Secondary Childhood glaucoma – a rare association in Seckel syndrome

A case of 12-year-old male with Seckel syndrome, presented with unilateral glaucoma leading to advanced disc damage hence, visual deterioration. Seckel syndrome being a rare inherited disorder characterized by growth delay and unique facial features, had been infrequently reported for ophthalmic anifestation especially glaucoma. Though glaucoma is a rare association in Seckel syndrome, screening at an early stage could help in preventing vision loss.

Cardiovascular anomalies in Seckel syndrome: report of two patients and review of the literature

Seckel syndrome is a very rare autosomal recessive disorder also known as bird headed dwarfism”. It is characterised by proportional short stature, low birth weight, dysmorphic facial appearance, and mental retardation. In addition to its dysmorphic features, skeletal, endocrine, gastrointestinal, haematologic, genitourinary, and nervous system has been involved. Cardiovascular features very rarely associate with Seckel syndrome. We report two patients with Seckel syndrome, one with dilated cardiomyopathy and the other with multiple ventricular septal defects. Dilated cardiomyopathy and isolated ventricular septal defect have not been previously reported in Seckel syndrome. Cardiovascular evaluation should be performed in all patients with Seckel syndrome. Early diagnosis of congenital and acquired heart diseases will reduce morbidity and mortality in these patients.

Central nervous system vasculopathy and Seckel syndrome: case illustration and systematic review

Purpose To systematically review reported cases of Seckel syndrome (SS) and point out cases associated with central nervous system (CNS) vasculopathy and provide a summary of their clinical presentation, management, and outcomes including our illustrative case. Methods We conducted a search on the MEDLINE, PubMed, Google Scholar, and Cochrane databases using the keywords “Seckel + syndrome.” We identified 127 related articles reporting 252 cases of SS apart from our case. Moreover, we searched for SS cases with CNS vasculopathies from the same databases. We identified 7 related articles reporting 7 cases of CNS vasculopathies in SS patients. Results The overall rate of CNS vasculopathy in SS patients is 3.16% (n = 8/253), where moyamoya disease (MMD) accounted for 1.97%. The mean age is 13.5 years (6–19 years), with equal gender distribution (M:F, 1:1). The most common presenting symptoms were headache and seizure followed by weakness or coma. Aneurysms were mostly located in the basilar artery, middle cerebral artery, and internal carotid artery, respectively. Regardless of the management approach, 50% of the cases sustained mild-moderate neurological deficit, 37.5% have died, and 12.5% sustained no deficit. Conclusion A high index of suspicion should be maintained in (SS) patients, and MMD should be part of the differential diagnosis. Prevalence of CNS vasculopathy in SS is 3.16% with a much higher prevalence of MMD compared to the general population. Screening for cerebral vasculopathy in SS is justifiable especially in centers that have good resources. Further data are still needed to identify the most appropriate management plan in these cases.

Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ

Congenital microcephaly is the clinical presentation of significantly reduced head circumference at birth. It manifests as both non-syndromic—microcephaly primary hereditary (MCPH)—and syndromic forms and shows considerable inter- and intrafamilial variability. It has been hypothesized that additional genetic variants may be responsible for this variability, but data are sparse. We have conducted deep phenotyping and genotyping of five Pakistani multiplex families with either MCPH (n = 3) or Seckel syndrome (n = 2). In addition to homozygous causal variants in ASPM or CENPJ, we discovered additional heterozygous modifier variants in WDR62, CEP63, RAD50 and PCNT—genes already known to be associated with neurological disorders. MCPH patients carrying an additional heterozygous modifier variant showed more severe phenotypic features. Likewise, the phenotype of Seckel syndrome caused by a novel CENPJ variant was aggravated to microcephalic osteodysplastic primordial dwarfism type II (MOPDII) in conjunction with an additional PCNT variant. We show that the CENPJ missense variant impairs splicing and decreases protein expression. We also observed centrosome amplification errors in patient cells, which were twofold higher in MOPDII as compared to Seckel cells. Taken together, these observations advocate for consideration of additional variants in related genes for their role in modifying the expressivity of the phenotype and need to be considered in genetic counseling and risk assessment.

Seckel Syndrome & Skull Morphology: Quantifying Characteristics

Seckel Syndrome is a rare genetic disorder which causes morphological changes throughout the body. Some of the most commonly reported changes are those present within the cranium and mandible such as microcephaly, a beak-like nose with convex nasal ridge, and mandibular deformities such as micrognathia. However, these clinical terms provide insufficient information to allow for proper diagnosis or to understand the distortions in physiology that take place with the disease. Therefore, quantification of the features of the skull are necessary to further explain this pathology, and comparisons to normal variation will help to understand the degree to which the anatomy is affected. Seckel Syndrome is classified as a member of the microcephaly family of pathologies; however, our results demonstrate that the overall volume of the skull is not as significantly decreased as the cranial vault itself, which may provide the catalyst for Chiari Type I malformations. The mandible, likewise, is severely altered by Seckel Syndrome decreases in approximately 44% of its volume and demonstrating altered physical proportions. Finally, the osteological measurements of the facial features demonstrated inconsistent findings between different anatomical structures providing evidence that Seckel Syndrome may have a variable effect on the different bones and tissues of the skull.

Progenitor death drives retinal dysplasia and neuronal degeneration in a mouse model of ATRIP-Seckel syndrome

ABSTRACTSeckel syndrome is a type of microcephalic primordial dwarfism (MPD) that is characterized by growth retardation and neurodevelopmental defects, including reports of retinopathy. Mutations in key mediators of the replication stress response, the mutually dependent partners ATR and ATRIP, are among the known causes of Seckel syndrome. However, it remains unclear how their deficiency disrupts the development and function of the central nervous system (CNS). Here, we investigated the cellular and molecular consequences of ATRIP deficiency in different cell populations of the developing murine neural retina. We discovered that conditional inactivation of Atrip in photoreceptor neurons did not affect their survival or function. In contrast, Atrip deficiency in retinal progenitor cells (RPCs) led to severe lamination defects followed by secondary photoreceptor degeneration and loss of vision. Furthermore, we showed that RPCs lacking functional ATRIP exhibited higher levels of replicative stress and accumulated endogenous DNA damage that was accompanied by stabilization of TRP53. Notably, inactivation of Trp53 prevented apoptosis of Atrip-deficient progenitor cells and was sufficient to rescue retinal dysplasia, neurodegeneration and loss of vision. Together, these results reveal an essential role of ATRIP-mediated replication stress response in CNS development and suggest that the TRP53-mediated apoptosis of progenitor cells might contribute to retinal malformations in Seckel syndrome and other MPD disorders.This article has an associated First Person interview with the first author of the paper.

Virchow Seckel Syndrome: The First Case in Iraq and the Early Documentation of the Syndrome in the Literature.

Background: Virchow Seckel syndrome or bird-headed dwarfism syndrome is a very rare genetic syndrome characterized by intrauterine and postnatal growth retardation with very poor growth of the body and head, narrow bird-like face with a peculiar nose, mental retardation and other congenital abnormalities. An autosomal recessive inheritance and a heterogeneous nature of the condition have been expected. This Virchow Seckel syndrome has not been reported in Iraq. Patients and methods: Four years and four months old girl was referred to the pediatric neuropsychiatry clinic of the Children Teaching Hospital of Baghdad Medical City because of significant growth and developmental retardation. The child was studied and the relevant medical literature was reviewed with aim of describing the early documentation of her rare condition in the medical literature. Results: The girl weight at birth was about 1.5 kilograms. She was experiencing very poor growth and her height was 72 cm and her weight 6 kilograms. She had low set ears, small head with narrow face, downward slanting eyebrows and a peculiar nose. She was also mentally retarded with poor language development. Family history was negative for similar cases. Bone age assessment was performed using radiographs of the left and wrist, left elbow, hips and knee and showed delayed bone age of about one year. Conclusion: During the first century of documentation of this syndrome (1882-1981, about 35 were reported in the literature and in this paper, the first case of this syndrome in Iraq is described.