A Cumulative Approach on Rare Case of Infantile Tremor Syndrome

Infantile Tremor Syndrome (ITS) is categorically determined as a self-limiting clinical presentation which is characterized by anaemia, tremors, pigmentary skin disease, muscular hypotonia, and mental development regression. The presenting tremors are coarse in nature which are either decreased or vanished during sleep and takes 4-6 weeks duration for complete resolution following its natural course. The aetiology for ITS has been hypothesized for various factors like metabolic, infectious, nutritional but remained inconclusive for effective statement. But the precipitation is on the developing deficiency of Vitamin B12 but it remained controversial in terms of different factors. As the aetiology remained undefined, the line of treatment for children with ITS has been considered as per the treatment for undernourished child which included nutritional management with external supplementation of trace elements like iron, magnesium, calcium, vitamin B12 along with other such multivitamins. The administration of tremors is most commonly managed with the administration of propranolol or phenytoin, phenobarbitone, and carbamazepine. An 8 months old male child was brought by parents with complaints of fever since 8 days, decreased appetite and vomiting since 3 days. The course of hospital followed by physiotherapy which helped in regaining the normal functional activity of the baby.

NBAS deficiency due to biallelic c.2809C > G variant presenting with recurrent acute liver failure with severe hyperammonemia, acquired microcephaly and progressive brain atrophy

Biallelic pathogenic variants in the neuroblastoma amplified sequence (NBAS) gene were firstly (2015) identified as a cause of fever-triggered recurrent acute liver failure (RALF). Since then, some patients with NBAS deficiency presenting with neurologic features, including a motor delay, intellectual disability, muscular hypotonia and a mild brain atrophy, have been reported. Here, we describe a case of pediatric patient diagnosed with NBAS deficiency due to a homozygous c.2809C > G, p.(Pro937Ala) variant presenting with RALF with severe hyperammonemia, acquired microcephaly and progressive brain atrophy. Not reported in the literature findings include severe hyperammonemia during ALF episode, and neurologic features in the form of acquired progressive microcephaly with brain atrophy. The latter raises the hypothesis about a primary neurologic phenotype in NBAS deficiency.

Early infantile epileptic encephalopathy type 54: clinical and neurophysiological aspects

A clinical case of a boy aged 20 months old with early infantile epileptic encephalopathy (EIEE) type 54 due to mutated HNRNPU gene presumably suffering from genetic generalized epilepsy and impaired psychomotor development is described. Exome-wide sequencing was carried out by using NextSeq 500 (Illumina, USA). Video electroencephalographic (VEEG) monitoring was conducted by using NeuroScope NS425 (Biola, Russia). The patient was noted to suffer from neonatal delayed motor development and muscular hypotonia with atypical petit mal epilepsy with regional onset at the occipital-parietal-posterior temporal areas based on VEEG data developed at age of eight months as well as progressive psychoemotional disorders. Ethosuximide and valproic acid administered together were efficient in alleviating EIEE seizures that requires to be further followed up. The data obtained allow to identify a precise etiology of epilepsy and apply a differential approach to administer anti-epileptic agents.

Prediction of persistence of hemodynamically significant open arterial duct in profoundlypreterm infants

Objective. To develop a method for predicting the persistence of hemodynamically significant ductus arteriosus in profoundly premature newborns based on the evaluation of clinical data and the results of additional studies. Material and methods. Sixty-nine profoundly preterm newborns were examined including 37 with very low and 32 with extremely low body weight. Clinical and anamnestic data, the results of laboratory radiographic and instrumental examinations were evaluated. The state of the arterial duct, as well as the parameters of central and intracardiac hemodynamics were determined by echocardiography. The criteria for hemodynamically significant open arterial duct (OAD) were the following: duct size greater than 1.5 mm, left-right blood bypass, the presence of retrograde blood flow in the aorta greater than 50 % of the antegrade value. There were 2 groups: comparison (n = 41) children with hemodynamically insignificant ductus arteriosus, main (n = 28) children with hemodynamically significant ductus arteriosus after 72 hours of postnatal life. Results. After 72 hours of the postnatal life, a hemodynamically significant ductus arteriosus is detected in 40.6 % of profoundly premature newborns. The factors of a long-term persistence of ductus arteriosus are as follows: birth at term of gestation less than 27 weeks with a low Apgar score within the first minute of life ( 4 points), a patient has a sharp weakening or absence of reflexes of the newborn, severe muscular hypotonia, signs of peripheral circulation, moist fine wheezing and crepitation in the lungs, strengthening of their images on the radiograph due to the interstitial and vascular components, dilation of the left and right ventricles and the left atrium. The method for predicting the dynamics of the open ductus arteriosus in profoundly premature newborns has been developed. Conclusion. The use of the developed prognostic table makes it possible to identify with an accuracy of 85.7 % profoundly premature newborns with a high risk of persistence of a hemodynamically significant ductus arteriosus after 72 hours of postnatal life.

Maternal transmission of a mild Coffin–Siris syndrome phenotype caused by a SOX11 missense variant

Here we report for the first time on the maternal transmission of mild Coffin–Siris syndrome (CSS) caused by a SOX11 missense variant. We present two sisters with intellectual disability and muscular hypotonia born to non-consanguineous parents. Cogan ocular motor apraxia was present in both sisters. Body measurements were in a normal range. The mother and both daughters showed hypoplastic nails of the fifth toes. A missense variant in SOX11 [c.139 G > A; p.(Gly47Ser)] in both sisters and their mother was identified. Since 2014, variants in SOX11 are known to cause mild CSS. Most described patients showed intellectual disability, especially concerning acquired language. All of them had hypoplastic nails of the fifth toes. It is of note, that some of these patients show Cogan ocular motor apraxia. The facial dysmorphic features seem not to be specific. We suggest that the combination of Cogan ocular motor apraxia, hypoplastic nails of fifth toes, and developmental delay give the important diagnostic clue for a variant in the SOX11 gene (OMIM 615866, MR 27).

Complex hereditary spastic paraplegia associated with episodic visual loss caused by ACO2 variants

Most patients with homozygous or compound heterozygous pathogenic ACO2 variants present with muscular hypotonia features, namely, infantile cerebellar-retinal degeneration. Recently, two studies reported rare familial cases of ACO2 variants presenting as complex hereditary spastic paraplegia (HSP) with broad clinical spectra. Here, we report the case of a 20-year-old Japanese woman with complex HSP caused by compound heterozygous ACO2 variants, revealing a new phenotype of episodic visual loss during febrile illness.

Tubulin Folding Cofactor D Deficiency: Missing the Diagnosis With Whole Exome Sequencing

Two siblings with an early onset of a neurodegenerative disease were presented with muscular hypotonia, secondary microcephaly, and severe developmental delay. Seizures were refractory to treatment but could be controlled with a ketogenic diet. Over the course of 5 years, whole exome sequencing (WES) was performed twice in both children. The first time the diagnosis was missed. The next one revealed compound heterozygous mutations in the gene coding for the tubulin folding cofactor D. Technical improvements in WES mandated a new investigation after a few years in children where the diagnosis has not been found.

A Report on a Family with TMTC3-Related Syndrome and Review

Recessive mutations in the TMTC3 gene have been reported in thirteen patients to date exhibiting development delay, intellectual disability (ID), seizures, and muscular hypotonia, accompanied occasionally by neuronal migration defects expressed as either cobblestone lissencephaly or periventricular hypertopia. Here, we report a new case of a TMTC3-related syndrome in a Lebanese family with two affected siblings showing severe psychomotor retardation, intellectual disability, microcephaly, absence of speech, muscular hypotonia, and seizures. Whole exome sequencing revealed a homozygous pathogenic variant c.211 C > T (p.R71C) in the TMTC3 gene in both siblings. A review of the literature on TMTC3-related syndrome and its causal mutations is provided.

De novo KMT2D heterozygous frameshift deletion in a newborn with a congenital heart anomaly

Kabuki syndrome (KS) is characterized by typical facial features and patients are also affected by multiple congenital anomalies, of which congenital heart anomalies (CHAs) are present in 28.0 to 80.0%. In approximately 75.0% of patients, the genetic causes of KS are caused by mutation in the KMT2D gene. Although KS is a well-characterized syndrome, reaching the diagnosis in neonates is still challenging. Namely, newborns usually display mild facial features; therefore the diagnosis is mainly based on congenital malformations. In our case, a newborn was referred for next generation sequencing (NGS) testing due to the prenatally observed CHA. After birth, a ventricular septal defect (VSD), vesicoureteral reflux, muscular hypotonia, cleft palate, mild microcephaly, and some dysmorphic features, were noted. The NGS analysis was performed on the proband’s genomic DNA using the TruSight One Sequencing Panel, which enriches exons of 4813 genes with clinical relevance to the disease. After variant calling, NGS data analysis was predominantly focused on rare variants in genes involved in VSD, microcephaly, and muscular hypotonia; features observed predominantly in our proband. With the aforementioned protocol, we were able to determine the previously unreported de novo frameshift deletion in the KMT2D gene resulting in translation termination. Although our proband is a typical representative of KS, his diagnosis was reached only after NGS analysis. Our proband thus represents the importance of genotypephenotype driven NGS analysis in diagnosis of patients with congenital anomalies.