Tommaso Bellini

Etiology of non-immune hydrops fetalis: An update

Hydrops fetalis is an excessive fluid accumulation within the fetal extra vascular compartments and body cavities. Non‐immune hydrops fetalis (NIHF), due to causes other than Rh alloimmunization, is the cause in >85% of all affected individuals. Herein we present an update of our earlier systematic literature review [Bellini et al., 2009] using all publications between 2007 and 2013. We excluded most of the initial 31,783 papers by using strict selection criteria, thus resulting in 24 relevant NIHF publications describing 1,338 individuals with NIHF. We subdivided the affected individuals into 14 classification groups based on the cause of NIHF (percentage of the total group): Cardiovascular (20.1%), Hematologic (9.3%), Chromosomal (9.0%), Syndromic (5.5%), Lymphatic Dysplasia (15.0%), Inborn Errors of Metabolism (1.3%), Infections (7.0%), Thoracic (2.3%), Urinary Tract Malformations (0.9%), Extra Thoracic Tumors (0.7%), TTTF‐Placental (4.1%), Gastrointestinal (1.3%), Miscellaneous (3.6%), Idiopathic (19.8%). We discuss the results of the review. There may be some shifts in the percentages of etiological categories as compared to the previous review, but the small numbers within each category make drawing firm conclusions hazardous. We highlight the need for multi‐center series of NIHF cases collected and classified using the same schemes in diagnostic work‐ups to allow for comparisons of larger numbers of cases.

Immunohistochemistry in non-immune hydrops fetalis: A single center experience in 79 fetuses†‡

The objective of our study was to evaluate the usefulness of immunohistochemical (IHC) staining techniques in the etiological diagnosis of non‐immune hydrops fetalis (NIHF). The records of all 1,098 autopsies performed between January 1987 and May 2008, by the Division of Fetal Pathology of the University of Genoa, were reviewed and all 79 fetuses diagnosed with NIHF were re‐evaluated. Additional IHC staining using antibodies that specifically stain blood and lymph vessels (CD31, CD34, smooth muscle actin antibody, D2‐40) were performed. Results were compared to results from the literature. Our results showed that in 67/79 cases, evaluation by standard autopsy protocol led to an etiologic diagnosis. Furthermore, we were able to identify the pathogenetic mechanisms that eventually caused NIHF in 42/79 cases. Adding IHC staining to all evaluations identified the pathogenetic mechanism in a further 17 cases (total 59/79 cases). Lymphatic dysplasia was diagnosed by standard autopsy protocol in 1/79 (1.3%), while adding IHC staining resulted in 18/79 (22.8%) cases being diagnosed (P = 0.0001). The present rate of 22.8% of lymphatic dysplasia in non‐immune hydrops fetalis is significantly higher than reported in the literature (36/818 or 4.4%; P = 0.01). In conclusion, specific IHC staining techniques aimed at detecting lymphatic dysplasia are needed and should be mandatory in autopsies of fetuses with non‐immune hydrops fetalis.

Rhombencephalosynapsis in a patient with mental retardation, epilepsy, and dysmorphisms

A 17-year-old man was referred for tonic–clonic and complex partial seizures starting from age 15 years. Examination revealed microcephaly (52 cm), mild mental retardation (IQ:60), and facial dysmorphisms, namely, narrow forehead, microcoria, low-set and malrotated ears, protruding tongue. Trigeminal sensation appeared normal, and alopecia was absent. The patient was appropriately socially interactive. High-resolution karyotype was normal. Brain MRI excluded supratentorial abnormalities but revealed a ‘keyhole’ narrow, diamond-shaped fourth ventricle and the almost complete absence of the vermis resulting in a single-lobed cerebellum. The cerebellar folia appeared continuous across the midline (arrows, a, c). The small median protuberance below the fastigium of the fourth ventricle indicated the nodulus (arrowheads, a, b). Single-voxel spectroscopy revealed reduced NAA/Cr ratio in the cerebellum when compared with the control spectra (d). This MRI picture indicated rhombencephalosynapsis, a rare congenital malformation-thought to occur via disruption of the developing cerebellum at 28–41 days of gestation, with variable presentation, ranging from early death to a large spectrum of neurological manifestations and usually good prognosis [1, 2]. Increased awareness of this cliniconeuroradiological picture among neurologists in training and general practitioners is warranted (Fig. 1).

Causes and manifestations of chylothorax in children

The authors affirmed that finding seven cases affected by congenital lymphatic malformations was surprisingly. It is not clear if seven cases were considered as a low or high incidence rate. Usually, congenital chylothorax of the newborn may be linked to congenital thoracic duct defects, isolated or associated with generalized lymphatic vessel dysplasia, which is the more likely cause; more rarely, congenital chylothorax is the result of trauma at birth, malignancies, thrombosis of the superior vena cava or subclavian vein causing high central venous pressure. It is well known the role of the lymphatic system on the physiological and pathophysiological dynamics of pleural effusion of chylothorax in the newborn; the efficacy of lymphatic function is the cornerstone of pleural fluid balance. Thus, each condition that can negatively influence the pleural and pulmonary lymphatic vessel function in the newborn, in primis lymphatic dysplasia, results in a lack of control of pleural fluid volume, eventually leading to congenital chylothorax.

A novel Xp22.13 microdeletion in Nance-Horan syndrome

BACKGROUND Nance-Horan syndrome (NHS) is a rare X-linked developmental disorder characterized by congenital cataract, dental anomalies and facial dysmorphisms. Notably, up to 30% of NHS patients have intellectual disability and a few patients have been reported to have congenital cardiac defects. Nance-Horan syndrome is caused by mutations in the NHS gene that is highly expressed in the midbrain, retina, lens, tooth, and is conserved across vertebrate species. Although most pathogenic mutations are nonsense mutations, a few genomic rearrangements involving NHS locus have been reported, suggesting a possible pathogenic role of the flanking genes. METHODS Here, we report a microdeletion of 170,6 Kb at Xp22.13 (17.733.948-17.904.576) (GRCh37/hg19), detected by array-based comparative genomic hybridization in an Italian boy with NHS syndrome. RESULTS The microdeletion harbors the NHS, SCLML1, and RAI2 genes and results in a phenotype consistent with NSH syndrome and developmental delay. CONCLUSION We compare our case with the previous Xp22.13 microdeletions and discuss the possible pathogenetic role of the flanking genes. Birth Defects Research 109:866-868, 2017.

Octreotide treatment for neonatal chylothorax

We have read the interesting paper by Costa and Saxena entitled ‘‘Surgical chylothorax in neonates: management and outcomes”, recently published in the World Journal of Pediatrics [1]. There are few points of the article that we would like to discuss. We recently published a systematic review focusing on the use of octreotide for congenital and acquired chylothorax in newborns [2]. Our review concluded that octreotide was safe and effective in the treatment of chylothorax in newborns, especially for the congenital forms, and that octreotide therapy should be considered as an adjunctive treatment in term and preterm neonates affected by congenital and acquired chylothorax. Costa and Saxena reported 12 further cases of acquired (post-surgical) chylothorax than those included in our review. It is reassuring that both articles [1, 2] obtained similar conclusions. The initial dose of octreotide varied from 0.5 to 10 μg/kg/h [1] and from 0.3 to 15 μg/kg/h [2], and the maximum dose reported was 10 vs 7.5 μg/kg/h, respectively [1, 2]. Apart from slight dose differences, in our opinion lacking practical clinical meaning, what we consider very important is that both reviews [1, 2] concluded that octreotide treatment is safe and effective and that the observed (scarce) adverse effects are mild and transient and generally well tolerated and not requiring discontinuation of the treatment. We, as certainly Costa and Saxena, are aware that given the very low incidence and the heterogeneity of chylothorax in neonates, randomized controlled trials to clarify octreotide use appear to be quite unfeasible, even in multicentric settings. Thus, we feel that reporting cases of neonatal chylothorax should be encouraged. Two independent large reviews including a wide number of patients have agreed that the conclusions show the use of octreotide to be the best available tool for the treatment of chylothorax in the neonatal age.

Erratum to “De novo 12q22.q23.3 duplication associated with temporal lobe epilepsy” [Seizure 57 (2018) 63–65]

Erratum to “De novo 12q22.q23.3 duplication associated with temporal lobe epilepsy” [Seizure 57 (2018) 63–65] Maria Stella Vari, Monica Traverso, Tommaso Bellini, Francesca Madia, Francesca Pinto, Pasquale Striano*, Carlo Minetti, Federico Zara a Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health University of Genoa, “G. Gaslini” Institute, Genova, Italy b Laboratory of Neurogenetics and Neuroscience, “G. Gaslini” Institute, Genova, Italy

De novo 12q22.q23.3 duplication associated with temporal lobe epilepsy

PURPOSE Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and may be associated with acquired central nervous system lesions or could be genetic. Various susceptibility genes and environmental factors are believed to be involved in the aetiology of TLE, which is considered to be a heterogeneous, polygenic, and complex disorder. Rare point mutations in LGI1, DEPDC5, and RELN as well as some copy number variations (CNVs) have been reported in families with TLE patients. METHODS We perform a genetic analysis by Array-CGH in a patient with dysmorphic features and temporal lobe epilepsy. RESULTS We report a de novo duplication of the long arm of chromosome 12. CONCLUSION We confirm that 12q22-q23.3 is a candidate locus for familial temporal lobe epilepsy with febrile seizures and highlight the role of chromosomal rearrangements in patients with epilepsy and intellectual disability.