A Dominant Heterozygous Mutation in COG4 Causes Saul–Wilson Syndrome, a Primordial Dwarfism, and Disrupts Zebrafish Development via Wnt Signaling

Saul–Wilson syndrome (SWS) is a rare, skeletal dysplasia with progeroid appearance and primordial dwarfism. It is caused by a heterozygous, dominant variant (p.G516R) in COG4, a subunit of the conserved oligomeric Golgi (COG) complex involved in intracellular vesicular transport. Our previous work has shown the intracellular disturbances caused by this mutation; however, the pathological mechanism of SWS needs further investigation. We sought to understand the molecular mechanism of specific aspects of the SWS phenotype by analyzing SWS-derived fibroblasts and zebrafish embryos expressing this dominant variant. SWS fibroblasts accumulate glypicans, a group of heparan sulfate proteoglycans (HSPGs) critical for growth and bone development through multiple signaling pathways. Consistently, we find that glypicans are increased in zebrafish embryos expressing the COG4p.G516R variant. These animals show phenotypes consistent with convergent extension (CE) defects during gastrulation, shortened body length, and malformed jaw cartilage chondrocyte intercalation at larval stages. Since non-canonical Wnt signaling was shown in zebrafish to be related to the regulation of these processes by glypican 4, we assessed wnt levels and found a selective increase of wnt4 transcripts in the presence of COG4p.G516R. Moreover, overexpression of wnt4 mRNA phenocopies these developmental defects. LGK974, an inhibitor of Wnt signaling, corrects the shortened body length at low concentrations but amplifies it at slightly higher concentrations. WNT4 and the non-canonical Wnt signaling component phospho-JNK are also elevated in cultured SWS-derived fibroblasts. Similar results from SWS cell lines and zebrafish point to altered non-canonical Wnt signaling as one possible mechanism underlying SWS pathology.

Terminating Twins: Survival of One/Twin Research Reviews: Twin Discordance for Primordial Dwarfism; Twin Study of Public Service Motivation; Four-Parameter Model for Twin Research; Global Twinning at a Peak; Germline Differences of Monozygotic Twins/In the News: Twins and Dyngus Day; Triplets Born in Austrian Displaced Persons’ Camp; Superior, Film About Estranged Identical Twin Sisters; Adopting Own Twins After Surrogacy; Twins and Primordial Dwarfism Revisited

Selective termination is the term used for the elimination of an abnormal fetus. In contrast, multifetal pregnancy reduction refers to the termination of one or more members of a twin or higher-order multiple birth set, respectively, to reduce the high risks associated with these pregnancies. The procedure can also be used when a serious physical condition is detected prenatally in a member of a multiple birth set. In a minority of cases, selective termination has reduced two healthy fetuses to one when parents wanted just one additional child in the family. In the present article, the perspectives of a surviving twin whose family wished to terminate both healthy fetuses are examined. Next, past and present twin studies of primordial dwarfism, public service motivation, an analytical model, the global twinning rate and germline differences are summarized. The article concludes with a synopsis of twin-related news that covers twins and Dyngus Day, triplets born in an Austrian displaced persons’ camp, the film Superior — about estranged identical twin sisters, a couple adopting their own twins after surrogacy and a new case of twins and primordial dwarfism, a condition introduced in the research reviews.

Microcephalic osteodysplastic primordial dwarfism type II is associated with global vascular disease

Background Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is the most common form of primordial dwarfism, caused by bialleic mutations in the pericentrin gene (PCNT). Aside from its classic features, there are multiple associated medical complications, including a well-documented risk of neurovascular disease. Over the past several years, it has become apparent that additional vascular issues, as well as systemic hypertension and kidney disease may also be related to MOPDII. However, the frequency and extent of the vasculopathy was unclear. To help address this question, a vascular substudy was initiated within our Primordial Dwarfism Registry. Results Medical records from 47 individuals, living and deceased, ranging in age from 3 to 41 years of age were interrogated for this purpose. Of the total group, 64% were diagnosed with moyamoya, intracranial aneurysms, or both. In general, the age at diagnosis for moyamoya was younger than aneurysms, but the risk for neurovascular disease was throughout the shortened lifespan. In addition to neurovascular disease, renal, coronary and external carotid artery involvement are documented. 43% of the total group was diagnosed with hypertension, and 17% had myocardial infarctions. A total of 32% of the entire cohort had some form of chronic kidney disease, with 4% of the total group necessitating a kidney transplant. In addition, 38% had diabetes/insulin resistance. Ages of diagnoses, treatment modalities employed, and location of vasculopathies were notated as available and applicable, as well as frequencies of other comorbidities. Conclusions It is now clear that vascular disease in MOPDII is global and screening of the cardiac and renal vessels is warranted along with close monitoring of blood pressure. We recommend a blood pressure of 110/70 mmHg as a starting point for an upper limit, especially if the individual has a history of neurovascular disease, chronic kidney disease and/or diabetes. Additionally, providers need to be at high alert for the possibility of myocardial infarctions in young adults with MOPDII, so that appropriate treatment can be initiated promptly in an acute situation.

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.

Short Stature Syndromes: Case Series from India

Syndromes causing short stature include Noonan syndrome (NS), Williams syndrome, and Silver–Russell syndrome (SRS). SRS is a primordial dwarfism with genetic heterogeneity. The SRS children present with prenatal growth retardation, neonatal hypoglycemia, feeding difficulties, physical asymmetry, with scoliosis and cardiac defect in some cases. The incidence is up to 1 in 100,000. Uniparental disomy, methylation abnormalities, and variants in some genes have been found underlying such phenotype. Growth hormone therapy has been used to improve the height gain in these patients. NS has genetic heterogeneity and most patients present with short stature with or without cardiac defect. Multiple genetic variants, mostly autosomal dominant, contribute to the phenotype. With the availability of next-generation sequencing, more and more genetic disorders causing short stature are being identified in different ethnic populations like Kabuki syndrome and Nance–Horan syndrome. Here, we present some cases of SRS and other additional syndromes with dysmorphism seen in past 5 years.

Dental Characteristics of Microcephalic Osteodysplastic Primordial Dwarfism Type II

Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is an autosomal recessive inherited disorder form of primordial dwarfism, caused by mutations in the pericentrin gene. The purpose of the study was to examine the clinical and radiological features, physicochemical properties and microstructures of the tooth affected with MOPD II.The mandibular 2nd molar was collected from the MOPD II patient. Micro-computerized tomography, scanning electron microscopy, energy dispersive spectrometry and Vickers microhardness analysis were performed on the MOPD II and the normal control.The morphology of the MOPD II tooth appeared to have malformed pulp and root and showed a small size. The mineral density measurement showed that the MOPD II tooth had similar scores in the enamel, but lower scores in the root 1/2 and apical dentin compared to the normal control. The microhardness values were smaller in the cusp enamel, root 1/2 dentin and apical dentin of the MOPD II compared to the normal control.In this study, the dental characteristics and the physicochemical properties of a tooth affected with MOPD II were analyzed to improve understanding of the oral manifestations of the disease and to assist in proper dental treatment by identifying precautions.