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SUMMARY The cranial ultrasound features of two neonates with neuronal migration disorders are described. One infant had lissencephaly and the other polymicrogyria in conjunction with the Pena-Shokeir syndrome type 1. A third infant is described who was born extremely prematurely and with Down's syndrome, who had similar ultrasound features. By two weeks of age, however, the scan of this third infant had become normal, which illustrates the need for caution in diagnosing migrational disorders in very preterm babies and those with Down's syndrome. The disorders of neuronal migration are discussed. RESUME Troubles de la migration neuronique: caracteristiques echographiques L'article decrit les images echographiques de deux nouveau-nes presentant des troubles de la migration neuronique. Un nourrisson presentait une lissencephalie, un autre une polymicrogyrie associee a un syndrome de Pena-Shokeir de type 1. Un troisieme enfant ne tres prematurement avec un mongolisme presentait des images echographiques identiques. Cependant, a l'âge de deux semaines le scanner de ce troisieme enfant etait devenu normal, ce qui doit rendre prudent dans le diagnostic de troubles migratoires chez les tres grands prematures et les mongoliens. Les desordres de la migration neuronique sont discutes. ZUSAMMENFASSUNG Erkrankungen infolge neuronaler Migration: sonographische Merkmale Es werden die cranialen Ultraschallbefunde bei zwei Neugeborenen mit Erkrankungen infolge neuronaler Migration beschrieben. Ein Kind hatte eine Lissencephalie und das andere eine Polymikrogyrie mit dem Pena-Shokeir Syndrom Typ I. Ein drittes Kind wird beschrieben, das sehr viel zu fruh mit einem Down Syndrom geboren wurde und bei dem ahnliche Ultraschallergebnisse gefunden wurden. Nach zwei Wochen jedoch hatte sich das Ultraschallbild des dritten Kindes normalisiert; hierdurch wird deutlich, das man bei der Diagnosestellung von Erkrankungen infolge neuronaler Migration bei sehr unreifen Kindern und bei Kindern mit Down Syndrom vorsichtig sein mus. Die Krankheitsbilder infolge neuronaler Migration werden diskutiert. RESUMEN Desordenes en la emigracion neuronal: caracteristicas sonograficas Se describen las caracteristicas de los ultrasonidos craneales de dos recien nacidos con alteraciones en la emigracion de las neuronas. Un lactante tenia lisencefalia y el otro polimicrogiria junto con sindrome de Pena-Shokeir del tipo I. Se describe un tercer nino que habia nacido extremadamente prematura y con un sindrome de Down y que tenia una caracteristicas ultrasonicas similares. Sin embargo a las dos semanas de edad la TAC de este tercer nino se habia hecho normal, lo cual ilustra la necesidad de ser prudente en el diagnostico de las alteraciones de la emigracion en ninos muy a pretermino y en los sindromes de Down. Se discuten las alteraciones de la emigracion neuronal.

A severely mentally handicapped Caucasian male with cataracts, deafness, distal muscle wasting and skeletal abnormalities, including calcification of the pinnae, is described. The findings in this patient strongly resemble those in a male described in 1982 by Primrose, and it suggested that this unusual pattern of abnormalities constitutes a discrete entity, which we propose should be known as 'Primrose syndrome'.

A profoundly mentally handicapped patient is described with the karyotype 47,X, fra (X) (q27), + 21. Her phenotype demonstrates features of both Down's Syndrome and fragilc-X syndrome. The authors believe only one other similar case has been described.

A mother and son, each showing the characteristic features of the Weill-Marchesani syndrome, are described. It is suggested that this family provides further evidence for genetic heterogeneity in this condition.

A brother and sister with developmental delay, relative macrocephaly and agenesis of the corpus callosum are described. The brother also had unilateral cerebellar hypoplasia and malrotation of the large bowel. Published cases of familial agenesis of the corpus callosum are reviewed and the value of ultrasonography in demonstrating agenesis of the corpus callosum in the neonate is emphasised.

This report describes the clinical and investigative findings in a 31-year-old man with Hunter's syndrome, showing evidence of severe multisystem involvement. Papilloedema has been present for at least 8 years with no evidence of progressive visual impairment. His most serious and life-threatening complications are laryngeal oedema and tracheal narrowing, which both compromise his respiratory function and constitute a major anaesthetic risk.

The objective of the study was to investigate childhood hearing impairment in a population-based sample from a genetic perspective. Participants included 82 families with hearing-impaired children (aged 4-13) previously ascertained in the Trent Health Region. A questionnaire was mailed to all families, followed by a home visit and Connexin-26 35delG mutation screen. The Connexin-26 35delG mutation was identified in seven families (approximately 10 per cent of non-syndromal hearing impairment). Children of these families were significantly more likely than children with other modes of inheritance to have a profound hearing loss with a flat audiogram profile. The families of children with a significant admission to a neonatal intensive care unit were significantly less likely to have had genetic counselling. Eight families visited were found to have features suggestive of a genetic syndrome that had not been previously assigned a specific diagnosis. The study concluded that hearing-impaired children should ...

International audience; We report a deletion of 1p36.3 in a child with microcephaly, mental retardation, broad forehead, deep set eyes, depressed nasal bridge, flat midface, relative prognathism, and abnormal ears. The phenotype is consistent with that described for partial monosomy for 1p36.3. Reverse chromosome painting and microsatellite and Southern blot analyses were used to map the extent of the deletion. Fluorescence in situ hybridisation (FISH) analysis using probes from every telomere indicates that the rearrangement is likely to be a chromosomal truncation or rearrangement involving subtelomeric repetitive DNA. The deletion was identified by screening a sample of children and adults with idiopathic mental retardation. In conjunction with previous work on this sample, we estimate that 7.4% of the group have subtelomeric rearrangements.

A clinical and genetic study of the Holt-Oram syndrome (HOS) has been carried out in the United Kingdom involving 55 cases designated Holt-Oram syndrome, together with their parents and sibs. Data from the clinical assessment of both familial and isolated cases were used to define the HOS phenotype and to outline the spectrum of abnormalities, especially factors affecting severity. Skeletal defects affected the upper limbs exclusively and were bilateral and asymmetrical. They ranged from minor signs such as clinodactyly, limited supination, and sloping shoulders to severe reduction deformities of the upper arm (4.5%). The radial ray was predominantly affected than the right. All affected cases showed evidence of upper limb involvement. Cardiac defects were seen in 95% of familial cases and included both atrial septal defect (ASD, 34%) and ventricular septal defect (VSD, 25%); 39% had only ECG changes. Cardiac involvement ranged from asymptomatic conduction disturbances to multiple structural defects requiring surgery in infancy. Sudden death could be caused by heart block. Inheritance was autosomal dominant with 100% penetrance and no evidence of reduced fitness. Increasing severity occurred in succeeding generations consistent with anticipation.

The clinical features of Wolf-Hirschhorn syndrome are described in a 29-year-old woman who shows severe retardation of growth and development. It is important for health care professionals involved with families in which this condition is present to realize that long-term survival may occur.

Epstein-Barr virus (EBV) DNA in renal tissue in acute interstitial nephritis (IN) has not been previously reported. An 18-year-old male presented with a sore throat, fever, cervical lymphadenopathy, and oliguric renal failure. The rapid slide test for heterophile antibodies associated with infectious mononucleosis was positive, and a renal biopsy showed an acute interstitial nephritis. A polymerase chain reaction (PCR) assay identified EBV DNA in the renal biopsy. In situ hybridization (ISH) for EBV RNA and immunohistochemistry for latent membrane protein 1 of EBV were negative. Hemodialysis and prednisone 60 mg PO OD were administered and the s-creatinine dropped from 1,224 to 75 µmol/l over 9 days. The identification of EBV DNA in the kidney raises the possibility that direct infection plays a role in acute IN associated with EBV.

Three patients with short stature, joint laxity, and peculiar pelvic radiology are described. The first case is similar to those described by Desbuquois et al. [3], with deviation of digitis and supernumerary metacarpal bones. The other two children are less severely affected and are compared with others reported in literature. The authors suggest the homogeneity of the Desbuquois syndrome in spite of the variability of expression.

A de novo case of 'pure' trisomy 14q21----qter is described which was detected at amniocentesis following an abnormal ultrasound scan of a 25-year-old woman. This is apparently the largest distal 14q duplication reported in a case surviving beyond the first trimester. The infant appeared to have an association of clinical abnormalities previously observed in distal 14q trisomy and proximal 14q trisomy/mosaic trisomy 14.

Patients with Angelman's syndrome have been reported to have ocular hypopigmentation and a number are now known to have a microdeletion of chromosome 15q 11----13. Detailed ocular examination of eight new cases revealed normal visual acuity and foveal reflexes, but a pigmentary deficiency which is limited to the choroid and iris stroma--both of neural crest origin. Patients with Prader-Willi syndrome have similar ocular features and many have a microdeletion of chromosome 15q 11----13. It is therefore possible that this region may influence neural crest development.

We report two pairs of siblings with the syndrome cranioectodermal dysplasia who have subsequently developed chronic renal failure secondary to tubulo-interstitial nephropathy. Renal disease has not been described before in this rare syndrome but has now occurred in four of the seven reported cases. Children with cranioectodermal dysplasia appear to be at significant risk of developing chronic renal failure. This is important information for clinicians looking after such children, and their families, when considering the long-term prognosis and management.

Deafness is the most frequent sensory impairment in humans, with significant social and psychological implications. Early-onset hearing loss can have major adverse effects on the development of a child’s speech and language with important potential long-term consequences for cognitive development (Davis and Hind, 1999).These problems may be exacerbated in developing countries where poor nutrition and/or limited access to educational and medical facilities, coupled with increased reliance on verbal communication skills, can result in social isolation and reduced occupational opportunities (Kumar, 1997; Elahi et al., 1998).

Objectives To establish precise incidence figures for trisomy 13 and trisomy 18 in the former Trent region, to identify current prenatal diagnostic practice, and to assess the potential impact of the introduction of recently devised prenatal diagnostic practices. Methods An audit of all cases of trisomy 13 and trisomy 18 ascertained through the records of the Trent Congenital Anomalies Register and the Trent Regional Cytogenetic Laboratories. Results Forty-four cases of trisomy 13 and 88 cases of trisomy 18 were ascertained. Advanced maternal age effects were observed. Of all cases, 64% were first detected through chromosomal analysis initiated because of abnormalities noted on fetal anomaly scanning in the second trimester, whereas only 3% of cases were detected through the serum-screening programme currently offered for Down syndrome. In 11% of cases, the diagnosis was first suspected after birth. Twelve percent of couples chose to continue pregnancy following chromosomal confirmation of a suspected diagnosis. Conclusion The introduction of a highly sensitive prenatal diagnostic screening programme would have a major impact on the timing and proportions of all trisomy 13 and 18 cases diagnosed in pregnancy as gauged by current practice. It is important that health professionals involved in prenatal counselling be aware that, as with Down syndrome and anencephaly, around 12% of prospective parents of a child with trisomy 13 or 18 choose to continue rather than terminate the pregnancy. Copyright © 2003 John Wiley & Sons, Ltd.

Holoprosencephaly (HPE) is a clinically variable and genetically heterogeneous central nervous system (CNS) malformation. Alobar HPE, which is its most severe form, is associated with a poor prognosis. At the milder end of the HPE spectrum microcephaly, hypotelorism, and single central maxillary incisor may be recognised. Currently, four genes have been identified for this condition. These include Sonic Hedgehog (SHH) on chromosome 7q36, which is thought to be responsible for a significant proportion of autosomal dominant HPE. We report an index case with alobar holoprosencephaly caused by an SHH mutation and six members of his family over two generations with this mutation, with a broad range of clinical presentation, including attention deficit hyperactivity disorder (ADHD). The combination of microcephaly, hypotelorism, subtle midline facial anomalies, and ADHD within a sibship should alert the physician to the possible diagnosis of HPE.

BACKGROUND—Submicroscopic subtelomeric chromosome defects have been found in 7.4% of children with moderate to severe mental retardation and in 0.5% of children with mild retardation. Effective clinical preselection is essential because of the technical complexities and cost of screening for subtelomere deletions. METHODS—We studied 29 patients with a known subtelomeric defect and assessed clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history. Controls were 110 children with mental retardation of unknown aetiology with normal G banded karyotype and no detectable submicroscopic subtelomeric abnormalities. RESULTS—Prenatal onset of growth retardation was found in 37% compared to 9% of the controls (p30%) among subtelomeric deletion cases were microcephaly, short stature, hypertelorism, nasal and ear anomalies, hand anomalies, and cryptorchidism. Two or more facial dysmorphic features were observed in 83% of the subtelomere patients. None of these features was significantly different from the controls. Using the results, a five item checklist was developed which allowed exclusion from further testing in 20% of the mentally retarded children (95% CI 13-28%) in our study without missing any subtelomere cases. As our control group was selected for the "chromosomal phenotype", the specificity of the checklist is likely to be higher in an unselected group of mentally retarded subjects. CONCLUSIONS—Our results suggest that good indicators for subtelomeric defects are prenatal onset of growth retardation and a positive family history for mental retardation. These clinical criteria, in addition to features suggestive of a chromosomal phenotype, resulted in the development of a five item checklist which will improve the diagnostic pick up rate of subtelomeric defects among mentally retarded subjects. Keywords: submicroscopic subtelomeric rearrangements; clinical preselection; checklist; chromosome deletion.

A male infant with lethal short limbed dwarfism is described. His father had spondyloepiphyseal dysplasia congenita and his mother had achondroplasia. It is believed that the infant inherited both of these disorders and that their combined effects resulted in early death owing primarily to severe pulmonary hypoplasia.

We describe a family with non-syndromic sensorineural hearing impairment inherited in a manner consistent with maternal transmission. Affected members were found to have a novel heteroplasmic mtDNA mutation, T7510C, in the tRNASer(UCN) gene. This mutation was not found in 661 controls, is well conserved between species, and disrupts base pairing in the acceptor stem of the tRNA, making it the probable cause of hearing impairment in this family. Sequencing of the other mitochondrial tRNA genes did not show any other pathogenic mutations. Four other mutations causing hearing impairment have been reported in the tRNASer(UCN) gene, two having been shown to affect tRNASer(UCN) levels. With increasing numbers of reports of mtDNA mutations causing hearing impairment, screening for such mutations should be considered in all cases unless mitochondrial inheritance can be excluded for certain. Keywords: hearing impairment; mtDNA mutation; tRNASer(UCN)

The clinical features in a 10-year-old girl with distal arthrogryposis, ectodermal dysplasia and a dilated cardiomyopathy are presented. Review of the relevant literature has not revealed any other similar report. Parental consanguinity points to autosomal recessive inheritance.

Campomelic dysplasia (CMD) is a rare skeletal disorder that is usually lethal. It is characterised by bowing of the lower limbs, severe respiratory distress, and many of the chromosomal (XY) males show sex reversal. Because of a number of reports of familial campomelic dysplasia it is considered to be inherited in an autosomal recessive manner. In this study, details of 36 patients with campomelic dysplasia were collected from genetic centres, radiologists, and pathologists in the United Kingdom. The chromosomal sex ratio was approximately 1:1. There was a preponderance of phenotypic females owing to sex reversal. Three quarters of the chromosomal males were sex reversed or had ambiguous genitalia. Three cases are still alive, two with chromosomal rearrangements involving chromosome 17q. The majority of the others died in the neonatal period. The 36 index cases had 41 sibs of whom only two were affected. Formal segregation analysis gave a segregation ratio of 0.05 (95% CI approximately 0.00 to 0.11). This excludes an autosomal recessive mode of inheritance. The data suggest a sporadic, autosomal dominant mode of inheritance. Patients with a chromosomal rearrangement involving 17q (q23.3-q25.1) show a milder phenotype. The molecular mechanism for the difference is still unknown.

An 18 month old girl with dysmorphic features, severe developmental delay, multiple strawberry naevi, and capillary naevi is described. No previous report of a similar association of features has been identified.

A family is described in which three males have been affected by congenital valvular dysplasia of one or more heart valves, in one case leading to neonatal death. The pedigree is consistent with sex linked inheritance.

The clinical and radiological features in a baby thought to have Blomstrand chondrodysplasia are presented. The hallmarks of this rare lethal disorder are an increase in bone density and advanced skeletal maturation. A high incidence of parental consanguinity is consistent with autosomal recessive inheritance.

Type II diabetes mellitus (DM) is characterized by amyloid deposition within the pancreatic islets of Langerhans [1, 2]. The major constituent of islet amyloid is a small protein designated islet amyloid polypeptide (IAPP), or amylin, which is synthesized by beta cells [3, 4]. The precise function of IAPP is unknown but it may act as a glucoregulatory hormone [5, 6] and may, possibly, play a pathogenetic role in Type II DM. This hypothesis in turn raises the question of the potential role of islet amyloid formation in the pathogenesis of Type II DM.

Serum amyloid A (SAA) is a family of acute phase proteins whose hepatic synthesis increases 500-1000 fold during inflammation [1]. Murine SAA consists of two markedly homologous apolipoproteins, SAA1 and SAA2, which circulate as components of HDL particles [2-4]. A third less homologous member of the murine SAA gene family, SAA3, is also induced by a variety of inflammatory stimuli [4-6] but a corresponding SAA3 protein has not been identified.

Two cases of Smith-Lemli-Opitz syndrome type II are presented. During the late stages of both pregnancies maternal oestriol levels were unrecordable and there was evidence of suppression of maternal adrenal function. We speculate on the existence of a primary defect in the fetal adrenals.

We describe a patient with hypomelanosis of Ito (HI) and typical characteristics. Cytogenetic analysis of fibroblast cultures showed mosaicism for trisomy 7. The trisomy cell line was first observed in an amniotic fluid culture and illustrates the problem of distinguishing pseudomosaicism from true mosaicism.

A phenotypically female fetus with campomelic dysplasia and a de novo reciprocal translocation, 46,XY,t(2;17) (q35;q23-24), is presented. This is the second case of campomelic dysplasia in which a rearrangement involving the long arm of chromosome 17 has been identified, indicating that this is likely to be the site of the campomelic dysplasia locus.

Editor—Deafness is the most frequent sensory impairment in humans, with significant social and psychological implications. At least half of all cases of permanent childhood hearing impairment have a genetic cause.1 However, there is almost universal agreement among clinical geneticists that only a small proportion of such families are referred to clinical genetics services.2 Increasing public awareness of genetics in general will lead to increased demand. Therefore, what do families want and how should genetic services be planned? Between September 1997 and October 1998, the parents of 522 hearing impaired children, aged between 4 and 13 years, in the Trent Health Region, were sent a questionnaire, which comprised 10 questions about their experience and opinion of clinical genetic services (see Appendix). The families had been identified in a previous geographically defined, population based ascertainment study of childhood hearing impairment.3 A further 104 families identified by that study were excluded from the questionnaire survey because (1) they had indicated an unwillingness to participate in further research, (2) they were lost to follow up, (3) the child had died, or (4) a local professional had indicated an approach would not be appropriate. The majority (n=416) of families were also sent an invitation to take part in a home visit, to investigate clinical aspects of non-syndromal hearing impairment. Those not invited to participate in a home visit (n=106) were the families of children who had a named syndrome (with hearing impairment as a recognised association) or who had a definite diagnosis of meningitis. Eighty two families were visited as part of this aspect of the study. (These data are to be published elsewhere.) Data from the previous study3 indicated that those not approached in the questionnaire survey were significantly less likely …

The clinical and radiological features are described in male and female siblings with a unique form of spondyloepimetaphyseal dysplasia. In addition to generalized platyspondyly with epiphyseal and metaphyseal involvement, these children also have thin tapering fingers with accentuated palmar creases and abnormal dentition with oligodontia and pointed incisors. Parental consanguinity suggests that this is an autosomal recessive disorder.

Ed Angus Clarke, Routledge, £13.99, pp 266, ISBN 0-415-08258-7 Why does genetic counselling arouse such strong emotions? Here we have an applied clinical science whose practitioners have striven for decades to maintain a non-controversial stance. Horror at the excesses of prewar eugenics movements and an unshakable belief in the principle of non- directive counselling have been the cornerstones of clinical genetic services throughout the Western world. Yet rarely a day passes without media attention. Where here we gone wrong? Perhaps we have become complacent. A prevailing …

A male fetus is described with multiple congenital abnormalities including craniosynostosis and bilateral radial aplasia. There are many similarities to the case recently reported by Imaizumi and Kuroki (Am J Med Genet 41: 162-163). These cases may represent a new syndrome with overlapping features of the Baller-Gerold and Roberts syndromes.

A 12 year old boy with neuraminidase deficiency (sialidosis, mucolipidosis I) is described. His clinical features included coarse facies, cherry red spot, ataxia, myoclonus, and dysotosis multiplex. The level of neuraminidase activity in cultured fibroblasts was very low and intermediate levels were observed in both parents. The clinical disorders associated with neuraminidase deficiency are reviewed.

A review of the literature concerning the more common complications of pregnancy indicates that recurrence risks are available for most and can be summarized as follows: hydatidiform mole--1.3 to 2.9 per cent; recurrent miscarriage--20 to 30 per cent; ectopic pregnancy--20 to 30 per cent; severe preeclampsia--7.5 per cent; mild preeclampsia--29 per cent; preterm labor--15 per cent after one and 30 per cent after two. While recognizing that each individual case merits full investigation and careful assessment, it is proposed that these risk figures provide a useful basis for use in pre- and postpregnancy counseling.

This paper discusses the results of a survey of medical and paramedical opinion relating to various difficult ethical issues in clinical genetics. These include the confidentiality of the doctor-patient relationship, prenatal diagnosis and termination, and Huntington's chorea. It is suggested that this method provides a useful means of assessing what is ethically acceptable in contemporary society.Questionnaires on dilemmas in genetic counseling were distributed to 446 health professionals, and 144 replies were received. In response to questions about disclosure, 63% thought that the employer of a worker at risk should be informed, but only 29% would disclose a genetic defect to at-risk relatives without permission. A majority believed that selective abortion is permissible when a fetus is likely to be severely handicapped; a majority also thought that the genetic counselor can offer advice when asked, or even "thrust" advice on patients. Almost all the respondents favored the development of a predictive test for Huntington's chorea.

Details of 22 members from three generations of a family exhibiting systemic and ocular abnormalities are presented. The former include mild mental retardation and a high incidence of abortion or death in the neonatal period. Ocular features comprise: microphthalmos, strabismus, hypermetropia, reduced ocular axial length and abnormal peripapillary pigmentation. The microphthalmos was seen in three forms: bilateral, severe or mild and severe microphthalmos of one eye with the fellow eye mildly affected. No individual with any degree of microphthalmos had a normal sized fellow eye and no normal individual produced an affected child. The genetic implications are discussed. The possible aetiologies of the various features are discussed and that this condition is a neurocristopathy is also considered.

The ultrasonographic and necropsy findings in a male fetus with the megacystis-microcolon-intestinal hypoperistalsis syndrome are reported. The presence of vacuolation and degeneration in smooth muscle of bowel and bladder wall supports a previous suggestion that the macroscopic findings in this syndrome are the consequence of an underlying visceral myopathy. The unusual degree of severity of the findings in this fetus may explain the marked skewing of the sex ratio observed in affected liveborn infants.