A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10.

Hirschsprung disease (HSCR) is a frequent congenital disorder (1 in 5,000 newborns) of unknown origin characterized by the absence of parasympathetic intrinsic ganglion cells of the hindgut. Taking advantage of a proximal deletion of chromosome 10q (del 10q11.2-q21.2) in a patient with total colonic aganglionosis, and of a high-density genetic map of microsatellite DNA markers, we performed genetic linkage analysis in 15 non-syndromic long-segment and short-segment HSCR families. Multipoint linkage analysis indicated that the most likely location for a HSCR locus is between loci D10S208 and D10S196, suggesting that a dominant gene for HSCR maps to 10q11.2, a region to which other neural crest defects have been mapped.

A gene for Stargardt's disease (fundus flavimaculatus) maps to the short arm of chromosome 1.

Stargardt's disease (fundus flavimaculatus) is one of the most frequent causes of macular degeneration in childhood and accounts for 7% of all retinal dystrophies. It is an autosomal recessive condition characterized by a bilateral loss of central vision occurring at age 7-12 years. Genetic linkage analysis of eight families has assigned the disease locus to chromosome 1p21-p13. Multipoint linkage analysis and haplotype analysis has allowed us to establish the best estimate for location of the gene over the locus D1S435 (maximum lod score of 12.66). Our results are consistent with the genetic homogeneity of this condition.

Genitopatellar syndrome: a new condition comprising absent patellae, scrotal hypoplasia, renal anomalies, facial dysmorphism, and mental retardation.

We report on the association of absent patellae, genital and renal anomalies, dysmorphic features, and mental retardation in seven children (six boys and one girl) belonging to five unrelated families. Flexion deformities of the knees and hips with club feet and absent patellae were consistently observed and scrotal hypoplasia and cryptorchidism were present in all boys (6/6). Dysmorphic features included a coarse face, a large nose with a high nasal bridge, and microcephaly. Other features included renal anomalies (multicystic kidneys or hydronephrosis, 7/7), agenesis of the corpus callosum (4/7), swallowing difficulties, micrognathia (4/7), and pulmonary hypoplasia (3/7). Bilateral hypoplasia of the ischia and brachydactyly were also consistently observed (5/5). In two out of seven cases, prenatal ultrasound detection of microcephaly and renal anomalies led to termination of the pregnancy at 27 weeks. Three children died during the first years of life and the remaining two who survived exhibit severe developmental delay. High resolution cytogenetic studies performed on lymphocytes or fibroblasts or both were normal in all cases. Recurrence in two families suggests an autosomal recessive mode of inheritance. We propose that this unusual association, similar to that observed in a 4 year old boy by Goldblatt et al, represents a new syndrome distinct from previously reported hypoplastic patella syndromes.

Neonatal myasthenia gravis. Anti-acetylcholine receptor antibodies in the amniotic fluid.

Neonatal myasthenia gravis (NMG) with mild arthrogryposis was observed at birth in the newborn infant of a myasthenic mother. Anti-acetylcholine receptor (anti-AChR) antibodies were present in the serum of both mother and child, in umbilical cord serum and in the amniotic fluid. The presence of anti-AChR antibodies in the amniotic fluid may be one of the causes of the NMG.

BBBG syndrome or Opitz syndrome: new family.

We report on a family where the propositus had G syndrome, including laryngeal cleft, and another relative had the facial anomalies typical of the BBB syndrome. We review the literature on the BBB and G syndrome, and argue that no clinical or laboratory criteria permit a differential diagnosis of the two syndromes. Therefore, we suggest that they should be considered variable expression of the same gene. The name BBBG syndrome is proposed for the amalgamated syndrome.

Neural tube defects in France: segregation analysis.

Segregation analysis was performed on a subset of a large body of French data comprising 298 nuclear families. Two models were used in this analysis: the transmission probability model [Elston and Stewart, 1971; Elston, 1981] and the mixed model [Morton and MacLean, 1974]. Both models are consistent with familial aggregation of neural tube defects, in this sample, being due to either the segregation of a recessive major gene or a sibling environmental effect, or both factors. In each case, other environmental factors are also involved. These results were compared to the findings of other studies and discussed in respect to the diversity of the epidemiological features displayed by different populations. Some observations of vertical transmission in a British study and the proportion of affected first cousins, in both France and Great Britain, lead us to reject a possible absence of transmission. We propose a monogenic component with a large influence of environmental factors, some of which may be common to sibs, to explain the occurrence of neural tube defects in this sample.

Acrofacial dysostoses.

A female baby was born with phocomelia, bilateral cleft lip and palate, marked micrognathia, malar hypoplasia, absence of lower eyelids, and absence of external ears. Radiological examination showed hypoplastic pectoral and pelvic girdles, short humeri and femora, with absence of forearms and legs, and oligodactyly of upper limbs. Her mother has triphalangism of the left thumb and a hypoplastic right thumb with stiff metacarpophalangeal joint. She also has downward-slanting palpebral fissures, malar hypoplasia, and deepset eyes. This observation offers an opportunity to revisit the acrofacial dysostoses syndromes, including Nager-Reynier syndrome, Genée-Wiedeman syndrome, and lethal forms.

CHARGE syndrome: report of 47 cases and review.

The acronym CHARGE refers to a syndrome of unknown cause. Here we report on 47 CHARGE patients evaluated for the frequency of major anomalies, namely coloboma (79%), heart malformation (85%), choanal atresia (57%), growth and/or mental retardation (100%), genital anomalies (34%), ear anomalies (91%), and/or deafness (62%). In addition, we comment on anomalies observed very frequently in neonates and infants with the CHARGE syndrome, including, minor facial anomalies, neonatal brain stem dysfunction with cranial nerve palsy, and, mostly, internal ear anomalies such as semicircular canal hypoplasia that were found in each patient that could be tested. We propose several criteria for poor survival including male gender, central nervous system and/or oesophageal malformations, and bilateral choanal atresia. No predictive factor regarding developmental prognosis could be identified in our series. A significantly higher mean paternal age at conception together with concordance in monozygotic twins and the existence of rare familial cases support the role of genetic factors such as de novo mutation of a dominant gene or subtle sub-microscopic chromosome rearrangement. Finally, the combination of malformations in CHARGE syndrome strongly supports the view that this multiple congenital anomalies/mental retardation syndrome is a polytopic developmental field defect involving the neural tube and the neural crests cells.

Scalp defect, nipples absence and ears abnormalities: an other case of Finlay syndrome.

Bilateral absence of nipples is an exceptional defect. We report the second family with the association of scalp defect, abnormally shaped ears and absence of nipples described by Finlay as an autosomal dominant trait.

[Neonatal screening for phenylketonuria and hypothyroidism in France. A 12-year experience]. / Le dépistage néonatal de la phénylcétonurie et de l'hypothyroïdie en France. Une expérience de 12 années.

The authors report their experience in the systematic, co-ordinated and controlled neonatal screening in France: a coverage of approximately 100 per cent for several years, nearly 13 millions of tests for phenylketonuria and more than 7 millions for hypothyroidism, almost 850 phenylketonuric children and more than 1,600 patients with hypothyroidism, screened and taken care of. The frequency of phenylketonuria is estimated at 1 for 16,394 and the frequency of hypothyroidism at 1 for 4,041. They insist on the need for a strict investigation of false negatives and point out a few specific points on the care of affected children. Overall, the assessment of neonatal screening is positive since it has allowed 2,500 children, doomed to mental retardation, to have a normal growth.

[Genetic screening in children]. / Les tests génétiques chez l'enfant.

Before giving a prescription on a genetic test, it is necessary to estimate if a real direct benefit exists for the children. This is right if the disease occurs during childhood and teenage and when the genetic status identified early may improve care, prevention and people accompaniment or if, on the contrary, knowing that the children has no risk to develop a disease will save him from a particularly restricted medical observation. At the opposite, letting him know his future may, for sure, cause him some trouble (disruption). The parents' distress and their hope for getting a negative test result should not be more important than the child's interest which has to prevail over his parents'. If the child has no risk to develop a genetic disease himself and if the risk concerns only his descendants, there is no reason for knowing his genetic status before he makes plans himself for his procreation.

[Neonatal screening for sickle cell anemia: evaluation of a five-year experience in an area of northern Paris]. / Dépistage néonatal ciblé de la drépanocytose: bilan de cinq années d'expérience dans le nord-francilien.

UNLABELLED: We report a five-year experience of targeted neonatal screening for sickle cell disease in the northern part of the Paris area as well as the follow-up procedure of screened patients. POPULATION: This geographic area in France is characterized by a high frequency of populations at risk for sickle cell disease. RESULTS: Among 115,480 tested newborns, 250 patients were diagnosed (frequency: 1/462). The quality of the screening was attested by the high frequency (5.34%) of newborn carriers for a hemoglobin abnormality (n = 6168). We developed an optimized strategy which avoids the majority of pitfalls (false positive and false negative responses), except for S/HPFH. More than 95% of sickle cell disease was followed, the majority by medical sickle cell disease experts from hospitals. Only two deaths were recorded during this time period. CONCLUSION: We demonstrate the efficiency of targeting the proposed methodological strategy and the follow-up of affected newborns, a major argument demonstrating the importance of newborn screening.

[Unilateral retinoblastomas with late bilateralization. Three case reports]. / Rétinoblastomes unilatéraux avec bilatéralisation tardive. A propos de 3 cas.

Three cases of unilateral retinoblastoma with late bilateralization are presented in this study. The rare occurrence of this event underlines the need for prolonged follow-up in the fellow-eye, even in the absence of familial retinoblastoma. In these three cases, the first affected eye was enucleated after a diagnosis made at three months, sixteen months and three years of age. New tumors appeared in the second eye when the children were sixteen years old in one case and five years old in two cases.

[National neonatal screening program for cystic fibrosis: management and organization]. / Le programme national de dépistage néonatal de la mucoviscidose: mise en place et organisation.

France has decided to add to the national neonatal screening program (Phenylketonuria, Hypothyroidism, Congenital Adrenal Hyperplasia, Sickle cell disease) the screening of cystic fibrosis (CF). The screening of CF will be implemented in all regions of France by the end of 2002 and will cover all newborn (near 800,000/year). Based on the recommendation of the French Screening Foundation, the project has been approved by the Health Ministry and will be financed by the social security. CF neonatal screening is now technically feasible and reliable. The proposed methodology includes: immunoreactive trypsin (IRT) dosage on all newborns at day 3 (by radioimmunology "Cis Bio" or immunofluorescence "Delfia") followed by genotype CFTR analysis if IRT level is above 60 micrograms/L. Screening for 29 mutations is planned. If genotype is negative, control of IRT at day 21 will be obtained. Several requirements are included in the program: a protocol of care for the newly diagnosed CF in a specialised CF center; information to all parents of newborns; results of CFTR genotype has to be given during a clinical visit, even if negative. This screening program should allow to screen 98% of the cystic fibrosis patients before the age of 1 month. In order to ensure perfect efficacy, the CF screening program will be evaluated and modified if necessary.

[National program for neonatal screening for cystic fibrosis: implementation and preliminary results]. / Programme national de dépistage néonatal de la mucoviscidose: mise en place et résultats préliminaires.

Neonatal screening for cystic fibrosis was decided by the national medical authorities after a common investigation conducted by the French association ADPHE and national health insurance fund. Based on therapeutic progress and the proposed method using determination of blood immunoreactive trypsin then study of the main CF mutations, there is strong hope of effective CF detection and clinical benefit for the patients.

[Placental sulfatase deficiency and sex-linked recessive ichthyosis. Two cases found in two sisters (author's transl)]. / Déficit en sulfatase placentaire et ichthyose récessive liée au sexe. Deux cas observés chez deux soeurs.

The diagnosis of placental sulfatase deficiency was made at the same time in two sisters who were pregnant. This is the first case history reported of two women who were carriers of this abnormality and who were linked by parentage. The inborn error of metabolism was able to be found in its post-natal state in two of the sons of one of the women in the form of retention cutaneous ichthyosis of a sex-linked type.

[Advances in genetics: what benefits children?]. / L'essor de la génétique: quels bénéfices pour les enfants?

The advent of genetic therapy has raised great hopes, but it is clear that for children and their parents, the primary benefit from recent progress is in the possibility of positive diagnosis and presymptomatic diagnosis allowing more adapted management. For the family, genetic counselling allows well informed family planning and birth of healthy children. For the child to be born, continuing progress in genotypic diagnosis often leads to very delicate questions during the antenatal period, especially since certain diagnoses are still difficult and prognosis less than sure. The wide range of tools in molecular genetics may provide the answer in many situations. The rapid development of genetic tools in developed countries should now raise the question of their use in developing countries. This point might have a particular impact in research on genetic factors and sensibility to frequent infectious diseases such as tuberculosis or malaria. In this case, the aim is not diagnosis but the discovery of genes regulating susceptibility which could lead to pharmaceutical developments. This is undoubtedly a long term objective, but should not be overlooked.

[Prenatal, neonatal and postnatal prevention in cystic fibrosis]. / La prévention anté-natale, néonatale et post-natale dans la mucoviscidose.

The efficiency of neonatal screening for CF could be improved by associating a molecular analysis to the immunoreactive trypsin test, on the same dried blood's sample. However the interest of such a screening for the patients benefit remains controversial. In most cases, antenatal diagnosis may be performed by a direct search of the mutation(s). However, the impact of antenatal diagnosis on CF's incidence will necessarily be limited if it can only be implemented after the birth of an affected child. Hence the interest of screening programs for the detection of healthy carriers. Carrier's detection does not raise any objection for the relatives of patients. It is still premature to recommend it to be undertaken in the general population.