Khaled R. Gaber

Microcephaly, malformation of brain development and intracranial calcification in sibs: Pseudo-TORCH or a new syndrome†

We report on five sibs affected by congenital microcephaly, growth retardation, sloping forehead, bitemporal grooving and micrognathia. Generalized tonic‐clonic seizures started very early in life. Postnatal brain computerized tomography (CT) presented cortical band‐like calcification, calcification of basal ganglia and brain stem while brain magnetic resonance imaging (MRI) revealed abnormal gyral pattern, marked loss of white matter, dysplastic ventricles, polymicrogyria, hypogenesis of corpus callosum and cerebellar hypoplasia. No abnormalities of the internal organs, eye, or skeleton were found to be associated with this syndrome. Fetal Magnetic resonance imaging helped reaching the diagnosis in utero in one patient. Three patients died in the first years of life while the others within days after birth preceded by high fever and status epilepticus. These patients present many overlapping features with pseudo TORCH syndrome, however, the imaging findings are quite different. We propose that the distinct pattern in these sibs constitutes genetic disorder of microcephaly, developmental brain malformation and intracranial calcification of likely autosomal recessive inheritance.

Fetal brain disruption sequence versus fetal brain arrest: A distinct autosomal recessive developmental brain malformation phenotype

The term fetal brain disruption sequence (FBDS) was coined to describe a number of sporadic conditions caused by numerous external disruptive events presenting with variable imaging findings. However, rare familial occurrences have been reported. We describe five patients (two sib pairs and one sporadic) with congenital severe microcephaly, seizures, and profound intellectual disability. Brain magnetic resonance imaging (MRI) revealed unique and uniform picture of underdeveloped cerebral hemispheres with increased extraxial CSF, abnormal gyral pattern (polymicrogyria‐like lesions in two sibs and lissencephaly in the others), loss of white matter, dysplastic ventricles, hypogenesis of corpus callosum, and hypoplasia of the brainstem, but hypoplastic cerebellum in one. Fetal magnetic resonance imaging (FMRI) of two patients showed the same developmental brain malformations in utero. These imaging findings are in accordance with arrested brain development rather than disruption. Molecular analysis excluded mutations in potentially related genes such as NDE1, MKL2, OCLN, and JAM3. These unique clinical and imaging findings were described before among familial reports with FBDS. However, our patients represent a recognizable phenotype of developmental brain malformations, that is, apparently distinguishable from either familial microhydranencephaly or microlissencephaly that were collectively termed FBDS. Thus, the use of the umbrella term FBDS is no longer helpful. Accordingly, we propose the term fetal brain arrest to distinguish them from other familial patients diagnosed as FBDS. The presence of five affected patients from three unrelated consanguineous families suggests an autosomal‐recessive mode of inheritance. The spectrum of fetal brain disruption sequence is reviewed.

Profound microcephaly, primordial dwarfism with developmental brain malformations: A new syndrome

We describe two sibs with a lethal form of profound congenital microcephaly, intrauterine and postnatal growth retardation, subtle skeletal changes, and poorly developed brain. The sibs had striking absent cranial vault with sloping of the forehead, large beaked nose, relatively large ears, and mandibular micro‐retrognathia. Brain magnetic resonance imaging (MRI) revealed extremely simplified gyral pattern, large interhemispheric cyst and agenesis of corpus callosum, abnormally shaped hippocampus, and proportionately affected cerebellum and brainstem. In addition, fundus examination showed foveal hypoplasia with optic nerve atrophy. No abnormalities of the internal organs were found. This profound form of microcephaly was identified at 17 weeks gestation by ultrasound and fetal brain MRI helped in characterizing the developmental brain malformations in the second sib. Molecular analysis excluded mutations in potentially related genes such as RNU4ATAC, SLC25A19, and ASPM. These clinical and imaging findings are unlike that of any recognized severe forms of microcephaly which is believed to be a new microcephalic primordial dwarfism (MPD) with developmental brain malformations with most probably autosomal recessive inheritance based on consanguinity and similarly affected male and female sibs.

Expanding the mutation and clinical spectrum of Roberts syndrome

Roberts syndrome and SC phocomelia syndrome are rare autosomal recessive genetic disorders representing the extremes of the spectrum of severity of the same condition, caused by mutations in ESCO2 gene. We report three new patients with Roberts syndrome from three unrelated consanguineous Egyptian families. All patients presented with growth retardation, mesomelic shortening of the limbs more in the upper than in the lower limbs and microcephaly. Patients were subjected to clinical, cytogenetic and radiologic examinations. Cytogenetic analysis showed the characteristic premature separation of centromeres and puffing of heterochromatic regions. Further, sequencing of the ESCO2 gene identified a novel mutation c.244_245dupCT (p.T83Pfs*20) in one family besides two previously reported mutations c.760_761insA (p.T254Nfs*27) and c.764_765delTT (p.F255Cfs*25). All mutations were in homozygous state, in exon 3. The severity of the mesomelic shortening of the limbs and craniofacial anomalies showed variability among patients. Interestingly, patient 1 had abnormal skin hypopigmentation. Serial fetal ultrasound examinations and measurements of long bones diagnosed two affected fetuses in two of the studied families. A literature review and case comparison was performed. In conclusion, we report a novel ESCO2 mutation and expand the clinical spectrum of Roberts syndrome.

The Role of Cadmium as a Causative Agent of Recurrent Abortion in Egyptian Women

ABSTRACT Environmental pollution is one of the ever surging problems receiving careful attention in Egypt, as well as in the world. It has been evidenced that environmental pollutants play an important role in the manifestations of severe reproductive-associated disorders. Among them, an environmental pollutant, Cd, has contributed to several deleterious effects. Maternal exposure to Cd is associated with low birthweight and an increase in spontaneous abortion. Spontaneous abortion is highly frustrating for both patients and physicians. The data from the present study reveal that there was a significant increase in blood level of Cd in the aborter groups as compared to the control group of healthy women. Also there was a significant decrease in serum ferritin, which correlated positively with abortion. Also, plasma levels of malondialdehyde were significantly elevated in aborter groups. There was also a highly significant increase in plasma 8-hydroxyl-2-deoxyguanosine in the aborter groups as compared to the control group, accompanied by a significant decrease in plasma carnosine in aborter groups as compared with the control group. In the same manner there was a reduction in the progesterone hormone in aborter groups. Our results suggest that exposure to Cd is associated with an increased risk of recurrent spontaneous abortion in Egyptian women.

Association between biomarkers of vitamin B12 status and the risk of neural tube defects

The aim of this study was to evaluate the association between vitamin B12 and its biomarkers and the risk of neural tube defects.

Identification of a novel homozygous ALX4 mutation in two unrelated patients with frontonasal dysplasia type-2

We report two unrelated boys with frontonasal dysplasias type‐2 (FND‐2) who shared an identical novel homozygous ALX4 mutation c.291delG (p.Q98Sfs*83). Both patients presented with a large skull defect but one had bilateral parietal meningocele‐like cysts that lie along with the bony defect and increased in size with age. Scalp alopecia, hypertelorism, and clefted alae nasi were also detected in both of them. Furthermore, impalpable gonads were noted, being unilateral in one and bilateral in the other. Neuroimaging showed small dysplastic occipital lobes with dysgyria and midline subarachnoid cyst. Additional dysplastic corpus callosum and small cerebellar vermis were observed in one patient. Parietal foramina were noted in the parents of one patient. Our findings highlight the dosage effect of ALX4 and underscore the challenges of prenatal genetic counseling. Further, the indirect role of ALX4 in the development of the occipital lobe and posterior fossa is discussed.