Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

Background: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study. Methods: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age.Results: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5-3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1-2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1-3.5), with trends up to 2-4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3-0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4-0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2.Conclusion: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants

Muscle architecture and passive lengthening properties of the gastrocnemius medialis and Achilles tendon in children who idiopathically toe-walk

Children who idiopathically toe-walk (ITW) habitually operate at greater plantarflexion angles and thus, at shorter muscle-tendon unit (MTU) lengths than typically developing (TD) children. Therefore, it is often assumed that habitual use of the gastrocnemius muscle in this way will cause remodelling of the muscle-tendon architecture compared to TD children. However, the gastrocnemius muscle architecture of children who ITW has never been measured. It is essential that we gain a better understanding of these muscle-tendon properties, to ensure that appropriate clinical interventions can be provided for these children. Five children who ITW (age 8 ± 2 years) and 14 TD children (age 10 ± 2 years) participated in this study. Ultrasound was combined with isokinetic dynamometry and surface electromyography, to measure muscle architecture at common positions and passive lengthening properties of the gastrocnemius muscle and tendon across full range of motion. Regardless of which common condition groups were compared under, both the absolute and normalised to MTU muscle belly and fascicle lengths were always longer, and the Achilles tendon length was always shorter in children who ITW than TD children (p 0.05); however, passive joint stiffness was greater in children who ITW at maximum dorsiflexion (p = 0.001) and at a joint moment common to all participants (p = 0.029). Consequently, the findings of this pilot study indicate a remodelling of the relative MTU that does not support the concept that children who ITW commonly experience muscle shortening. Therefore, greater consideration of the muscle and tendon properties are required when prescribing clinical interventions that aim to lengthen the MTU, and treatments may be better targeted at the Achilles tendon in children who ITW

Geochemistry and Os-Nd-Sr isotopes of the Gaositai Alaskantype ultramafic complex from the northern North China craton: implications for mantle-crust interaction

We report petrological, chemical and Os-Nd-Sr isotopic data for the Gaositai ultramafic complex from northern North China craton (NCC) to reveal its petrogenesis. The complex shows features of Alaskan-type intrusions, including (1) the concentric zoning from dunite core, to clinopyroxenite and hornblendite in the rim, and the common cumulative textures; (2) the abundance of olivine, clinopyroxene and hornblende, and the scarcity of orthopyroxene and plagioclase, and (3) the systematic decrease in Mg# of ferromagnesian phases from core to rim, accompanied by the Fe-enrichment trend of accessory spinel. The different rock types show highly varied, radiogenic Os isotopic ratios (0.129-5.2), and unradiogenic Nd isotopic composition (ε Nd(t) = -8 to -15), but are homogeneous in I Sr ratios (0.7054-0.7066). The ( 187Os/ 188Os) i ratios are found to be anti-correlated with ε Nd(t) values and whole-rock Mg# as well. These data suggest significant crustal contamination during magma evolution. The crustal contaminants are dominantly Archean mafic rocks in the lower crust, and subordinate TTG gneisses at shallower crustal levels. The parental magma was hydrous picritic in composition, derived from an enriched lithospheric mantle source above a subduction zone. The zoned pattern of the complex formed probably through "flow differentiation" of a rapidly rising crystal mush along a fracture zone that was developed as a result of lithospheric extension in a back-arc setting in the northern margin of the NCC at ca. 280 Ma

Geochemistry of basalts from Manda Hararo, Ethiopia: LREE-depleted basalts in Central Afar

Major, trace element and isotopic (Sr, Nd and O) data are presented for a series of Quaternary basalts from the Manda Hararo Rift in the Afar depression of Ethiopia. Two types of basalts were erupted. The first and most abundant was a light rare earth element (LREE)-enriched type (Lan/Smn=1.5–3.0) with a restricted range in 87Sr/86Sr ratios from 0.70362 to 0.70373. These basalts display homogeneous 143Nd/144Nd ratios (Nd=+5.2) and are comparable to those reported for the other Quaternary volcanics from Afar suggesting the involvement of similar mantle sources. More interestingly, the 18O values vary significantly between +5.15‰ and +6.1‰ and are strongly correlated with the Ta/Th ratios. It is proposed that this may be due to contamination by hydrothermally altered gabbroic cumulates.The second type of basalt is represented by the rare occurrence of LREE-depleted basalts, which are chemically and isotopically distinct from the N-MORB erupted by the nascent oceanic ridges of the Red Sea and the Aden Gulf. They display small positive Eu anomalies (Eu/Eu*=1.03–1.08) and have high Ba/Rb and Sr/Ce ratios. Such anomalies have been previously reported for the strongly LREE-depleted olivine tholeiites and picrites from Iceland (e.g. [J. Geophys. Res. 98 (1993) 15803]) and in one Oligocene basalt from the Ethiopian Plateau [Geochim. Cosmochim. Acta 63 (1999) 2263]. Trace element, Sr and Nd isotope systematics suggest the involvement of a discrete but minor LREE-depleted component in the genesis of these basalts. The latter is not depleted MORB mantle but is possibly an intrinsic part of the plume. By analogy with the Icelandic case, we tentatively propose that this subordinate component could be a remnant of an old recycled oceanic lithosphere

Origin and geodynamic evolution of the Archean crust of eastern Finland

The Archaean crust of eastern Finland is composed of three main lithological units: ‒ Gneissic basement. It was originally composed of tonalites, trondhjemites and granodiorites emplaced at 2.86 G.a. and 2.62 G.a. and subsequently transformed into grey gneisses. The parental magmas originated from the mantle in a two-stage process: (i) formation of a basaltic crust, (ii) melting of this crust transformed into garnet-bearing amphibolite. Field, petrological and geochemical data argue in favour of a subduction-like process rather than an underplate accretion model. ‒ Greenstone belt (Kuhmo‒Suomussalmi). The lower volcanic sequence of this greenstone belt is composed of mafic and ultramafic lavas with komatiitic and tholeiitic affinities and was emplaced at about 2.65 G.a. The uprising of a mantle diapir initiated the breaking of the preexisting sialic crust (grey gneisses) and induced the emplacement of the greenstones in a proto-oceanic rift geodynamic environment. ‒ Calc-alkaline magmatism. The calc-alkaline magmas were emplaced as volcanic rocks in the greenstone belt 2.5 G.a. ago (Luoma acid volcanics), or as K-feldspar phenocryst granodiorites in the immediate vicinity of the Kuhmo‒ Suomussalmi greenstone belt 2.5 G.a. ago (Suomussalmi and Arola augen gneisses). The younger plutons were emplaced as pink leucogranites 2.41 G.a. ago. The origin of this magmatism is thought to be correlated to the late tectonic evolution of the Kuhmo‒Suomussalmi greenstone belt. The high density (d ~ 3.3) lavas of the lower volcanic sequence were emplaced over a low density (d ~ 2.7) sialic crust. This created an inverse density gradient and generated a gravity instability that initiated the subsidence (sagduction) of the greenstone belt with respect to its basement. This later was carried down in the vicinity of the belt and underwent partial melting, thus generating the calc-alkaline magmas. It must be pointed out that, in the course of time, petrogenetic processes have changed from ensimatic to ensialic, implying a major reworking of the preexisting crustal materials