RNA-based mutation screening in German families with Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is a rare autosomal recessively inherited disorder characterised by mental retardation, spasticity and ichthyosis. SLS patients have a profound deficiency in fatty aldehyde dehydrogenase (FALDH) activity. The human cDNA of FALDH has been shown to map to the SLS locus on chromosome 17p11.2. Here we describe a method based on reverse transcriptase-polymerase chain reaction (RT-PCR) and protein truncation test to identify mutations in the FALDH gene in nine German SLS families. Using this detection system both disease-causing mutations were found in eight of the nine SLS families examined (17/18 chromosomes). Seven different mutations were identified: an exon 2 skipping due to exon 2 splice donor mutation; two different exon 3 splice donor mutations resulting in combined exon 2 and 3 skipping; a 906delT deletion in exon 6; a genomic deletion of about 6 kb including exon 9; a 1277T > G transversion resulting in a Leu426Ter nonsense mutation; and a 1297delGA deletion. Two of the mutations identified, the genomic exon 9 deletion and the 906delT in exon 6 affected five out of seven SLS patients from a small region of Northern Bavaria. Therefore these two mutations accounted for 71% (10/14 chromosomes) of Bavarian SLS alleles and so far have not been described in SLS families from other countries. Our findings do not support our 'historical' hypothesis, that a possible region clustering in Northern Bavaria could be due to the presence of Swedish soldiers during the 30 Years War (1618-1648), but suggest that two mutations causing SLS syndrome originated in Northern Bavaria.

Further evidence of genetic homogeneity in Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome is an autosomal recessive disorder characterized by congenital ichthyosis, spastic di- or tetraplegia and mental retardation. In 1994 Sjögren-Larsson syndrome was mapped to chromosome 17, close to the genetic marker D17S805 in a study of 24 Swedish families. We have analysed 12 microsatellite markers in 10 additional non-Swedish families with Sjögren-Larsson syndrome originating from Germany, Lebanon, Spain and Canada. The results are consistent with earlier data and give further evidence of Sjogren-Larsson syndrome being a homogeneous disorder. Swedish soldiers were bivouacking in Germany during the 30-year war in the 17th century and it has been suggested that they could have introduced the Sjögren-Larsson syndrome gene to the German population. Haplotypes from 7 German families with Sjögren-Larsson syndrome were compared with earlier analysed Swedish haplotypes. No evidence of all German patients carrying the same mutation or the major "Swedish Sjögren-Larsson syndrome gene" was found.

Spectrum of mutations and sequence variants in the FALDH gene in patients with Sjögren-Larsson syndrome.

The gene encoding the human fatty aldehyde dehydrogenase (FALDH) is located on 17p11.2, causing Sjögren-Larsson syndrome (SLS) when mutated. SLS is an autosomal recessive disorder characterized by a combination of mental retardation, congenital ichthyosis, and spastic di- or tetraplegia. We report here on studies of 16 SLS families from Europe and the Middle East, which resulted in identification of 11 different mutations. The spectrum of mutations characterized in the present study are five nucleotide substitutions resulting in amino acid changes, five frameshift mutations introducing a stop codon, and one in-frame deletion with insertion at the same position. We also observed silent sequence variants in the FALDH gene and a base pair substitution in exon 5 that alters aspartic acid to asparagine, all of which are considered polymorphisms.

Variant of Coffin-Siris syndrome or previously undescribed syndrome?

We describe a 23-year-old woman with growth and mental retardation, hypoplasia of the nails and distal phalanges, particularly of the fifth fingers and toes, hirsutism, and a "coarse" face with large mouth and large tongue, and bushy eyebrows. Follow-up from birth to adulthood showed that developmental delay and hypoplasia of nails and distal phalanges are permanent signs. Sparse scalp hair, hypotonia, and feeding difficulties were present in early infancy. Later, growth retardation, hirsutism, and a "coarse" face with midface hypoplasia, broad nose, and large mouth became more impressive. Differential diagnosis includes a number of conditions, particularly Coffin-Siris syndrome, which is the most likely but not completely convincing diagnosis. Therefore, this woman might represent a variant of Coffin-Siris syndrome or a new entity.

De novo direct duplication 3 (p25-->pter): a previously undescribed chromosomal aberration.

We report on a case of de novo direct duplication for the distal part of chromosome 3p: 46,XY,dir dup (3) (p25-->pter). At the age of 4 years and 7 months, the boy presented with moderate growth and mental retardation, muscular hypotonia, hypoplasia of the left kidney, a short neck, and a square-shaped face characterized by a broad and flat nasal bridge, slight epicanthus, and full cheeks. So far, only a few cases with such a small distal 3p duplication have been described, and none of them has a de novo direct duplication for this region. In our patient, dysmorphic signs are less impressive, and developmental delay is relatively moderate.

MURCS association: case report and review.

We report on a 25 year old woman with aplasia of the Müllerian duct, unilateral renal agenesis, and anomalies of the cervicothoracic somites (MURCS association). Growth retardation and facial asymmetry were also present. A review of published reports allows MURCS association to be distinguished from related associations, sequences, and syndromes. Moreover, sporadic occurrence, the broad spectrum of associated anomalies, and the involvement of different organ systems closely related in early embryogenesis are arguments for considering MURCS association as the consequence of a developmental field defect.

Isochromosome 18p results from maternal meiosis II nondisjunction.

Microsatellite analysis with 13 microsatellites spread over 18p was performed to determine the origin of the marker chromosome in 9 patients with additional metacentric marker chromosomes. Phenotypes and banding patterns suggested that the markers were isochromosomes 18p. Maternal origin was determined in all 8 cases where both parents were available for study. Six cases showed 3 alleles (one paternal, one maternal each in single and double dose) of informative markers located close to the telomere while markers close to the centromere on 18p were reduced to homozygosity (one paternal allele in single dosage and one maternal allele presumably in triple dosage). A similar result was obtained in the patient with no parents available for examination. The other 2 patients were uninformative for maternal hetero- versus homozygosity, but at some loci the maternal band was clearly stronger than the paternal one whereas the opposite was never observed. Trisomy 18 differs from trisomy 21, XXX and XXY of maternal origin through a preponderance of meiosis II versus meiosis I nondisjunction. Thus, the results of our study and the advanced mean maternal age at delivery of patients with additional i(18p) indicate that in most if not all cases the marker chromosome originates from maternal meiosis II nondisjunction immediately followed by isochromosome formation in one of the 2 maternal chromosomes 18. Possible explanations of these results include a maternally imprinted gene on 18q with a lethal effect if the paternal homologue is lost and a mechanism through which nondisjunction in some cases could be connected with isochromosome formation.

Genetic nosology and counseling of humeroradial synostosis.

From published cases of humeroradial synostoses three entities can be delineated: AD ankylosis of the elbow as a part of a systemic disorder causing multiple synostoses (symphalangism), AR humeroradial synostosis with dysgenesis of the ulna (and fibula?) but without oligodactyly as part of a syndromal disorder, non-germinal uni- or bilateral humeroradial synostosis as part of ulnar malformation and oligodactyly. Three new observations are considered examples of the latter entity.