Overgrowth Disorder Research Articles

Comparison of Quantitative Analysis of Methylated Alleles Real-Time PCR and Methylation-Specific MLPA for Molecular Diagnosis of Beckwith-Wiedemann Syndrome

Background/Aims: Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth disorder predisposing to tumorigenesis caused by abnormal expression or function of imprinted genes of the chromosome 11p15.5 imprinting gene cluster. This real-time PCR-based assay determines the methylation status of a selected CpG island and has been proposed for use in high-throughput methylation analysis. Methods: Here, we use quantitative analysis of methylated alleles (QAMA) for the detection of methylation status of the KCNQ10T1 gene, in a region immediately upstream of the transcription initiation site, and the CTCF binding site 6, located approximately 2 kb upstream of the SmaI site currently used for clinical laboratory testing. We assayed a series of controls and patients diagnosed with BWS at two different loci at 11p15.5 to assess the diagnostic yield of QAMA PCR for clinical laboratory testing. Results: These results compare favorably with methylation-specific multiple ligation probe amplification (MS-MLPA) analysis at both differentially methylated region (DMR)1 and DMR2. There are several advantages of the QAMA PCR over MS-MLPA. The QAMA PCR is less labor-intensive and therefore more cost-effective and does not require dedicated analysis software. A second advantage is that the assay is amenable to high-throughput analysis. Conclusions: The small sample size reflects the rare nature of this epigenetic disorder, and the range of ages was quite wide, as was the degree of disease severity. Therefore, further validation with larger cohorts is warranted.

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown–Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.

A mouse model of Proteus syndrome.

Proteus syndrome is a mosaic, progressive overgrowth disorder caused by a somatic activating variant c.49G > A p.(E17K) in AKT1. The presentation in affected individuals is variable, with a diversity of tissues demonstrating abnormalities. Common manifestations include skin and bony overgrowth, vascular malformations (VMs), cysts and benign tumors. We used two methods to create mouse models that had endogenously-regulated mosaic expression of the Proteus syndrome variant. Variant allele fractions (VAFs) ranged from 0% to 50% across numerous tissues in 44 Proteus syndrome mice. Mice were phenotypically heterogeneous with lesions rarely observed before 12months of age. VMs were the most frequent finding with a total of 69 found in 29 of 44 Proteus syndrome mice. Twenty-eight cysts and ectasia, frequently biliary, were seen in 22 of 44 Proteus syndrome mice. Varying levels of mammary hyperplasia were seen in 10 of 16 female Proteus syndrome mice with other localized regions of hyperplasia and stromal expansion noted in several additional animals. Interestingly, 27 of 31 Proteus syndrome animals had non-zero blood VAF that is in contrast to the human disorder where it is rarely seen in peripheral blood. Identification of variant-positive cells by green fluorescent protein (GFP) staining in chimeric Proteus syndrome mice showed that in some lesions, hyperplastic cells were predominantly GFP/Akt1E17K-positive and showed increased pAKT signal compared to GFP-negative cells. However, hyperplastic mammary epithelium was a mixture of GFP/Akt1E17K-positive and negative cells with some GFP/Akt1E17K-negative cells also having increased pAKT signal suggesting that the variant-positive cells can induce lesion formation in a non-cell autonomous manner.

Diagnosis and management of the phenotypic spectrum of twins with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with a heterogeneous phenotypic spectrum. There is an increased prevalence of monozygotic twinning in BWS. Given the epigenetic nature and phenotypic spectrum that defines BWS, twins are often discordant for clinical features, and clinicians are faced with the challenge of diagnosing and managing these twins. We present a cohort of multiple pregnancies in which one or more child from each pregnancy was diagnosed with BWS. We conducted a chart review of monochorionic and dichorionic gestations. Clinical scores for monochorionic twins demonstrated phenotypic discordance between the proband and twin. Based on linear regression analysis, a higher clinical score in the proband correlated with larger phenotypic discordance between twin siblings. Despite phenotypic discordance, however, we observed a consistent additive clinical score for a pregnancy (proband's plus twin's scores from a pregnancy). This idea of a finite degree of affectedness for a pregnancy implies a finite number of epigenetically affected cells. This further corroborates the idea that timing of monozygotic monochorionic twinning correlates with the disruption of establishment and/or maintenance of imprinting. The difference in clinical score between a proband and their twin may be due to diffused mosaicism, whereby there is an asymmetric distribution of affected cells among the multiple fetuses in a monozygotic monochorionic pregnancy, leading to a spectrum of variably affected phenotypes. Based on these findings, we recommend an algorithm for a conservative approach to clinically evaluate all children in a monozygotic multiple gestation affected by BWS.

SUN-049 Growth Hormone Deficiency Associated with a Rare Overgrowth Syndrome

Background: The Megalencephaly Capillary Malformation syndrome (MCAP) is a genetic overgrowth disorder characterized by brain overgrowth, polymicrogyria, vascular malformations, and segmental somatic overgrowth secondary to activating mutations in the PI3K-AKT-mTOR pathway (PIK3CA). Congenital macrosomia and postnatal asymmetric overgrowth is typical in this condition, however both growth failure and hypoglycemia have been reported in a significant fraction of affected children raising the concern for growth hormone deficiency (GHD). Methods: We performed an observational multi-institution study of children with MCAP and GHD. Medical records were abstracted including growth trajectories, laboratory data, and treatment response to growth hormone (GH), if applicable. Results: Eight participants (4 female, 4 male) were diagnosed with GHD at mean age of 3.2 years. All had very low or undetectable insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGF-BP3) concentrations. Four underwent GH stimulation testing and all had insufficient responses with a median peak GH of 3.1 ng/ml (range 1.1-7.3). Growth patterns revealed a drastic decline in height z-scores within the first year of life from greater than 2.0 at birth to less than -2.0 z-score by 12 months of age. Growth velocity was in the low-normal range between 1-4 years of age therefore height z-scores were stable but remained low. Four of the 8 had hypoglycemia with fasting. Central hypothyroidism was diagnosed in one and adrenal insufficiency in another. Brain MRI reports were available in 7 children and all had a structurally normal pituitary gland. Three children were treated with GH; one became inconsolable after one week of treatment and it was discontinued. The other two children have continued on GH with excellent responses in linear growth velocity. Conclusion: Profound GHD is a notable feature of MCAP, a condition with gain-of-function mutations promoting cell growth and proliferation. Therefore, children with MCAP and either hypoglycemia and/or postnatal growth failure should be evaluated for GHD. The universally low IGF-BP3 levels in this cohort were striking given this is an unusual finding even in GHD. Additional research is needed into the mechanisms underlying this phenomenon as well as whether treatment with GH is effective and safe in this condition.

Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner

The PIK3CA gene, which encodes the p110α catalytic subunit of PI3 kinase (PI3K), is mutationally activated in cancer and in overgrowth disorders known as PIK3CA-related overgrowth spectrum (PROS). To determine the consequences of genetic PIK3CA activation in a developmental context of relevance to both PROS and cancer, we engineered isogenic human induced pluripotent stem cells (iPSCs) with heterozygous or homozygous knockin of PIK3CAH1047R While heterozygous iPSCs remained largely similar to wild-type cells, homozygosity for PIK3CAH1047R caused widespread, cancer-like transcriptional remodeling, partial loss of epithelial morphology, up-regulation of stemness markers, and impaired differentiation to all three germ layers in vitro and in vivo. Genetic analysis of PIK3CA-associated cancers revealed that 64% had multiple oncogenic PIK3CA copies (39%) or additional PI3K signaling pathway-activating "hits" (25%). This contrasts with the prevailing view that PIK3CA mutations occur heterozygously in cancer. Our findings suggest that a PI3K activity threshold determines pathological consequences of oncogenic PIK3CA activation and provide insight into the specific role of this pathway in human pluripotent stem cells.

Obstructive Sleep Apnea in Children With Beckwith-Wiedemann Syndrome.

Beckwith-Wiedemann syndrome (BWS) is a rare pediatric overgrowth disorder that includes a spectrum of clinical findings including macroglossia, especially in those with loss of methylation at the imprinting control region (IC2 LOM) on chromosome 11. Children with BWS can have very severe obstructive sleep apnea (OSA), but the prevalence of OSA in this population is poorly understood, as is the relationship between OSA and the BWS genotype/phenotype. We hypothesized that there would be a high prevalence of OSA in children with BWS, and that OSA would be more severe in children with IC2 LOM. Medical records from children evaluated from March 2015 through January 2018 were reviewed for results from polysomnography, genetic testing, and clinical assessment. A total of 26 children with BWS not previously treated for OSA underwent polysomnography, genetic testing, and clinical assessment. Median (range) age was 5 months (3 days to 33 months). Most children, 20 (76.9%), had an obstructive apnea-hypopnea index (OAHI) > 2 events/h. Median (range) OAHI was 4.4 events/h (0 to 56.1 events/h). OAHI was significantly greater in participants younger than 6 months compared with those older than 6 months (P = .008). Those with IC2 LOM did not have a greater OAHI (P = .61) than those with other genetic causes of BWS, but OAHI had a strong positive correlation with BWS clinical score (Spearman rho = .54, P = .004). There is a high prevalence of OSA in children with BWS with macroglossia. Younger children with BWS and those with more phenotypic features may be at greatest risk of OSA.

Novel familial distal imprinting centre 1 (11p15.5) deletion provides further insights in imprinting regulation

BackgroundDeletions of the imprinting centre 1 (IC1) in 11p15.5 are rare and their clinical significance is not only influenced by their parental origin but also by their exact genomic localization. In case the maternal IC1 allele is affected, the deletion is associated with the overgrowth disorder Beckwith-Wiedemann syndrome (BWS) and a gain of methylation (GOM) of the IC1. The consequences of deletions of the paternal IC1 allele depend on the localization and probably the binding sites of methylation-specific DNA-binding factors affected by the change. It has been suggested that distal deletions of the paternal allele are associated with a normal IC1 methylation and phenotype, whereas proximal alterations cause a loss of methylation (LOM) and Silver-Russell syndrome (SRS) features.ResultsIn a patient referred for molecular BWS testing and his family, a deletion within the IC1 was identified by MLPA. It was associated with a GOM, corresponding to the transmission of the alteration via the maternal germline. Accordingly, the deletion was also detectable in the maternal grandmother, but here the paternal chromosome 11p15.5 was affected and a IC1 LOM was observed. By nanopore sequencing, the localization of the deletion could be precisely determined.ConclusionsWe report for the first time both GOM and LOM of the IC1 in the same family, caused by transmission of a 2.2-kb deletion in 11p15.5. Nanopore sequencing allowed the precise characterization of the change by long-read sequencing and thereby provides further insights in the regulation of imprinting in the IC1.

Beckwith-Wiedemann syndrome in diverse populations.

Beckwith-Wiedemann syndrome (BWS) is the most common epigenetic overgrowth disorder and presents with patients affected by a variety of clinical features. Although genotype-phenotype correlations have been demonstrated in BWS and although BWS has been reported to occur equally among racial and ethnic backgrounds, no study to date has evaluated the frequency of findings in different backgrounds. In this study, we evaluated the incidence of clinical features and molecular diagnoses among patients with BWS in Caucasian, Mixed, and non-Caucasian groups. These results suggest that clinical features and molecular diagnoses differ between race/ethnicity groups and raise the possibility of race and ethnicity effects on genotype-phenotype correlations in BWS.

Cloves syndrome: A rare disorder of overgrowth with unusual features – An uncommon phenotype?

CLOVES syndrome characterized by Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, and Skeletal anomalies is a recently described sporadic syndrome from postzygotic activating mutations in PIK3CA. This 3-year-old boy, born to nonconsanguineous and healthy parents, had epidermal verrucous nevus, lower limb length discrepancy and bilateral genuvalgum, anterior abdominal wall lipomatous mass, central beaking of L2 and L3, and fibrous dysplasia of the left frontal bone. Ocular and dental abnormalities (ptosis, esotropia, delayed canine eruption, dental hypoplasia), ipsilateral asymmetrical deformity of skull, and large left cerebral hemisphere with mild ipsilateral ventriculomegaly were peculiar to him denoting an uncommon phenotype. The parents did not consent for magnetic resonance imaging and genetic studies because of financial constraints. The CLOVES syndrome has emerged as an uncommon yet distinct clinical entity with some phenotypic variations. Its diagnosis is usually from cutaneous, truncal, spinal, and foot anomalies in clinical and radioimaging studies. Proteus syndrome remains the major differential.

CREB activation in hypertrophic chondrocytes is involved in the skeletal overgrowth in epiphyseal chondrodysplasia Miura type caused by activating mutations of natriuretic peptide receptor B.

Natriuretic peptide receptor B (NPRB) produces cyclic guanosine monophosphate (cGMP) when bound by C-type natriuretic peptide (CNP). Activating mutations in NPRB cause a skeletal overgrowth disorder, which has been named epiphyseal chondrodysplasia, Miura type (ECDM; OMIM #615923). Here we explored the cellular and molecular mechanisms for the skeletal overgrowth in ECDM using a mouse model in which an activating mutant NPRB is specifically expressed in chondrocytes. The mutant mice (NPRB[p.V883M]-Tg) exhibited postnatal skeletal overgrowth and increased cGMP in cartilage. Both endogenous and transgene-derived NPRB proteins were localized at the plasma membrane of hypertrophic chondrocytes. The hypertrophic zone of growth plate was thickened in NPRB[p.V883M]-Tg. An in vivo BrdU-labeling assay suggested that some of the hypertrophic chondrocytes in NPRB[p.V883M]-Tg mice continued to proliferate, although wild-type (WT) chondrocytes stopped proliferating after they became hypertrophic. In vitro cell studies revealed that NPRB activation increased the phosphorylation of cyclic AMP-responsive element binding protein (CREB) and expression of cyclin D1 in matured chondrocytes. Treatment with cell-permeable cGMP also enhanced the CREB phosphorylation. Inhibition of cyclic adenosine monophosphate (cAMP)/protein kinase A pathway had no effects on the CREB phosphorylation induced by NPRB activation. In immunostaining of the growth plates for the proliferation marker Ki67, phosphorylated CREB and cyclin D1, most signals were similarly observed in the proliferating zone in both genotypes, but some cells in the hypertrophic zone of NPRB[p.V883M]-Tg were also positively stained. These results suggest that NPRB activation evokes its signal in hypertrophic chondrocytes to induce CREB phosphorylation and make them continue to proliferate, leading to the skeletal overgrowth in ECDM.

Placental Pathology in Beckwith–Wiedemann Syndrome According to Genotype/Epigenotype Subgroups

Objectives: To evaluate the frequency of placental pathological lesions in Beckwith–Wiedemann syndrome (BWS), an overgrowth disorder that exhibits etiologic molecular heterogeneity and variable phenotypic expression. Materials and methods: The study included 60 BWS patients with a proven molecular diagnosis and a placental pathological examination. Placentomegaly, placental mesenchymal dysplasia (PMD), chorangioma/chorangiomatosis, and extravillous trophoblastic (EVT) cytomegaly were evaluated and their frequencies in the different molecular subgroups were compared. Immunohistochemistry and fluorescent in situ hybridization (FISH) were performed on EVT cytomegaly. Results: Placentomegaly was found in 70.9% of cases, PMD in 21.7%, chorangioma/chorangiomatosis in 23.3%, and EVT cytomegaly in 21.7%; there was no significant intergroup difference. EVT cytomegaly showed loss of p57 expression, increased Ki67 proliferating index, and polyploidy on FISH analysis. Conclusions: There was no genotype/epigenotype-phenotype correlation concerning placental lesions in BWS. Diffuse EVT cytomegaly with polyploidy may represent a placental finding suggestive of BWS.

Somatic mosaicism and neurodevelopmental disease.

Traditionally, we have considered genetic mutations that cause neurodevelopmental diseases to be inherited or de novo germline mutations. Recently, we have come to appreciate the importance of de novo somatic mutations, which occur postzygotically and are thus present in only a subset of the cells of an affected individual. The advent of next-generation sequencing and single-cell sequencing technologies has shown that somatic mutations contribute to normal and abnormal human brain development. Somatic mutations are one important cause of neuronal migration and brain overgrowth disorders, as suggested by visible focal lesions. In addition, somatic mutations contribute to neurodevelopmental diseases without visible lesions, including epileptic encephalopathies, intellectual disability, and autism spectrum disorder, and may contribute to a broad range of neuropsychiatric diseases. Studying somatic mutations provides insight into the mechanisms underlying human brain development and neurodevelopmental diseases and has important implications for diagnosis and treatment.

Characterization of a severe case of PIK3CA‐related overgrowth at autopsy by droplet digital polymerase chain reaction and report of PIK3CA sequencing in 22 patients

PIK3CA-related overgrowth spectrum (PROS) refers to a group of disorders of segmental overgrowth of a wide variety of tissues as well as venous and lymphatic malformations. Clinical and molecular diagnosis can be challenging due to phenotypic heterogeneity and difficulties detecting low-level mosaicism using standard methods. Here, we report a patient with a severe presentation of PIK3CA-related overgrowth with analysis of 27 posthumously collected tissues by droplet digital polymerase chain reaction (PCR) at autopsy. This patient had a complicated medical course, with coagulopathy, ischemic brain injury, and sepsis resulting in multi-organ failure and death at age 2 months despite sirolimus therapy. Five of the 27 tissues analyzed possessed a mosaic PIK3CA mutation (p.E545K), with mutation levels ranging from 3 to 20% across affected tissues. We found no correlation between tissue-specific disease severity and mutation levels, likely reflecting sampling limitations. We also tested a series of 22 individuals with somatic overgrowth and/or vascular-lymphatic malformations using a targeted next generation sequencing panel and found PIK3CA mutations in nine individuals, identifying three novel PIK3CA variants. This report expands the clinical and molecular spectrum of PROS, emphasizes that different molecular methods can be complimentary in the diagnosis of these disorders, and highlights the risk of coagulopathy in a subset of patients with PIK3CA-related overgrowth.

Tongue reduction in Beckwith–Wiedemann syndrome: outcome and treatment algorithm

Beckwith–Wiedemann syndrome is a rare congenital overgrowth disorder with macroglossia being one of the cardinal symptoms. In pronounced cases, macroglossia can lead to airway obstruction, musculoskeletal alterations and functional deficits. Surgical tongue reduction is performed at varying ages and with different techniques. This study evaluated perioperative complications, as well as long-term aesthetic and functional outcomes, in a large cohort. A total of 68 patients, treated either surgically or conservatively, were included. Depending on the severity of macroglossia, patients were divided into three groups to determine the treatment algorithm. Complications after surgical tongue reduction were prolonged intubation and revision due to dehiscence or haematoma. In the long term, no patient suffered from impaired sense of taste or paresthesia, although the shape of the tongue was disproportional in 85%. With the present treatment algorithm, operative tongue reduction exerts a positive influence on skeletal, dentoalveolar and functional development with sufficient long-term outcome and high grade of satisfaction of the patients. Supportive therapy in an interdisciplinary centre is of fundamental importance for both surgical and conservative treatment.

Molecular and in silico analyses validates pathogenicity of homozygous mutations in the NPR2 gene underlying variable phenotypes of Acromesomelic dysplasia, type Maroteaux.

Homozygous and/or heterozygous loss of function mutations in the natriuretic peptide receptor B (NPR2) have been reported in causing acromesomelic dysplasia, type Maroteaux with variable clinical features and idiopathic short stature with nonspecific skeletal deformities. On the other hand, gain of function mutations in the same gene result in overgrowth disorder suggesting that NPR2 and its ligand, natriuretic peptide precursor C (CNP), are the key players of endochondral bone growth. However, the precise mechanism behind phenotypic variability of the NPR2 mutations is not fully understood so far. In the present study, three consanguineous families of Pakistani origin (A, B, C) with variable phenotypes of acromesomelic dysplasia, type Maroteaux were evaluated at clinical and molecular levels. Linkage analysis followed by Sanger sequencing of the NPR2 gene revealed three homozygous mutations including p.(Leu314 Arg), p.(Arg371*), and p.(Arg1032*) in family A, B and C, respectively. In silico structural and functional analyses substantiated that a novel missense mutation [p.(Leu314 Arg)] in family A allosterically affects binding of NPR2 homodimer to its ligand (CNP) which ultimately results in defective guanylate cyclase activity. A nonsense mutation [p.(Arg371*)] in family B entirely removed the transmembrane domain, protein kinase domain and guanylate cyclase domains of the NPR2 resulting in abolishing its guanylate cyclase activity. Another novel mutation [p.(Arg1032*)], found in family C, deteriorated the guanylate cyclase domain of the protein and probably plundered its guanylate cyclase activity. These results suggest that guanylate cyclase activity is the most critical function of the NPR2 and phenotypic severity of the NPR2 mutations is proportional to the reduction in its guanylate cyclase activity.

Further delineation of Malan syndrome.

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype‐phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall‐Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall–Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.

Frequency of Pathologic Changes in the Oral Cavity in Patients Subjected to Long-term Pharmacologic Immunosuppressive Therapy After Kidney, Liver, and Hematopoietic Cell Transplantation

IntroductionPatients subjected to long-term immunosuppressive therapy after organ and cells transplantation are more susceptible than healthy people to the development of the pathologic changes in the oral cavity, including precancerous lesions, oral cancers, lesions following viral infections (herpes simplex virus, Epstein-Barr virus, and cytomegalovirus), fungal infections mainly caused by Candida albicans, drug-induced gingival overgrowth, stomatitis, and tongue disorders. Material and methodsClinical case material included 38 patients after kidney, liver, or blood-forming cells transplantation subjected to various immunosuppressive therapy schemes. The study comprised standard case taking and physical examination of the patient, including detailed intraoral and extraoral stomatological examinations. ResultsExtraoral examination confirmed 1 case of multifocal basal cell carcinoma in the auricular region and one case of systemic lupus erythematosus. Intraoral examination revealed gingivitis (60.5%), gingival recession (58%), periodontitis (55.26%), macroglossia (15.8%), lingual papillary atrophy (13.16%), leukoplakia aphthae/ulcerations (10.5%), lichen planus, pallor of mucous membranes (7.9%), pathologic pigmentation of oral mucosa, geographic tongue (5.26%) and erythroplakia (2.6%). When their histories were taken, patients reported xerostomia (68.42%), halitosis (23.68%), gum bleeding while brushing teeth (18.42%), and dysgeusia (15.78%). DiscussionBoth the patients after organ and hematopoietic stem cells transplantations and those qualified for a transplant should undergo multispecialty treatment, particularly dental treatment, to enable the detection of pathologies at an early stage and commencement of effective therapy. Cooperation between the main doctor and the dentist is crucial in the process of treatment of this group of patients.

Impact of Bone Volume Upon Condylar Activity in Patients With Unilateral Condylar Hyperplasia

Unilateral condylar hyperplasia or hyperactivity (UCH) is a bone overgrowth disorder affecting the mandible. The purpose of this study was to determine the relations among age, condylar bone structure, condylar bone volume, and condylar bone activity on single-photon emission computed tomographic (SPECT) scans in patients with UCH. This study included 20 patients with a clinical presentation of progressive mandibular asymmetry and a positive bone SPECT scan. A bone SPECT-derived standardized uptake value (bSUV) for the condylar region was determined. All patients underwent condylectomy to arrest further progression of the disease. The resected condyles were scanned with a micro-computed tomographic scanner (18-μm resolution). Bone architectural parameters were calculated with routine morphometric software. The mean bSUV of the condyle on the affected side was 15.32 (standard deviation [SD], 8.98) compared with 9.85 (SD, 4.40) on the nonaffected side (P=.0007). For trabecular bone structure, there was a nonsignificant correlation between the SUV of the affected condyle and the measured bone volume fraction (r=0.13; P=.58) and trabecular thickness (r=0.03; P=.90). No meaningful relation was found between condylar bone volume fraction and condylar activity on bone scan; therefore, the impact of bone volume fraction on the results of bone scans is limited. The measured condylar activity on SPECT scan seems to be primarily a reflection of the remodeling rate of bone.

Optimal Gestational Weight Gain for Women with Gestational Diabetes and Morbid Obesity.

Our aim was to investigate the greatest gestational weight gain (GWG) without adverse pregnancy complications in women with gestational diabetes mellitus (GDM) and morbid obesity. An observational retrospective study including 3284 patients with single pregnancies and GDM was completed. Of the patients, 131 (4.0%) were classified as having pre-pregnancy morbid obesity (BMI ≥ 35kg/m2). Perinatal complications were compared among BMI groups. In the group with morbid obesity, GWG threshold values to predict outcomes were examined based on sensitivity and specificity values under the receiver operating characteristic curve. GWG was higher in mothers with morbid obesity and macrosomic neonates: 11.3 (4.4-15.7) versus 4.8 (1.5-8.2) kg (p = 0.033). The GWG and neonatal ponderal index were positively correlated (r = 0.305, p = 0.001). The GWG was 7.0 (2.9-11.6) kg in women with hypertensive disorder versus 4.5 (1.0-7.5) kg in normotensive women (p = 0.017). A GWG above 5kg was a risk factor for macrosomia (87.8% sensitivity, 54.7% specificity) and hypertensive disorder (70.0% sensitivity, 48.4% specificity). GWG associations were maintained after controlling for glycemic control, maternal and gestational age, parity, smoking and neonatal sex. A GWG below 5kg is recommended for women with GDM and morbid obesity. In these women, adequate GWG may prevent macrosomia, fetal overgrowth and hypertensive disorder.