Newborn Screening for SCID and Other Severe Primary Immunodeficiency in the Polish-German Transborder Area: Experience From the First 14 Months of Collaboration.

In 2017, in the Polish-German transborder area of West Pomerania, Mecklenburg-Western Pomerania, and Brandenburg, in collaboration with two centers in Warsaw, a partnership in the field of newborn screening (NBS) for severe primary immunodeficiency diseases (PID), mainly severe combined immunodeficiency (SCID), was initiated. SCID, but also some other severe PID, is a group of disorders characterized by the absence of T and/or B and NK cells. Affected infants are susceptible to life-threatening infections, but early detection gives a chance for effective treatment. The prevalence of SCID in the Polish and German populations is unknown but can be comparable to other countries (1:50,000-100,000). SCID NBS tests are based on real-time polymerase chain reaction (qPCR) and the measurement of a number of T cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and beta-actin (ACTB) as a quality marker of DNA. This method can also be effective in NBS for other severe PID with T- and/or B-cell lymphopenia, including combined immunodeficiency (CID) or agammaglobulinemia. During the 14 months of collaboration, 44,287 newborns were screened according to the ImmunoIVD protocol. Within 65 positive samples, seven were classified to immediate recall and 58 requested a second sample. Examination of the 58 second samples resulted in recalling one newborn. Confirmatory tests included immunophenotyping of lymphocyte subsets with extension to TCR repertoire, lymphoproliferation tests, radiosensitivity tests, maternal engraftment assays, and molecular tests. Final diagnosis included: one case of T-BlowNK+ SCID, one case of atypical Tlow BlowNK+ CID, one case of autosomal recessive agammaglobulinemia, and one case of Nijmegen breakage syndrome. Among four other positive results, three infants presented with T- and/or B-cell lymphopenia due to either the mother's immunosuppression, prematurity, or unknown reasons, which resolved or almost normalized in the first months of life. One newborn was classified as truly false positive. The overall positive predictive value (PPV) for the diagnosis of severe PID was 50.0%. This is the first population screening study that allowed identification of newborns with T and/or B immunodeficiency in Central and Eastern Europe.

Expanding Cyst of the Septum Pellucidum - Endoscopic Observations on the Mechanism of Development and Results of Treatment.

Cysts of the septum pellucidum (CSP) are usually asymptomatic; however, in some cases they can begin expanding and cause neurological deterioration. The mechanism leading to the formation of an expanding cyst of the septum pellucidum (ECSP) is not known. Based on observations made during endoscopic treatment of ECSP we analyzed intraoperative findings in respect to cyst formation mechanism and treatment prognosis. A group of 31 patients was studied. Only cases with bulging cyst walls occupying the frontal horns observed on imaging studies were included. The main symptom was a severe, intermittent headache. In three cases short term memory deficits were diagnosed. In one case papilloedema was observed. All patients underwent endoscopic fenestration of the ECSP. There were no cases of cyst reocclusion during a follow-up period of 1-14 years (mean 6.2 years). In 30 cases headaches resolved completely and in one case its intensity was significantly smaller. There was one case of postoperative hemiparesis. In all but two cases the thin, translucent region in the anterior part of the cyst floor was found. In the region small fissures and in three cases choroid plexus were observed. Endoscopic fenestration is the efficient treatment for ECSP. ECSP is formed on the basis of not completely closed, developmental communication of the cyst with other fluid spaces. The communication is opened by transient elevation of intraventricular pressure, and acts as a valve leading to fluid accumulation among the walls of the previously asymptomatic cavum septum pellucidum.

Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans.

Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting.

The significance of molecular studies in the long-term follow-up of children with beckwith- wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a congenital disorder of imprinting caused by epimutations and mutations affecting two imprinted loci on chromosome 11p15. Its clinical features are heterogeneous, including macrosomia, macroglossia, hemihyperplasia, abdominal wall defects, neonatal hypoglycemia, and increased risk of embryonal tumors such as Wilms tumor, adrenocortical carcinoma, hepatoblastoma, and neuroblastoma. The molecular and clinical heterogeneity of BWS makes the diagnosis challenging, but essential, since different etiologies of BWS have different clinical prognoses - most crucially, patients with gain of maternal methylation at imprinting control region type 1 (ICR1) are at significant risk of Wilms tumor or hepatoblastoma. We present three cases of BWS with different symptomatology and two different molecular diagnoses. The authors emphasize the importance of molecular studies in the long-term follow-up of children with BWS, including refinement of phenotype-genotype correlation and its connection with optimal management and tumor surveillance.

Incomplete expression of Klippel-Trenaunay syndrome.

UNLABELLED: Klippel-Trenaunay syndrome (KTS) is a rare, congenital vascular anomaly, defined as a triad including a port-wine stain, underlying bone and soft tissue hypertrophy and varicose veins and/or venous malformations. AIM: Our aim is to present the case of a 13-year-old girl with a delayed proper diagnosis of incomplete expression of KTS presenting with a port-wine stain of her left lower extremity associated with hypertrophy of the affected limb (upon the moment of diagnosis no varicose veins were observed). The patient did not experience any pain in the affected limb, nor was she diagnosed with neuropathy - both of above mentioned symptoms are often a significant issue. To ensure proper diagnosis, the patient underwent a broad spectrum of diagnostic tests, including physical examination with anthropometric measuring, biochemical tests, as well as radiological examinations including CT scan, Doppler vein ultrasound and bone X-ray. Based on physical examination and test results we were able to establish the diagnosis of incomplete expression of Klippel-Trenaunay syndrome. SUMMARY: The authors aim to emphasise the very rare incidence of KTS, as well as the low level of awareness of the described disease, which resulted in the significantly delayed final diagnosis in the presented case. Establishing the diagnosis of KTS before the onset of severe vascular complications, regular check-ups in the Outpatient Clinic of Haemangioma Care and compression dressing may help avoid/diminish the severity and significantly delay the development of venous failure of the affected limb.

Congenital nasolacrimal duct mucocele--a case report.

Congenital nasolacrimal duct mucocele (CNDM) is a very rare condition in newborns. Prolapse or expansion of the mucocele into the nose may lead to respiratory distress and difficulty in feeding. The triad of cystic medial canthal mass, dilatation of the nasolacrimal duct and a contiguous sub-mucosal nasal mass on computed tomography (CT) is indicative in the diagnosis of CNDM. The case of a five-week-old girl with infected CNDM is described. The authors aim to emphasize the very rare incidence of CNDM in Polish newborns, delayed diagnosis in the case described and the paramount importance of CT of the head for the correct diagnosis and treatment.

Noncystic white matter injury--a case report.

Magnetic resonance imaging (MRI) of the brain in preterm infants at term-equivalent age demonstrated that apart from cystic periventricular leukomalacia (PVL), noncystic white matter injury may take place, detected as diffuse excessive high signal intensity (DEHSI) in the white matter on T2-weighted imaging. Magnetic resonance imaging of the brain is conducted in few neonatal intensive care units. Consequently, the literature on the subject lacks descriptions of sequelae of noncystic white matter injury in premature newborns with very low birth weight (VLBW). We present the results of a three-year long observation of a child born at the 27th week of pregnancy diagnosed with DEHSI. The boy exhibited cerebral palsy, hyperexcitability and hypoacusis. In the authors' opinion, noncystic white matter injury may not just be one of the reasons for cognitive/behavioral deficits--it may also be responsible for some cases of cerebral palsy in premature infants.

[Endoscope-guided placement of the ventriculoperitoneal shunt: technique and applications]. / Metoda endoskopowego umieszczania drenu komorowego zastawki--technika i zastosowanie.

INTRODUCTION: The routine surgical procedure for placement of the ventricular shunt catheter is straightforward. However, the topography of the ventricular system in complex hydrocephalus is so distorted that orientation on the basis of standard external topographic points does not ensure satisfactory positioning of the drain. AIMS: 1. To test the clinical efficiency of endoscope-guided placement of the ventricular catheter in cases of complex hydrocephalus. 2. To present and popularize the surgical technique of endoscope-guided placement of the ventricular shunt catheter which hitherto was not published in the Polish literature. MATERIAL AND METHODS: This study was done in 38 patients aged 2 days to 45 years (mean 7 years and 5 months). Multiloculated hydrocephalus was found in 7, lateral ventricle isolation in 14, fourth ventricle isolation in 3, intraventricular cyst accompanied hydrocephalus in 6, and adherent ventricular catheter of the shunt implanted previously in 8 cases. Endoscopy was performed through coronal or occipital burr hole. Peelaway sheath was used for placement of the catheter in the desired position. Computerized tomography was performed within 24 hours after surgery, after 6 months, and subsequently every 12 months during follow-up. The time of follow-up ranged from 1 to 5 years (mean 27 months). There were eight cases (15.78%) of postoperative occlusion of the ventricular catheter. In two of them, occlusion was caused by catheter tip displacement. In the remaining cases, occlusion was caused by growing membranes of the multiloculated hydrocephalus (four cases) or by infection (two cases) and was not related to the catheter position. There were no cases of catheter position change during follow-up. DISCUSSION: In complex hydrocephalus, proper placement of the ventricular catheter without direct visual control is very difficult if not impossible. Therefore, use of the endoscope facilitates proper catheter placement in multiloculated hydrocephalus, hydrocephalus complicated by isolation of the ventricle or intraventricular cyst. CONCLUSIONS: 1. The technique of endoscope-guided placement of the ventricular catheter is relatively simple and useful for reliable positioning of the drain in the right location. 2. Our cases show that the method is clinically effective. However, comparison with the conventional method will require a controlled and matched trial.