Gene conversion between red and defective green opsin gene in blue cone monochromacy.

Blue cone monochromacy is an X-linked condition in which the function of both the red pigment gene (RCP) and the green pigment gene (GCP) is impaired. Blue cone monochromacy can be due to a red/green gene array rearrangement existing of a single red/green hybrid gene and an inactivating C203R point mutation in GCP. We describe here a family with blue cone monochromacy due to the presence of the C203R mutation in both RCP and GCP. The flanking sequences of the C203R mutation in exon 4 of RCP were characteristic for GCP, indicating that this mutation was transferred from GCP into RCP by gene conversion.

Chromosome 13q deletion with Waardenburg syndrome: further evidence for a gene involved in neural crest function on 13q.

Waardenburg syndrome (WS) is an autosomal dominant disorder characterised by pigmentary abnormalities and sensorineural deafness. It is subcategorised into type 1 (WS1) and type 2 (WS2) on the basis of the presence (WS1) or absence (WS2) of dystopia canthorum. WS1 is always caused by mutations in the PAX3 gene, whereas WS2 is caused by mutations in the microphthalmia (MITF) gene in some but not all families. An association of WS symptoms with Hirschsprung disease (HSCR) has been reported in many families. We report here a patient with characteristics of WS2 and a de novo interstitial deletion of chromosome 13q. We also describe a family with two sibs who have both WS2 and HSCR. In this family, all possible genes for WS and HSCR, but not chromosome 13q, could be excluded. As an association between chromosome 13q and HSCR/WS has been reported previously, these data suggest that there is a gene on chromosome 13q that is responsible for WS or HSCR or both.

Recurrent mis-splicing of fibrillin exon 32 in two patients with neonatal Marfan syndrome.

The Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue. Variable and pleiotropic clinical features are observed in the skeletal, ocular, and cardiovascular systems. The most severe end of the phenotypic spectrum of this disorder comprises a group of patients usually diagnosed at birth, who have a life expectancy of little more than a year. To distinguish this group of patients from those with classical MFS, we refer to them as neonatal Marfan syndrome (nMFS). These infants usually die of congestive heart failure rather than aortic aneurysmal disease, the most frequent cause of morbidity and mortality in classical MFS. Defects in fibrillin, an elastin-associated microfibrillar glycoprotein, are now known to cause both the classical and neonatal forms of MFS. Here we report the recurrent mis-splicing of fibrillin (FBN1) exon 32, a precursor EGF-like calcium binding domain, in two unrelated infants with nMFS. The mis-splicing, in one patient, was due to an A-->T transversion at the -2 position of the consensus acceptor splice site; while that in the second patient was caused by a G-->A transition at the +1 position of the donor splice site. Characterization of FBN1 mutations in individuals at the most severe end of the Marfan syndrome spectrum should provide greater understanding of the multiple domains and regions of fibrillin.

Monozygotic twins discordant for spondylocostal dysostosis.

Spondylocostal dysostosis (SCD) is a rare skeletal dysplasia with clinical and radiological manifestations, consisting of short neck and trunk, barrel-shaped chest, protuberant abdomen, scoliosis and abnormalities of vertebral segmentation and of the ribs. Both autosomal recessive and autosomal dominant inheritance have been described. We report on monozygotic twins discordant for the syndrome, either due to a post-zygotic mutation or development of a phenocopy. To our best knowledge, this is the fourth report of SCD in identical twins, and the first one of discordance in monozygotic twins.

Multiple pterygium syndrome with body asymmetry.

We report on a fetus with multiple pterygia in the popliteal, antecubital, intercrural, axillary, and nuchal region, arthrogryposis, camptodactyly, anal atresia, hypospadias, ambiguous genitalia, and neonatal death. Arthrogryposis was much more pronounced at the left than at the right side. Moreover, there was gross body asymmetry with hypoplasia of the left arm, leg, pelvis, and kidney. As this spectrum of anomalies does not fit any of the known multiple pterygium syndromes, this patient adds another clinical entity to the already wide spectrum of multiple pterygium syndromes.

Reciprocal translocation between the proximal regions of the long arms of chromosomes 13 and 15 resulting in unbalanced offspring: characterization by fluorescence in situ hybridization and DNA analysis.

We describe two female siblings with similar clinical features consisting of hydrocephalus, scaphocephaly, hypotonia, mongoloid eye slant, blepharophimosis, micrognathia, supernumerary mouth frenula and mental retardation. Routine cytogenetic studies in the elder patient did not reveal any abnormality, and initially it was assumed that the syndrome had an autosomal recessive inheritance. However, a slightly larger chromosome 13 was seen in routine G-banded metaphases of the mother and the youngest of the two siblings. A shorter chromosome 15 was detected in the mother only. High resolution banding showed that the abnormal chromosome 13 contained an extra G-positive band at 13q12. The short chromosome 15 in the mother appeared to have a deletion of band q12. Fluorescence in situ hybridization using DNA markers specific to chromosomes 13 and 15 unequivocally showed that the mother was a carrier of a balanced reciprocal translocation t(13;15)(q12;q13), whereas the youngest sibling's karyotype was 46,XX,-13,+der(15)t(13;15)(q12;q13)mat, resulting in partial monosomy 13pter----q12 and partial trisomy 15pter----q13. The proband is thus trisomic for the critical region responsible for Prader-Willi syndrome and Angelman syndrome; this was confirmed by DNA analysis demonstrating one paternal and two maternal alleles from multiallelic marker loci mapping to 15q11-q13. This report illustrates the sensitivity and specificity offered by fluorescence in situ hybridization and its usefulness in the diagnosis and delineation of subtle chromosomal rearrangements.

Retinal manifestations in fibromuscular dysplasia.

Fibromuscular dysplasia of the arteries (FMD) is a segmental angiopathy which may produce obstruction of the carotid, cerebral, renal, mesenteric, coronary or iliac arteries. Except for lesions related to arterial hypertension, retinal manifestations have not yet been reported. This paper describes the case of a 10-year-old boy with progressive deafness, a history of an unexplained stroke and progressive occlusions of the retinal arterioles in the fundus periphery. This resulted in retinal neovascularization and recurrent retinal and vitreous hemorrhages. Despite repeated photo- and cryocoagulation the eyes progressed to a tractional retinal detachment which was successfully treated by vitrectomy and scleral buckling. The diagnosis of FMD was made on the basis of a histopathological examination of a temporal artery biopsy. The child also presented an asymptomatic but severe aneurysmal dilatation of the aorta and CT scan and MRI showed dilated cerebral arteries. The father of our patient had died at the age of 27 years either from myocardial infarction or rupture of a dissecting aortic aneurysm. He was highly myopic and had lost one eye from retinal detachment. The younger brother of our patient also presents aneurysmal dilatation of the aorta and tortuous cerebral vessels. Ocular examination is still normal. The findings in this family are compatible with an autosomal dominant inheritance with variable expression.

Marshall-Smith syndrome: new aspects.

A 4-year-old girl with the Marshall-Smith syndrome (MSS) is described. A muscle biopsy was performed because of hypotonia and muscular weakness. Selective hypoplasia of type IIa and IIb fibers was found. Additional not previously reported findings in this girl were a partial growth hormone deficiency, a partial villous atrophy of the small bowel and a pronounced dicarboxylic aciduria. The significance of these findings in MSS is not clear and the results of similar investigations in other MSS patients have to be awaited.