Jacobsen Syndrome

A number sign (#) is used with this entry because Jacobsen syndrome (JBS) is a contiguous gene deletion syndrome involving terminal chromosome 11q.

Clinical Features

The Jacobsen syndrome is a clinically characteristic disorder due to deletion of the terminal band 11q23. This band is known to harbor a heritable folate-sensitive fragile site (Sutherland and Hecht, 1985). The disorder was first observed by Jacobsen et al. (1973). As reviewed by Fryns et al. (1986) and Epstein (1986), the features of the syndrome are growth retardation, psychomotor retardation, trigonocephaly, divergent intermittent strabismus, epicanthus, telecanthus, broad nasal bridge, short nose with anteverted nostrils, carp-shaped upper lip, retrognathia, low-set dysmorphic ears, bilateral camptodactyly, hammertoes, and isoimmune thrombocytopenia.

In a 45,X male with a translocation (Y;11)(q11.2;q24), Van Hemel et al. (1992) found features characteristic of Jacobsen syndrome: trigonocephaly, ptosis, 'deep-set' short nose, carp-shaped mouth, high-implanted short thumbs, narrow chest, diastasis recti, and anterior-situated anus. In addition to the dysmorphic features, the boy had hypoglycemia and pancytopenia. Aalfs et al. (1999) described a patient with Jacobsen syndrome with a de novo translocation involving (6;11)(p21;q25).

In a review of 48 published cases of 11q deletions and translocations, Lewanda et al. (1995) found that 80% were associated with abnormal head shape. They described 2 patients referred for abnormal head shape associated with partial monosomy of 11q.

Pivnick et al. (1996) reported a 2-year-old girl with Jacobsen syndrome in whom chromosome analysis showed a 46,XX,del(11)(q23q25) de novo karyotype. In addition to typical manifestations, this girl had colobomata of the iris, choroid, and retina, endocardial cushion defect, growth hormone deficiency, and central hypothyroidism. Endocrinologic defects had not previously been described in patients with this syndrome.

Using electron microscopy to examine the platelets of an infant with an 11q23.3-qter deletion and clinical features of Jacobsen syndrome, Krishnamurti et al. (2001) identified giant alpha-granules identical to those described in Paris-Trousseau syndrome (188025). They suggested that TCPT may be a variant of Jacobsen syndrome and that the thrombocytopenia in all cases of 11q23.3 deletion is due to dysmegakaryopoiesis, with formation of giant alpha-granules during prolonged residence in the bone marrow.

Laleye et al. (2002) described a child with a deletion of 11q24-qter who had severe hypotonia, dolichocephaly, hypertelorism, long philtrum, and poorly formed and low-set ears. She also had a very mild thrombocytopenia and giant platelets with a mean platelet volume of 12.8 fL (normal, 7-9.5 fL). Several platelet glycoproteins were assayed and found to be normally expressed.

Favier et al. (2003) reported 10 unrelated children with deletions of 11q23 and Paris-Trousseau thrombocytopenia, 9 of whom were found to be heterozygous for a deletion of the FLI1 gene (193067). Favier et al. (2003) noted clinical, hematologic, and cytogenetic similarities between this cohort of patients and patients with Jacobsen syndrome and stated that their findings demonstrated a clear overlap between the 2 syndromes.

Haghi et al. (2004) studied 9 children with Jacobsen syndrome, 8 of whom had short stature. Low levels of insulin-like growth factor-1 (IGF1; 147440) were found in 4 of the 8 children with short stature, 3 being low for age and 1 low for Tanner stage. Cryptorchidism was present in 4 of 6 males, suggesting hypogonadism.

Zahn et al. (2005) reported a 4-year-old boy and his mother's cousin who had identical chromosomal imbalances involving a 9.3- to 9.5-Mb partial monosomy of chromosome 11q24.2-qter and a 4.9- to 5.4-Mb partial trisomy of chromosome 16q24.1-qter. Findings in these patients further refined the phenotype map for several Jacobsen syndrome features including abnormal brain imaging, renal malformations, thrombocytopenia/pancytopenia, inguinal hernia, testicular ectopy, pes equinovarus, and hearing deficiency.

Giampietro et al. (2006) described a 15-year-old girl with a deletion spanning 11q24.2-q25, who had features consistent with 11q deletion disorder but also had osteopenia and sensorineural hearing loss. Because there was no family history of osteoporosis or hearing loss, Giampietro et al. (2006) concluded that these features are most likely related to the chromosome 11q deletion and expand the clinical spectrum of the syndrome.

In a study of 4 patients with Jacobsen syndrome, Miller et al. (2006) identified the following ocular manifestations: hypertelorism/telecanthus, abnormally slanted palpebral fissures, abnormal retinal findings (including mild transient cherry-red spot, macular hypoplasia, coloboma, and nonspecific granular appearance of the retinal pigment epithelium), nasolacrimal duct obstruction, anomalous extraocular muscles, amblyopia, and microcornea (diameter 9.5 mm). In a literature review they identified the following as the most common ocular abnormalities in Jacobsen syndrome: telecanthus and/or hypertelorism, ptosis, epicanthal folds, and strabismus. Other ocular abnormalities included unilateral or bilateral coloboma with or without microphthalmia, nuclear cataract, abnormal eyelashes/eyebrows, and iris discoloration.

Maas et al. (2008) investigated sleep characteristics and problems in 43 patients with Jacobsen syndrome and found that 10 (23%) were reported to have a sleep problem, including settling problems, frequent night waking, and early waking. Twenty-two individuals (54%) had a history of sleep problems, 25 (60%) showed restless sleep, and 23 (54%) slept in an unusual position. No significant association was found between sleep problems and other variables such as breathing problems, heart defects, or behavioral diagnosis.

Association with Transverse Limb Defects

Von Bubnoff et al. (2004) reported a 34-year-old German man with features of Jacobsen syndrome, including short stature, mental retardation, strabismus, congenital heart disease, cryptorchidism, distal hypospadia glandis, and mild thrombocytopenia. Chromosome analysis disclosed a mosaic 46,XY,del(11)(q24.1)/46,XY karyotype with a very low percentage of normal cells. In addition, the patient had imperforate anus and hearing impairment, as well as a transverse upper limb defect, involving complete absence of the right hand and wrist with a hypoplastic forearm that showed 4 rudimentary cutaneous finger-like 'stubs' distally. Cellular anomalies included functional impairment and deficiency of T-helper cells, and a low serum level of IgM. Von Bubnoff et al. (2004) concluded that the range of abnormalities seen in Jacobsen syndrome should be broadened to include severe upper transverse limb defect, primary immunodeficiency, and imperforate anus.

Fujita et al. (2010) reported a Japanese female infant born with prominent forehead, natal teeth, and absent anterior half of the left foot, with abrupt truncation from a normally formed calf. Evaluation of a cardiac murmur by echocardiography revealed ventricular and atrial septal defects. The patient was thrombocytopenic without other hematologic abnormalities. Chromosome analysis showed a 46,XX,del(11)(q23.2) karyotype; array CGH analysis demonstrated a deletion of the 11q24.3 region including the FLI1 gene (193067). Noting that the combination of Jacobsen syndrome and transverse limb defect had been previously reported by von Bubnoff et al. (2004), Fujita et al. (2010) suggested that thrombocytopenia and transverse limb defect might be causally related.

Cytogenetics

Fryns et al. (1986) identified the crucial band for this syndrome as 11q24.1; a very distal 11q24.2 deletion resulted in a completely different phenotype. In a typical case, Hausmann et al. (1988) were unable to identify the folate-sensitive fragile site at 11q23.2 in lymphocytes from either parent. Voullaire et al. (1987) suggested that the origin of the 11q23.3 deletion, which they demonstrated in the karyotype of a patient with typical Jacobsen syndrome, was a familial folate-sensitive 11q23.3 fragility carried by the mother. They suggested that the fragile chromosome 11 was transmitted to the embryo and subsequently broke at the site of fragility, producing a predominant cell line with the deleted chromosome 11, while the nondeleted chromosome persisted in the mosaic as a minor line.

Jones et al. (1994) presented evidence consistent with the role of the inherited folate-sensitive fragile site in band 11q23.3, FRA11B (600651), in the etiology of this chromosome deletion syndrome. With fluorescence in situ hybridization experiments using YACs and cosmids from a 600-kb region of 11q23.3, Jones et al. (1994) localized FRA11B to an interval of approximately 100 kb containing the 5-prime end of the CBL2 oncogene (165360), which includes a CCG trinucleotide repeat. Jones et al. (1994) showed that the deletion breakpoint of the Jacobsen syndrome child reported by Voullaire et al. (1987) mapped within the same interval as the fragile site. The breakpoint had apparently been repaired and stabilized by the de novo addition of a telomere. As stated by Jones et al. (1995), who presented further evidence for the role of FRA11B in the generation of the deletion, this was the first demonstration of a direct link between a fragile site and chromosome breakage in vivo. The demonstration of an inherited component in the development of at least some cases of Jacobsen syndrome challenges the dogma that chromosomal deletions and rearrangements associated with clinical manifestations occur de novo, with little or no impact of genetic background.

To define the critical region responsible for the clinical abnormalities of the Jacobsen syndrome, Penny et al. (1995) studied 17 individuals with de novo terminal deletions of 11q. The patients were characterized in a loss-of-heterozygosity analysis using polymorphic dinucleotide repeats. The breakpoints in the complete 2-generation families were localized with an average resolution of 3.9 cM. In 8 patients with the largest deletions (extending from 11q23.3 to 11qter), breakpoints were found between D11S924 and D11S1341. This cytogenetic region accounts for most 11q- patients and may be related to the FRA11B fragile site in 11q23.3. One patient with a small terminal deletion distal to D11S1351 had facial dysmorphism, cardiac defects, and thrombocytopenia, suggesting that the genes responsible for these features may lie distal to D11S1351.

Michaelis et al. (1998) reported on 2 patients with Jacobsen syndrome and deletion of 11q23.3. In both cases, microsatellite and fluorescence in situ hybridization analyses indicated that the deletion breakpoint was approximately 1.5 to 3 Mb telomeric to FRA11B. There was no evidence of expansion of the CBL2 (CCG)n repeat in the parents of either patient. The deleted chromosome was of paternal origin in both cases, although it was of maternal origin in the cases reportedly caused by FRA11B.

Jones et al. (2000) identified and characterized 6 CCG-trinucleotide repeats within a 40-Mb YAC contig spanning distal chromosome 11q23.3-q24. The breakpoints in 11 cases of Jacobsen syndrome colocalized with one of these 6 CCG repeats. The authors concluded that these data provided strong evidence for the nonrandom clustering of chromosome deletion breakpoints with CCG repeats, and suggested that they may play an important role in a common mechanism of chromosome breakage.

Hart et al. (2000) found that all 14 patients with Jacobsen syndrome, in which thrombocytopenia is a feature, had hemizygous terminal deletions of 11q including the FLI1 gene (193067). Based on mouse studies, the authors suggested that hemizygous loss of FLI1 was responsible for the dysmegakaryopoiesis in these patients.

Gadzicki et al. (2006) described an infant with typical clinical features of Jacobsen syndrome including trigonocephaly, thrombocytopenia, congenital heart defect, urethral stenosis, and partial agenesis of the corpus callosum. Conventional karyotyping, FISH, spectral karyotyping (SKY), and comparative genomic hybridization (CGH) showed that the region distal to the MLL locus (159555) on 11q23 was lost and replaced by the distal region of 11p, leading to partial trisomy of 11p and partial monosomy of 11q. Array CGH analysis allowed Gadzicki et al. (2006) to narrow the breakpoints to 11p15.1 and 11q24.1. Methylation analyses of genes located on 11p showed an increased level of the nonmethylated paternal allele of the KCNQ1OT1 gene (604115), confirming the concomitant presence of Beckwith-Wiedemann syndrome (BWS; 130650).

In a cognitive assessment of 14 patients with 11q terminal deletion, Coldren et al. (2009) found that all 9 with a deletion of at least 12.1 Mb had severe global cognitive impairment, whereas all 5 patients with smaller deletions less than or equal to 11.8 Mb had milder cognitive impairment. Based on the phenotype, the findings suggested a role for the presence of a proximal critical region on chromosome 11q that contains a gene important for global cognitive function in the proximal region, and a gene important for auditory attention in the distal region. Coldren et al. (2009) identified BSX (611074) in the proximal region and neurogranin (NRGN; 602350) in the distal region as possible candidate genes.

Ye et al. (2009) studied the breakpoints of a paracentric inversion in distal chromosome 11q in a female infant with hypoplastic left heart and severe thrombocytopenia, and found that the distal breakpoint was within a 70-kb region spanning exon 1 of the JAM3 gene (606871). The authors performed comprehensive cardiac analysis in mice with deletion of the mouse Jam3 gene and observed a normal cardiac phenotype, indicating that haploinsufficiency of JAM3 is unlikely to cause the congenital heart defects that occur in 11q-deleted patients.

Ji et al. (2010) reported 2 unrelated Chinese patients with Jacobsen syndrome ascertained from a cohort of 451 patients with unexplained developmental delay/mental retardation. Multiplex ligation-dependent probe amplification (MLPA) studies showed that 1 patient had a de novo 4.1-Mb deletion of chromosome 11q25 and the other had a de novo 12.8-Mb deletion of chromosome 11q23.3-q25. Both patients had severe developmental delay, microcephaly, and facial dysmorphism. The patient with the larger deletion also had a ventricular septal defect and skeletal anomalies. Neither had thrombocytopenia at the time of diagnosis. Ji et al. (2010) noted that the 4.1-Mb deletion was the smallest reported in association with Jacobsen syndrome and thus may define the critical region for developmental delay/mental retardation.

Grossfeld et al. (2004) previously identified an approximately 7-Mb cardiac critical region in distal chromosome 11q that contained a putative causative gene(s) for human congenital heart disease. Ye et al. (2010) used chromosomal microarray mapping to characterize 3 patients with congenital heart defects and interstitial distal 11q deletions that overlap the 7-Mb cardiac critical region. The 1.2-Mb region of overlap contains 6 genes, including the ETS1 (164720) gene, which is expressed in the endocardium and neural crest during early mouse heart development. Gene-targeted deletion of Ets1 in C57/B6 mice caused large membranous ventricular septal defects and a bifid cardiac apex, and less frequently a non-apex-forming left ventricle. Ye et al. (2010) proposed an important role for ETS1 in mammalian heart development and suggested that hemizygosity for this locus may be responsible for the cardiac lesions seen in Jacobsen syndrome.

Genotype/Phenotype Correlations

Grossfeld et al. (2004) provided a molecular analysis of the deletion breakpoints in 65 patients with the 11q terminal deletion disorder and defined genetic 'critical regions' for 14 clinical phenotypes.

Bernaciak et al. (2008) reported a 4-year-old girl with partial JBS associated with a 5-Mb deletion at chromosome 11q24.3-qter. She had psychomotor retardation (IQ of 45), chronic constipation, and dysmorphic facial features, including square face, high forehead, hypertelorism, epicanthal folds, broad flat nasal bridge, malformed ears, and short neck. Unusual features in this patient included white matter abnormalities on brain MRI and insensitivity to pain. Family history revealed that her mother and maternal uncle carried the same deletion and had mild features of the disorder, including chronic constipation and mild facial dysmorphism. The mother had an IQ of 97. The uncle had an IQ of 70, dementia, and psychoorganic delusions. None of the patients had thrombocytopenia. The deletion did not include the FLI1 gene (193067), suggesting that deletion of this gene is responsible for the thrombocytopenia that occurs in most patients with JBS. Bernaciak et al. (2008) noted that this was the smallest deletion reported in JBS.

Population Genetics

Ji et al. (2010) noted that the incidence of distal 11q deletions in the population is difficult to estimate, but JBS occurs in about 1 in 100,000 births, and the female:male ratio is 2:1.