Severe microcephaly, choreiform movements, cataracts and sensorineural deafness in two patients: a new syndrome?

Two unrelated male patients are described with severe microcephaly, early-onset choreiform movements, cataracts, sensorineural deafness and profound developmental delay. Our patients have much in common with the three male siblings described by Tomiwa et al., who also had cataracts, deafness and developmental delay, but much less severe microcephaly and a different type of movement disorder with later onset [Tomiwa K et al. (1987). Neuropediatrics 18:231-234]. An extensive literature search did not reveal any other reports of patients with a similar condition. We discuss the differential diagnosis.

Lethal micromelic short-rib skeletal dysplasia with triangular-shaped humerus.

We report two brothers with a new type of lethal, micromelic, short-rib, skeletal dysplasia characterised by short limbs with distinctive triangular-shaped humeri. This condition is most likely caused by either an autosomal recessive or X-linked recessive gene.

A new syndrome of spondyloepimetaphyseal dysplasia, eczema and hypogammaglobulinaemia.

We describe a female infant with a combination of very short stature, severe eczema and IgG deficiency causing recurrent infections in infancy. The radiological features of this condition are presented in the neonatal period, at the age of 5 months and at 2 years and 6 months. We propose that this condition is a previously undescribed type of spondyloepimetaphyseal dysplasia.

A new syndrome of short stature, distinctive facial features and periventricular grey matter heterotopia.

We report on a male infant with distinctive facial features, short stature and rhizomelic upper limb shortening. His MRI brain scan showed abnormal ventricular architecture and bilateral periventricular nodular grey matter heterotopia (BPNH). This child represents an apparently new dysmorphic syndrome.

Acromelic frontonasal dysostosis.

We report on 3 male and 2 female infants with acromelic frontonasal dysostosis. All 5 had a frontonasal malformation of the face and nasal clefting associated with striking symmetrical preaxial polysyndactyly of the feet and variable tibial hypoplasia. In contrast, the upper limbs were normal. This rare variant of frontonasal dysplasia may represent a distinct autosomal-recessive disorder. We suggest that the molecular basis of this condition may be a perturbation of the Sonic Hedgehog (SHH) signalling pathway, which plays an important part in the development of the midline central nervous system/craniofacial region and the limbs.

An autosomal or X linked mutation results in true hermaphrodites and 46,XX males in the same family.

It is now well established that the differentiation of the primitive gonad into the testis during early human embryonic development depends on the presence of the SRY gene. However, the existence of total or partial sex reversal in 46,XX males with genetic mutations not linked to the Y chromosome suggests that several autosomal genes acting in association with SRY may contribute to normal development of the male phenotype. We report a family in which four related 46,XX subjects with no evidence of Y chromosome DNA sequences underwent variable degrees of male sexual differentiation. One 46,XX male had apparently normal male external genitalia whereas his brother and two cousins had various degrees of sexual ambiguity and were found to be 46,XX true hermaphrodites. The presence of male sexual development in genetic females with transmission through normal male and female parents indicates that the critical genetic defect is most likely to be an autosomal dominant mutation, the different phenotypic effects arising from variable penetrance. Other autosomal loci have been implicated in male sexual development but the genetic mechanisms involved are unknown. In this family there may be an "activating" mutation which mimics the initiating role of the SRY gene in 46,XX subjects.

Parent-child transmission of infantile cholestasis with lymphoedema (Aagenaes syndrome).

We report a mother and daughter with features of Aagenaes syndrome. Unlike most previous cases, there is no Norwegian ancestry and the pedigree favours dominant rather than recessive inheritance.

Congenital cervical spinal fusion: a study in Apert syndrome.

The occurrence and pattern of cervical spinal fusions have been assessed in 59 cases of Apert syndrome (acrocephalosyndactyly type 1). Radiological evidence of vertebral fusion either in progress or completed was observed in 37 (63%) of the cases. Fusion was limited to a single vertebral level in 18 cases and multiple levels, involving either contiguous or skipped levels in the remaining 19+ C3-4 and C5-6 were the levels most commonly involved. This distribution of fusions is different from other instances of congenital spinal fusion including those associated with other varieties of craniosynostosis. There was a significant association between age at the time of radiograph and the presence of spinal fusions (p < 0.001, Wilcoxon 2-sample test). Analysis of sequential radiographs in 17 patients revealed evidence of progressive fusion in 10. Small size of the vertebral body and reduced intervertebral disc space were indicators of subsequent bony fusion. The fusions seen in Apert syndrome thus appear to be progressive, occurring at the site of subtle congenital vertebral anomalies and may not be apparent as a congenital feature. The implications for the aetiology of so-called "congenital' spinal fusions in Apert syndrome and other situations are discussed.

Exclusive paternal origin of new mutations in Apert syndrome.

Apert syndrome results from one or other of two specific nucleotide substitutions, both C-->G transversions, in the fibroblast growth factor receptor 2 (FGFR2) gene. The frequency of new mutations, estimated as 1 per 65,000 live births, implies germline transversion rates at these two positions are currently the highest known in the human genome. Using a novel application of the amplification refractory mutation system (ARMS), we have determined the parental origin of the new mutation in 57 Apert families: in every case, the mutation arose from the father. This identifies the biological basis of the paternal age effect for new mutations previously suggested for this disorder.

Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome.

Apert syndrome is a distinctive human malformation characterized by craniosynostosis and severe syndactyly of the hands and feet. It is caused by specific missense substitutions involving adjacent amino acids (Ser252Trp or Pro253Arg) in the linker between the second and third extracellular immunoglobulin domains of fibroblast growth factor receptor 2 (FGFR2). We have developed a simple PCR assay for these mutations in genomic DNA, based on the creation of novel (SfiI) and (BstUI) restriction sites. Analysis of DNA from 70 unrelated patients with Apert syndrome showed that 45 had the Ser252Trp mutation and 25 had the Pro253Arg mutation. Phenotypic differences between these two groups of patients were investigated. Significant differences were found for severity of syndactyly and presence of cleft palate. The syndactyly was more severe with the Pro253Arg mutation, for both the hands and the feet. In contrast, cleft palate was significantly more common in the Ser252Trp patients. No convincing differences were found in the prevalence of other malformations associated with Apert syndrome. We conclude that, although the phenotype attributable to the two mutations is very similar, there are subtle differences. The opposite trends for severity of syndactyly and cleft palate in relation to the two mutations may relate to the varying patterns of temporal and tissue-specific expression of different fibroblast growth factors, the ligands for FGFR2.

Hemifacial hypoplasia and hypomelanosis of Ito.

We present three cases of hemifacial hypoplasia associated with hypomelanosis of Ito. The facial deformity is often severe with marked soft tissue shortage and underlying skeletal hypoplasia posing difficulty in reconstruction. The external ear is relatively uninvolved, although a degree of hypoplasia is usually present. The hallmark of hypomelanosis of Ito is linear depigmentation of skin often associated with asymmetric abnormalities. It is a heterogenous disorder due to chromosomal mosaicism, but cytogenetic confirmation of the diagnosis may be difficult. The relationship between mosaicism and anatomical asymmetry is discussed.

Mutations in the third immunoglobulin domain of the fibroblast growth factor receptor-2 gene in Crouzon syndrome.

Craniosynostosis, which affects approximately 1 in 2000 children, is the result of the abnormal development and/or premature fusion of the cranial sutures. Studies of mutations in patients with craniosynostosis have shown that the family of fibroblast growth factor receptor genes are extremely important in the correct formation of the skull, and digits. Mutations in the third immunoglobulin domain of fibroblast growth factor receptor 2 (FGFR2), in part of the molecule corresponding to a tissue specific isoform (IIIc), can cause both Crouzon and Pfeiffer syndromes. Two specific mutations in the linking region between the second and third immunoglobulin domains of FGFR2 occur in Apert syndrome. We present here mutations associated with the Crouzon syndrome, also in the third immunoglobulin domain but in an upstream exon. This exon is expressed in both tissue isoforms. Five different mutations were detected in 11 unrelated individuals. A cysteine to phenylalanine change was found in six individuals. This cysteine forms half of the disulphide bridge maintaining the secondary structure of the immunoglobulin domain. The first deletion within an FGFR gene is reported. Together with mutations in exon IIIc these account for 25 mutations out of 40 Crouzon patients studied in our combined series (5).

MURCS in a male?

A man with Klippel-Feil deformity, unilateral renal agenesis, and azoospermia is presented as a possible case of MURCS.

Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes.

Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been identified in Crouzon syndrome, an autosomal dominant condition causing premature fusion of the cranial sutures (craniosynostosis). A mutation in FGFR1 has been established in several families with Pfeiffer syndrome, where craniosynostosis is associated with specific digital abnormalities. We now report point mutations in FGFR2 in seven sporadic Pfeiffer syndrome patients. Six of the seven Pfeiffer syndrome patients share two missense mutations, which have also been reported in Crouzon syndrome. The Crouzon and Pfeiffer phenotypes usually breed true within families and the finding of identical mutations in unrelated individuals giving different phenotypes is a highly unexpected observation.

Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.

Apert syndrome is a distinctive human malformation comprising craniosynostosis and severe syndactyly of the hands and feet. We have identified specific missense substitutions involving adjacent amino acids (Ser252Trp and Pro253Arg) in the linker between the second and third extracellular immunoglobulin (Ig) domains of fibroblast growth factor receptor 2 (FGFR2) in all 40 unrelated cases of Apert syndrome studied. Crouzon syndrome, characterized by craniosynostosis but normal limbs, was previously shown to result from allelic mutations of the third Ig domain of FGFR2. The contrasting effects of these mutations provide a genetic resource for dissecting the complex effects of signal transduction through FGFRs in cranial and limb morphogenesis.

DNA testing for fragile X syndrome in schools for learning difficulties.

Fragile X syndrome is the most common inherited cause of mental retardation. Early diagnosis is important not only for appropriate management of individuals but also to identify carriers who are unaware of their high risk of having an affected child. The disorder is associated with a cytogenetically visible fragile site (FRAXA) at Xq27.3, caused by amplification of a (CGG)n repeat sequence within the gene at this locus designated FMR1. Clinical and molecular studies have been undertaken to screen for fragile X syndrome in 154 children with moderate and severe learning difficulties of previously unknown origin. Southern blot analysis of peripheral blood showed the characteristic abnormally large (CGG)n repeat sequence associated with fragile X syndrome in four of the 154 children. The findings were confirmed by cytogenetic observation of the fragile site and by further molecular studies. The families of the affected children were offered genetic counselling and DNA tests to determine their carrier status. These findings show that there are still unrecognised cases of fragile X syndrome. Given the difficulty of making a clinical diagnosis and the implications for families when the diagnosis is missed, screening in high risk populations may be justified. The issues involved in screening all children in special schools for fragile X syndrome are discussed.

Asymmetry and skin pigmentary anomalies in chromosome mosaicism.

We report six persons mosaic for a chromosome anomaly. All were mentally retarded and dysmorphic. Unilateral or asymmetrical features were found in all cases, in one an unusual transverse terminal limb anomaly, and in the others various degrees of hemiatrophy of the left side of the body. Five of the subjects had skin pigmentary anomalies which were distributed in the lines of Blaschko. The abnormal cell lines found were ring chromosome 22, trisomy 22, a large acrocentric marker, a deletion of 18q, a deletion of 8q, and triploidy. In four cases the clinical diagnosis was only confirmed by skin biopsy. In one case low level mosaicism in blood was fortuitously detected because of cytogenetic fragile X screening and confirmed in a skin biopsy. The sixth case was of dynamic mosaicism of a non-mosaic deletion 18q with a chromosome 18 derived marker present in a proportion of cells. Chromosome mosaicisn may cause subtle and asymmetrical clinical features and can require repeated cytogenetic investigations. The diagnosis should be actively sought as it enables accurate genetic counselling to be given.