rAAV-CRISPRa therapy corrects Rai1 haploinsufficiency and rescues selective disease features in Smith-Magenis syndrome mice.

Haploinsufficiency in retinoic acid induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), a severe neurodevelopmental disorder characterized by neurocognitive deficits and obesity. Currently, curative treatments for SMS do not exist. Here, we take a recombinant adeno-associated virus (rAAV)-clustered regularly interspaced short palindromic repeats activation (CRISPRa) approach to increase expression of the remaining intact Rai1 allele. Building upon our previous work that found the paraventricular nucleus of hypothalamus plays a central role in SMS pathogenesis, we performed paraventricular nucleus of hypothalamus-specific rAAV-CRISPRa therapy by increasing endogenous Rai1 expression in SMS (Rai1±) mice. We found that rAAV-CRISPRa therapy rescues excessive repetitive behavior, delays the onset of obesity, and partially reduces hyperphagia in SMS mice. Our work provides evidence that rAAV-CRISPRa therapy during early adolescence can boost the expression of healthy Rai1 allele and modify disease progression in a mouse model of Smith-Magenis syndrome.

Comparison of real-world treatment patterns in chronic lymphocytic leukemia management before and after availability of ibrutinib in the province of British Columbia, Canada.

We performed a retrospective study comparing treatment patterns and overall survival (OS) in chronic lymphocytic leukemia (CLL) patients with the advent of ibrutinib to provide current real-world data. METHODS: Using a provincial population-based database, we analyzed CLL patients who received upfront treatment in British Columbia before ibrutinib availability (1984-2014), during ibrutinib access for: relapse only (2014-2015) and for upfront treatment of patients (with 17p deletion or unfit for chemotherapy) (2015-2016). Analysis included up to third-line treatment. RESULTS: Of 1729 patients meeting inclusion criteria (median age, 66 years; 1466, period 1; 140, period 2; 123, period 3), FR was the most common first-line therapy (35.8 %, 54.3 % and 40.7 %, periods 1-3, respectively) and 18.7 % received ibrutinib upfront in period 3. The most common therapies in relapse were chemoimmunotherapy (36.1 % and 55.6 %, periods 1 and 2, second-line; 29.2 %, period 1, third-line) and ibrutinib (69.8 %, period 3, second-line; 46.4 % and 70.3 %, periods 2 and 3, third-line). OS improved for patients treated in periods 2-3 over period 1 (median OS not reached vs. 11.9 years, p < 0.001; no difference in OS for periods 2-3, p = 0.385). CONCLUSION: Ibrutinib has replaced chemoimmunotherapy as the preferred therapy in relapse. Overall survival has improved over time with access to ibrutinib.

Malignant teratoma of the thyroid: A difficult diagnosis by fine-needle aspiration.

Primary thyroid teratomas are rare, usually benign, and typically occur in children. We report the unusual occurrence of a malignant thyroid teratoma in a young man. Initial ultrasound and CT studies revealed an 8.5 heterogeneous mass involving the entire right thyroid lobe causing tracheal compression and deviation. Fine-needle aspiration (FNA) revealed malignant cells with possible neuroendocrine features. Similar findings have been previously reported, with an occasional interpretation as possible medullary thyroid carcinoma. In no report, as with our case, has the correct diagnosis been suggested with FNA. The surgical specimen contained abundant primitive neuroepithelium with a very minor component of mature ectodermal tissue in one area. Like this case, an abundance of immature neuroepithelium has been reported in essentially all previous reports of primary malignant thyroid teratoma, sometimes creating a challenge to find another type of germ cell tissue. Array comparative genomic hybridization studies in this case revealed a markedly complex karyotype including gain of chromosome 12 and loss of 17p. Amplification of MYCN, EWSR1 rearrangement and isochromosome 12p were not identified, providing no evidence for neuroblastoma or Ewing sarcoma/peripheral neuroectodermal tumor, both of which have also rarely been reported as primary thyroid tumors. With the use of cisplatinum-based chemotherapy combined with radiation, survival times have increased dramatically. Our patient is now disease free and back to his normal activities after relatively short follow-up. Although rare, it is important to be aware that teratomas may present as a thyroid nodule. Recognition by FNA is challenging, and requires multiple modalities for full identification.

Prognostic and therapeutic stratification in CLL: focus on 17p deletion and p53 mutation.

Chronic lymphocytic leukemia (CLL), a disorder for which B cell heterogeneity and increased cellular proliferation play central pathogenic roles, displays several genetic abnormalities that are associated with poor prognosis and have therapeutic implications. In this review, we discuss the prognostic role and therapeutic implications of chromosome 17p deletions and TP53 mutations in CLL. Unlike other recurrent genetic abnormalities, the frequency of TP53 alterations is relatively low in newly diagnosed patients, but increases sharply with disease progression, which suggests that these alterations represent an evolutionary mechanism of resistance. In comparison with patients without such abnormalities, those with 17p deletions and TP53 mutations have lower response rates and more aggressive disease. One important consequence of the diverse molecular mechanisms that affect the TP53 pathway is the need to assess both the presence of 17p deletion and TP53 mutations before treatment initiation. Several authors have attempted to incorporate TP53 abnormalities in different prognostic models for CLL, and the recent International Prognostic Index for Chronic Lymphocytic Leukemia formally considers patients with TP53 abnormalities (deletion 17p or TP53 mutation or both) as high-risk. Several novel agents may improve results in patients with CLL, including in those with TP53 mutations. Ibrutinib, idelalisib, and venetoclax have been approved in various settings and countries for treatment of CLL. Further progress in targeted therapy and judicious use of chemotherapy, monoclonal antibodies, and reduced-intensity allogeneic transplantation will provide patients with CLL in general, and those with TP53 abnormalities in particular, with a better prognosis.

An Update on Common Chromosome Microdeletion and Microduplication Syndromes.

This review summarizes common microdeletion and microduplication syndromes and highlights important updates in patient-care needs for people with these conditions (22q11.2, 7q11.23, 17p11.2, and 16p11.2). These conditions are in chromosomal "hotspots" and have an estimated prevalence of 1 in 1,000 to 1 in 25,000. Some conditions have possible increased or decreased genetic risk of schizophrenia (22q11.2 deletion and duplication), or risk of aortic dilation (7q11.23 duplication) versus aortic stenosis (7q11.23 deletion). Many of these conditions are associated with developmental delay, autism, and/or multiple congenital anomalies and would not be detected with a karyotype. Chromosomal microarray analysis will detect all these conditions with a single screening test, allowing for the appropriate diagnosis and management of these patients. [Pediatr Ann. 2018;47(5):e198-e203.].

Novel agents in chronic lymphocytic leukemia.

The advent of novel small-molecule inhibitors has transformed the treatment approaches for patients with chronic lymphocytic leukemia (CLL). These therapies are becoming increasingly used in patients with relapsed disease, patients with 17p deletion, and, as of recently, also in the frontline setting for previously untreated patients with CLL. Moreover, many of these are oral therapies that are significantly less myelosuppressive than chemoimmunotherapy. However, these agents have their own set of unique toxicities with which providers must gain familiarity. There is also ongoing development of second-generation agents which have the promise of less toxicity than the US Food and Drug Administration (FDA)-approved compounds. In addition, immunotherapy and the role of the microenvironment are becoming increasingly important and have therapeutic implications in the treatment of patients with CLL. Ultimately, investigators need to evaluate how to position these and other new exciting therapies and decide on the ultimate role for chemoimmunotherapy in modern times.

17P deleted multiple myeloma presenting with intracranial disease: durable remission after tailored management.

In multiple myeloma (MM), del(17p) is associated with a poor outcome if present in greater than half the tumour cells. Similarly, intracranial involvement, often seen in the context of advanced disease, also heralds short survival. We present a rare case of MM presenting with intracranial disease and carrying del(17p) in 100% of tumour cells. This patient was successfully treated with combination chemotherapy employing central nervous system directed agents and bortezomib, followed by autologous stem cell transplant and consolidation with radiotherapy, bortezomib and thalidomide. We also present the outcomes of our single-centre experience of MM patients presenting with del(17p) disease. Copyright © 2015 John Wiley & Sons, Ltd.

Smith-Magneis syndrome: behavioural phenotype mimics ADHD.

A mentally retarded 7-year-old male child presented with inattention and hyperactivity which was initially diagnosed as attention deficit hyperactivity disorder (ADHD). However, a careful evaluation of symptomatology along with clues provided by specific features of facial dysmorphism in this case along with genetic testing clinched the diagnosis of Smith-Magneis syndrome the behavioural phenotype of which closely resembles ADHD.

Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is a mental retardation syndrome with distinctive behavioral characteristics, dysmorphic features, and congenital anomalies ascribed to an interstitial deletion of chromosome 17p11.2. Severe sleep disturbances and maladaptive daytime behavior have been linked to an abnormal circadian rhythm of melatonin with a diurnal instead of nocturnal secretion of this hormone. SMS provides a demonstration of a biological basis for sleep disorder in a genetic disease. Considering that clock genes mediate the generation of circadian rhythm, haploinsufficiency for a circadian system gene, mapping to chromosome 17p11.2, may cause the inversion of the melatonin circadian rhythm in SMS. The disorder of circadian timing in SMS may also affect entrainment pathway (retinohypothalamic tract), pacemaker functions (suprachiasmatic nuclei), or synthesis and release of melatonin by the pineal gland. Elucidating pathophysiological mechanisms of behavioral phenotypes in genetic disease can provide an original therapeutic approach in SMS: blockade of endogenous melatonin production during the day combined with exogenous melatonin administration in the evening.

Potocki-Lupski syndrome: a microduplication syndrome associated with oropharyngeal dysphagia and failure to thrive.

OBJECTIVE: Failure to thrive (FTT) is a feature of children with Potocki-Lupski syndrome (PTLS) [duplication 17p11.2]. This study was designed to describe the growth characteristics of 24 subjects with PTLS from birth through age 5 years in conjunction with relevant physical features and swallow function studies. STUDY DESIGN: We evaluated 24 individuals with PTLS who were ascertained by chromosome analysis and/or array comparative genome hybridization. Clinical assessments included review of medical records, physical examination, otolaryngological examination, and swallow function studies. Measures of height and weight were converted to Z-scores. RESULTS: The mean weight-for-age and weight-for-length Z-scores at birth were lower (P < .01) than the reference standard and did not change with age. A history of poor feeding, hypotonia, and FTT were reported in 92%, 88%, and 71%, respectively. Individuals with hypotonia had lower weight-for-age and body mass index-for-age Z-scores (P = .01). Swallow function studies demonstrated at least one abnormality in all subjects. CONCLUSIONS: FTT is common in children with PTLS. We hypothesize that oropharyngeal dysphagia and hypotonia likely contribute to FTT in patients with PTLS and recommend that once a diagnosis is established, the individual be assessed for feeding and growth issues and be availed of oromotor therapy and nutritional services.