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We studied 14 individuals with partial deletions of the long arm of chromosome 18, including terminal and interstitial de novo and inherited deletions. Study participants were examined clinically and by brain MRI. The size of the deletion was determined by segregation analysis using microsatellite markers. We observed that the phenotype was highly variable, even in two families with three 1st degree relatives. Among the 14 individuals, general intelligence varied from normal to severe mental retardation. The more common features of 18q-deletions (e.g., foot deformities, aural atresia, palatal abnormalities, dysmyelination, and nystagmus) were present in individuals lacking only the distal portion 18q22.3-qtel. Interstitial deletions exerted very heterogeneous effects on phenotype. In individuals with distal 18q22.3-q23 deletions, brain MRI was very distinctive with poor differentiation of gray and white matter on T2-weighted images., (Copyright (c) 2006 Wiley-Liss, Inc.)

The Shprintzen-Goldberg syndrome (SGS) is a disorder of unknown cause comprising craniosynostosis, a marfanoid habitus and skeletal, neurological, cardiovascular, and connective-tissue anomalies. There are no pathognomonic signs of SGS and diagnosis depends on recognition of a characteristic combination of anomalies. Here, we describe 14 persons with SGS and compare their clinical findings with those of 23 previously reported individuals, including two families with more than one affected individual. Our analysis suggests that there is a characteristic facial appearance, with more than two thirds of all individuals having hypertelorism, down-slanting palpebral fissures, a high-arched palate, micrognathia, and apparently low-set and posteriorly rotated ears. Other commonly reported manifestations include hypotonia in at least the neonatal period, developmental delay, and inguinal or umbilical hernia. The degree of reported intellectual impairment ranges from mild to severe. The most common skeletal manifestations in SGS were arachnodactyly, pectus deformity, camptodactyly, scoliosis, and joint hypermobility. None of the skeletal signs alone is specific for SGS. Our study includes 14 mainly German individuals with SGS evaluated over a period of 10 years. Given that only 23 other persons with SGS have been reported to date worldwide, we suggest that SGS may be more common than previously assumed.

We report on a 23-month-old boy with bilateral cleft lip and palate, marked hypertelorism, frontal bossing and severe bilateral, asymmetric hypoplasia of toes. The mother used bisoprolol, naproxen and sumatriptan for migraine until the fifth postmenstrual week of pregnancy. We suggest that this patient's features represent a previously undescribed entity of as yet unknown aetiology.

We report on a patient with severe pre- and post-natal growth retardation, moderate mental retardation, microcephaly, unusual face with marked micrognathia and cleft palate, minor skeletal abnormalities, atrioseptal defect, hypospadias, hearing loss, and secondary adrenal insufficiency due to isolated ACTH deficiency diagnosed at 7 years of age. Family history was negative. Adrenal insufficiency is an uncommon feature in multiple malformation syndromes and may thus serve as a diagnostic handle for recognizing other possible patients with a similar syndrome., (Copyright 2003 Wiley-Liss, Inc.)

CFC (cardiofaciocutaneous) syndrome (MIM 115150) has been considered by several authors to be a more severe expression of Noonan syndrome. Affected patients present with congenital heart defects, cutaneous abnormalities, Noonan-like facial features and severe psychomotor developmental delay. We have recently demonstrated that Noonan syndrome can be caused by missense mutations in PTPN11(MIM 176876), a gene that encodes the non-receptor protein tyrosine phosphatase SHP-2. In this report, we have evaluated the possible involvement of mutations in PTPN11 in CFC syndrome. A cohort of 28 CFC subjects rigorously assessed as having CFC based on OMIM diagnostic criteria was examined for mutations in the PTPN11 coding sequence by using DHPLC analysis. The results showed no abnormalities in the coding region of the PTPN11 gene in any CFC patient, nor any evidence of major deletions within the gene suggesting that mutations in other gene(s) are responsible for this syndrome.

The fetal valproate syndrome (FVS) is characterized by distinctive facial appearance, major and minor malformations, and developmental delay. Generally, only a small proportion of prenatally exposed children are affected. The authors describe three families in whom the occurrence of FVS in all the siblings strongly suggests hereditary susceptibility to valproic acid-induced adverse outcome. The risk for recurrence in a subsequent pregnancy may be high and should be taken into account in the counseling of parents and in considering drug treatment.

Stickler and Marshall syndromes are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural-hearing deficit. Since the characteristics of these syndromes overlap, it has been argued whether they are distinct entities or different manifestations of a single syndrome. Several mutations causing Stickler syndrome have been found in the COL2A1 gene, and one mutation causing Stickler syndrome and one causing Marshall syndrome have been detected in the COL11A1 gene. We characterize here the genomic structure of the COL11A1 gene. Screening of patients with Stickler, Stickler-like, or Marshall syndrome pointed to 23 novel mutations. Genotypic-phenotypic comparison revealed an association between the Marshall syndrome phenotype and splicing mutations of 54-bp exons in the C-terminal region of the COL11A1 gene. Null-allele mutations in the COL2A1 gene led to a typical phenotype of Stickler syndrome. Some patients, however, presented with phenotypes of both Marshall and Stickler syndromes.

Wolf-Hirschhorn syndrome (WHS) is a multiple malformation syndrome characterised by mental and developmental defects resulting from the absence of a segment of one chromosome 4 short arm (4p16.3). Due to the complex and variable expression of this disorder, it is thought that the WHS is a contiguous gene syndrome with an undefined number of genes contributing to the phenotype. In an effort to identify genes that contribute to human development and whose absence results in this syndrome, we have utilised a series of landmark cosmids to characterise a collection of WHS patient derived cell lines. Fluorescence in situ hybridisation with these cosmids was used to refine the WHS critical region (WHSCR) to 260 kb. The genomic sequence of this region is available and analysis of this sequence through BLAST detected several cDNA clones in the dbEST data base. A total of nine independent cDNAs, and their predicted translation products, from this analysis show no significant similarity to members of DNA or protein databases. Furthermore, these genes have been localised within the WHS critical region and reveal an interesting pattern of transcriptional organisation. A previously published report of a patient with proximal 4p- syndrome further refines the WHSCR to 165 kb defined by the loci D4S166 and D4S3327. This work provides the starting point to understand how multiple genes or other mechanisms can contribute to the complex phenotype associated with the Wolf-Hirschhorn syndrome.

The PEHO syndrome (progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy) is a recently recognised disorder of unknown biochemical background. Diagnostic features have been found in neuroradiological and neuropathological studies, which show characteristic severe cerebellar atrophy. In combined neuroradiological and ophthalmological studies, 10 out of 21 possible PEHO patients fulfilled the criteria for true PEHO syndrome. All were abnormal at birth showing hypotonia, drowsiness, or poor feeding. Head circumference was normal, but usually dropped to 2 SD below average during the first year of life. Visual fixation was either absent from birth or lost during the first months of life. Nine patients had peripheral oedema in early childhood. The mean age of onset of infantile spasms was 4.9 months. All patients were extremely hypotonic and no motor milestones were reached. Patellar reflexes were brisk. Brain stem and somatosensory evoked potentials were abnormal in each case studied, cortical responses of somatosensory evoked potentials could not be elicited, and motor conduction velocities became delayed with age. Altogether 19 PEHO patients were found in 14 Finnish families. Autosomal recessive inheritance is likely.

A 15-year-old boy with a terminal deletion of the short arm of chromosome 4 is described. The patient has a mild clinical phenotype that is incompatible with Wolf-Hirschhorn syndrome. Careful neurological examination including CT scan did not show any signs of Huntington disease. The chromosomal breakpoint was analyzed by means of polymorphic DNA probes localized close to the tentative Huntington (HD) locus. The breakage has occurred between D4S43 and D4S90 loci and thus deletes part of the chromosomal candidate regions for the HD locus.

A girl with the oral-facial-digital syndrome type I (OFD I) developed precocious puberty at early infancy. This is presumed to be due to a hamartoma in the tuber cinereum region. Hypothalamic hamartomas have not been described in OFD I earlier, whereas lingual hamartomas are a common feature in this condition.