciprocal interaction between the saccade and the vergence is present only for saccades combined with divergence; for saccades combined with convergence such interaction is abnormal: the saccade is slowed down by the convergence but the convergence is not accelerated by the saccade. Orthoptic training improves significantly the accuracy of all eye movements; such improvement was significant for all types of eye movements except for divergence (pure and combined). Furthermore, convergence remains abnormal and the lack of acceleration by the saccade persists. These specific convergence deficits could be of both subcortical and cortical origin. Orthoptic training improves the accuracy presumably via visual attentional mechanisms, but cannot completely override deficits related to subcortical deficiencies.

Relationships between black tea consumption and key health indicators in the world: an ecological study

Objectives The aim of this study was to investigate potential statistical relationships between black tea consumption and key health indicators in the world. The research question is: Does tea consumption is correlated with one or more epidemiological indicators? Design Ecological study using a systematic data-mining approach in which the unit of the analysis is a population of one country. Setting Six variables, black tea consumption data and prevalence data of respiratory diseases, infectious diseases, cancer, cardiovascular diseases and diabetes, have been studied at a global level. Participants Data from 50 participating countries in the World Health Survey were investigated. Primary and secondary outcomes measures Level of statistical relationships between variables. Results Principal component analysis established a very high contribution of the black tea consumption parameter on the third axis (81%). The correlation circle confirmed that the ‘black tea’ vector was negatively correlated with the diabetes vector and was not correlated with any of the other four health indicators. A linear correlation model then confirmed a significant statistical correlation between high black tea consumption and low diabetes prevalence. Conclusions This innovative study establishes a linear statistical correlation between high black tea consumption and low diabetes prevalence in the world. These results are consistent with biological and physiological studies conducted on the effect of black tea on diabetes and confirm the results of a previous ecological study in Europe. Further epidemiological research and randomised studies are necessary to investigate the causality.

High Proportion of Pituitary Abnormalities and Other Congenital Defects in Children with Congenital Nasal Pyriform Aperture Stenosis

We aimed to determine the occurrence of pituitary dysfunction and additional malformations in patients with congenital nasal pyriform aperture stenosis (CNPAS) and to predict which patients are at risk of pituitary dysfunction. Among the 40 studied patients, hypothalamo-pituitary (HP) axis abnormalities were found in 16 patients (40%), with endocrine dysfunction (n = 9) and/or abnormal HP MRI findings (n = 15). A normal HP axis on MRI was highly predictive of normal endocrine function. Of the 40 patients, 31 had additional abnormalities in the cranio-facial area (n = 26), the brain (n = 12), the vertebrae (n = 5), the limbs (n = 4), the heart (n = 7) and the kidney (n = 3). Six patients had syndromic associations: VACTERL (n = 4), CHARGE (n = 1) and RHYNS (n = 1) syndromes. Craniofacial and brain malformations were more common in patients with HP axis abnormalities than in patients with normal HP axis. Familial history of midline defects and/or consanguinity were found in 30% of patients.In conclusion, HP axis abnormalities are frequent in patients with CNPAS and justify MRI of the brain early in life and clinical evaluation to screen for patients with pituitary insufficiency. CNPAS may be a genetically heterogeneous condition with a large phenotypic variability that shares common etiological mechanisms with the various forms of the holoprosencephaly phenotype.

Binocular coordination of saccades in children with vertigo: dependency on the vergence state.

The present study examines the quality of binocular coordination of saccades at far and near distance in 15 children with symptoms of vertigo headache and equilibrium disorders; these children show normal vestibular function but abnormal convergence eye movements (e.g., long time preparation, slow execution and poor accuracy, see ). The results show normal binocular saccade coordination at far distance, but large abnormal disconjugacy for saccades at near distance. During combined saccade-vergence movements (studied in six of these children), convergence remains abnormally slow. This supports the interpretation according to which poor binocular yoking of the saccades is linked to the reduced ability to produce fast convergence during the saccade; a learning mechanism based on rapid vergence would help to reduce the abducting-adducting asymmetry of the saccades. An alternative interpretation would be reduced learning ability for monocular adjustment of the saccade signals.