Thursday, April 11, 2019

Jacobsen syndrome

Patel H, Kumar A, Raymond G, Mainali G. Teaching NeuroImages: A rare case of Jacobsen syndrome with global diffuse hypomyelination of brain. Neurology. 2019 Apr 2;92(14):e1665-e1666.

An 8-month-old boy presented with developmental delay, diffuse hypotonia, hypoplastic left heart syndrome, undescended testes, neonatal thrombocytopenia, and unusual facies. Chromosome microarray showed an 11q23-11q24 deletion, consistent with Jacobsen syndrome.

Initial head MRI at 18 months showed severe diffuse hypomyelination of cerebral white matter believed to be consistent with leukodystrophy (figure 1). Repeat MRI at 3 years of age showed less extensive hypomyelination (figure 2). The child, while still delayed, had made some developmental progression.

Figure 1

Figure 2

While delayed myelination has been reported, there are few reports of neuroimages. Awareness of the MRI presentation of JS is crucial to prevent unnecessary evaluation in this condition.

Conrad S, Demurger F, Moradkhani K, Pichon O, Le Caignec C, Pascal C, Thomas C, Bayart S, Perlat A, Dubourg C, Jaillard S, Nizon M. 11q24.2q24.3 microdeletion in two families presenting features of Jacobsen syndrome, without intellectual disability: Role of FLI1, ETS1, and SENCR long noncoding RNA. Am J Med Genet A. 2019 Mar 19. doi: 10.1002/ajmg.a.61113. [Epub ahead of print]

This report presents two families with interstitial 11q24.2q24.3 deletion, associated with malformations, hematologic features, and typical facial dysmorphism, observed in Jacobsen syndrome (JS), except for intellectual disability (ID). The smallest 700 Kb deletion contains only two genes: FLI1 and ETS1, and a long noncoding RNA, SENCR, narrowing the minimal critical region for some features of JS. Consistent with recent literature, it adds supplemental data to confirm the crucial role of FLI1 and ETS1 in JS, namely FLI1 in thrombocytopenia and ETS1 in cardiopathy and immune deficiency. It also supports that combined ETS1 and FLI1 haploinsufficiency explains dysmorphic features, notably ears, and nose anomalies. Moreover, it raises the possibility that SENCR, a long noncoding RNA, could be responsible for limb defects, because of its early role in endothelial cell commitment and function. Considering ID and autism spectrum disorder, which are some of the main features of JS, a participation of ETS1, FLI1, or SENCR cannot be excluded. But, considering the normal neurodevelopment of our patients, their role would be either minor or with an important variability in penetrance. Furthermore, according to literature, ARHGAP32 and KIRREL3 seem to be the strongest candidate genes in the 11q24 region for other Jacobsen patients.

Kawai M, Tsutsumi M, Suzuki F, Sameshima K, Dowa Y, Kyoya T, Inagaki H, Kurahashi H. Two siblings with 11qter deletion syndrome that had been rescued in their mother by uniparental disomy. Eur J Med Genet. 2019 Mar;62(3):224-228.

Jacobsen syndrome refers to a congenital anomaly caused by deletion at 11q23.3-qter. We here describe two siblings with the same 11q23.3-qter deletion. Both parents were healthy with a normal karyotype. Cytogenetic microarray analysis revealed no mosaicism in either parent but the mother showed uniparental disomy encompassing the deleted region found in the two siblings. The pattern of X chromosome inactivation was almost completely skewed in the mother. These data suggested that the mother was a carrier of the 11q23.3-qter deletion but that this had been rescued by disomy formation during early embryogenesis except for her germinal cells. 

Puvabanditsin S, Chen CW, Botwinick M, Hussein K, Mariduena J, Mehta R. Ventriculomegaly and cerebellar hypoplasia in a neonate with interstitial 11q 24 deletion in Jacobsen syndrome region. Clin Case Rep. 2018 May 22;6(7):1268-1275.

Jacobsen syndrome (JS) is a rare contiguous gene disorder caused by partial deletion of the distal part of the long arm of chromosome 11 ranging in size from 7 to 20 Mb. We report a term male neonate with an interstitial deletion of about 12.3 megabase (Mb) of chromosome 11q24.1qter. Our case is the first reported newborn patient with 11q24 deletion.

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