case_images: PMC11762408_01
case_images: A Pedigree of Family I. Black filled symbols refer to individuals with ESAM phenotype, gray filled symbols refer to individuals with obesity, and black and gray filled symbols refers to the co-occurrence of ESAM phenotype and obesity in Patient I.V.3. T/T, T/C are the genotypes of the MC4R variant in the family. B Portions of the sequencing electropherograms showing the segregation of the c.731-2A>G in the family. Arrow indicates the site of variant. C A schematic diagram and 1% agarose gel showing partial amplification of the cDNA of the ESAM (from exons 4 to 7) in Patient I.V.3 and a normal control subject. Note that the patient had a shorter band in comparison to normal control. D Portion of the sequencing electropherograms showing skipping of exon 6. E Pedigree of Family II. F Portions of the sequencing electropherograms showing the segregation of the c.561G>C (p.Trp187Cys) in the family. Arrow indicates the site of variant. G The conservation of the p.Trp187 across different species. H The prediced 3D structure resulting from the change of p.Trp187 (wild type) to p.Cys187 (mutant) using PremPS tool. This substitution significantly alters the bonding network and the number of interacting amino acids within the protein structure. I Schematic diagram showing the ESAM and its protein domains and the location of all reported variants to date including our new variants (in red)
case_images: 10038_2024_1297_Fig1_HTML.jpg
case_images: PMC11762408_03_10038_2024_1297_Fig1_HTML.jpg
case_images: Fig1
case_images: A two-year-old Egyptian female patient is the third offspring of healthy consanguineous parents (Fig. 1E).
case_images: First row is for brain CT of Patient 1 at the age of 2 weeks showing multiple porencephalic cysts and severe ventriculomegaly (A), at the age of 4 months showing moderate ventriculomegaly and punctuate calcification after the shunt operation (B), and at the age of 6 months showing subdural hemorrhage (C). Second row is for CT of Patient 2 done at the age of 3 months and showing mild ventriculomegaly, right porencephalic cyst, intracranial calcification, and areas of encephalomalacia (D), at the of 4 years showing marked obstructed hydrocephalus (E) and infarction in the brainstem (F). Frontal facial photographs of Patient 2 at the age of 4 years showing macrodoilcocephaly, bitemporal narrowing and midface hypoplasia (G). Third row is for brain MRI of Patient 3 at the age of 4 months showing cortical and central atrophy, ventriculomegaly, cavum septum pellucidum, porencephalic cysts, hemorrhagic ischemic lesions of white matter, hemosiderin staining along the ependymal surfaces of the ventricular system, indicating previous parenchymal and intraventricular hemorrhage and mild cerebellar atrophy. H, I, J Frontal facial photographs of Patient 3 at the age of 3 years and 6 months showing high forehead, bitemporal narrowing, arched eyebrow and bulbous nasal tip, upturned nostrils, long eyelashes, wide nasal bridge upslanted palpebral fissures, and bow shaped mouth (K). Fourth row is for Patient 4. CT scan at the age of 3 weeks showing multifocal intraparenchymal hemorrhages, and diffusely hypodense brain parenchyma (L). Brain MRI at the age of 18 months showing subdural hemorrhage, stretched and dysmorphic corpus callosum, white matter loss, dysgyria and widened 4th ventricle stretched and atrophy of vermis and brainstem (M, N). Follow up CT scan at the age of 4 years showing increased extraaxial CSF, atrophic brain, rippled ventricles, encephalomalacia (O). Frontal facial photographs of Patient 4 at the age of 41/2 years showing asymmetry of the skull, deep-seated eyes, squint, low-set ears, bulbous nasal tip, and bow shaped mouth (P)
case_images: 10038_2024_1297_Fig2_HTML.jpg
case_images: PMC11762408_03_10038_2024_1297_Fig2_HTML.jpg
case_images: Fig2
case_images: Brain CT revealed multifocal intraparenchymal hemorrhages, and diffusely hypodense brain parenchyma (Fig. 2L). At that time, her brain MRI showed subdural hemorrhage, stretched and dysmorphic corpus callosum, white matter loss, dysgyria and widened 4th ventricle stretched and atrophy of vermis and brainstem (Fig. 2M, N). Asymmetry of the skull, deep-seated eyes, squint, low-set ears, bulbous nasal tip, bow shaped mouth and high arched palate were noted (Fig. 2P). Follow up brain CT showed increased extraaxial CSF, atrophic brain, rippled ventricles, and encephalomalacia (Fig. 2O).
case_images: PMC11762408_02
case_images: First row is for brain CT of Patient 1 at the age of 2 weeks showing multiple porencephalic cysts and severe ventriculomegaly (A), at the age of 4 months showing moderate ventriculomegaly and punctuate calcification after the shunt operation (B), and at the age of 6 months showing subdural hemorrhage (C). Second row is for CT of Patient 2 done at the age of 3 months and showing mild ventriculomegaly, right porencephalic cyst, intracranial calcification, and areas of encephalomalacia (D), at the of 4 years showing marked obstructed hydrocephalus (E) and infarction in the brainstem (F). Frontal facial photographs of Patient 2 at the age of 4 years showing macrodoilcocephaly, bitemporal narrowing and midface hypoplasia (G). Third row is for brain MRI of Patient 3 at the age of 4 months showing cortical and central atrophy, ventriculomegaly, cavum septum pellucidum, porencephalic cysts, hemorrhagic ischemic lesions of white matter, hemosiderin staining along the ependymal surfaces of the ventricular system, indicating previous parenchymal and intraventricular hemorrhage and mild cerebellar atrophy. H, I, J Frontal facial photographs of Patient 3 at the age of 3 years and 6 months showing high forehead, bitemporal narrowing, arched eyebrow and bulbous nasal tip, upturned nostrils, long eyelashes, wide nasal bridge upslanted palpebral fissures, and bow shaped mouth (K). Fourth row is for Patient 4. CT scan at the age of 3 weeks showing multifocal intraparenchymal hemorrhages, and diffusely hypodense brain parenchyma (L). Brain MRI at the age of 18 months showing subdural hemorrhage, stretched and dysmorphic corpus callosum, white matter loss, dysgyria and widened 4th ventricle stretched and atrophy of vermis and brainstem (M, N). Follow up CT scan at the age of 4 years showing increased extraaxial CSF, atrophic brain, rippled ventricles, encephalomalacia (O). Frontal facial photographs of Patient 4 at the age of 41/2 years showing asymmetry of the skull, deep-seated eyes, squint, low-set ears, bulbous nasal tip, and bow shaped mouth (P)
case_images: 10038_2024_1297_Fig2_HTML.jpg
case_images: PMC11762408_03_10038_2024_1297_Fig2_HTML.jpg
case_images: Fig2
case_images: Brain CT revealed multifocal intraparenchymal hemorrhages, and diffusely hypodense brain parenchyma (Fig. 2L). At that time, her brain MRI showed subdural hemorrhage, stretched and dysmorphic corpus callosum, white matter loss, dysgyria and widened 4th ventricle stretched and atrophy of vermis and brainstem (Fig. 2M, N). Asymmetry of the skull, deep-seated eyes, squint, low-set ears, bulbous nasal tip, bow shaped mouth and high arched palate were noted (Fig. 2P). Follow up brain CT showed increased extraaxial CSF, atrophic brain, rippled ventricles, and encephalomalacia (Fig. 2O).
case_images: PMC11762408_03
case_images: A Pedigree of Family I. Black filled symbols refer to individuals with ESAM phenotype, gray filled symbols refer to individuals with obesity, and black and gray filled symbols refers to the co-occurrence of ESAM phenotype and obesity in Patient I.V.3. T/T, T/C are the genotypes of the MC4R variant in the family. B Portions of the sequencing electropherograms showing the segregation of the c.731-2A>G in the family. Arrow indicates the site of variant. C A schematic diagram and 1% agarose gel showing partial amplification of the cDNA of the ESAM (from exons 4 to 7) in Patient I.V.3 and a normal control subject. Note that the patient had a shorter band in comparison to normal control. D Portion of the sequencing electropherograms showing skipping of exon 6. E Pedigree of Family II. F Portions of the sequencing electropherograms showing the segregation of the c.561G>C (p.Trp187Cys) in the family. Arrow indicates the site of variant. G The conservation of the p.Trp187 across different species. H The prediced 3D structure resulting from the change of p.Trp187 (wild type) to p.Cys187 (mutant) using PremPS tool. This substitution significantly alters the bonding network and the number of interacting amino acids within the protein structure. I Schematic diagram showing the ESAM and its protein domains and the location of all reported variants to date including our new variants (in red)
case_images: 10038_2024_1297_Fig1_HTML.jpg
case_images: PMC11762408_03_10038_2024_1297_Fig1_HTML.jpg
case_images: Fig1
case_images: A two-year-old Egyptian female patient is the third offspring of healthy consanguineous parents (Fig. 1E).
case_images: First row is for brain CT of Patient 1 at the age of 2 weeks showing multiple porencephalic cysts and severe ventriculomegaly (A), at the age of 4 months showing moderate ventriculomegaly and punctuate calcification after the shunt operation (B), and at the age of 6 months showing subdural hemorrhage (C). Second row is for CT of Patient 2 done at the age of 3 months and showing mild ventriculomegaly, right porencephalic cyst, intracranial calcification, and areas of encephalomalacia (D), at the of 4 years showing marked obstructed hydrocephalus (E) and infarction in the brainstem (F). Frontal facial photographs of Patient 2 at the age of 4 years showing macrodoilcocephaly, bitemporal narrowing and midface hypoplasia (G). Third row is for brain MRI of Patient 3 at the age of 4 months showing cortical and central atrophy, ventriculomegaly, cavum septum pellucidum, porencephalic cysts, hemorrhagic ischemic lesions of white matter, hemosiderin staining along the ependymal surfaces of the ventricular system, indicating previous parenchymal and intraventricular hemorrhage and mild cerebellar atrophy. H, I, J Frontal facial photographs of Patient 3 at the age of 3 years and 6 months showing high forehead, bitemporal narrowing, arched eyebrow and bulbous nasal tip, upturned nostrils, long eyelashes, wide nasal bridge upslanted palpebral fissures, and bow shaped mouth (K). Fourth row is for Patient 4. CT scan at the age of 3 weeks showing multifocal intraparenchymal hemorrhages, and diffusely hypodense brain parenchyma (L). Brain MRI at the age of 18 months showing subdural hemorrhage, stretched and dysmorphic corpus callosum, white matter loss, dysgyria and widened 4th ventricle stretched and atrophy of vermis and brainstem (M, N). Follow up CT scan at the age of 4 years showing increased extraaxial CSF, atrophic brain, rippled ventricles, encephalomalacia (O). Frontal facial photographs of Patient 4 at the age of 41/2 years showing asymmetry of the skull, deep-seated eyes, squint, low-set ears, bulbous nasal tip, and bow shaped mouth (P)
case_images: 10038_2024_1297_Fig2_HTML.jpg
case_images: PMC11762408_03_10038_2024_1297_Fig2_HTML.jpg
case_images: Fig2
case_images: Brain CT revealed multifocal intraparenchymal hemorrhages, and diffusely hypodense brain parenchyma (Fig. 2L). At that time, her brain MRI showed subdural hemorrhage, stretched and dysmorphic corpus callosum, white matter loss, dysgyria and widened 4th ventricle stretched and atrophy of vermis and brainstem (Fig. 2M, N). Asymmetry of the skull, deep-seated eyes, squint, low-set ears, bulbous nasal tip, bow shaped mouth and high arched palate were noted (Fig. 2P). Follow up brain CT showed increased extraaxial CSF, atrophic brain, rippled ventricles, and encephalomalacia (Fig. 2O).