Chromosome 18q Deletion Syndrome
A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome. Like Wolf-Hirschhorn syndrome (194190), cri-du-chat syndrome (123450), and Miller-Dieker syndrome (247200), it is a terminal deficiency or macrodeletion syndrome characterized by mental retardation and congenital malformations.
Clinical FeaturesThe phenotype is highly variable, but is characterized by mental retardation, short stature, hypotonia, hearing impairment, and foot deformities. Tapered digits and wide mouth have been described.
Hecht (1969) found low levels of immunoglobulin A in some cases of the 18q- syndrome. Wilson et al. (1979) noted that autoimmune disease, a known accompaniment of selective IgA deficiency (137100), has been found in some cases of the 18q- syndrome.
Wilson et al. (1979) found that 80% of individuals affected with the 18q- syndrome are below the 5th centile in height. Schwarz and Duck (1990) and Andler et al. (1992) each reported an individual with the 18q- syndrome who was growth hormone (139250) deficient. Ghidoni et al. (1997) evaluated growth hormone deficiency in 5 patients with the 18q- syndrome, 3 of whom had growth failure with weight and height below the 3rd centile; the remaining 2 had normal growth. In 3 patients, there was a failure to produce adequate growth hormone following stimulation with clonidine. Of the 3 patients with inadequate growth hormone production, 1 had normal growth (above the 3rd centile). Thus, only 1 of 5 patients had normal GH production and normal growth parameters. Ghidoni et al. (1997) suggested that a gene(s) on 18q is involved in growth hormone production.
Cody et al. (1999) reported 42 individuals with deletions of 18q. Common features included short stature, microcephaly, palatal defects, short frenulum, carp-like mouth, short palpebral fissures, and external ear anomalies. Cardiac anomalies were observed in 24%, including atrial and ventricular septal defects and pulmonary stenosis. Skeletal defects included scoliosis, foot deformities, and tapering fingers. Serum IgA levels were decreased in 24%.
Hale et al. (2000) studied the spectrum of growth abnormalities in children with 18q deletions. They investigated the growth axis of 50 individuals with a cytogenetically and molecularly confirmed 18q deletion by determining height, growth velocity, IGF1 (147440), IGFBP3 (146732), bone maturation, and response to pituitary stimulants of growth hormone. Children with 18q deletions are short; 64% had a height more than -2 SD below the mean. Affected children also grow slowly; 68% had a growth velocity more than -1 SD below the mean. Half of the individuals had delayed bone maturation. Growth factors are skewed downward; 72% of the IGF1 values and 83% of the IGFBP3 values were below the mean for chronologic age. Similarly, 72% of the children had a reduced or absent response to either of the growth hormone stimulants arginine and clonidine. In the total group of 50 children, only 2 were normal for all parameters evaluated.
Versacci et al. (2005) reported 3 unrelated patients with syndromic absent pulmonary valve, intact ventricular septum, and patent ductus arteriosus associated with terminal deletion of chromosome 18q. All patients also had aortic valve stenosis with dilatation of the ascending aorta. The first patient had additional facial anomalies including low frontal hairline with narrow biparietal diameter, bulbous nose, thick lips, high palate, large ears, and prognathism as well as cryptorchidism, clubfeet, choanal stenosis, and Marfan-like body habitus including thin body, pectus excavatum, kyphoscoliosis, arachnodactyly, and joint hypermobility. Chromosome analysis showed a 46,XY,-18,del(18)(2;18)(q37.3;q22.3) karyotype; his mother had a balanced reciprocal translocation 46,XX,t(2;18)(q37.3;q22.3) and Marfan-like habitus. The second patient also had facial anomalies including downslanted palpebral fissures, midface hypoplasia, short philtrum, thin lips, prognathism, and dysmorphic ears. Other features included cryptorchidism, scoliosis, clubfeet, short stature, and mental retardation. Chromosome analysis showed a 46,XY,del(18)(q22-qter). The third patient had a flat nasal bridge, epicanthal folds, carp-shaped mouth, dysmorphic ears, hypotonia, and developmental retardation. Chromosomal analysis showed 46,XX,del(18)(q21.3-qter).
Linnankivi et al. (2006) reported 14 Finnish individuals with partial deletions of 18q, including 2 families with 2 affected children each. There was phenotypic variability even within families with the same deletion. Common features included short stature, facial dysmorphism, palatal defects, tapering digits, foot deformities, cryptorchidism, atopic disorders, and recurrent respiratory infections with IgA deficiency. Cognitive function ranged from normal intelligence to severe mental retardation. Other neurologic features included nystagmus, seizures, hypotonia, clumsiness, hearing loss, and diffuse white matter abnormalities on MRI. The maximum estimated size of the deletion ranged from 7.7 to 29.4 Mb. All individuals shared only a small common 1.1-Mb region between D18S469 and D18S812. All individuals with abnormal myelination shared a deletion of 18q22.3-q23 between markers D18S469 and D18S1141, which includes the myelin basic protein gene (MBP; 159430). Congenital atresia or stenosis of the external ear canals was associated with deletions between D18S812 and D18S1141 (18q22.3-q23).
Feenstra et al. (2011) described a sporadic case and a mother and 2 sons with 18q22.3-q23 microdeletions, noting that the phenotype in the mother and sons closely resembled that of 3 males and 3 females in a family with bilateral atresia of the external auditory canal and congenital vertical talus described by Rasmussen et al. (1979) (see Rasmussen syndrome, 133705).
InheritanceSubrt and Pokorny (1970) described the 18q deletion syndrome in a mother and her 4 daughters. Sulzer and Zierler (1976) reported dominant transmission of partial deletion of 18q from a mother to her daughter. Fryns et al. (1979) also reported 18q deletion syndrome in a mother and daughter. Both had an identical balanced t(14;18)(p11;q21) translocation, suggesting that chromosomal material near 18q21 was lost in the translocation process. Chen et al. (2006) reported direct transmission of del(18)(q22.2) from a mother to her daughter. Both showed characteristic phenotypic features of the syndrome, including short stature, microcephaly, facial dysmorphism, moderate mental retardation, and abnormal brain myelination. Chen et al. (2006) emphasized that affected females are clearly fertile and should have genetic counseling.
CytogeneticsCody et al. (1997) evaluated 33 children with the 18q- syndrome for growth hormone production and identified a region of approximately 2 Mb that was deleted in every growth hormone insufficient patient. They pointed to 2 genes contained in this region, MBP (159430) and the galanin receptor (GALNR; 600377), as candidates for the growth hormone insufficiency phenotype.
Brkanac et al. (1998) analyzed the DNA from 35 patients who originally were diagnosed as having de novo terminal deletions of chromosome 18. Molecular analysis was performed with polymorphic markers throughout the 18q- region. Cytogenetic fluorescence in situ hybridization was performed with 2 human 18q telomeric probes, a chromosome 18-specific alpha-satellite probe, and whole chromosome 18-specific paint. Of 35 patients previously reported to have terminal deletions of 18q, they found that 5 (14%) had more complex cryptic rearrangements and that 3 (9%) retained the most distal portion of 18q, consistent with an interstitial rather than a terminal deletion. These findings indicated that a standard karyotype can lead to insufficient characterization in 18q- syndrome.
To gain insight into the mechanism of chromosomal loss and stabilization in the terminal deficiency or macrodeletion syndromes characterized by mental retardation and congenital malformations, Katz et al. (1999) cloned a putative terminal deletion breakpoint found in a 18q- syndrome patient. The 18q21.3 breakpoint occurred between 2 serine protease inhibitor (serpin) genes, SCCA1 (600517) and SCCA2 (600518). Although cytogenetic studies suggested that this chromosomal aberration was formed by a simple terminal deletion, DNA sequence analysis, pulsed-field gel electrophoresis, and fluorescence in situ hybridization showed that the breakpoint was contiguous with a 35-bp filler sequence followed by a satellite III DNA-containing telomeric fragment of 475 to 1,000 kb. This type of satellite III DNA sequence was not detected on the normal chromosome 18, but was highly homologous with types of satellite III DNA sequences normally located on the short arms (p11) of the acrocentric chromosomes and other heterochromatic regions. This DNA sequence analysis suggested that the terminal deficiency in this 18q- syndrome patient arose via illegitimate (nonhomologous) recombination. Moreover, these data raised the possibility that a subset of chromosomal aberrations appearing cytogenetically and molecularly as simple terminal truncations or deletions are caused by small (less than 1,000 kb) cryptic rearrangements.
Genotype/Phenotype CorrelationsFeenstra et al. (2007) used array comparative genomic hybridization (array CGH) to analyze in detail the chromosome 18 anomalies of 29 patients with cytogenetic 18q deletions, including 6 with a proximal interstitial deletion and 22 with a terminal deletion. One patient had a complex aberration involving several chromosomes. All patients had different breakpoints, indicating that there is no hotspot. The results refined genotype/phenotype correlations for several critical regions, including microcephaly (18q21.33), short stature (18q12.1-q12.3, 18q21.1-q21.33, and 18q22.3-q23), white matter disorders and delayed myelination (18q22.3-q23), growth hormone insufficiency (18q22.3-q23), and congenital aural atresia (18q22.3). The overall level of mental retardation appeared to be mild in patients with deletions distal to 18q21.33 and severe in patients with deletions proximal to 18q21.31. The critical region for the typical 18q-phenotype was a 4.3-Mb region within 18q22.3-q23.
In an analysis of the phenotype and deletion sizes of 151 individuals with deletions of 18q using oligo-array CGH, Cody et al. (2009) were able to narrow critical regions associated with particular phenotypes. These regions were all within 18q22.3-q23. The regions for dysmyelination and failure of growth hormone stimulation response were identical and narrowed to a 1.62-Mb region containing 5 known genes, including MBP (159430). The region for aural atresia was 2.3-Mb and included 3 additional genes. The region for kidney malformations was 3.21-Mb and included an additional 4 genes. Penetrance rates were calculated by comparing the number of individuals hemizygous for a critical region with the phenotype to those without the phenotype. The kidney malformations region was 25% penetrant, the dysmyelination region was 100% penetrant, the failure of growth hormone stimulation region was 90% penetrant with variable expressivity, and the aural atresia region was 78% penetrant.
Feenstra et al. (2011) performed SNP-array analysis in affected individuals with syndromic congenital aural atresia from 2 families with 18q22.3-q23 microdeletions and found a 459-kb deletion overlap, a region containing a single known gene, TSHZ1 (614427). Sequencing TSHZ1 in 11 patients with an isolated, bilateral form of congenital aural atresia (607842) revealed heterozygous loss-of-function mutations in 4 patients (614427.0001 and 614427.0002). The mutation-positive individuals had no facial dysmorphism or other features associated with 18q deletion syndrome. Feenstra et al. (2011) concluded that 18q deletion syndrome is a true contiguous gene syndrome, in which the CAA endophenotype is explained by deletion of TSHZ1.