An Endocrinological Perspective on 22q11.2 Deletion Syndrome: A Single-center Experience

Objective: 22q11.2 deletion syndrome (22q11.2 DS) is the most common chromosomal microdeletion disorder. Associated problems in 22q11.2 DS may include cardiac abnormalities, immune dysfunction, facial dysmorphism, with endocrine, genitourinary and gastrointestinal problems, and developmental delay. The aim of this study was to evaluate and present all endocrinological findings of patients with 22q11.2 DS from a single center. Methods: All participants had confirmed 22q11.2 DS by fluorescence in situ hybridization with hypoparathyroidism. Data were retrieved by retrospective review of patient records. Results: A total of 17 patients were reviewed. On physical examination, all patients had similar dysmorphic features. The median age at diagnosis was 45 days (1 day-13 years). Most cases (64.7%, 11/17) were diagnosed with hypoparathyroidism incidentally after routine tests. At the time of diagnosis, mean calcium was 7.04±0.80 mg/dL, phosphorus was 6.2±1.1 mg/dL, and median parathyroid hormone (PTH) was 11.5 (3.7-47.6) ng/L. Transient hypoparathyroidism was detected in five cases (29.4%). There was no significant difference between patients with permanent or transient hypoparathyroidism regarding gender, age at diagnosis, calcium, phosphorus, and PTH levels. However, vitamin D levels were significantly lower in the transient group (p=0.036). During follow-up, short stature, obesity, and type 2 diabetes mellitus were absent. Thyroid autoantibodies were detected in two patients with normal thyroid function tests. Despite there being no pathological short stature, final stature was shorter than the general population (mean height standard deviation score: -0.94±0.83). Conclusion: Hypocalcemia may be detected during acute illness in some cases where hypocalcemia appears at later ages. There was no significant difference between permanent and transient hypoparathyroidism cases in terms of PTH level. Recognition of the more specific facial findings is important to trigger investigation of genetic variants, additional anomalies, and for follow-up.

Zinc deficiency and supplementation in autism spectrum disorder and Phelan-McDermid syndrome.

Approximately 1 in 36 children are diagnosed with autism spectrum disorder (ASD). The disorder is four times more common in males than in females. Zinc deficiency and mutations in SHANK2 and SHANK3 (members of a family of excitatory postsynaptic scaffolding proteins) are all risk factors that may contribute to the pathophysiology of the disease. The presence of shankopathies (loss of one copy of the SHANK3 gene) can lead to the development of Phelan-McDermid syndrome (PMDS)-a rare genetic disorder characterized by developmental delay, intellectual disability, poor motor tone, and ASD-like symptoms. We reviewed the relationship between zinc, ASD, and PMDS as well as the effect of zinc supplementation in improving symptoms of ASD and PMDS based on 22 studies published within 6 years (2015-2020). Zinc deficiency (assessed by either dietary intake, blood, hair, or tooth matrix) was shown to be highly prevalent in ASD and PMDS patients as well as in preclinical models of ASD and PMDS. Zinc supplements improved the behavioral deficits in animal models of ASD and PMDS. Clinical trials are still needed to validate the beneficial therapeutic effects of zinc supplements in ASD and PMDS patients.

Multiregional sequencing and circulating tumour DNA analysis provide complementary approaches for comprehensive disease profiling of small lymphocytic lymphoma.

We aimed at molecularly dissecting the anatomical heterogeneity of small lymphocytic lymphoma (SLL), by analysing a cohort of 12 patients for whom paired DNA from a lymph node biopsy and circulating cells, as well as plasma-circulating tumour DNA (ctDNA) was available. Notably, the analyses of the lymph node biopsy and of circulating cells complement each other since a fraction of mutations (20·4% and 36·4%, respectively) are unique to each compartment. Plasma ctDNA identified two additional unique mutations. Consistently, the different synchronous sources of tumour DNA complement each other in informing on driver gene mutations in SLL harbouring potential prognostic and/or predictive value.

Lymphedema complicated by protein-losing enteropathy with a 22q13.3 deletion and the potential role of CELSR1: A case report.

INTRODUCTION: 22q13.3 deletion syndrome is a well-known syndrome characterized by typical clinical findings including neonatal hypotonia, absent or severely delayed speech, intellectual disability, and other various features, and detection of a heterozygous deletion of chromosome 22q13.3 with the involvement of at least part of SHANK3. It is reported that 10% to 29% of patients with 22q13.3 deletion syndrome present lymphedema. Protein-losing enteropathy (PLE) has never been reported in 22q13.3 deletion syndrome. PATIENT CONCERNS: The patient presented to our institution for refractory hypoalbuminemia and chronic lymphedema in both legs. DIAGNOSIS: The patient manifested intellectual disability, absent speech, tooth grinding, dysmorphic face, and abnormal hands and toenails. Copy-number variation sequencing confirmed the maternal deletion in 22q13.31-q13.33 (chr22:46285592-51244566, hg19). The patient was genetically diagnosed with 22q13.3 deletion syndrome. INTERVENTIONS: Low-fat diets and medium-chain triglycerides supplements were prescribed. The patient was recommended to wear compression garments and elevate legs. OUTCOMES: The symptom of diarrhea was resolved, but hypoalbuminemia persisted. Lower extremities lymphedema was gradually becoming severe. CONCLUSIONS: Primary lymphedema and PLE can occur simultaneously in a patient with 22q13.3 deletion syndrome. The 2 phenotypes could share the same genetic etiology of congenital lymphatic abnormalities. CELSR1 deletion may play a role in lymphatic dysplasia. The case also provides additional proof of the pathogenic effect of CELSR1 on hereditary lymphedema.

The Yin and Yang-Like Clinical Implications of the CDKN2A/ARF/CDKN2B Gene Cluster in Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is a malignant clonal expansion of lymphoid hematopoietic precursors that exhibit developmental arrest at varying stages of differentiation. Similar to what occurs in solid cancers, transformation of normal hematopoietic precursors is governed by a multistep oncogenic process that drives initiation, clonal expansion and metastasis. In this process, alterations in genes encoding proteins that govern processes such as cell proliferation, differentiation, and growth provide us with some of the clearest mechanistic insights into how and why cancer arises. In such a scenario, deletions in the 9p21.3 cluster involving CDKN2A/ARF/CDKN2B genes arise as one of the oncogenic hallmarks of ALL. Deletions in this region are the most frequent structural alteration in T-cell acute lymphoblastic leukemia (T-ALL) and account for roughly 30% of copy number alterations found in B-cell-precursor acute lymphoblastic leukemia (BCP-ALL). Here, we review the literature concerning the involvement of the CDKN2A/B genes as a prognosis marker of good or bad response in the two ALL subtypes (BCP-ALL and T-ALL). We compare frequencies observed in studies performed on several ALL cohorts (adult and child), which mainly consider genetic data produced by genomic techniques. We also summarize what we have learned from mouse models designed to evaluate the functional involvement of the gene cluster in ALL development and in relapse/resistance to treatment. Finally, we examine the range of possibilities for targeting the abnormal function of the protein-coding genes of this cluster and their potential to act as anti-leukemic agents in patients.

Hypoxaemia and interstitial lung disease in an infant with hypothyroidism and hypotonia.

A 7-month-old-term male infant presented with cough, tachypnoea, hypoxaemia and post-tussive emesis. Clinical history was significant for respiratory failure and pulmonary hypertension in the neonatal period requiring assisted ventilation, congenital hypothyroidism, mild hypotonia, recurrent respiratory infections, hypoxaemia requiring supplemental oxygen and nasogastric tube feeds. Physical examination showed tachypnoea, coarse bilateral breath sounds and mild hypotonia. Chest radiograph revealed multifocal pulmonary opacities with coarse interstitial markings and right upper lobe atelectasis. Following antibiotic therapy for suspected aspiration pneumonia, chest CT scan was performed and showed multiple areas of pulmonary consolidation and scattered areas of bilateral ground-glass opacities. Genetic studies showed a large deletion of chromosome 14q13.1-14q21.1, encompassing the NK2 homeobox 1 (NKX2-1) gene consistent with a diagnosis of brain-thyroid-lung (BTL) syndrome. Our case highlights the importance of genetic studies to diagnose BTL syndrome in infants with hypothyroidism, hypotonia and lung disease.

Autologous stem cell transplantation in the treatment of multiple myeloma with 17p deletion.

INTRODUCTION: Deletion of chromosome 17p [del(17p)] in patients with multiple myeloma is associated with a poor prognosis. High­dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains the standard of treatment in this population. OBJECTIVES: The aim of the study was to compare the treatment outcomes with high­dose chemotherapy and ASCT with standard treatment in patients with del(17p). PATIENTS AND METHODS: We collected data from 12 Polish centers between 2011 and 2017. The records of 97 patients with p53 deletion were assessed, including 29 individuals treated with ACST and 68 receiving standard treatment alone. RESULTS: During the follow­up, 45 patients died and the overall survival (OS) for the whole group was 33 months (range, 1-66 months), with a median progression­free survival (PFS) of 13 months (range, 1-46 months). The prognostic factors of OS in a multivariable analysis were calcium levels at diagnosis within the reference range (hazard ratio [HR], 0.24; 95% CI, 0.12-0.48) and at least partial remission achieved after the first­line treatment (HR, 0.25; 95% CI, 0.12-0.51). Treatment with ASCT was an important factor in improving survival (HR, 3.23; 95% CI, 1.52-6.84). Abnormal kidney function at the time of diagnosis reduced the PFS (HR, 0.46; 95% CI, 0.22-0.94). When the analysis was limited only to patients who could be candidates for ASCT, the survival benefit of the procedure was lost (P = 0.21). CONCLUSIONS: Patients with multiple myeloma with del(17p) do not benefit from high­dose chemotherapy followed by ACST.

Caralluma fimbriata extract activity involves the 5-HT2c receptor in PWS Snord116 deletion mouse model.

INTRODUCTION: In Prader-Willi syndrome (PWS), nonprotein coding small nucleolar (sno) RNAs are involved in the paternally deleted region of chromosome 15q11.2-q13, which is believed to cause the hyperphagic phenotype of PWS. Central to this is SnoRNA116. The supplement Caralluma fimbriata extract (CFE) has been shown to decrease appetite behavior in some individuals with PWS. We therefore investigated the mechanism underpinning the effect of CFE on food intake in the Snord116del mouse. Experiments utilized appetite stimulants which included a 5-hydroxytryptamine (5-HT) 2c receptor antagonist (SB242084), as the 5-HT2cR is implicated in central signaling of satiety. METHODS: After 9-week chronic CFE treatment (33 mg or 100 mg kg-1  day-1 ) or placebo, the 14-week-old Snord116del (SNO) and wild-type mice (n = 72) were rotated through intraperitoneal injections of (a) isotonic saline; (b) 400 mg/kg of 2-deoxyglucose (2DG) (glucose deprivation); (c) 100 mglkg beta-mercaptoacetate (MA), fatty acid signaling; and (d) SB242084 (a selective 5HT2cR antagonist), with 5 days between reagents. Assessments of food intake were from baseline to 4 hr, followed by immunohistochemistry of neural activity utilizing c-Fos, neuropeptide Y, and alpha-melanocyte-stimulating hormone within hypothalamic appetite pathways. RESULTS: Caralluma fimbriata extract administration decreased food intake more strongly in the SNO100CFE group with significantly stimulated food intake demonstrated during coadministration with SB242084. Though stimulatory deprivation was expected to stimulate food intake, 2DG and MA resulted in lower intake in the snord116del mice compared to the WT animals (p = <0.001). Immunohistochemical mapping of hypothalamic neural activity was consistent with the behavioral studies. CONCLUSIONS: This study identifies a role for the 5-HT2cR in CFE-induced appetite suppression and significant stimulatory feeding disruptions in the snord116del mouse model.

Impaired melanocortin pathway function in Prader-Willi syndrome gene-Magel2 deficient mice.

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder causing social and learning deficits, impaired satiety and severe childhood obesity. Genetic underpinning of PWS involves deletion of a chromosomal region with several genes, including MAGEL2, which is abundantly expressed in the hypothalamus. Of appetite regulating hypothalamic cell types, both AGRP and POMC-expressing neurons contain Magel2 transcripts but the functional impact of its deletion on these cells has not been fully characterized. Here, we investigated these key neurons in Magel2-null mice in terms of the activity levels at different energy states as well as their behavioral function. Using cell type specific ex vivo electrophysiological recordings and in vivo chemogenetic activation approaches we evaluated impact of Magel2 deletion on AGRP and POMC-neuron induced changes in appetite. Our results suggest that POMC neuron activity profile as well as its communication with downstream targets is significantly compromised, while AGRP neuron function with respect to short term feeding is relatively unaffected in Magel2 deficiency.

Atypical erythroblastosis in a patient with Diamond-Blackfan anemia who developed del(20q) myelodysplasia.

Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia arising from ribosomal protein (RP) defects. Affected patients present with neonatal anemia, occasional dysmorphism, and cancer predisposition. An anemic newborn was diagnosed with DBA due to RPL5 mutation (c.473_474del, p.K158SfsX26). Refractory anemia required regular transfusions and iron chelation therapy. Pancytopenia occurred at age 16 years. Bone-marrow studies showed myelodysplasia, erythroblastosis, and clonal evolution of del(20)(q11.2q13.3). Severe anemia required transfusions. Del(20q), including the L3MBTL1 gene, is reported to be relevant to the hematological phenotype of Shwachman-Diamond syndrome. A combined defect of RPL5 and L3MBTL1 may contribute to the aberrant erythropoiesis in the present case.

Atypical microdeletion in 22q11 deletion syndrome reveals new candidate causative genes: A case report and literature review.

RATIONALE: 22q11 deletion syndrome, the most common chromosomal microdeletion disease, is caused by megabase-sized deletions on chromosome 22q11.2. It is characterized by a wide spectrum of congenital anomalies in velopharyngeal and facial, cardiac, genitourinary, vertebroskeletal, respiratory, digestive, and central nervous systems. Phenotype-genotype studies have revealed several causative genes that regulate the development of the third and fourth pharyngeal arches in human. However, the exact pathogenesis of this syndrome remains unknown. Herein, we report a case of 22q11 deletion syndrome with an atypical microdeletion of 125 kb. PATIENT CONCERNS: A 15-year-old Chinese girl presented with symptoms of facial dysmorphia, cardiac defects, velopharyngeal insufficiency, splenomegaly, immunodeficiency, and thrombocytopenia. DIAGNOSES: Microarray analysis revealed a 22q11.23 deletion of 125 kb (chromosome 22: 24276973-24402263), suggesting the diagnosis of 22q11 deletion syndrome. The haploinsufficient genes included GSTT2B, GSTT2, DDTL, DDT, GSTTP1, LOC391322, GSTT1, and GSTTP2. INTERVENTIONS: The patient was administrated glucocorticoids and calcium supplements. OUTCOMES: No epistaxis or petechiae episode occurred during the follow-up; her platelet count ranged between 60 × 10 and 80 × 10/L. LESSONS: Although none of the previous reported causative genes were affected in the patient, her clinical manifestations were typical of 22q11 deletion syndrome, apart from her progressive splenomegaly. This case indicated 8 new candidate pathogenic genes for 22q11 deletion syndrome. Given that the loss of these genes was sufficient to induce 22q11DS defects, whether these genes directly influence the pathogenesis of 22q11DS or through interactions with known hotspot mutations is worthy of research.

MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.

Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.

Schizophrenia-Related Microdeletion Impairs Emotional Memory through MicroRNA-Dependent Disruption of Thalamic Inputs to the Amygdala.

Individuals with 22q11.2 deletion syndrome (22q11DS) are at high risk of developing psychiatric diseases such as schizophrenia. Individuals with 22q11DS and schizophrenia are impaired in emotional memory, anticipating, recalling, and assigning a correct context to emotions. The neuronal circuits responsible for these emotional memory deficits are unknown. Here, we show that 22q11DS mouse models have disrupted synaptic transmission at thalamic inputs to the lateral amygdala (thalamo-LA projections). This synaptic deficit is caused by haploinsufficiency of the 22q11DS gene Dgcr8, which is involved in microRNA processing, and is mediated by the increased dopamine receptor Drd2 levels in the thalamus and by reduced probability of glutamate release from thalamic inputs. This deficit in thalamo-LA synaptic transmission is sufficient to cause fear memory deficits. Our results suggest that dysregulation of the Dgcr8-Drd2 mechanism at thalamic inputs to the amygdala underlies emotional memory deficits in 22q11DS.

Poor Prognosis in Acute Myeloid Leukemia Patients with Monosomal Karyotypes.

OBJECTIVE: This study aimed to investigate the clinical characteristics and prognostic significance of monosomal karyotypes (MKs) in patients with acute myeloid leukemia (AML). MATERIALS AND METHODS: We retrospectively analyzed the clinical data for 498 patients with AML, of whom 233 (46.8%) had an abnormal karyotype, including 42 with MKs (8.4%) and 70 with a complex karyotype (CK) (14.1%). RESULTS: Patients with MKs were older (median age 62.5 vs. 52 years, p=0.003) and had lower median hemoglobin levels (62.5 vs. 77 g/L, p=0.009) and lower white blood cell counts (7.0×109/L vs. 11.7×109/L, p=0.008). Univariate analysis showed that patients with MKs or CKs had shorter overall survival than patients without these karyotypes (median survival time 7.3 vs. 26.3 months for MK, p<0.001, and 14.8 vs. 26.3 months for CK, p<0.001). In multivariable analysis for overall survival, MK and National Comprehensive Cancer Network prognostic group were the only significant factors. CONCLUSION: MK is an independent risk factor for poor prognosis in AML patients.

Auditory Evoked M100 Response Latency is Delayed in Children with 16p11.2 Deletion but not 16p11.2 Duplication.

Individuals with the 16p11.2 BP4-BP5 copy number variant (CNV) exhibit a range of behavioral phenotypes that may include mild impairment in cognition and clinical diagnoses of autism spectrum disorder (ASD). To better understand auditory processing impairments in populations with this chromosomal variation, auditory evoked responses were examined in children with the 16p11.2 deletion, 16p11.2 duplication, and age-matched controls. Stimuli consisted of sinusoidal binaural tones presented passively while children underwent recording with magnetoencephalography (MEG). The primary indicator of auditory processing impairment was the latency of the ∼100-ms "M100" auditory response detected by MEG, with the 16p11.2 deletion population exhibiting profoundly delayed M100 latencies relative to controls. This delay remained even after controlling for potential confounds such as age and cognitive ability. No significant difference in M100 latency was observed between 16p11.2 duplication carriers and controls. Additionally, children meeting diagnostic criteria for ASD (16p11.2 deletion carriers) exhibited nonsignificant latency delays when compared with the corresponding CNV carriers not meeting criteria for ASD. Present results indicate that 16p11.2 deletion is associated with auditory processing delays analogous to (but substantially more pronounced than) those previously reported in "idiopathic" ASD.

Azacitidine and Sorafenib Therapy in a Pediatric Patient With Refractory Acute Myeloid Leukemia With Monosomy 7 and Somatic PTPN11 Mutation.

Monosomy 7 is a well-documented cytogenetic aberration in pediatric acute myeloid leukemia (AML) and may occur in combinations with molecular abnormalities including PTPN11 mutation. PTPN11 mutations contribute to leukemogenesis through upregulation of Ras pathway signaling. We present the case of a 3-year-old female with AML with monosomy 7 and somatic PTPN11 mutation who was refractory to conventional AML chemotherapy but responded to a novel regimen of azacitidine and sorafenib followed by stem cell transplantation. Combination therapy with azacitidine and sorafenib may be an effective therapeutic strategy for patients with AML with Ras pathway abnormalities.

Hereditary neuropathy with liability to pressure palsies presenting with sciatic neuropathy.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal-dominant disorder associated with recurrent mononeuropathies following compression or trivial trauma. Reports on sciatic neuropathy as the presenting manifestation of HNPP are very scarce. We report on a 21-year-old previously healthy man who was admitted with sensorimotor deficits in his left leg. He had no history of preceding transient episodes of weakness or sensory loss. Clinical and electrophysiological examinations were consistent with sciatic neuropathy. Cerebrospinal fluid investigation and MRI of the nerve roots, plexus, and sciatic nerve did not indicate the underlying aetiology. When extended electrophysiological tests revealed multiple subclinical compression neuropathies in the upper limbs, HNPP was contemplated and eventually confirmed by genetic testing.