Expanding the Phenotypic Spectrum of APMR4 Syndrome Caused by a Novel Variant in LSS Gene and Review of Literature.

Alopecia intellectual disability syndromes 4 (APMR4) is a very rare autosomal recessive condition caused by a mutation in the LSS gene present on chromosome 21. This syndrome has a clinical heterogeneity mainly exhibited with variable degrees of intellectual disability (ID) and congenital alopecia, as well. Eight families with 13 cases have been previously reported. Herein, we provide a report on an Egyptian family with two affected siblings and one affected fetus who was diagnosed prenatally. Whole-exome sequencing (WES) revealed a novel pathogenic missense variant (c.1609G > T; p.Val537Leu) in the lanosterol synthase gene (LSS) related to the examined patients. The detected variant was confirmed by Sanger sequencing. Segregation analyses confirmed that the parents were heterozygous. Our patient was presented with typical clinical manifestations of the disease in addition to new phenotypic features which included some dysmorphic facies as frontal bossing and bilateral large ears, as well as bilateral hyperextensibility of the fingers and wrist joints, short stature, umbilical hernia, and teeth mineralization defect. This study is the first study in Egypt and the 9th molecularly proven family to date. The aim is to expand the clinical and mutational spectrum of the syndrome. Moreover, the report gives a hint on the importance of prenatal testing and the proper genetic counseling to help the parents to take their own decision based on their beliefs.

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.