Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome.

Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/).

Cerebro-oculo-facio-skeletal syndrome: three additional cases with CSB mutations, new diagnostic criteria and an approach to investigation.

BACKGROUND: The cerebro-oculo-facio-skeletal syndrome (COFS syndrome) is an autosomal recessive disorder which was initially described in a specific aboriginal population from Manitoba. In recent years, COFS syndrome has been linked in this original population to a defective DNA repair pathway and to a homozygous mutation in the major gene underlying Cockayne syndrome (CSB). However, most reports of suspected COFS syndrome outside this population have not been confirmed at the molecular level, leading to considerable heterogeneity within the syndrome and confusing overlaps between COFS syndrome and other eye and brain disorders. OBJECTIVE: To refine the delineation of the syndrome on genetically proven COFS cases. METHODS: We report the exhaustive clinical, cellular and molecular data of three unrelated COFS patients with mutations in the CSB gene. RESULTS: All three patients present the cardinal features of COFS syndrome including extreme microcephaly, congenital cataracts, facial dysmorphism and arthrogryposis. They also exhibit a predominantly postnatal growth failure, a severe psychomotor retardation, with axial hypotonia and peripheral hypertonia and neonatal feeding difficulties. Fibroblasts from the patients show the same DNA repair defect which can be complemented by transfection of the CSB wild-type cDNA. Five new mutations in the CSB gene have been identified in these patients. CONCLUSIONS: Our data indicate that COFS syndrome represents the most severe end of the Cockayne spectrum. New diagnostic criteria for COFS syndrome are proposed, based on our findings and on the few genetically proven COFS cases from the literature.

Cerebroretinal microangiopathy with calcifications and cysts (CRMCC).

Extensive intracranial calcifications and leukoencephalopathy are seen in both Coats plus and leukoencephalopathy with calcifications and cysts (LCC; Labrune syndrome). Coats plus syndrome is additionally characterized by the presence of bilateral retinal telangiectasia and exudates while LCC shows the progressive formation of parenchymal brain cysts. Despite these apparently distinguishing features, recent evidence suggests that Coats plus and LCC represent the same clinical entity with a common primary pathogenesis involving a small vessel obliterative microangiopathy. Here, we describe eight previously unreported cases, and present an update on one of the original Coats plus patients to highlight the emerging core clinical features of the "cerebroretinal microangiopathy with calcification and cysts" (CRMCC) phenotype.

A novel acropectoral syndrome maps to chromosome 7q36.

F syndrome (acropectorovertebral syndrome) is a dominantly inherited skeletal dysplasia affecting the hands, feet, sternum, and lumbosacral spine, which has previously been described in only two families. Here we report a six generation Turkish family with a related but distinct dominantly inherited acropectoral syndrome. All 22 affected subjects have soft tissue syndactyly of all fingers and all toes and 14 also have preaxial polydactyly of the hands and/or feet. In addition, 14 have a prominent upper sternum and/or a blind ending, inverted U shaped sinus in the anterior chest wall. Linkage studies and haplotype analysis carried out in 16 affected and nine unaffected members of this family showed that the underlying locus maps to a 6.4 cM interval on chromosome 7q36, between EN2 and D7S2423, a region to which a locus for preaxial polydactyly and triphalangeal thumb-polysyndactyly has previously been mapped. Our findings expand the range of phenotypes associated with this locus to include total soft tissue syndactyly and sternal deformity, and suggest that F syndrome may be another manifestation of the same genetic entity. In mice, ectopic expression of the gene Sonic hedgehog (Shh) in limb buds and lateral plate mesoderm during development causes preaxial polydactyly and sternal defects respectively, suggesting that misregulation of SHH may underlie the unusual combination of abnormalities in this family. A recently proposed candidate gene for 7q36 linked preaxial polydactyly is LMBR1, encoding a novel transmembrane receptor which may be an upstream regulator of SHH.

Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness.

Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. Mutations in PNPLA6 also cause human spastic paraplegia characterized by motor neuron degeneration. Here we identify PNPLA6 mutations in childhood blindness in seven families with retinal degeneration, including Leber congenital amaurosis and Oliver McFarlane syndrome. PNPLA6 localizes mostly at the inner segment plasma membrane in photoreceptors and mutations in Drosophila PNPLA6 lead to photoreceptor cell death. We also report that lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness.

A lethal multiple pterygium syndrome with apparent X-linked recessive inheritance.

We describe three male fetuses with a lethal multiple pterygium syndrome (LMPS). The family was ascertained when the first pregnancy of healthy, unrelated Scottish parents ended with a miscarriage at 23 weeks gestation. The macerated male fetus had a cystic hygroma, cleft palate, and webbing of the neck, elbows, and thighs. Radiographs showed lack of modeling of long bones, with broad ribs and clavicles, hypoplastic radii and ulnae, abnormal jaw angle, and dislocated femoral heads. Two other fetuses with similar anomalies were born to a first cousin of the propositus. These three male fetuses with a similar lethal multiple pterygium syndrome born to mothers who are second-degree relatives through the female line suggest X-linked recessive inheritance of LMPS in this family.

Oliver McFarlane syndrome: a 25-year follow-up.

We describe findings in a 29-year-old woman with Oliver McFarlane syndrome after 25 years of follow-up, and we review findings in six other reported cases. Pigmentary retinal degeneration, trichomegaly, prenatal onset growth failure, anterior pituitary deficiencies, and peripheral neuropathy characterize the condition.

Microcephaly: genetic counselling and antenatal diagnosis after the birth of an affected child.

We describe the clinical and genetic details of a series of microcephalic patients who were referred to the Genetic Counselling Service for the West of Scotland. There were 29 isolated cases of microcephaly and 9 families with recurrent microcephaly. The sib recurrence risk was 19%, which reflects the high incidence of autosomal recessive microcephaly in this series. There was evidence for several varieties of recessive microcephaly. The most frequent, affecting 5 sib pairs, was associated with spastic quadriplegia, seizures, and profound mental handicap. In 15 families with one microcephalic child, prenatal diagnosis by serial ultrasound scans was undertaken in 21 subsequent pregnancies. Four recurrences of microcephaly were detected in the third trimester and one recurrence was missed because no scans were performed after 24 wk gestation when the ultrasound measurements indicated satisfactory head growth. The main reason for late diagnosis of affected fetuses was that head growth did not slow appreciably until the last trimester. The high recurrence risk in this prospective series emphasizes the contribution of autosomal recessive inheritance of microcephaly amongst patients of our Genetic Counselling Service.

The Neu-Laxova syndrome in female sibs: clinical and pathological features with prenatal diagnosis in the second sib.

We report on affected sisters with the Neu-Laxova syndrome. Prenatal diagnosis of the condition was achieved by serial ultrasound examinations which demonstrated abnormal fetal growth in the second affected fetus before 24 weeks gestation.

Genetic aspects of early childhood scoliosis.

Eighty-seven families with early onset scoliosis were evaluated. These were divided into 3 groups: resolving infantile idiopathic scoliosis (15 families), progressive infantile idiopathic scoliosis (21 families), and congenital scoliosis due to vertebral malformations (51 families). The children with congenital scoliosis were subdivided into those who had closed neural arch defects (19 families) and those who did not (32 families). Resolving infantile idiopathic scoliosis was usually associated with plagiocephaly, and both deformations tended to show spontaneous recovery. These children were otherwise normal. Seven (33%) of the children with progressive infantile idiopathic scoliosis were mentally retarded, but only 2 had a congenital malformation. In contrast, 18 (33%) of the children with congenital scoliosis had other malformations, but only 2 were mentally retarded. The recurrence risk for scoliosis was low in each group studied. However, there was an increased risk (4% for sibs) of neural tube defects in the families with congenital scoliosis (with or without neural arch defects). This sib risk was apparent for probands with only a single hemivertebrum in addition to probands with more extensive vertebral defects and would support an etiological relationship between neural tube defects and other vertebral malformations.

Cleft palate, hypotelorism, and hypospadias: Schilbach-Rott syndrome.

A mother and two sons have cleft palate and facial appearance closely resembling cases described by Schilbach and Rott in 1988. One of the two males has hypospadias and learning disability and, like his mother, is of short stature. The family described by Schilbach and Rott also supports an autosomal dominant inheritance pattern.

Detection of a 15q deletion in a child with Angelman syndrome by cytogenetic analysis and flow cytometry.

A proximal 15q deletion, del(15) (q11:q13), was detected in a child with Angelman syndrome by cytogenetic analysis of peripheral lymphocytes. The chromosomes of both parents appeared normal. Flow karyotype analysis carried out on lymphoblastoid cell lines derived from the child and her parents confirmed the presence of a de novo 15 deletion. The estimated size of the deleted segment ranged from 6.1-9.5% of chromosome 15 (approximately 6-9.3 million base pairs). The parental origin of the deleted chromosome could not be resolved by flow cytometry, but cytogenetic evidence suggested that it was derived from the smaller chromosome 15 homologue in the mother.

Simpson-Golabi-Behmel syndrome: genotype/phenotype analysis of 18 affected males from 7 unrelated families.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth disorder recently shown to be caused by mutations in the heparan sulfate proteoglycan GPC3 [Pilia et al., Nat Genet; 12:241-247 1996]. We have used Southern blot analysis and polymerase chain reaction amplification of intra-exonic sequences to identify four new GPC3 mutations and further characterize three previously reported SGBS mutations. De novo GPC3 mutations were identified in 2 families. In general, the mutations were unique deletions ranging from less than 0.1 kb to more than 300 kb in length with no evidence of a mutational hot spot discerned. The lack of correlation between the phenotype of 18 affected males from these 7 families and the location and size of the GPC3 gene mutations suggest that SGBS is caused by a nonfunctional GPC3 protein.

A novel pattern of oculocerebral malformation.

AIMS/BACKGROUND: To report a novel pattern of oculocerebral malformation related to the group of diseases characterised by cobblestone lissencephaly. METHODS: By means of a case report with specialist descriptions of the novel neuropathological and ophthalmic pathology features. RESULTS: The patient, born to healthy consanguineous parents, presented in the neonatal period with jaundice, convulsions, and macrocephaly. Computed tomography demonstrated hydrocephalus and abnormal cerebral gyration. Ophthalmic examination revealed severe myopia and segments of retinal atrophy. Cytogenetic investigation revealed a balanced reciprocal translocation (46,XX,t(5p11;19q13.1)) that was inherited from the mother and was present in several normal relatives. Mild short stature and profound mental handicap were evident. The child died aged 7 years. At necropsy the brain showed 'cobblestone' (type II) lissencephaly. Cerebellar cortical architecture was abnormal and the brain stem lacked cerebral peduncles, basis pontis, and pyramids. Biopsies of skeletal muscles were normal. The ocular abnormalities included discrete sectors of retina of varying thickness with disordered neuronal lamination and gliosis. The optic nerve was gliotic and contained few nerve fibres. The anterior iris surface was studded with cellular stromal nodules which appear to be melanocytic in nature. CONCLUSION: Retinal dysgenesis occurs in the group of syndromes with 'cobblestone lissencephaly', the best known being Walker-Warburg syndrome. In this case, relatively long survival, lack of muscular dystrophy, and novel ocular pathology distinguish it from the other diagnoses in this group of syndromes. We suggest this child was affected by a distinct and novel oculocerebral syndrome.

Spondylothoracic and spondylocostal dysostosis. Hereditary forms of spinal deformity.

Two siblings with spondylothoracic dysostosis, and two siblings and three unrelated children with spondylocostal dysostosis are described. Both conditions are inherited and characterised by malformed thoracic and lumbar vertebrae. Spondylothoracic dysostosis produces "crab-like" deformities of the ribs, and is usually fatal during early infancy due to respiratory failure. Spondylocostal dysostosis causes short-trunked dwarfism but does not usually reduce life expectancy. These clinical features are distinct from congenital scoliosis, although all three conditions are associated with a particular group of malformations.

The Southwest of Scotland Structural Chromosomal Abnormalities Database: an assessment of its contribution to genetic counselling in affected families.

AIM: To assess the effect of establishing a genetic database on the provision of genetic counselling to individuals and families with structural chromosomal abnormalities. METHOD: For the four year period 1997-2000, we compared all cytogenetics laboratory records with entries on the database to determine its completeness. We assessed the extent to which families had been followed up, compared these findings with a previous four year period (1977-1980) and sought to discover why some families were not followed up. RESULTS: Of 215 probands identified during 1997-2000, 19 (9%) were not recorded on the register. Approximately one third of families were followed up completely, one third were partially followed up and one third had had no follow-up, for a variety of reasons. In this last group, there was evidence that some had received inadequate or incorrect genetic advice. There was no evidence that the database improved follow-up in families with structural chromosome abnormalities. Over 20 years, there has been a downward trend in the proportion of cases referred to the genetic clinic. CONCLUSIONS: Our register can be used to monitor trends in clinical practice but has had no direct effect on the service provided to patients and their families.

Severe prenatal infantile cortical hyperostosis (Caffey's disease).

We describe three cases of prenatal infantile cortical hyperostosis (Caffey's disease) from two families, all associated with maternal polyhydramnios. Case 1 (family 1) was an early early neonatal death after delivery at 27 weeks gestation, case 2 (family 2) an intrauterine death at 33 weeks. Case 3 (family 2) had limited skeletal involvement and followed a course typical for Caffey's disease. Only six cases of prenatal Caffey's disease with extensive skeletal involvement have previously been described. Polyhydramnios was reported in all but one and the condition was lethal unless pregnancy reached term. To our knowledge cases 2 and 3 reported here represent the first description of Caffey's disease in which the prenatal lethal form was not sporadic.

A new case of Myhre syndrome.

Myhre Syndrome is a rare condition associated with mental retardation, short stature, generalized muscle hypertrophy, cardiac defects and a distinct facial appearance. There have only been five reported cases and we now present a sixth, together with a review of the clinical features of this syndrome.

Spondylocostal dysostosis associated with a 46, XX,+15,dic(6;15)(q25;q11.2) translocation.

We describe a female neonate with spondylocostal dysostosis and a translocation resulting in monosomy for the region 6q25-->qter and trisomy for the region 15q11.1-->pter. The finding of a Mendelian disorder with a chromosomal abnormality may help in the localization of the gene(s) involved in this disease.

Syndromes associated with trichothiodystrophy.

Sparse, brittle, sulphur-deficient hair is an excellent marker for several autosomal recessive neurocutaneous syndromes. The term 'trichothiodystrophy' is commonly used in publications on such syndromes and the best characterized trichothiodystrophy syndrome is associated with skin photosensitivity and intellectual impairment. Patients with these three cardinal signs usually have an underlying DNA repair defect. Here we describe clinical and laboratory findings in two patients with trichothiodystrophy and defective DNA repair alongside findings in three other cases who have different trichothiodystrophy syndromes without defective DNA repair. These patients' features are discussed in the light of a practical classification scheme which is based upon a check-list of clinical abnormalities associated with trichothiodystrophy syndromes (Van Neste, 1991).