Melorheostosis, a rare mesenchymal dysplasia of bone, generally affects about 0.001% of people globally with about 400 cases total being reported. Melorheostosis of the hand, especially in the pediatric population, has been seldom reported. Previous studies have investigated potential genetic mutations associated with melorheostosis however, questions still remain regarding effective treatment options for this disease. This case report describes a unique case of pediatric melorheostosis of the hand and further clarifies current theories on melorheostosis with regards to pathogenesis, best treatment practices, and future research.

BACKGROUND: Placental mesenchymal dysplasia (PMD) is a rare vascular and connective placental anomaly, which is often associated with severe fetal and/or maternal complications. The diversity of presentation of PMD challenges diagnosis and effective pregnancy management.
OBJECTIVE: We aimed to review cases presenting at 7 tertiary centers worldwide over the last decade and to study the occurrence of obstetric and neonatal complications.
METHODS: Pathology databases from 7 tertiary hospitals were screened for cases of PMD (between 2007-2017). Pregnancy history, outcomes and ultrasound images were then reviewed for each case.
RESULTS: Twenty-two cases of PMD were identified. Mean gestational age at diagnosis was 23 weeks (16-39 weeks). Prenatal biochemical screening was abnormal in 8 cases (36%). Of the 12 cases that underwent invasive genetic testing, 4 were abnormal. Six patients (27%) developed maternal complications (preeclampsia/gestational hypertension). Fetal growth restriction was identified in 11 cases (50%) and fetal death in 4 (18%). Four (18%) pregnancies were terminated, 9/14 (64%) delivered preterm and only three (14%) progressed normally. Fourteen babies were born alive; 5 (35%) died in the first sixty-one days after birth, 5 (35%) had transient thrombopenia and 1 (7%) had developmental delay at last follow-up. Our series identified four potential new associations with PMD: placental triploidy mosaicism, CHARGE syndrome, fetal pleuropulmonary blastoma and fetal skeletal dysplasia.
CONCLUSIONS: PMD was substantially under-diagnosed before delivery in this cohort. Sonographers, fetal medicine specialists, obstetricians and pathologists should all suspect PMD in cases of an enlarged placenta and should look for fetal abnormalities. Diagnostic genetic testing should be discussed to exclude partial molar pregnancy. Close pregnancy follow-up is indicated due to the high risk of associated fetal or maternal adverse outcomes.

Background: Mesenchymal dysplasias or inherited connective tissue diseases are the group of diseases with deficiency of various components of connective tissue. Connective tissue disorders can affect different organs: skeleton, sight organ, skin, lungs, heart. But the most dangerous is vascular wall insufficiency leading to high risk of hemorrhage, especially during pregnancy and delivery due to hemodynamic and hormonal effects on the walls of the modified vessels.Aim: To evaluate the risk of complications during the pregnancy and delivery in patients with mesenchymal dysplasias.Study design: Fifty-six pregnancies in patients with mesenchymal dysplasias, including subclinical forms of diseases: 23 with Marfan syndrome (I group), 22 with Ehlers-Danlos syndrome (II group), and 11 with Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia) (III group) of the age from 18 to 36. The study included retrospective analysis (for the period from 1993 to 2005) and prospective study. Results of study showed high risk of life-threatening complications during pregnancy and delivery, especially the risk of hemorrhage and cardiovascular complications. In all the patients, we observed the progression of bleeding or development of bleeding in new localizations (epistaxis in 27 patients, easy brushing in 22, skin and mucosa telangiectasia in 20, gastrointestinal bleedings in 4, hemoptysis in 4, hematomas for minor traumas in 14, conjunctivas hemorrhages in 5).Conclusion: The pathogenesis of bleeding in such patients has mixed pattern: besides vascular wall pathology coagulation deficiency plays some role. The preferred delivery method for such patients is caesarean section. Deep vaginal ruptures and serious hemorrhage accompany vaginal delivery.

The C19MC gene on chromosome band 19q13.4 encodes a cluster of 46 microRNAs; those microRNAs are normally only expressed from the paternal allele and in the placenta. Placental expression correlates with selective demethylation of the paternal C19MC promoter, in contrast to methylation of both maternal and paternal alleles in nonplacental tissues. Prior investigations demonstrated \"ectopic\" activation of this gene in most hepatic mesenchymal hamartomas, including sporadic tumors and others with androgenetic-biparental mosaicism (subset of cells are diploid, but contain only paternally derived chromosomes). In the present investigation of C19MC promoter methylation status in a series of 14 mesenchymal hamartomas, a demethylated allele was identified in 6 tumors, including all 4 with androgenetic-biparental mosaicism. Conversely, only methylated alleles were cloned from sporadic hamartomas, including 3 tumors with chromosomal rearrangements thought likely to activate C19MC expression independent of the native promoter. In conjunction with published data, the findings suggest multiple molecular mechanisms for C19MC activation in hepatic mesenchymal hamartoma, including the existence of a normal placental imprinting pattern in mesenchymal cells in a subset of cases. Some or all of the latter hamartomas may result from placental \"grafting,\" a hypothesis supported by endothelial expression of the placental vascular marker, glucose transporter-1, in 1 of the 6 cases with a demethylated allele.

Mesenchymal dysplasia (mes) mice harbour a truncation in the C-terminal region of the Hh-ligand receptor, Patched-1 (mPtch1). While the mes variant of mPtch1 binds to Hh-ligands with an affinity similar to that of wild type mPtch1 and appears to normally regulate canonical Hh-signalling via smoothened, the mes mutation causes, among other non-lethal defects, a block to mammary ductal elongation at puberty. We demonstrated previously Hh-signalling induces the activation of Erk1/2 and c-src independently of its control of smo activity. Furthermore, mammary epithelial cell-directed expression of an activated allele of c-src rescued the block to ductal elongation in mes mice, albeit with delayed kinetics. Given that this rescue was accompanied by an induction in estrogen receptor-alpha (ERα) expression and that complex regulatory interactions between ERα and c-src are required for normal mammary gland development, it was hypothesized that expression of ERα would also overcome the block to mammary ductal elongation at puberty in the mes mouse. We demonstrate here that conditional expression of ERα in luminal mammary epithelial cells on the mes background facilitates ductal morphogenesis with kinetics similar to that of the MMTV-c-src(Act) mice. We demonstrate further that Erk1/2 is activated in primary mammary epithelial cells by Shh-ligand and that this activation is blocked by the inhibitor of c-src, PP2, is partially blocked by the ERα inhibitor, ICI 182780 but is not blocked by the smo-inhibitor, SANT-1. These data reveal an apparent Hh-signalling cascade operating through c-src and ERα that is required for mammary gland morphogenesis at puberty.