Is PATCHED an important candidate gene for neural tube defects? Cranial and thoracic neural tube defects in a family with Gorlin syndrome: a case report.

. The relationship of mutations in the patched gene PTCH and nevoid basal cell carcinoma (NBCC) or Gorlin syndrome is well established. Animal studies have implicated the hedgehog-patched signalling pathway in neurulation and neural tube defects (NTDs). Spina bifida occulta and bifid vertebrae are well recognized in NBCCS, but there appears to be only one report of open spina bifida. We report a father and two sons with a truncating PTCH mutation and the major features of NBCCS. One son had open thoracic spina bifida and the other had an occipital meningocoele. We believe this to be the first report of cranial NTD in NBCCS and suggest that consideration be given to including PTCH analysis in genetic association studies in NTDs as the hedgehog pathway is integral to normal human neurulation.

Genetic predisposition to cancer: the consequences of a delayed diagnosis of Gorlin syndrome.

This report outlines a case of Gorlin syndrome, the diagnosis of which was delayed for many years, and raises a number of important issues. These are the spectrum of late radiotherapy effects, particularly after treatment for benign disease, and the importance of considering the possibility of the presence of a genetic syndrome predisposing to cancer in all individuals before starting any treatment. As our knowledge of genetic syndromes expands, this will become increasingly important. Finally, if a genetic predisposition to cancer is suspected, consideration should be given to obtaining a blood sample from the affected patient for DNA storage, particularly if their prognosis is limited. Currently, genetic testing can only be instituted in most families by first obtaining DNA from an individual affected by cancer, as most genetic mutations are unique to a family. If all relatives with cancer have died, then, at this time, genetic testing cannot usually be attempted, unless such samples have previously been stored.

Gorlin syndrome: the PTCH gene links ocular developmental defects and tumour formation.

AIM: To identify a gene linking microphthalmia with cyst with early onset medulloblastoma. METHODS: Mutation analysis of the PTCH gene. RESULTS: A mutation in exon 10 of the PTCH gene was identified, confirming a diagnosis of Gorlin syndrome. CONCLUSIONS: This is the first genetically identified mutation giving rise to microphthalmia with cyst and provides a valuable link in the eye developmental gene pathway.

Prenatal diagnosis of succinate semialdehyde dehydrogenase deficiency in non-identical twins.

Prenatal diagnosis was performed by both DNA and enzymatic analysis on non-identical twins conceived by in vitro fertilization and at risk of succinate semialdehyde dehydrogenase deficiency. One fetus was predicted to be affected and one unaffected and selective fetal reduction was performed.

A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO).

Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth, hair, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant and recessive forms exist. We have studied males from four families with HED and immunodeficiency (HED-ID), in which the disorder segregates as an X-linked recessive trait. Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections. Recently, mutations in IKK-gamma (NEMO) have been shown to cause familial incontinentia pigmenti (IP). Unlike HED-ID, IP affects females and, with few exceptions, causes male prenatal lethality. IKK-gamma is required for the activation of the transcription factor known as "nuclear factor kappa B" and plays an important role in T and B cell function. We hypothesize that "milder" mutations at this locus may cause HED-ID. In all four families, sequence analysis reveals exon 10 mutations affecting the carboxy-terminal end of the IKK-gamma protein, a domain believed to connect the IKK signalsome complex to upstream activators. The findings define a new X-linked recessive immunodeficiency syndrome, distinct from other types of HED and immunodeficiency syndromes. The data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factor receptor-like signaling pathway, with the IKK signalsome complex playing a significant role.

A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene.

Usher syndrome type 1 describes the association of profound, congenital sensorineural deafness, vestibular hypofunction and childhood onset retinitis pigmentosa. It is an autosomal recessive condition and is subdivided on the basis of linkage analysis into types 1A through 1E. Usher type 1C maps to the region containing the genes ABCC8 and KCNJ11 (encoding components of ATP-sensitive K + (KATP) channels), which may be mutated in patients with hyperinsulinism. We identified three individuals from two consanguineous families with severe hyperinsulinism, profound congenital sensorineural deafness, enteropathy and renal tubular dysfunction. The molecular basis of the disorder is a homozygous 122-kb deletion of 11p14-15, which includes part of ABCC8 and overlaps with the locus for Usher syndrome type 1C and DFNB18. The centromeric boundary of this deletion includes part of a gene shown to be mutated in families with type 1C Usher syndrome, and is hence assigned the name USH1C. The pattern of expression of the USH1C protein is consistent with the clinical features exhibited by individuals with the contiguous gene deletion and with isolated Usher type 1C.

Prenatal diagnosis of tuberous sclerosis with intracerebral signs at 14 weeks' gestation.

We report the ultrasound detection of cranial abnormalities at 14 weeks' gestation in a fetus subsequently confirmed as having tuberous sclerosis using DNA linkage analysis within the affected family. The presence of asymmetrical ventricular enlargement persisted antenatally. Magnetic resonance imaging at 26 weeks indicated the possibility of poor gyral formation consistent with a neuronal migration disorder. Cardiac rhabdomyomata were not visualized on ultrasound scan until 30 weeks' gestation. Postnatal cranial ultrasound confirmed the significant neuropathology which was manifested by severe developmental delay and intractable fits in the child. The potential benefits of earlier diagnosis of tuberous sclerosis by cranial imaging are discussed, although in this patient the routine booking scan resulted in a path of prenatal diagnosis being undertaken which had originally been declined. A mechanism is proposed to explain the variable expression of tuberous sclerosis within this family based on altered TSC2 activity affecting neuronal migration.

A trisomic germ cell line and precocious chromatid segregation leads to recurrent trisomy 21 conception.

A chromosomally normal 37-year-old woman was referred for preimplantation genetic diagnosis after having several conceptuses with trisomy 21. Segregation of chromosome 21 was assessed in unfertilised meiosis II oocytes and preimplantation embryos from PGD cycles using fluorescent in situ hybridisation (FISH). Of 7 preimplantation embryos, 5 were chromosomally abnormal with 4 having trisomy 21 and one being tetraploid. Of 4 oocytes, 3 had an abnormal chromosomal constitution with either an extra chromosome 21 or an extra chromatid 21. In one oocyte an extra chromatid 21 was detected in both the metaphase II complement and the first polar body providing the first direct evidence of a maternal trisomic germ cell line. Moreover, this result shows that the extra chromosome 21 can precociously divide into its two chromatids at the first meiotic division.

Analysis of 133 meioses places the genes for nevoid basal cell carcinoma (Gorlin) syndrome and Fanconi anemia group C in a 2.6-cM interval and contributes to the fine map of 9q22.3.

Four disease genes (NBCCS, ESS1, XPAC, FACC) map to 9q22.3-q31. A fine map of this region was produced by linkage and haplotype analysis using 12 DNA markers. The gene for nevoid basal cell carcinoma syndrome (NBCCS, Gorlin) has an important role in congenital malformations and carcinogenesis. Phase-known recombinants in a study of 133 meioses place NBCCS between (D9S12/D9S151) and D9S176. Haplotype analysis in a two-generation family suggests that NBCCS lies in a smaller interval of 2.6 cM centromeric to D9S287. These flanking markers will be useful clinically for gene tracking. Recombinants also map FACC (Fanconi anemia, group C) to the same region, between (D9S196/D9S197) and D9S287. The recombination rate between (D9S12/D9S151) and D9S53 in males is 8.3% and 13.2% in females, giving a sex-specific male:female ratio of 1:1.6 and a sex-averaged map distance of 10.4 cM. No double recombinants were detected, in agreement with the apparently complete level of interference predicted from the male chiasmata map.

Ear anomalies, clefting and limb reduction defects: a new autosomal recessive condition?

We report a pair of siblings whose common clinical features of cleft palate, hypoplastic auditory meati and preauricular skin tags suggest the common inheritance of an autosomal recessive gene despite the findings between the siblings of disparate clinical features involving the central nervous and skeletal systems.

Epidermal mosaicism and Blaschko's lines.

To test the hypothesis that epidermal rather than dermal mosaicism determines Blaschko's lines in hypomelanosis of Ito (HI), we studied the distribution of chromosomal mosaicism in four patients. In two, mosaicism had not been detected in lymphocytes or dermal fibroblasts, but was clearly shown in epidermal keratinocytes; furthermore, the abnormal cell line was confirmed to the hypopigmented epidermis and the normal epidermis contained only normal cells. Negative findings in the other two patients might be because of mosaicism which was undetected either because it was submicroscopic or because it was present in melanocytes, which have not yet been studied. These preliminary results support the ideas that (1) Blaschko's lines represent single clones of epidermal cells; (2) in patients with HI and severe neurological involvement mosaicism, if detectable, is best shown in keratinocytes; and (3) the cytogenetic defect in epidermal cells may be directly responsible for the failure of pigmentation in HI.

Complications of the naevoid basal cell carcinoma syndrome: results of a population based study.

There are many potential complications which have been reported in association with the naevoid basal cell carcinoma syndrome. We have been able to show the relative frequencies of these problems in a population based study of 84 cases in the north west of England. The major complications of basal cell carcinomas and jaw cysts occur in over 90% of patients by 40 years of age, but may both occur before 10 years of age. Less well described complications are ovarian calcification or fibroma (24%), medulloblastoma (5%), cardiac fibroma (3%), cleft palate (5%), and ophthalmic abnormalities such as squint or cataract (26%). This study more clearly defines the possible complications of the syndrome and gives clearer guidelines for counselling and screening affected and at risk persons.

Location of gene for Gorlin syndrome.

The Gorlin (naevoid-basal-cell-carcinoma) syndrome is an autosomal dominant disorder characterised by multiple naevoid basal-cell carcinomas, recurrent odontogenic keratocysts, skeletal anomalies, intracranial calcification, and developmental malformations. Characterisation of the gene that causes the syndrome may improve our understanding of the pathogenesis of other basal-cell carcinomas. By linkage analysis, we have shown that the gene is located on chromosome 9q22.3-q31; the most likely position is between DNA markers D9S12 and D9S53. Location of the gene for Gorlin syndrome offers the possibility that DNA markers can be used in risk estimation and presymptomatic identification of patients for surveillance.

The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma.

We have investigated the incidence of Gorlin syndrome (GS) in patients with the childhood brain tumour, medulloblastoma. One hundred and seventy-three consecutive cases of medulloblastoma in the North-West Regional Health Authority between 1954 and 1989 (Manchester Regional Health Board before 1974) were studied. After review of case notes, X-rays and health surveys only 2/173 cases had evidence supporting a diagnosis of GS. A further case at 50% risk of GS died of a brain tumour aged 4 years. The incidence of GS in medulloblastoma is, therefore, probably between 1-2%. A population based study of GS in the region started in 1983 was used to assess the incidence of medulloblastoma in GS, which was found to be between 3-5%. This figure is lower than previous estimates, but this is the first population based study undertaken. In view of the early age of onset in GS (mean 2 years) children presenting with medulloblastoma, especially under 5 years, should be examined for signs of the syndrome. Those at high risk of developing multiple invasive basal cell carcinomata will then be identified.

Ablepharon macrostomia syndrome.

The association of congenital ablepharon with the absence of eyelashes and eyebrows, a wide mouth (macrostomia), and auricular, nasal, genital, and other systemic anomalies has been termed the ablepharon macrostomia syndrome. One such case is reported which illustrates the importance of immediate postnatal ocular management to minimise severe visual loss.

A recombination map of the human X-chromosome.

A family with 11 normal boys has been typed with DNA probes spanning the whole of the X-chromosome to observe directly the recombination events in 11 meioses from one female. This has (a) identified apparent recombination hot-spots on the X-chromosome; (b) shown the positions and numbers of cross-overs that have occurred in the p and q arms; (c) not shown any cross-overs in the centromeric region and (d) enabled the calculation of the genetic length of the X-chromosome.

Linkage data for Marfan syndrome and markers on chromosomes 1 and 11.

Six large families with classical Marfan syndrome were studied using markers on chromosomes 1 and 11. Two of three families tested showed negative scores using D1S7 but a third family gave a positive score (0.92) at theta = 0.1. The other chromosome 1 markers typed (MUCI, NGFB, D1S8) excluded close linkage. Negative lod scores with two chromosome 11q22 markers (D11S84, D11S148) excluded at least 20 cM in this area (Z = less than -2), which was chosen for study as two enzymes responsible for collagen degradation (collagenase and stromelysin) are localised to this region.

An exclusion map of Marfan syndrome.

The combined genetic data between the Marfan syndrome and 75 informative loci on 18 autosomes were used to construct an exclusion map for this disorder. Data are also presented for a further two unmapped markers. The most likely location of the Marfan syndrome gene is highlighted and all the unexcluded areas of the genome are displayed in a graphical form. This exclusion map shows that almost 75% of the genome has been excluded as a likely location for the Marfan syndrome gene in the majority of the families studied. Apart from chromosomes 8, 13, 21, and 22, for which no data were available, other regions not excluded yet include 5p, 6p, 9p, 10p, 12p, 15, 17p, 18, and 20p. Future linkage analysis using markers located in the highlighted regions should facilitate the identification of the site of the Marfan syndrome gene.

Examination of fetuses after induced abortion for fetal abnormality.

OBJECTIVE: To determine the accuracy of midtrimester diagnosis of fetal abnormality by examination and investigation of fetuses after induced abortion. DESIGN: Prospective study over five years of fetuses aborted in the midtrimester because of abnormalities detected by ultrasonography and amniocentesis. Techniques included a full external examination by a clinical geneticist with experience in dysmorphology and other investigations including necropsy. SETTING: Regional genetic centre. PARTICIPANTS: Clinicians working within the North Western region who wished to use the service offered. RESULTS: 133 Fetuses were aborted because of abnormalities detected on ultrasonography and 115 because of abnormal findings on amniotic fluid analysis. In a further two cases fetal abnormality was diagnosed by molecular genetic and biochemical techniques. Among the fetuses with abnormal scans the pretermination diagnosis was changed or refined in a way which affected genetic counselling in 53 of 133 cases. Among the 115 fetuses diagnosed as abnormal by amniocentesis the pretermination diagnosis was confirmed in 112 cases and altered in three. CONCLUSION: Fetuses aborted because of abnormalities detected by screening should be examined by suitably experienced clinicians, both for accurate genetic counselling of the families and for quality control of the tests employed.