A Novel Pathogenic TUBA1A Variant in a Croatian Infant Is Linked to a Severe Tubulinopathy with Walker-Warburg-like Features.

Tubulinopathies are associated with malformations of cortical development but not Walker-Warburg Syndrome. Intensive monitoring of a Croatian infant presenting as Walker-Warburg Syndrome in utero began at 21 weeks due to increased growth of cerebral ventricles and foetal biparietal diameter. Monitoring continued until Caesarean delivery at 34 weeks where the infant was eutrophic. Clinical assessment of a progressive neurological disorder of unknown aetiology found a macrocephalic head and markedly hypoplastic genitalia with a micropenis. Neurological examination showed generalized hypotonia with very rare spontaneous movements, hypotonia-induced respiratory insufficiency and ventilator dependence, and generalized myoclonus intensifying during manipulation. With clinical features of hypotonia, lissencephaly, and brain malformations, Walker-Warburg Syndrome was suspected; however, eye anomalies were absent. Genetic trio analysis via whole-exome sequencing only identified a novel de novo mutation in the TUBA1A gene (NM_006009.4:c.848A>G; NP_006000.2:p.His283Arg) in the infant, who died at 2 months of age, as the likely cause. We report a previously unpublished, very rare heterozygous TUBA1A mutation with clinical features of macrocephaly and hypoplastic genitalia which have not previously been associated with the gene. The absence of eye phenotypes or mutations in Walker-Warburg-associated genes confirm this as not a new presentation of Walker-Warburg Syndrome but a novel TUBA1A tubulinopathy for neonatologists to be aware of.

The Association of Different Genetic Variants with the Development of Hypoxic-Ischemic Encephalopathy.

The aim of this study is to investigate the frequency of six tag SNPs (single nucleotide polymorphisms) within specific genes (F2, F5, F7, MTHFR, NOS2A, PAI 2-1, PAI 2-2, and PAI 3-3): F2 (rs1799963), F5 (rs6025), F7 (rs6046), NOS 2 (rs1137933), PAI 2 (SERPINB2) (rs6103), MTHFR (rs1801133). The study also investigates their association with the development and severity of HIE. The genes F2, F5, and F7 code for proteins involved in blood clotting. MTHFR is a gene that plays a significant role in processing amino acids, the fundamental building blocks of proteins. NOS2A, PAI 2-1, PAI 2-2, and PAI 3-3 are genes involved in the regulation of various physiological processes, such as the relaxation of smooth muscle, regulation of central blood pressure, vasodilatation, and synaptic plasticity. Changes in these genes may be associated with brain injury. This retrospective study included 279 participants, of which 132 participants had Hypoxic-Ischemic Encephalopathy (HIE) and 147 subjects were in the control group. Our study found that certain genetic variants in the rs61103 and rs1137933 polymorphisms were associated with hypoxic-ischemic encephalopathy (HIE) and the findings of the magnetic resonance imaging. There was a correlation between Apgar scores and the degree of damage according to the ultrasound findings. These results highlight the complex relationship between genetic factors, clinical parameters, and the severity of HIE.

First Croatian Case of Double Aneuploidy: A Child With Klinefelter and Edwards Syndrome (48,XXY,+18) - Possible Causes and Contributing Factors.

We report a case of double aneuploidy in a preterm male newborn with karyotype 48,XXY,+18 whose mother was of advanced age and infected with the SARS-CoV-2 virus during the early stages of her pregnancy. The clinical features observed in the newborn included intrauterine growth retardation, dysmorphic facial features, overlapping fingers on both hands, respiratory distress syndrome, ventricular septal defect, patent ductus arteriosus, persistent pulmonary hypertension, and bilateral clubfoot, a phenotype that mainly correlates with Edwards syndrome (trisomy 18). To our knowledge, this is the first reported case of double aneuploidy in Croatia. This paper provides a detailed description of the clinical presentation and treatment strategies used, with the aim of providing valuable data for future recognition and management of similar cases. Furthermore, we discuss the mechanisms of nondisjunction that might account for this rare form of aneuploidy.