A Stepwise Algorithmic Approach and External Validation Study for Noninvasive Prediction of Advanced Fibrosis in Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Advanced F3-4 fibrosis predicts liver-related mortality in nonalcoholic fatty liver disease (NAFLD). Noninvasive tests, designed to rule in/out advanced fibrosis, are limited by indeterminates, necessitating biopsy. We aimed to determine whether stepwise combinations of noninvasive serum-based tests and elastography (VCTE) could predict F3-4, reduce indeterminates, and decrease liver biopsies. METHODS AND RESULTS: Five hundred forty-one biopsy-proven NAFLD cases were identified between 2010 and 2018 from two Canadian centers. Characteristics of training (n = 407)/validation (n = 134) cohorts included: males 54%/59%; mean age 48.5/52.5 years; mean body mass index 32.3/33.6 kg/m2; diabetes mellitus 30%/34%; and F3-4 48%/43%. For training/validation cohorts, area under the receiver operating curve (AUROC) for FIB-4, AST-platelet ratio index (APRI), NAFLD fibrosis score (NFS), BARD score, and AST/ALT ratio ranged from 0.70 to 0.83/0.68 to 0.81, with indeterminates 25-39%/34-45%, for F3-4. In the training cohort, parallel FIB-4 + NFS had good accuracy (AUROC = 0.81) but was limited by 38% indeterminates and 16% misclassified. Sequential FIB-4 → NFS reduced indeterminates to 10%, and FIB-4 → VCTE to 0%, misclassified 20-22%, while maintaining high specificity (0.88-0.92) and accuracy (AUROC 0.75-0.78) for combined cohorts. Liver biopsy could have been avoided in 27-29% of patients using sequential algorithms. CONCLUSIONS: Sequential FIB-4 âž” NFS/VCTE predicts F3-4 with high specificity and good accuracy, while reducing indeterminates and need for biopsy. Parallel algorithms are limited by high indeterminates. Sequential FIB-4 âž” NFS had similar accuracy to VCTE-containing algorithms. Validation in low-prevalence cohorts may allow for potential use in community or resource-limited areas for risk stratification.

Phenotypic Characterization of Immortalized Chondrocytes from a Desbuquois Dysplasia Type 1 Mouse Model: A Tool for Studying Defects in Glycosaminoglycan Biosynthesis.

The complexity of skeletal pathologies makes use of in vivo models essential to elucidate the pathogenesis of the diseases; nevertheless, chondrocyte and osteoblast cell lines provide relevant information on the underlying disease mechanisms. Due to the limitations of primary chondrocytes, immortalized cells represent a unique tool to overcome this problem since they grow very easily for several passages. However, in the immortalization procedure the cells might lose the original phenotype; thus, these cell lines should be deeply characterized before their use. We immortalized primary chondrocytes from a Cant1 knock-out mouse, an animal model of Desbuquois dysplasia type 1, with a plasmid expressing the SV40 large and small T antigen. This cell line, based on morphological and biochemical parameters, showed preservation of the chondrocyte phenotype. In addition reduced proteoglycan synthesis and oversulfation of glycosaminoglycan chains were demonstrated, as already observed in primary chondrocytes from the Cant1 knock-out mouse. In conclusion, immortalized Cant1 knock-out chondrocytes maintained the disease phenotype observed in primary cells validating the in vitro model and providing an additional tool to further study the proteoglycan biosynthesis defect. The same approach might be extended to other cartilage disorders.

GATA6 is a crucial regulator of Shh in the limb bud.

In the limb bud, patterning along the anterior-posterior (A-P) axis is controlled by Sonic Hedgehog (Shh), a signaling molecule secreted by the "Zone of Polarizing Activity", an organizer tissue located in the posterior margin of the limb bud. We have found that the transcription factors GATA4 and GATA6, which are key regulators of cell identity, are expressed in an anterior to posterior gradient in the early limb bud, raising the possibility that GATA transcription factors may play an additional role in patterning this tissue. While both GATA4 and GATA6 are expressed in an A-P gradient in the forelimb buds, the hindlimb buds principally express GATA6 in an A-P gradient. Thus, to specifically examine the role of GATA6 in limb patterning we generated Prx1-Cre; GATA6(fl/fl) mice, which conditionally delete GATA6 from their developing limb buds. We found that these animals display ectopic expression of both Shh and its transcriptional targets specifically in the anterior mesenchyme of the hindlimb buds. Loss of GATA6 in the developing limbs results in the formation of preaxial polydactyly in the hindlimbs. Conversely, forced expression of GATA6 throughout the limb bud represses expression of Shh and results in hypomorphic limbs. We have found that GATA6 can bind to chromatin (isolated from limb buds) encoding either Shh or Gli1 regulatory elements that drive expression of these genes in this tissue, and demonstrated that GATA6 works synergistically with FOG co-factors to repress expression of luciferase reporters driven by these sequences. Most significantly, we have found that conditional loss of Shh in limb buds lacking GATA6 prevents development of hindlimb polydactyly in these compound mutant embryos, indicating that GATA6 expression in the anterior region of the limb bud blocks hindlimb polydactyly by repressing ectopic expression of Shh.

The Dynamics of the Frequency of Polydactyly, Reduction Defects of Limbs and Multiple Congenital Malformations in Newborns of Radioactively Contaminated Areas of the Bryansk Region (1999-2014).

On the basis of official statistical data for 1999-2014 the authors assessed the frequency of polydactyly, reduction defects of limbs and multiple congenital malformations in newborns of the Bryansk region living in the areas with different densities of radioactive contamination by long-lived radionuclides cesium-137.(3.0 to 2523.4 kBq/m(2)) and strontium-90 (from 0.02 to 42.5 kBq/M(2)). The findings did not reveal statistically significant differences in the frequency of polydactyly, reduction defects of limbs and multiple congenital malformations in newborns in the South-Western Territories compared with medium-regional values, although the maximum value of the sum of congenital. developmental anomalies (polydactyly, reduction limb defects and multiple congenital malformations) are detected in the above-mentioned most contaminated areas.

Vascular limb defects and maternal age.

BACKGROUND: The prenatal diagnosis procedure chorionic villus sampling is associated with increased risk of vascular disruption limb defects. Some studies have suggested that these defects are more common among infants born to women 35 years and older while other studies have shown a correlation with younger mothers. METHODS: All infants with vascular disruption defects were identified in the Active Malformations Surveillance Program at Brigham and Women's Hospital in the years 1972-1974, 1979-2011. We compared the rate of occurrence of infants with vascular limb defects among women in theses age groups: ≤19, 20 to 34, and ≥35 years to the rate of occurrence of infants with preaxial polydactyly, adjusting for race. Infants with an identifiable cause of their defects were excluded. RESULTS: 106 infants with vascular disruption defects and 67 with preaxial polydactyly were identified. Seventeen percent of the infants with vascular disruption defects and 25% of the infants with preaxial polydactyly were born to women 35 and older (p = 0.23). In contrast, 16% of the infants with vascular disruption defects were born to young mothers (≤19 years) compared with 6.0% of the mothers of infants with preaxial polydactyly (adjusted odds ratio vs. 35+ years = 5.3, 95% confidence interval 1.4-21, p = 0.017). CONCLUSION: Women 35 years old or older did not have increased risk for having a child with vascular disruption defects, but these defects were more common among infants of young (≤19) mothers, compared with the preaxial polydactyly group.

[Ellis van Creveld. Case report]. / Ellis van Creveld: reporte de caso.

INTRODUCTION: Ellis-van Creveld (EVC) (OMIM # 225500) syndrome is a rare skeletal dysplasia disorder transmitted by autosomal recessive inheritance. The diagnosis is made based on phenotypic characteristics such as chondrodysplasia, heart defects and polydactyly. The prognosis depends mainly on the severity of the disease, diagnosis and comprehensive management of the condition. OBJECTIVE: To describe a patient diagnosed with EVC syndrome. CASE REPORT: Newborn diagnosed with EVC syndrome who presented dysmorphic facies, shortened long bones, rhizomelic shortening, small hands, brachydactyly, single transverse palmar crease, postaxial polydactyly in the upper limbs, bilateral preaxial polysyndactyly in lower limbs and hypoplastic nails, complex heart defects and narrow thorax. The evolution was unfavorable; the patient died 8 weeks after birth from complications due to heart defects. CONCLUSIONS: EVC syndrome is rare and unknown; therefore, it is important to spread its characteristics within the pediatric community, emphasizing that it affects multiple organ systems and requires a multidisciplinary approach to treat individually each patient, to provide genetic and reproductive counseling to couples and to give information regarding child development expectations.

Epidemiology of isolated preaxial polydactyly type I: data from the Polish Registry of Congenital Malformations (PRCM).

BACKGROUND: Polydactyly represents a heterogeneous group of congenital hand and foot anomalies with variable clinical features and diverse etiology. Preaxial polydactyly type I (PPD1) is the most frequent form of preaxial polydactyly. The etiology of sporadic PPD1 remains largely unknown and the relative contribution of genetic and environmental factors is not clearly defined. The primary goals of this study are twofold: (1) to examine the epidemiology and clinical features of sporadic PPD1 in comparison to a healthy control group, and (2) to contrast the characteristics of sporadic PPD1 with familial forms of isolated polydactyly. METHODS: Among 2,530,349 live births registered in the Polish Registry of Congenital Malformations (PRCM), we identified 459 children with isolated sporadic PPD1 and 353 children with familial polydactyly, including 57 children with familial PPD1. RESULTS: In comparison with the matched group of 303 controls, sporadic PPD1 cases had significantly lower birth order (P = 0.01) and birthweight (P < 0.0001). Similarly, when compared to familial cases of polydactyly, lower birth order (P = 0.047) and lower birthweight (P < 0.0001) were characteristic of sporadic PPD1 cases. Moreover, our analyses suggested several additional risk factors for sporadic PPD1, including lower paternal education levels (P = 0.01), upper respiratory tract infections during the first trimester of pregnancy (P = 0.049), and maternal history of epilepsy (P = 0.01). CONCLUSIONS: In summary, our study provides support to the hypothesis that non-genetic factors play an important role in the etiology of non-familiar PPD1.

Bardet-Biedl Syndrome-Multiple Kaleidoscope Images: Insight into Mechanisms of Genotype-Phenotype Correlations.

Bardet-Biedl Syndrome is a rare non-motile primary ciliopathy with multisystem involvement and autosomal recessive inheritance. The clinical picture is extremely polymorphic. The main clinical features are retinal cone-rod dystrophy, central obesity, postaxial polydactyly, cognitive impairment, hypogonadism and genitourinary abnormalities, and kidney disease. It is caused by various types of mutations, mainly in genes encoding BBSome proteins, chaperonins, and IFT complex. Variable expressivity and pleiotropy are correlated with the existence of multiple genes and variants modifiers. This review is focused on the phenomena of heterogeneity (locus, allelic, mutational, and clinical) in Bardet-Biedl Syndrome, its mechanisms, and importance in early diagnosis and proper management.

Bardet-Biedl 9 Syndrome, A Rare Mutation.

Bardet- biedl syndrome (BBS) is a rare heterogenous autosomal recessive disease due to defects in primary cilia which until now, up to 21 types have been detected. A few reports of BBS in Iran have been published but this is the first type 9 genotyped and clinically discussed case. This type can cause severe and delayed onset renal failure.

Prehistoric polydactylism: Biological evidence and rock art representation from the Atacama Desert in northern Chile.

A review of the bioarchaeological collections from the site Morro de Arica in northern Chile allowed the identification of two cases of human polydactyly. Both cases are from the Chinchorro culture, hunters, fishers, and gatherers with a maritime orientation who inhabited the coast of the Atacama Desert (9000-3400 BP). Additionally, the analyses of 75 rock art sites in the area, from the Formative to Late Intermediate Periods (3000-550 BP), allowed the identification of hands and feet with six digits. Given the bioarchaeological record of polydactyly, it is highly probable that the rock art images were based on real individuals with polydactyly. However, the Sr chemical signal in a juvenile with polydactyly is the same as the Sr chemical signal in the rest of the individuals buried in the same site, proving that all the individuals were born and lived on the coast. We discuss the idea that, although these anomalies could have been the result of genetic mutations, endogamy and exposition to ecotoxic environments could also be at play within the Chinchorro groups.

Empty sella associated with growth hormone deficiency and polydactyly.

Empty sella means the absence of the pituitary gland on cranial computed tomography or magnetic resonance imaging. Empty sella syndrome is the pathological variant of the imaging-described empty sella. We present the case of a male Caucasian child, aged four years and two months, for short stature and diagnosed by imaging procedures as empty sella. The cause of short stature was isolated growth hormone (GH) deficiency. Associated he presented left hand postaxial polydactyly. In connection with this particular case, we propose a review of current knowledge in empty sella syndrome. The particularity of reported case consists of association empty sella with GH deficiency and polydactyly. The association of empty sella with polydactyly is not reported yet in the medical literature and is probably coincidental.

Congenital panfollicular nevus associated with polydactyly.

A 2-year-old girl presented with ulnar-sided duplication of the left thumb distal to the interphalangeal joint and syndactyly of the first web space. She also had several asymptomatic pink-tan cutaneous papules, involving the first and second ray of the left hand and wrist, clinically resembling a linear epidermal nevus. Microscopically, the papules were composed of well-circumscribed aggregates of basaloid epithelium within the dermis. No normal hair follicles were identified. Follicular germ and papillae were identified, representing abortive attempts at hair follicle formation. The features were remarkably similar to a novel entity described by Finn and Argenyi as congenital panfollicular nevus. In our case, the congenital panfollicular nevus was associated with distal thumb polysyndactyly, which may suggest an important link between limb patterning and hair follicle development.

Single nucleotide polymorphisms in the chicken Lmbr1 gene are associated with chicken polydactyly.

Polydactyly is a common malformation of vertebrate limbs. Preaxial polydactyly (PPD) has been mapped in human, mouse and chicken to the syntenic region of human 7q36. Lmbr1 was thought as the critical candidate gene for human and mouse PPD. To understand the molecular mechanism underlying chicken polydactyly, we have cloned the open reading frame (ORF) of chicken Lmbr1, which contains 1467 nucleotides. Within this ORF, we found one short and one long splice forms. The short splice form has a complete deletion of exon 4. Six cSNPs were found in the chicken ORF, and two of these cSNPs, G797A and G1255A, lead to amino acid substitutions. However, G797A substitution had no significant association with polydactyly and the G1255A substitution had very low frequency in the population. The T1254C polymorphism in exon 13 was found to be strongly associated with polydactyly. Radiation hybrid mapping of a DNA fragment containing intron 13 of the chicken Lmbr1 assigned the gene to chromosome 2 between MCW071 (a marker within the EN2 gene) and ADL0270, a syntenic region to human 7q36.

Teratogenic effects of static magnetic field on mouse fetuses.

A short period of exposure of pregnant mice to a strong static magnetic field of 400 mT -- 8000 times that of the earth -- in a dorso-ventral direction had teratogenic effects on developing fetuses. Fetuses were exposed to the static magnetic field in utero for 6 min on 1 day from 7.5 to 14.5 days of pregnancy. Exposed and control groups consisted of 10 pregnant mice each; thus 160 animals were used in total. Various malformations were observed in 15.1%, 13.4%, 15.8%, 16.7%, 20.8%, 24.3%, 24.4%, and 14.1% of fetuses exposed on days 7.5, 8.5, 9.5, I0.5, 11.5, 12.5, 13.5, and 14.5 of pregnancy, respectively. Types of malformations were polydactylism, abdominal fissure, fused rib, vestigial 13th rib, lumbar rib, brain hernia, and curled tail, while only a low incidence (up to 2.8%) of curled tail was detected in control group. These deformations apparently caused by SMF exposure but the effect did not reflect so-called exposure period specificity.

[Association of neonatal polydactyly and maternal glucose tolerance impairment in the Congolese environment]. / Association de la polydactylie du nouveau-né avec l'intolérance glucidique maternelle en milieu congolais.

OBJECTIVES: To determine the expression of neonatal polydactyly in Kinshasa along with its association with maternal glucose tolerance impairment. MATERIALS AND METHODS: The study group is made of 151 non diabetic women whose neonates had polydactyly (isolated in 115 cases and associated with other malformations in 36 cases). The control group was made up of mothers with normal infants, 151 who had no history of congenital malformations and 39 others with a history of polydactyly in the family. The mothers had an Oral Glucose Tolerance Test (OGTT) within 24 hours after delivery. RESULTS: Bilateral type B postaxial Hand polydactyly was the most frequent form (42.3% of cases). Polydactyly was associated with other congenital malformations in 23.1%. In the study group, carbohydrate intolerance was observed in 24.3% when polydactyly was isolated, and 44.4% when it was associated with other congenital malformations. In the control group the frequency of carbohydrate intolerance was 1.9%. The positive predictive value of carbohydrate intolerance by Bilateral type B Hand polydactyly was 80.6%, while the negative predictive value was 70.1%. CONCLUSION: These results suggest a carbohydrate intolerance during the peri-conceptional period. An OGTT can be recommended for mothers whose newborns have Bilateral type B Hand polydactyly.

Poland syndrome (anomaly) with congenital hemangioma: a new association.

Unilateral defect of pectoral muscle and ipsilateral syndactyly constitute Poland syndrome. Absence or hypoplasia of the breast and nipple, axillary hair loss and dermatoglyphic abnormalities have also been reported in this syndrome. The primary defect could be in the development of the proximal subclavian artery with early deficit of blood flow to the distal limb and the pectoral region, resulting in partial loss of tissue in those regions. However, the association of congenital hemangioma with Poland sequence has not been observed so far. Such an association is being reported here in a 1-year-old infant, second-born of nonconsanguineous parents, who also had polydactyly instead of the documented syndactyly.

[Thumb duplication: an analysis of 72 thumbs]. / Cift basparmak anomalisi: 72 olgunun degerlendirilmesi.

OBJECTIVES: The aim of this study was to evaluate patients who were operated on for a duplicated thumb. METHODS: Sixty-seven patients (41 females, 26 males; mean age 2.5 years; range 6 months to 20 years) underwent surgery for a total of 72 duplicated thumbs between 1982 and 2003. Five patients had bilateral involvement. The anomaly was on the right in 39 cases, and on the left in 33 cases. Clinical and radiographic evaluations were made according to the Wassel classification. The Bilhaut-Cloquet technique was used in 13 symmetrically duplicated thumbs, while simple excision of the unserviceable part was performed in the remaining. Patient satisfaction was assessed with the use of a visual analog scale after a mean follow-up period of 3.6 years (range 1 to 10 years). RESULTS: Nail deformity was present in all cases treated by the Bilhaut-Cloquet technique. These thumbs did not exhibit growth retardation, but interphalangeal joint motion was limited in five, while seven had a larger size compared to the normal side. Limited range of motion was detected in eight cases (11.9%), affecting the metacarpophalangeal joint in one, and the interphalangeal joint in the others. Seventeen patients (25.4%) developed an angulation of more than 10 degrees in the alignment of the thumb. Secondary procedures were necessary in 25 cases (37.3%), including collateral ligament reconstruction (n=12; 17.9%), tendon rerouting (n=3; 4.5%), corrective osteotomy (n=5; 7.5%), and arthrodesis of the interphalangeal joint (n=5; 7.5%). Patient satisfaction with the surgical outcome was 85% (n=57). CONCLUSION: It is important to evaluate and treat the skin, nail, bone, and the ligaments in a simultaneous manner in order to obtain a good reconstruction and to decrease both the complications and the need for subsequent operations.

The fibulin-1 gene (FBLN1) is disrupted in a t(12;22) associated with a complex type of synpolydactyly.

Molecular analysis of the reciprocal chromosomal translocation t(12;22)(p11.2;q13.3) cosegregating with a complex type of synpolydactyly showed involvement of an alternatively spliced exon of the fibulin-1 gene (FBLN1 located in 22q13.3) and the C12orf2 (HoJ-1) gene on the short arm of chromosome 12. Investigation of the possible functional involvement of the fibulin-1 protein (FBLN1) in the observed phenotype showed that FBLN1 is expressed in the extracellular matrix (ECM) in association with the digits in the developing limb. Furthermore, fibroblasts derived from patients with the complex type of synpolydactyly displayed alterations in the level of FBLN1-D splice variant incorporated into the ECM and secreted into the conditioned culture medium. By contrast, the expression of the FBLN1-C splice variant was not perturbed in the patient fibroblasts. Based on these findings, we propose that the t(12;22) results in haploinsufficiency of the FBLN1-D variant, which could lead to the observed limb malformations.

Visual loss as the presenting sign of Jeune syndrome.

We describe a 5-year-old girl with Jeune syndrome. The presenting symptoms included visual loss and night blindness only. In the neonatal period she had surgery on both hands for bilateral polydactyly. Following clinical and radiological examination a diagnosis of Jeune syndrome was proposed. Although Jeune syndrome is often characterized by multiple organ abnormalities, our patient presented with ocular symptoms at the age of 5 years.