A New Patient with Potocki–Lupski Syndrome: A Literature Review

Speech delay, intellectual disability, and behavioral disturbances are the main clinical manifestations of Potocki–Lupski syndrome. Other features include infantile hypotonia, the absence of major dysmorphism, sleep disorders, and congenital anomalies, particularly of the cardiovascular system. A male patient with Potocki–Lupski syndrome is reported herein. He showed speech and borderline cognitive delay, behavioral troubles with no signs suggestive of autism, in the absence of major dysmorphism. A de novo 17p12-p11.2 duplication spanning 3.6 Mb was detected, with boundaries from 15,284,052 to 18,647,233 (hg19 assembly). At the age of 5 years, the child showed a noticeable improvement of speech skills and a moderate scholastic performance was reached. Upon analysis of the clinical manifestations of the present patient and those reported in existing literature, we found that the syndrome may present in various degrees of clinical expressivity. Affected patients may manifest symptoms ranging from mild behavioral disturbances to severe degrees of autism.

A Deletion Of About 11kb Starting From 0.5 Kb 5’ To The β-Globin Gene Reactivates Foetal Haemoglobin and Leads To β Thalassemia Intermedia When Associated To a β-Zero Thalassemic Mutation

Background and Aims Thalassemia intermedia is characterized by severe but not transfusion dependent anemia secondary to seriously decreased production of hemoglobin (Hb). In the majority of cases, thalassemia intermedia concerns β-globin gene pathology. The molecular basis of thalassemia intermedia is heterogeneous. Here we describe a case of an adopted child native of Myanmar suffering from β-thalassemia intermedia which was proved to be secondary to a β-zero thalassemia associated with a not yet described deletional form of HPFH. Patient, Material and Methods Male child born in 1994 with Hb varying between 50 and 60 g/l, with Hb A2 of 2.1% and Hb F of 97.9%. No α-thalassemia or α-gene triplication was found. Sequencing of β-globin gene put in evidence the IVS-I-1 (G>T) or c.92+1G>T mutation in a “homozygous” state. This mutation is known to produce a β-zero thalassemia. The patient was treated with hydroxyurea as well as with erythropoietin and the Hb value was improved up to 86 g/l with normal leucocytes and platelets count. No transfusion was given during this period of treatment. Because the clinical phenotype was not typical for β-thalassemia major homozygous for the above mentioned mutation, we analyzed β-globin cluster looking for the presence of a possible deletion responsible for Hb F activation. Patient’s DNA was extracted with commercial columns from peripheral blood cells. Analysis of deletion in the beta cluster was performed by MLPA (Multiplex Ligation Probe Analysis) MRC-Holland P-102 probe mix. The data obtained were analyzed with the Coffyanalyzer software. The exact size of the deletion was determined by PCR with the primers: DelHBB_F: 5’-AGGCTTGGCTCCTGTTTAGT-3’, DelHBB_R: 5’-TGAGAG CTGCTGAGTTGTGT-3’ Results A heterozygous deletion in the beta-globin cluster has been detected by MLPA. This deletion was located between the coordinated 5,237,089 and 5,251,133 on chromosome 11 - (GRCh37/hg19 Assembly). The deletion starts about 0.5 kb 5’ upstream the HBB gene, between HBB and HBD genes, and ends about 9 kb downstream the 3’ end of HBB gene. The density of the MLPA probes is not sufficient to determinate the exact size of the deletion (between 14.3kb and 9.6 kb). A PCR using the primers DelHBB_F and DelHBB_R determined the size of this deletion to around 11kb. Conclusions Our molecular biology studies confirmed our clinical suspicion of association of HPFH with β-zero thalassemia. In fact, we put in evidence a not yet described (to our knowledge) 11kb deletion, which is very similar to the 12.6kb deletion of the Dutch β-zero thalassemia (Br J Haematol 67:369;1987) and to the Asian Indian 10.3kb deletion described by Craig et al (Br J Haematol 82:735;1992). Our deletion starts between δ and β-globin gene, almost 0.5 kb upstream of the β-gene, and goes about 9 kb downstream of 3’ end of the β-gene. The exact borders of the deletion are currently under investigation by PCR and appropriate primers. The pathophysiology of reactivation of γ-globin genes in our case is not yet known. We raise the following hypothesis: does this deletion bring an enhancer located 3’ to β-globin gene, close enough to the γ-genes, so that transcription of these genes continues after birth? In vitro studies in expression systems (constructs) are currently performed to elucidate the exact mechanism of γ-globin activation. Disclosures: No relevant conflicts of interest to declare.