Contribution to the 18q- syndrome. A patient with del (18) (q22.3qter)

A patient with the typical features of the 18q- syndrome, but with the deletion restricted to the most distal part, bands q22.3----qter is reported. The cytogenetic finding is supported by a decrease in activity of the enzyme peptidase A.     

Magnetic resonance imaging demonstrates incomplete myelination in 18q- syndrome

Magnetic resonance imaging (MRI) and MRI relaxometry were used to investigate disturbed brain myelination in 18q- syndrome, a disorder characterized by mental retardation, dysmorphic features, and growth failure. T1-weighted and dual spin-echo T2-weighted MR images were obtained, and T1 and T2 parametric image maps were created for 20 patients and 12 controls. MRI demonstrated abnormal brain white matter in all patients. White matter T1 and T2 relaxation times were significantly prolonged in patients compared to controls at all ages studied, suggesting incomplete myelination. Chromosome analysis using fluorescence in situ hybridization techniques showed that all patients with abnormal MRI scans and prolonged white matter T1 and T2 relaxation times were missing one copy of the myelin basic protein (MBP) gene. The one patient with normal-appearing white matter and normal white matter T1 and T2 relaxation times possessed two copies of the MBP gene. MRI and molecular genetic data suggest that incomplete cerebral myelination in 18q- is associated with haploinsufficiency of the gene for MBP. Am. J. Med. Genet. 74:422–431, 1997. © 1997 Wiley-Liss, Inc.     

Growth hormone deficiency associated in the 18q deletion syndrome

The 18q- syndrome is one of the commonest deletion syndromes. Clinical characteristics are variable but may include: hypotonia, tapered digits, “carp-like” mouth, mental retardation, and hearing impairment. Growth failure (GF; both weight and height <3%) was reported in 80% of affected individuals. We evaluated growth hormone (GH) sufficiency in 5 18q- syndrome patients, 3 of whom had growth failure (<3% weight and height); the remaining 2 had normal growth parameters. Laboratory evaluation of growth included measurement of IGF-1, IGFBP-3, bone ages and GH response to pituitary provocative agents. Three patients failed to produced adequate GH following stimulation testing. Of 3 patients with inadequate GH production, 1 had normal growth (above 3%). Only 1 of 5 patients had normal GH production and normal growth parameters. Our findings to date suggest that GH deficiency is common in individuals with the 18q- syndrome. The pathogenesis of this finding is unknown. We postulate that a gene(s) on 18q is involved in GH production. Am. J. Med. Genet. 69:7–12, 1997. © 1997 Wiley-Liss, Inc.     

Parental origin of the supernumerary chromosome in trisomy 18

Ya-gang X, Robinson WP, Spiegel R, Binkert F, Ruefenacht U, Schinzel AA. Parental origin of the supernumerary chromosome in trisomy 18. Clin Genet 1993: 44: 57–61. Munksgaard, 1993
The parental origin of an extra chromosome in Edwards syndrome has been investigated in 23 families by the combination of the VNTR probe pERT25, two microsatellite polymorphisms for D18S34 and D18S40, and several two-allele polymorphisms. Of the 23 cases, 22 were informative, with 17 (77%) being maternal and 5 (23%) paternal in origin. These results support the previous investigations, suggesting that trisomy 18 is predominantly of maternal origin, although a higher rate of paternally derived cases was observed than previously reported. A significant increase in maternal age was found to be associated with meiotic nondisjunction. Parental age was increased in both the maternally and paternally derived cases, but the size of the latter class was small and did not reach statistical significance.     

Clinical, cytogenetic and molecular investigations in three patients with Wolf-Hirschhorn syndrome

Clinical, cytogenetic and molecular studies were performed in three patients with Wolf-Hirschhorn syndrome (WHS). In all cases the altered chromosome 4 appeared to be the result of a de novo deletion. Cytogenetic investigations located the breakpoint at 4p15.3 and 4p13. With cytogenetic methods it was not possible to decide whether these deletions were terminal or interstitial. DNA methods also failed to define a distal breakpoint within the 4p16.3 region which might have indicated an interstitial deletion. According to the literature, the paternal chromosome 4 is preferentially deleted in most patients with WHS. DNA analysis with polymorphic markers out of the 4p16.3 region revealed that in two of the cases reported here the deleted segment was of paternal and in one case of maternal origin.     

18q-mosaicism associated with Rett syndrome phenotype

Rett syndrome consists of a characteristic progressive encephalopthy in females. The cause of this syndrome is unknown. We present a patient with 18q-mosaicism who, along with the characteristics of this autosomal deletion, also fulfills the clinical criteria for Rett syndrome. This may demonstrate heterogeneity within this as yet cinically defined syndrome. A thorough chromosomal analysis should be performed in suspected cases of Rett syndrome. © 1993 Wiley-Liss, Inc.     

Molecular and clinical study of 61 Angelman syndrome patients

We analyzed 61 Angelman syndrome (AS) patients by cytogenetic and molecular techniques. On the basis of molecular findings, the patients were classified into the following 4 groups: familial cases without deletion, familial cases with submicroscopic deletion, sporadic cases with deletion, and sporadic cases without deletion. Among 53 sporadic cases, 37 (70%) had molecular deletion which commonly extended from D15S9 to D15S12, although not all deletions were identical. Of 8 familial cases, 3 sibs from one family had a molecular deletion involving only 2 loci, D15S10 and GABRB3, which define the critical region for AS phenotypes. The parental origin of deletion, both in sporadic and familial cases, was exclusively maternal and consistent with a genomic imprinting hypothesis. Among sporadic and familial cases without deletion, no uniparental disomy was found and most of them were shown to inherit chromosomes 15 from both parents (biparental inheritance). A discrepancy between cytogenetic and molecular deletion was observed in 14 (26%) of 53 patients in whom cytogenetic analysis could be performed. Ten (43%) of 23 patients with a normal karyotype showed a molecular deletion, and 4 (13%) of 30 patients with cytogenetic deletion, del(15) (q11q13), showed no molecular deletion. Most clinical manifestations, including neurological signs and facial characteristics, were not distinct in each group except for hypopigmentation of skin or hair. Familial cases with submicroscopic deletion were not associated with hypopigmentation. These findings suggested that a gene for hypopigmentation is located is located outside the critical region of AS and is not imprinted. © 1994 Wiley-Liss, Inc.     

Syndromes associated with deletion of the long arm of chromosome 18[del(18q)]

We studied eight persons whose karyotypes demonstrated deletion of a portion of the long arm of chromosome 18. Seven of these persons who showed the typical del(18q) syndrome had a common deletion in band 18q21, most likely band q21.3, and in at least two persons the deletion was interstitial. Another mentally retarded child, dissimilar in appearance, had a more proximal deletion within band 18q12. Two different clinical syndromes resulted from deletions of these different segments of the long arm of chromosome 18.     

Recognizable behavioral and somatic phenotype in patients with proximal interstitial 18q deletion: Report on a new affected child and follow-up on the original reported familial cases

We describe a moderately retarded boy with a chromosome 18 deletion involving the regions q11.2q12.2. His phenotype is similar to that of other reported cases of proximal interstitial deletions involving 18q. We also provide follow-up information on the first 4 cases of proximal interstitial deletion of 18q from a family with a complex chromosome rearrangement originally reported in 1974. © 1992 Wiley-Liss, Inc.     

Analysis of clinical variation seen in patients with 18q terminal deletions

Twenty-six patients with deletions of 18q were analyzed at the clinical and molecular levels in an attempt to delineate regions of chromosome 18 important to the 18q– syndrome phenotype. Molecular cytogenetic analysis was carried out using fluorescence in situ hybridization (FISH), and deletions ranging from 18q21.1–qter to 18q22.3–qter were detected. The parental origin of the deletions was determined by the analysis of inheritance of microsatellite markers. No correlation between size, parental origin, or severity of the resulting phenotype was found. The results suggest that a critical region for the 18q– syndrome lies in the most distal portion of 18q and that it confers susceptibility for the various clinical manifestations of the 18q– syndrome when present in one copy. © 1995 Wiley-Liss, Inc.     

Gonadal dysgenesis in del(18p) syndrome

We report on a girl with syndromal gonadal dysgenesis and a de novo del(18p). Genetic factors controlling gonadal development are located not only on the X chromosome, but also on autosomes. The present case suggests that one of these genes is situated on 18p. We conclude that patients with del(18p) syndrome should be evaluated for gonadal dysgenesis. © 1995 Wiley-Liss, Inc.     

Familial del(18p) syndrome

We report on sibs and their mother, all with del(18p). The propositus, an 11‐month‐old, had developmental delay, round face, hypertelorism, large ears, broad nasal bridge, upturned nostrils, micrognathia, a high palate, redundant skin around the neck, micropenis, and cryptorchidism . The elder sister, a two and 7/12‐year‐old, had round face, hypertelorism, broad nasal bridge, narrow and high palate, redundant skin around the neck, short fingers, and hypoplastic genitalia. Their mother had microcephaly, hypertelorism, prominent colu‐ mella, broad nasal bridge, wide mouth, high palate, malaligned teeth, and clinodactyly of the fifth fingers. Serial photographs of the mother showed that the characteristic round face in infancy changed to long face with age. The present report suggests that the mother with del(18p) may be fertile, and proper genetic counseling and long follow‐up is necessary for the patient with del(18p) syndrome. © Wiley‐Liss. Inc.     

A patient with Edwards syndrome caused by a rare pseudodicentric chromosome 18 of paternal origin

We report on a male patient with a de novo derivative chromosome 9. From clinical and conventional cytogenetic data, it was assumed that the derivative chromosome might be caused by a translocation between the short arms of chromosomes 7 and 9: der(9)t(7;9)(p21.2;p23.5). Fluorescence in situ hybridization with a chromosome 7-specific and a chromosome 9-specific paint confirmed this supposition. The phenotype of the patient described is compared to cases in the literature.     

Congenital anomalies and anthropometry of 42 individuals with deletions of chromosome 18q

Deletions of chromosome 18q are among the most common segmental aneusomies compatible with life. The estimated frequency is approximately 1/40,000 live births [Cody JD, Pierce JF, Brkanac Z, Plaetke R, Ghidoni PD, Kaye CI, Leach RJ. 1997. Am. J. Med. Genet. 69:280–286]. Most deletions are terminal encompassing as much as 36 Mb, but interstitial deletions have also been reported. We have evaluated 42 subjects with deletions of 18q at our institution. This is the largest number of individuals with this chromosome abnormality studied by one group of investigators. Here we report the physical findings in these individuals. We have compared our findings with those of previously reported cases and have found a significantly different incidence of several minor anomalies in our subjects. We also describe here several anomalies not previously reported in individuals with deletions of 18q, including short frenulum, short palpebral fissures, disproportionate short stature, overlap of second and third toes, and a prominent abdominal venous pattern. Characteristics found in subjects were analyzed for correlation with cytogenetic breakpoints. Several traits were found to correlate with the extent of the deletion. Large deletions were associated with significantly decreased head circumference and ear length as well as the presence of proximally placed and/or anomalous thumbs. Individuals with the smallest deletions were more likely to have metatarsus adductus. Although relatively few genotype/phenotype correlations were apparent, these data demonstrate that correlations with breakpoint are possible. This implies that more correlations will become evident when the more precise molecularly based genotyping is completed. These correlations will identify critical regions on the chromosome in which genes responsible for specific abnormal phenotypes are located. Am. J. Med. Genet. 85:455–462, 1999. © 1999 Wiley-Liss, Inc.     

CHD7 mutations causing CHARGE syndrome are predominantly of paternal origin

CHARGE (coloboma, heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia, ear anomalies and deafness) syndrome is a congenital malformation syndrome caused by mutations in the CHD7 gene in approximately 2/3 of cases. In the vast majority of cases, CHARGE syndrome is sporadic. There are only a few reports of parent-to-child transmission and somatic or gonadal mosaicism. To determine the parental origin of CHD7 mutations in sporadic CHARGE syndrome, we screened 30 families for informative exonic or intronic polymorphisms located near the detected CHD7 mutation. An informative polymorphism could be identified in 13 out of 30 families. Linkage analysis was performed between the CHD7 mutation and the polymorphism in the child. In 12 out of 13 families, the mutation affected the paternal allele (92.3%). In our cohort, the mean paternal age at birth was 32.92 years. Comparing the age of fathers of an affected CHARGE patient with the paternal age of the German population in general, we could not observe any paternal age effect. Taken together, we show in this study that de novo CHD7 mutations occur predominantly in the male germ line.     

Growth hormone insufficiency associated with haploinsufficiency at 18q23

Growth hormone insufficiency is a common cause of growth failure in children with the 18q- syndrome. Individuals with this syndrome have a deletion as large as 36 Mb from the long arm of chromosome 18. We have evaluated 33 children with this syndrome for growth hormone production and have identified a region of approximately 2 Mb, which is deleted in every growth hormone insufficient patient. Two genes contained in this region, myelin basic protein, and the galanin receptor, are candidate genes for the growth hormone insufficiency phenotype. Am. J. Med. Genet. 71:420–425, 1997. © 1997 Wiley-Liss, Inc.