Genotype and clinical care correlations in craniosynostosis: findings from a cohort of 630 Australian and New Zealand patients.

Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis.

Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype.

BACKGROUND: The 9q subtelomeric deletion syndrome (9qSTDS) is clinically characterised by moderate to severe mental retardation, childhood hypotonia and facial dysmorphisms. In addition, congenital heart defects, urogenital defects, epilepsy and behavioural problems are frequently observed. The syndrome can be either caused by a submicroscopic 9q34.3 deletion or by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene. So far it has not been established if and to what extent other genes in the 9q34.3 region contribute to the phenotype observed in deletion cases. This study reports the largest cohort of 9qSTDS cases so far. METHODS AND RESULTS: By a multiplex ligation dependent probe amplification (MLPA) approach, the authors identified and characterised 16 novel submicroscopic 9q deletions. Direct sequence analysis of the EHMT1 gene in 24 patients exhibiting the 9qSTD phenotype without such deletion identified six patients with an intragenic EHMT1 mutation. Five of these mutations predict a premature termination codon whereas one mutation gives rise to an amino acid substitution in a conserved domain of the protein. CONCLUSIONS: The data do not provide any evidence for phenotype-genotype correlations between size of the deletions or type of mutations and severity of clinical features. Therefore, the authors confirm the EHMT1 gene to be the major determinant of the 9qSTDS phenotype. Interestingly, five of six patients who had reached adulthood had developed severe psychiatric pathology, which may indicate that EHMT1 haploinsufficiency is associated with neurodegeneration in addition to neurodevelopmental defect.

Malignant peripheral nerve sheath tumours in neurofibromatosis 1.

BACKGROUND: Cross sectional studies have shown that 1-2% of patients with neurofibromatosis 1 (NF1) develop malignant peripheral nerve sheath tumours (MPNST). However, no population based longitudinal studies have assessed lifetime risk. METHODS: NF1 patients with MPNST were ascertained from two sources for our north west England population of 4.1 million in the 13 year period 1984-1996: the North West Regional NF1 Register and review of notes of patients with MPNST in the North West Regional Cancer Registry. RESULTS: Twenty-one NF1 patients developed MPNST, equivalent to an annual incidence of 1.6 per 1000 and a lifetime risk of 8-13%. There were 37 patients with sporadic MPNST. The median age at diagnosis of MPNST in NF1 patients was 26 years, compared to 62 years in patients with sporadic MPNST (p<0.001). In Kaplan-Meier analyses, the five year survival from diagnosis was 21% for NF1 patients with MPNST, compared to 42% for sporadic cases of MPNST (p=0.09). One NF1 patient developed two separate MPNST in the radiation field of a previous optic glioma. CONCLUSION: The lifetime risk of MPNST in NF1 is much higher than previously estimated and warrants careful surveillance and a low threshold for investigation.

Mutations in PAX1 may be associated with Klippel-Feil syndrome.

Pax genes are a highly conserved family of developmental control genes that encode transcription factors. In vertebrates, Pax genes play a role in pattern formation during embryogenesis. Mutations in Pax genes have been associated with both spontaneous mouse mutants and congenital human diseases. The mouse Pax1 mutant phenotype undulated is characterised by vertebral segmentation defects reminiscent of the human disorder Klippel-Feil syndrome (KFS). To determine whether PAX1 haploinsufficiency plays a role in KFS, we have defined the gene structure of the human PAX1 gene and screened 63 KFS patients for mutations in this gene. Differences in the PAX1 sequence were detected in eight patients. Two patients had a silent change within the paired box that was also seen in 2/303 control chromosomes. The other variants were missense, silent or intronic changes not represented in the control panel tested. The significance of these results and the possible role of PAX1 in the pathogenesis of KFS are discussed.

Toriello-Carey syndrome: case report with additional findings.

Toriello-Carey syndrome comprises agenesis of the corpus callosum, telecanthus, small palpebral fissures, Pierre Robin sequence, abnormal ears, nuchal laxity and cardiac defects. We report on a female patient who has some additional findings including an anteriorly placed anus. This anomaly adds to the list of other midline anomalies seen in this syndrome. We compare the findings to those seen in the Opitz BBBG syndrome, a well-defined syndrome of the midline developmental field. Our patient, having a severe manifestation of complicated congenital heart disease, died in the neonatal period, which argues against the likelihood that this is an X-linked disorder with more severe manifestations in males.

Trisomy of 3pter in a patient with apparent C (trigonocephaly) syndrome.

The C syndrome is a multiple congenital anomaly/mental retardation (MCA/MR) syndrome first described in sibs. The inheritance has been assumed to be autosomal recessive. Several authors have commented that the combination of anomalies found in the conditions suggest an underlying chromosomal anomaly and in a few apparent cases chromosome anomalies have been described. Our patient had findings consistent with the C syndrome and a duplication of 3p by use of subtelomere probes. This shows that new cytogenetic techniques continue to be important in defining the underlying cause of MCA/MR conditions.

Prenatal diagnosis of Smith-Lemli-Opitz syndrome.

An abnormality in cholesterol synthesis was described recently in the Smith-Lemli-Opitz (SLO) syndrome. Here we describe how the application of this finding has enabled an accurate prenatal diagnosis. We also discuss the possible use of this test in detecting heterozygotes.

Geleophysic dysplasia: a report of three affected boys--prenatal ultrasound does not detect recurrence.

Geleophysic dysplasia is characterized by short stature with short limbs and brachydactyly, a "happy" facial appearance, and joint contractures. Infiltration of heart valves and liver with a mucopolysaccharide-like substance has been demonstrated in some patients. A metabolic pathogenesis is suspected, but has not yet been identified. We report on 3 boys with the condition, 2 of whom are brothers. Serial ultrasound scans were performed on 2 of the cases during pregnancy, but short limbs did not become obvious until after 28 weeks of gestation, making it an uninformative procedure for prenatal diagnosis.

Fanconi anemia and primary cataracts: first case.

Fanconi anemia or pancytopenia is an autosomal recessive condition presenting with a combination of pancytopenia with a mean age of onset of about eight years, a tendency to leukemia, and congenital anomalies. Although ocular abnormalities have been described, cataracts have not been previously reported. We present a patient with proven Fanconi anemia and cataracts.

Compound heterozygosity at the FMR1 gene.

Individuals affected with Fragile X syndrome are usually characterized at the DNA level by the presence of at least 200 CGG repeats in the 5' untranslated region of the FMR1 gene; this number of repeats is defined as a full mutation. Repeats that number 50-200 usually define those with premutations and are termed unaffected carriers. We report here a compound heterozygous female who carried CGG repeats in the FMR1 gene that fall within the premutation and full mutation ranges. The former appears to have been inherited from the father, whereas the latter is an expansion of the premutation carried by the proband's mother. Therefore, the offspring of the proband will carry a significant risk of being affected with Fragile X syndrome, and the paternal uncle and any cousins should be counselled for being at risk for this syndrome.

Another case of preaxial polydactyly and white forelock in branchio-oculo-facial syndrome.

A 1-year-old male with branchio-oculo-facial syndrome together with preaxial polydatyly and a white forelock at birth is described. This is only the second case where preaxial polydactyly has been described in branchio-oculo-facial syndrome. In both cases a diagnosis of Waardenburg syndrome had been considered.

MURCS in a male: a further case.

A third case of male with MURCS is described. The case is compared with two others previously reported and it is suggested that ARCS (azoospermia, renal anomaly and cervicothoracic spine disorder) might be a more appropriate acronym.

Clinical phenotypes of nine cases of Kabuki syndrome from New Zealand.

Nine cases of Kabuki syndrome have been identified in Auckland and surrounding regions in the North Island, New Zealand since 1995. All have the characteristic facial dysmorphism and many of the well-described associated anomalies. Some of the abnormalities were unusual including a case with severe congenital mitral stenosis, two cases of eventration of the diaphragm, idiopathic thrombocytopaenic purpura and vitiligo. One child had an Arnold Chiari type 1 malformation and another had epibulbar dermoids, neither of which has previously been reported in this syndrome. There was a wide diversity of ethnic origin, with the syndrome being described in patients from the Pacific Islands for the first time. The cases described emphasize the broad range of associated anomalies found in Kabuki syndrome and further illustrate its presence in all ethnic groups.

Syndactyly, micrognathia and skeletal anomalies: a new syndrome?

We report a fetus with micrognathia, cleft palate, polysyndactyly, brachycephaly and proximal radial hypoplasia. We believe the abnormalities represent a new syndrome not previously described.

Precocious puberty, endometriosis, skeletal anomalies and mild hearing loss: a new autosomal dominant syndrome?

Two sisters presented at 13 and 15 years-of-age respectively with a history of precocious puberty, short stature, endometriosis and mild mixed hearing loss. They had mild learning difficulties and a number of skeletal features in common. Some of these features were present in their father, suggesting a new autosomal dominant entity.