Lissencephaly with Congenital Hypothyroidism: A Case Report.

Lissencephaly is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The lissencephaly spectrum consists of agyria, pachygyria, and subcortical band heterotopia. At least 19 genes have been identified in the causation of lissencephaly and related syndrome. Lissencephaly is associated with many other congenital disorders but the association of lissencephaly with congenital hypothyroidism is rarely reported. We report a case of a 10-year-old girl having lissencephaly with congenital hypothyroidism. Early diagnosis of lissencephaly and genetic counselling can be made in suspected cases and further possible interventions can be taken. Also, regular follow-up, monitoring, and better conservative management lead to a better prognosis. Keywords: congenital abnormalities; hypothyroidism; lissencephaly; neuronal migration disorders.

Prenatal diagnosis of Miller-Dieker syndrome by chromosomal microarray.

OBJECTIVE: To assess the experience on prenatal diagnosis of Miller-Dieker syndrome (MDS) to further delineate the fetal presentation of this syndrome. METHODS: This was a retrospective study. Fetal MDS was diagnosed prenatally by chromosomal microarray (CMA). Clinical data were reviewed for these cases, including maternal characteristics, indications for prenatal diagnosis, sonographic findings, CMA results, and pregnancy outcomes. RESULTS: Four cases were diagnosis as MDS by CMA. The most common sonographic features were ventriculomegaly (3/4) and polyhydramnios (2/4). Deletion sizes ranged from 1.5 to 5.4 Mb. All microdeletions were located at the MDS critical region and showed haploinsufficiency of the YWHAE, CRK, and PAFAH1B1. All patients chose to terminate the pregnancy. Parental chromosome analysis were preformed in three cases and demonstrated that two cases were de novo and one case was caused by inherited derivative chromosomes from parental balanced translocations. CONCLUSION: The most common prenatal ultrasound findings of MDS were ventriculomegaly and polyhydramnios. CMA can improve diagnostic precision for detecting MDS.

Electrographic pattern recognition: A simple tool to predict clinical outcome in children with lissencephaly.

PURPOSE: To describe and correlate the clinical, radiological and EEG findings in children with lissencephaly. METHOD: Retrospective record analysis of children with lissencephaly presenting to tertiary health centre in Northern India was performed. Radiological classification and severity scoring were done. EEG findings were categorized into three patterns and its association with clinical severity was studied. RESULTS: Twenty-eight children (males = 17) with lissencephaly were enrolled. Median age at diagnosis was 6.5months (range 3days-3years). Global developmental delay (median social quotient (SQ) = 25 (range15-68) was seen in all; motor deficits in 23 (82 %); epilepsy in 21 (75 %); behavioural problems in 18 (64 %); ophthalmic problems in 17 (61 %); microcephaly in 13 (46 %); feeding difficulty in 12 (43 %). Radiologically, classical Type I lissencephaly was seen in 18(64 %), cobblestone variant (Type II) in 5 (18 %) and microlissencephaly in 5 (18 %). Grade 4 (diffuse pachygyria) radiologic severity was most common (severity grade 1-6); no cases with severity score 5 or 6 were seen. The clinical profile did not correspond with radiological severity grading. EEG pattern recognition revealed pattern I in 14 (50 %); pattern II in 6 (21 %); pattern III in 8 (29 %). Children with pattern III EEG had drug resistant epilepsy and severe developmental delay. No relationship between EEG patterns and radiological severity grading was evident. CONCLUSION: EEG is better predictor of clinical status and outcome rather than radiological severity grading. EEG pattern III is associated with severe developmental delay and drug resistant epilepsy.

[Prenatal diagnosis of a fetus with Miller-Dieker syndrome].

OBJECTIVE: To carry out genetic diagnosis for a fetus. METHODS: Chromosome G-banding and chromosomal microarray analysis (CMA) were carried out for a fetus with abnormal morphology of lateral cerebral fissure. RESULTS: The karyotype of the fetus was normal, but CMA showed that it has carried a 1.4 Mb deletion at 17p13.3 region, which suggested a diagnosis of Miller-Dieker syndrome (MDS). CONCLUSION: Familiarity with clinical features and proper selection of genetic testing method are crucial for the diagnosis of MDS. Attention should be paid to microdeletions and microduplications which can be missed by conventional chromosomal karyotyping.

Neuronal migration genes and a familial translocation t (3;17): candidate genes implicated in the phenotype.

BACKGROUND: While Miller-Dieker syndrome critical region deletions are well known delineated anomalies, submicroscopic duplications in this region have recently emerged as a new distinctive syndrome. So far, only few cases have been described overlapping 17p13.3 duplications. METHODS: In this study, we report on clinical and cytogenetic characterization of two new cases involving 17p13.3 and 3p26 chromosomal regions in two sisters with familial history of lissencephaly. Fluorescent In Situ Hybridization and array Comparative Genomic Hybridization were performed. RESULTS: A deletion including the critical region of the Miller-Dieker syndrome of at least 2,9 Mb and a duplication of at least 3,6 Mb on the short arm of chromosome 3 were highlighted in one case. The opposite rearrangements, 17p13.3 duplication and 3p deletion, were observed in the second case. This double chromosomal aberration is the result of an adjacent 1:1 meiotic segregation of a maternal reciprocal translocation t(3,17)(p26.2;p13.3). CONCLUSIONS: 17p13.3 and 3p26 deletions have a clear range of phenotypic features while duplications still have an uncertain clinical significance. However, we could suggest that regardless of the type of the rearrangement, the gene dosage and interactions of CNTN4, CNTN6 and CHL1 in the 3p26 and PAFAH1B1, YWHAE in 17p13.3 could result in different clinical spectrums.

Rare Concurrence of Two Congenital Disorders: Miller-Dieker Syndrome and T-Cell Lymphopenia.

Miller-Dieker syndrome (MDS; OMIM 247200) is a rare contiguous gene deletion syndrome associated with lissencephaly and characteristic facial dysmorphism. T-cell lymphopenia is an immunodeficiency disorder which can be early detected by newborn blood screening, and all live vaccines should be avoided. We report a 2.32-Mb microdeletion at chromosome 17p13.3p13.2 and T-cell lymphopenia in a 6-month-old male infant with MDS. This is, to our knowledge, the first description of these 2 conditions co-occurring in the same patient.

17p13.3 quadruplication: a prenatal and postpartum clinical characterization of a copy number variant.

Prenatal genetic testing has advanced rapidly in the past decade. However, not all results, including variants, are well understood. We report the finding of a 2.5-Mb gene region quadruplication of Chromosome 17p13.3. This region is well characterized for the deletion leading to Miller-Dieker syndrome but has an unclear replication phenotype. Invasive testing performed after ultrasound abnormalities were seen revealed the quadruplication sequence as well as a short segment (850 kb) with x5 copy number variation. This region has previously been reported in a collection of duplications with shared phenotype; our quadruplication suggests similarities in phenotype. This raises the hypothesis of a potential spectrum or copy number variant-based phenotype.

Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.

PURPOSE: To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia. METHODS: We collected DNA from 756 children with lissencephaly over 30 years. Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and ARX, but few other genes. Among those tested, 216 remained unsolved and were tested by a targeted panel of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN, and VLDLR) or by whole-exome sequencing. Fifty-five patients studied at another institution were added as a validation cohort. RESULTS: The overall mutation frequency in the entire cohort was 81%. LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%). Other genes accounted for 1% or less of patients. Nineteen percent remained unsolved, which suggests that several additional genes remain to be discovered. The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia, or mild frontal pachygyria. CONCLUSION: The brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways. We propose the first LIS classification system based on the underlying molecular mechanisms.

[Prenatal diagnosis of a fetus with Miller-Dieker syndrome].

OBJECTIVE: To report on prenatal diagnosis of a fetus with Miller-Dieker syndrome (MDS) and explore its genotype - phenotype correlation. METHODS: Chromosome karyotyping, bacterial artificial chromosome on beads (BACs-on-Beads, BoBs), fluorescence in situ hybridization (FISH), and single nucleotide polymorphism microarray (SNP array) were applied in conjunction for the prenatal diagnosis of a fetus with abnormal ultrasound findings. RESULTS: A 17p13.3 microdeletion was detected with the BoBs assay, and the result was confirmed by FISH. With the SNP array, the deletion was mapped to chromosome 17, with its range determined to be 5.2 Mb. On high-resolution banding analysis and BoB assay, the deletion was not found in either parent. CONCLUSION: The combined use of BoBs, FISH and SNP array has enabled prenatal diagnosis of a fetus with MDS. Attention should be paid to microdeletions and microduplications which can be missed by conventional chromosomal karyotyping analysis.

Miller-Dieker Syndrome with unbalanced translocation 45, X, psu dic(17;Y)(p13;p11.32) detected by fluorescence in situ hybridization and G-banding analysis using high resolution banding technique.

Lissencephaly is one of the central nervous system anomalies of Miller-Dieker Syndrome (MDS). Fetuses with lissencephaly have an abnormal smooth brain with fewer folds and grooves that will be detected by ultrasounds or fetal magnetic resonance imaging (MRI) after 30 weeks of gestation. We report a fetus with lissencephaly diagnosed as Miller-Dieker Syndrome postnatally. G banded chromosome analysis revealed 45,X,psu dic(17;Y)(p13;p11.32).ish dic (17;Y)(LIS1-,RARA+, SRY+, DYZ3+) by G-banding analysis using high resolution banding technique. Fetal delayed cortical development will be the findings to perform further investigations including fluorescence in situ hybridization analysis for MDS, a 17p13.3 microdeletion syndrome, pre/postnatally. This will be the first case of MDS with unbalanced translocation between deleted short arm of chromosome 17 and Y chromosome.

[Prenatal diagnosis of fetal gray matter heteropia in one case and literature review].

OBJECTIVE: To investigate the prenatal ultrasonic manifestations of fetal gray matter heterotopias (FGMH) and evaluate the optimal method its prenatal diagnosis. METHODS: The prenatal and postnatal ultrasound images and MRI images were analyzed for a fetus with a definitive diagnosis of FGMH. The detection rates of FGMH by prenatal ultrasound and MRI reported in literature were compared. RESULTS: We identified 11 reports of FGMH from 1998 to 2015, involving 43 cases with prenatal diagnoses. Of the total of 44 cases (including our case), 32 that had been confirmed postpartum had prenatal ultrasound and MRI data, which showed a significantly lower detection rates of FGMH by prenatal ultrasound than by MRI (43.8% vs 93.8%, P<0.001). CONCLUSION: Prenatal ultrasound can only detect subependymal heterotopia with characteristic manifestations, and the detection of other types of FGMH relies on MRI, which is currently the best option for prenatal diagnosis of FGMH.

Common genetic and epigenetic syndromes.

Cytogenetic anomalies should be considered in individuals with multiple congenital anomalies. DNA methylation analysis is the most sensitive initial test in evaluating for Prader-Willi and Angelman syndromes. The timely identification of cytogenetic anomalies allows for prompt initiation of early intervention services to maximize the potential of every individual as they grow older. Although many of these conditions are rare, keeping them in mind can have a profound impact on the clinical course of affected individuals. This article reviews some of the more common genetic syndromes.

Mimics and chameleons in Guillain-Barré and Miller Fisher syndromes.

Guillain-Barré syndrome (GBS) and its variant, Miller Fisher syndrome (MFS) have several subtypes, together forming a continuous spectrum of discrete and overlapping syndromes. Such is the heterogeneity within this spectrum that many physicians may be surprised to learn that these disorders are related pathophysiologically, and therefore share certain clinical features. These include history of antecedent infection, monophasic disease course and symmetrical cranial or limb weakness. The presence of cerebrospinal fluid albuminocytological dissociation (raised protein, normal cell count), antiganglioside antibodies and neurophysiological evidence of axonal or demyelinating neuropathy also support a diagnosis in many cases, but should not be relied upon. Mimics of GBS and MFS can broadly be divided into those presenting with symmetrical limb weakness and those presenting with brainstem signs. MFS and the pharyngeal-cervical-brachial variant of GBS are frequently mistaken for brainstem stroke, botulism or myasthenia gravis, whereas Bickerstaff's brainstem encephalitis is often diagnosed as Wernicke's encephalopathy. Chameleons or atypical presentations of GBS-related disorders include: paraparetic GBS, bifacial weakness with paraesthesias, acute ataxic neuropathy, acute ophthalmoparesis, acute ptosis and acute mydriasis. Many neurologists may also not be aware that deep tendon reflexes remain present or may even appear brisk in up to 10% of patients with GBS. Correct diagnosis of GBS-related disorders helps to avoid unnecessary investigations and allows early immunotherapy if appropriate.