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1. Pathogenic variants in the paired-related homeobox 1 gene (PRRX1) cause craniosynostosis with incomplete penetrance

Author: Tooze, RS, Miller, KA, Swagemakers, SMA, Calpena, E, McGowan, SJ, Boute, O, Collet, C, Johnson, D, Laffargue, F, de Leeuw, N, Morton, JV, Noons, P, Ockeloen, CW, Phipps, JM, Tan, TY, Timberlake, AT, Vanlerberghe, C, Wall, SA, Weber, A, Wilson, LC, Zackai, EH, Mathijssen, IMJ, Twigg, SRF, Wilkie, AOM, Pathology, and Plastic and Reconstructive Surgery and Hand Surgery
Subjects: Genetics (clinical)
Abstract: Purpose Studies previously implicated PRRX1 in craniofacial development, including demonstration of murine Prrx1 expression in the pre-osteogenic cells of the cranial sutures. We investigated the role of heterozygous missense and loss-of-function variants in PRRX1 associated with craniosynostosis. Methods Trio-based genome, exome or targeted sequencing were used to screen PRRX1 in patients with craniosynostosis; immunofluorescence analyses were used to assess nuclear localization of wild-type and mutant proteins. Results Genome sequencing identified 2 of 9 sporadically affected individuals with syndromic/multisuture craniosynostosis who were heterozygous for rare/undescribed variants in PRRX1. Exome or targeted sequencing of PRRX1 revealed a further 9/1449 patients with craniosynostosis harboring deletions or rare heterozygous variants within the homeodomain. By collaboration, seven additional individuals (four families) were identified with putatively pathogenic PRRX1 variants. Immunofluorescence analyses showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localization. Of patients with variants considered likely pathogenic, bicoronal or other multi-suture synostosis was present in 11/17 (65% of the cases). Pathogenic variants were inherited from unaffected relatives in many instances, yielding a 12.5% penetrance estimate for craniosynostosis. Conclusion This work supports a key role for PRRX1 in cranial suture development and shows that haploinsufficiency of PRRX1 is a relatively frequent cause of craniosynostosis.
Published: 2023
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2. Prevalence of Pro250Arg mutation of fibroblast growth factor receptor 3 in coronal craniosynostosis

Author: Moloney, DM, Wall, SA, Ashworth, GJ, Oldridge, M., Glass, IA, Francomano, CA, Muenke, M., and Wilkie, Aom
Published: 1997

3. A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis

Author: Justice, CM, Justice, CM, Cuellar, A, Bala, K, Sabourin, JA, Cunningham, ML, Crawford, K, Phipps, JM, Zhou, Y, Cilliers, D, Byren, JC, Johnson, D, Wall, SA, Morton, JEV, Noons, P, Sweeney, E, Weber, A, Rees, KEM, Wilson, LC, Simeonov, E, Kaneva, R, Yaneva, N, Georgiev, K, Bussarsky, A, Senders, C, Zwienenberg, M, Boggan, J, Roscioli, T, Tamburrini, G, Barba, M, Conway, K, Sheffield, VC, Brody, L, Mills, JL, Kay, D, Sicko, RJ, Langlois, PH, Tittle, RK, Botto, LD, Jenkins, MM, LaSalle, JM, Lattanzi, W, Wilkie, AOM, Wilson, AF, Romitti, PA, Boyadjiev, SA, Justice, CM, Justice, CM, Cuellar, A, Bala, K, Sabourin, JA, Cunningham, ML, Crawford, K, Phipps, JM, Zhou, Y, Cilliers, D, Byren, JC, Johnson, D, Wall, SA, Morton, JEV, Noons, P, Sweeney, E, Weber, A, Rees, KEM, Wilson, LC, Simeonov, E, Kaneva, R, Yaneva, N, Georgiev, K, Bussarsky, A, Senders, C, Zwienenberg, M, Boggan, J, Roscioli, T, Tamburrini, G, Barba, M, Conway, K, Sheffield, VC, Brody, L, Mills, JL, Kay, D, Sicko, RJ, Langlois, PH, Tittle, RK, Botto, LD, Jenkins, MM, LaSalle, JM, Lattanzi, W, Wilkie, AOM, Wilson, AF, Romitti, PA, and Boyadjiev, SA
Abstract: Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10–8): rs781716 (P = 4.71 × 10–9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10–8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10–9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10–8, OR = 0.45; P = 3.31 × 10–8, OR = 0.45; P = 1.09 × 10–8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10–8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10–6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821–55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.
Published: 2020

4. SMAD6 variants in craniosynostosis: genotype and phenotype evaluation

Author: Calpena, E, Cuellar, A, Bala, K, Swagemakers, Sigrid, Koelling, N, McGowan, SJ, Phipps, JM, Balasubramanian, M, Cunningham, ML, Douzgou, S, Lattanzi, W, Morton, JEV, Shears, D, Weber, A, Wilson, LC, Lord, H, Lester, T, Johnson, D, Wall, SA, Twigg, SRF, Mathijssen, Irene, Boardman-Pretty, F, Boyadjiev, SA, Wilkie, AOM, Calpena, E, Cuellar, A, Bala, K, Swagemakers, Sigrid, Koelling, N, McGowan, SJ, Phipps, JM, Balasubramanian, M, Cunningham, ML, Douzgou, S, Lattanzi, W, Morton, JEV, Shears, D, Weber, A, Wilson, LC, Lord, H, Lester, T, Johnson, D, Wall, SA, Twigg, SRF, Mathijssen, Irene, Boardman-Pretty, F, Boyadjiev, SA, and Wilkie, AOM
Published: 2020

5. De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

Author: Reijnders, MRF, Miller, KA, Alvi, M, Goos, JAC, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Deciphering Developmental Disorders Study, Baralle, D, Blair, EM, Engels, H, Lüdecke, H-J, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, MF, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, PJ, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, SMA, Douzgou, S, Wall, SA, Küry, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, IMJ, Nellaker, C, Brunner, HG, and Wilkie, AOM
Subjects: Adult, Male, Adolescent, kinase, Messenger, Inheritance Patterns, Translocation, Medical and Health Sciences, Cell Line, Young Adult, Genetic, Clinical Research, Loss of Function Mutation, Genetics, 2.1 Biological and endogenous factors, Humans, Aetiology, Child, Preschool, Genetic Association Studies, Genetics & Heredity, Tousled-like, Base Sequence, Human Genome, Neurosciences, Facies, Infant, Deciphering Developmental Disorders Study, Biological Sciences, Brain Disorders, haploinsufficiency, Neurodevelopmental Disorders, intellectual disability, RNA, Female, Protein Kinases, facial averaging, Biotechnology
Abstract: Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.
Published: 2018

6. De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder

Author: Babbs, C, Lloyd, D, Pagnamenta, A, Twigg, SR, Green, J, McGowan, S, Mirza, G, Naples, R, Sharma, V, Volpi, E, Buckle, V, Wall, SA, Knight, S, Parr, JR, and Wilkie, A
Subjects: Psychiatry, Gene Rearrangement, Male, Chromosomes, Human, Pair 22, Infant, Sequence Analysis, DNA, Chromosome Breakpoints, Chromosomal, Child Development Disorders, Pervasive, mental disorders, Mutation, Genetics, Humans, Cognitive and Behavioural Genetics, Molecular genetics, Clinical genetics, Child, In Situ Hybridization, Fluorescence, Transcription Factors
Abstract: BACKGROUND: Autism spectrum disorders (ASDs) are common and have a strong genetic basis, yet the cause of ∼70-80% ASDs remains unknown. By clinical cytogenetic testing, we identified a family in which two brothers had ASD, mild intellectual disability and a chromosome 22 pericentric inversion, not detected in either parent, indicating de novo mutation with parental germinal mosaicism. We hypothesised that the rearrangement was causative of their ASD and localised the chromosome 22 breakpoints. METHODS: The rearrangement was characterised using fluorescence in situ hybridisation, Southern blotting, inverse PCR and dideoxy-sequencing. Open reading frames and intron/exon boundaries of the two physically disrupted genes identified, TCF20 and TNRC6B, were sequenced in 342 families (260 multiplex and 82 simplex) ascertained by the International Molecular Genetic Study of Autism Consortium (IMGSAC). RESULTS: IMGSAC family screening identified a de novo missense mutation of TCF20 in a single case and significant association of a different missense mutation of TCF20 with ASD in three further families. Through exome sequencing in another project, we independently identified a de novo frameshifting mutation of TCF20 in a woman with ASD and moderate intellectual disability. We did not identify a significant association of TNRC6B mutations with ASD. CONCLUSIONS: TCF20 encodes a transcriptional coregulator (also termed SPBP) that is structurally and functionally related to RAI1, the critical dosage-sensitive protein implicated in the behavioural phenotypes of the Smith-Magenis and Potocki-Lupski 17p11.2 deletion/duplication syndromes, in which ASD is frequently diagnosed. This study provides the first evidence that mutations in TCF20 are also associated with ASD.
Published: 2014

7. De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

Author: Reijnders, M R F, Miller, KA, Alvi, M, Goos, Jacqueline, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Baralle, D, Blair, EM, Engels, H, Ludecke, HJ, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, Marieke, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, Peter, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, Sigrid, Douzgou, S, Wall, SA, Kury, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, Irene, Nellaker, C, Brunner, HG, Wilkie, AOM, Reijnders, M R F, Miller, KA, Alvi, M, Goos, Jacqueline, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Baralle, D, Blair, EM, Engels, H, Ludecke, HJ, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, Marieke, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, Peter, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, Sigrid, Douzgou, S, Wall, SA, Kury, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, Irene, Nellaker, C, Brunner, HG, and Wilkie, AOM
Published: 2018

8. Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

Author: Twigg, SR, Babbs, C, van den Elzen, ME, Goriely, A, Taylor, S, McGowan, SJ, Giannoulatou, E, Lonie, L, Ragoussis, J, Sadighi Akha, E, Knight, SJ, Zechi-Ceide, RM, Hoogeboom, JA, Pober, BR, Toriello, HV, Wall, SA, Rita Passos-Bueno, M, Brunner, HG, Mathijssen, IM, Wilkie, AO, and Plastic and Reconstructive Surgery and Hand Surgery
Subjects: Hemizygote, Male, Heterozygote, Sex Characteristics, Mosaicism, Infant, Newborn, Infant, Articles, Ephrin-B1, Pedigree, Craniofacial Abnormalities, Phenotype, X Chromosome Inactivation, Child, Preschool, Humans, Point Mutation, Female, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], Child, Gene Deletion
Abstract: Contains fulltext : 118112.pdf (Publisher’s version ) (Open Access) Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries-a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5' untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5' UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.
Published: 2013

9. Frank-ter Haar syndrome associated with sagittal craniosynostosis and raised intracranial pressure

Author: Bendon, CL, Fenwick, AL, Hurst, JA, Nürnberg, G, Nürnberg, P, Wall, SA, Wilkie, AO, and Johnson, D
Subjects: Heart Defects, Congenital, Male, lcsh:Internal medicine, lcsh:QH426-470, Intracranial Pressure, Developmental Disabilities, Genetics (medical sciences), food and beverages, Case Report, Osteochondrodysplasias, Frank-ter Haar syndrome, Pedigree, Craniofacial Abnormalities, lcsh:Genetics, Craniosynostoses, Craniosynostosis, Mutation, Genetics, Humans, Genetics(clinical), Female, Sagittal synostosis, lcsh:RC31-1245, human activities, Adaptor Proteins, Signal Transducing
Abstract: Background Frank-ter Haar syndrome is a rare disorder associated with skeletal, cardiac, ocular and craniofacial features including hypertelorism and brachycephaly. The most common underlying genetic defect in Frank-ter Haar syndrome appears to be a mutation in the SH3PXD2B gene on chromosome 5q35.1. Craniosynostosis, or premature fusion of the calvarial sutures, has not previously been described in Frank-ter Haar syndrome. Case presentation We present a family of three affected siblings born to consanguineous parents with clinical features in keeping with a diagnosis of Frank-ter Haar syndrome. All three siblings have a novel mutation caused by the deletion of exon 13 of the SH3PXD2B gene. Two of the three siblings also have non-scaphocephalic sagittal synostosis associated with raised intracranial pressure. Conclusion The clinical features of craniosynostosis and raised intracranial pressure in this family with a confirmed diagnosis of Frank-ter Haar syndrome expand the clinical spectrum of the disease. The abnormal cranial proportions in a mouse model of the disease suggests that the association is not coincidental. The possibility of craniosynostosis should be considered in individuals with a suspected diagnosis of Frank-ter Haar syndrome.
Published: 2016

10. Mutations of TCF12, encoding a basic-helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis

Author: Sharma, V, Fenwick, A, Brockop, MS, McGowan, S, Goos, J, Hoogeboom, A, Brady, A, Jeelani, O, Lynch, SA, Mulliken, J, Murray, D, Phipps, J, Sweeney, E, Tomkins, SE, Wilson, L, Bennett, S, Cornall, R, Broxholme, J, Kanapin, A, Donnelly, P, Johnson, D, Wall, SA, van der Spek, P, Mathijssen, I, and Maxson, R
Published: 2016

11. A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis.

Author: Schwerd, T, Twigg, SRF, Aschenbrenner, D, Manrique, S, Miller, KA, Taylor, IB, Capitani, M, McGowan, SJ, Sweeney, E, Weber, A, Chen, L, Bowness, P, Riordan, A, Cant, A, Freeman, AF, Milner, JD, Holland, SM, Frede, N, Müller, M, Schmidt-Arras, D, Grimbacher, B, Wall, SA, Jones, EY, Wilkie, AOM, Uhlig, HH, Schwerd, T, Twigg, SRF, Aschenbrenner, D, Manrique, S, Miller, KA, Taylor, IB, Capitani, M, McGowan, SJ, Sweeney, E, Weber, A, Chen, L, Bowness, P, Riordan, A, Cant, A, Freeman, AF, Milner, JD, Holland, SM, Frede, N, Müller, M, Schmidt-Arras, D, Grimbacher, B, Wall, SA, Jones, EY, Wilkie, AOM, and Uhlig, HH
Abstract: Multiple cytokines, including interleukin 6 (IL-6), IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF), signal via the common GP130 cytokine receptor subunit. In this study, we describe a patient with a homozygous mutation of IL6ST (encoding GP130 p.N404Y) who presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis. The p.N404Y missense substitution is associated with loss of IL-6, IL-11, IL-27, and OSM signaling but a largely intact LIF response. This study identifies a novel immunodeficiency with phenotypic similarities to STAT3 hyper-IgE syndrome caused by loss of function of GP130.
Published: 2017

12. Diagnostic value of exome and whole genome sequencing in craniosynostosis.

Author: Miller, KA, Twigg, SRF, McGowan, SJ, Phipps, JM, Fenwick, AL, Johnson, D, Wall, SA, Noons, P, Rees, KEM, Tidey, EA, Craft, J, Taylor, J, Taylor, JC, Goos, JAC, Swagemakers, SMA, Mathijssen, IMJ, van der Spek, PJ, Lord, H, Lester, T, Abid, N, Cilliers, D, Hurst, JA, Morton, JEV, Sweeney, E, Weber, A, Wilson, LC, Wilkie, AOM, Miller, KA, Twigg, SRF, McGowan, SJ, Phipps, JM, Fenwick, AL, Johnson, D, Wall, SA, Noons, P, Rees, KEM, Tidey, EA, Craft, J, Taylor, J, Taylor, JC, Goos, JAC, Swagemakers, SMA, Mathijssen, IMJ, van der Spek, PJ, Lord, H, Lester, T, Abid, N, Cilliers, D, Hurst, JA, Morton, JEV, Sweeney, E, Weber, A, Wilson, LC, and Wilkie, AOM
Abstract: BACKGROUND: Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ∼1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing. METHODS: We used exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high-priority cases, and in whom prior clinically driven genetic testing had been negative. RESULTS: We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (two families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3). CONCLUSIONS: This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results.
Published: 2017

13. Familial External Angular Dermoid: Evidence for A Genetic Link?

Author: McIntyre Jd, Wall Sa, and Rannan-Eliya Sv
Subjects: Family Health, External angular dermoid, Pathology, medicine.medical_specialty, Adolescent, Epibulbar dermoid, General Medicine, Anatomy, Biology, Otorhinolaryngology, Embryology, otorhinolaryngologic diseases, Etiology, medicine, Humans, Female, Surgery, Facial Neoplasms, Craniofacial, Dermoid Cyst
Abstract: Congenital craniofacial dermoid cysts are hamartomas of ectodermal and mesodermal origin, made up of keratinizing epithelium lining a cavity containing dermal skin appendages. They usually present as an asymptomatic, firm, round mass, usually noticed at birth or in the first year. They are thought to occur as a result of ectodermal sequestration at lines of fusion during embryological development. Although nasal and epibulbar dermoid cysts have occurred in families and have been associated with inheritable gene defects, there has previously been no evidence for a similar etiology in external angular cases. We present the first description of external angular dermoids occurring in siblings suggesting that this subgroup may, in some instances, also have a genetic origin.
Published: 2002
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14. Identification of Intragenic Exon Deletions and Duplication of TCF12 by Whole Genome or Targeted Sequencing as a Cause of TCF12-Related Craniosynostosis

Author: Goos, Jacqueline, Fenwick, AL, Swagemakers, Sigrid, McGowan, SJ, Knight, SJL, Twigg, SRF, Hoogeboom, Jeannette, van Dooren, Marieke, Magielsen, Frank, Wall, SA, Mathijssen, Irene, Wilkie, AOM, van der Spek, Peter, van den Ouweland, Ans, Goos, Jacqueline, Fenwick, AL, Swagemakers, Sigrid, McGowan, SJ, Knight, SJL, Twigg, SRF, Hoogeboom, Jeannette, van Dooren, Marieke, Magielsen, Frank, Wall, SA, Mathijssen, Irene, Wilkie, AOM, van der Spek, Peter, and van den Ouweland, Ans
Abstract: TCF12-related craniosynostosis can be caused by small heterozygous loss-of-function mutations in TCF12. Large intragenic rearrangements, however, have not been described yet. Here, we present the identification of four large rearrangements in TCF12 causing TCF12-related craniosynostosis. Whole-genome sequencing was applied on the DNA of 18 index cases with coronal synostosis and their family members (43 samples in total). The data were analyzed using an autosomal-dominant disease model. Structural variant analysis reported intragenic exon deletions (of sizes 84.9, 8.6, and 5.4 kb) in TCF12 in three different families. The results were confirmed by deletion-specific PCR and dideoxy-sequence analysis. Separately, targeted sequencing of the TCF12 genomic region in a patient with coronal synostosis identified a tandem duplication of 11.3 kb. The pathogenic effect of this duplication was confirmed by cDNA analysis. These findings indicate the importance of screening for larger rearrangements in patients suspected to have TCF12-related craniosynostosis.
Published: 2016

15. Mutations of TCF12, encoding a basic-helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis

Author: Sharma, VP, Fenwick, AL, Brockop, MS, McGowan, SJ, Goos, JAC, Hoogeboom, AJM, Brady, AF, Jeelani, O, Lynch, SA, Mulliken, JB, Murray, DJ, Phipps, JM, Sweeney, E, Tomkins, SE, Wilson, LC, Bennett, S, Cornall, RJ, Broxholme, J, Kanapin, A, Donnelly, P, Johnson, D, Wall, SA, van der Spek, PJ, Mathijssen, IMJ, Maxson, RE, Twigg, SRF, and Wilkie, AOM
Published: 2013

16. Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis (vol 45, pg 304, 2013)

Author: Sharma, VP, Fenwick, AL, Brockop, MS, McGowan, SJ, Goos, Jacqueline, Hoogeboom, Jeannette, Brady, AF, Jeelani, NO, Lynch, SA, Mulliken, JB, Murray, DJ, Phipps, JM, Sweeney, E, Tomkins, SE, Wilson, LC, Bennett, S, Cornall, RJ, Broxholme, J, Kanapin, A, Johnson, D, Wall, SA, van der Spek, Peter, Mathijssen, Irene, Maxson, RE, Twigg, SRF, Wilkie, AOM, Plastic and Reconstructive Surgery and Hand Surgery, Clinical Genetics, and Pathology
Published: 2013

17. Gain-of-Function Mutations in ZIC1 Are Associated with Coronal Craniosynostosis and Learning Disability

Author: Twigg, SRF, Forecki, J, Goos, Jacqueline, Richardson, ICA, Hoogeboom, Jeannette, van den Ouweland, Ans, Swagemakers, Sigrid, Lequin, MH, Van Antwerp, D, McGowan, SJ, Westbury, I, Miller, KA, Wall, SA, van der Spek, Peter, Mathijssen, Irene, Pauws, E, Merzdorf, CS, Wilkie, AOM, Twigg, SRF, Forecki, J, Goos, Jacqueline, Richardson, ICA, Hoogeboom, Jeannette, van den Ouweland, Ans, Swagemakers, Sigrid, Lequin, MH, Van Antwerp, D, McGowan, SJ, Westbury, I, Miller, KA, Wall, SA, van der Spek, Peter, Mathijssen, Irene, Pauws, E, Merzdorf, CS, and Wilkie, AOM
Abstract: Human ZIC1 (zinc finger protein of cerebellum 1), one of five homologs of the Drosophila pair-rule gene odd-paired, encodes a transcription factor previously implicated in vertebrate brain development. Heterozygous deletions of ZIC1 and its nearby paralog ZIC4 on chromosome 3q25.1 are associated with Dandy-Walker malformation of the cerebellum, and loss of the orthologous Zic1 gene in the mouse causes cerebellar hypoplasia and vertebral defects. We describe individuals from five families with heterozygous mutations located in the final (third) exon of ZIC1 (encoding four nonsense and one missense change) who have a distinct phenotype in which severe craniosynostosis, specifically involving the coronal sutures, and variable learning disability are the most characteristic features. The location of the nonsense mutations predicts escape of mutant ZIC1 transcripts from nonsense-mediated decay, which was confirmed in a cell line from an affected individual. Both nonsense and missense mutations are associated with altered and/or enhanced expression of a target gene, engrailed-2, in a Xenopus embryo assay. Analysis of mouse embryos revealed a localized domain of Zic1 expression at embryonic days 11.5-12.5 in a region overlapping the supraorbital regulatory center, which patterns the coronal suture. We conclude that the human mutations uncover a previously unsuspected role for Zic1 in early cranial suture development, potentially by regulating engrailed 1, which was previously shown to be critical for positioning of the murine coronal suture. The diagnosis of a ZIC1 mutation has significant implications for prognosis and we recommend genetic testing when common causes of coronal synostosis have been excluded.
Published: 2015

18. Intracranial hypertension in TWIST1-confirmed Saethre-Chotzen syndrome

Author: Woods, R, Ul-Haq, E, Wilkie, A, Jayamohan, J, Richards, P, Johnson, D, Lester, T, and Wall, SA
Published: 2009

19. Erratum: Clinical dividends from the molecular genetic diagnosis of craniosynostosis (Journal of Medical Genetics Part A 140A, (2631-2639))

Author: Wilkie, A, Bochukova, E, Hansen, R, Taylor, I, Rannan-Eliya, S, Byren, J, Wall, SA, Ramos, L, Venâncio, M, Hurst, J, O'Rourke, A, Williams, L, Seller, A, and Lester, T
Published: 2007

20. Molecular screening for microdeletions at 9p22-p24 and 11q23-q24 in a large cohort of patients with trigonocephaly

Author: Jehee, F, Johnson, D, Alonso, L, Cavalcanti, D, de Sá Moreira, E, Alberto, F, Kok, F, Kim, C, Wall, SA, Jabs, E, Boyadjiev, SA, Wilkie, A, and Passos-Bueno, MR
Abstract: Trigonocephaly is a rare form of craniosynostosis characterized by the premature closure of the metopic suture. To contribute to a better understanding of the genetic basis of metopic synostosis and in an attempt to restrict the candidate regions related to metopic suture fusion, we studied 76 unrelated patients with syndromic and non-syndromic trigonocephaly. We found a larger proportion of syndromic cases in our population and the ratio of affected male to female was 1.8 : 1 and 5 : 1 in the non-syndromic and syndromic groups, respectively. A microdeletion screening at 9p22-p24 and 11q23-q24 was carried out for all patients and deletions in seven of them were detected, corresponding to 19.4% of all syndromic cases. Deletions were not found in non-syndromic patients. We suggest that a molecular screening for microdeletions at 9p22-p24 and 11q23-q24 should be offered to all syndromic cases with an apparently normal karyotype because it can potentially elucidate the cause of trigonocephaly in this subset of patients. We also suggest that genes on the X-chromosome play a major role in syndromic trigonocephaly.
Published: 2005

21. Apparently synonymous substitutions in FGFR2 affect splicing and result in mild Crouzon syndrome

Author: Fenwick, AL, Goos, Jacqueline, Rankin, J, Lord, H, Lester, T, Hoogeboom, Jeannette, van den Ouweland, Ans, Wall, SA, Mathijssen, Irene, Wilkie, AOM, Fenwick, AL, Goos, Jacqueline, Rankin, J, Lord, H, Lester, T, Hoogeboom, Jeannette, van den Ouweland, Ans, Wall, SA, Mathijssen, Irene, and Wilkie, AOM
Abstract: Background: Mutations of fibroblast growth factor receptor 2 (FGFR2) account for a higher proportion of genetic cases of craniosynostosis than any other gene, and are associated with a wide spectrum of severity of clinical problems. Many of these mutations are highly recurrent and their associated features well documented. Crouzon syndrome is typically caused by heterozygous missense mutations in the third immunoglobulin domain of FGFR2. Case presentation: Here we describe two families, each segregating a different, previously unreported FGFR2 mutation of the same nucleotide, c.1083A>G and c.1083A>T, both of which encode an apparently synonymous change at the Pro361 codon. We provide experimental evidence that these mutations affect normal FGFR2 splicing and document the clinical consequences, which include a mild Crouzon syndrome phenotype and reduced penetrance of craniosynostosis. Conclusions: These observations add to a growing list of FGFR2 mutations that affect splicing and provide important clinical information for genetic counselling of families affected by these specific mutations.
Published: 2014

22. Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

Author: Twigg, SRF, Babbs, C, Elzen, Marijke, Goriely, A, Taylor, S, McGowan, SJ, Giannoulatou, E, Lonie, L, Ragoussis, J, Akha, ES, Knight, SJL, Zechi-Ceide, RM, Hoogeboom, JAM, Pober, BR, Toriello, HV, Wall, SA, Passos-Bueno, MR, Brunner, HG, Mathijssen, Irene, Wilkie, AOM, Twigg, SRF, Babbs, C, Elzen, Marijke, Goriely, A, Taylor, S, McGowan, SJ, Giannoulatou, E, Lonie, L, Ragoussis, J, Akha, ES, Knight, SJL, Zechi-Ceide, RM, Hoogeboom, JAM, Pober, BR, Toriello, HV, Wall, SA, Passos-Bueno, MR, Brunner, HG, Mathijssen, Irene, and Wilkie, AOM
Abstract: Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundariesua process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5 untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69. The 5 UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.
Published: 2013

23. Inactivation of IL11 Signaling Causes Craniosynostosis, Delayed Tooth Eruption, and Supernumerary Teeth

Author: Nieminen, P, Morgan, NV, Fenwick, AL, Parmanen, S, Veistinen, L, Mikkola, ML, van der Spek, Peter, Giraud, A, Judd, L, Arte, S, Brueton, LA, Wall, SA, Mathijssen, Irene, Maher, ER, Wilkie, AOM, Kreiborg, S, Thesleff, I, Nieminen, P, Morgan, NV, Fenwick, AL, Parmanen, S, Veistinen, L, Mikkola, ML, van der Spek, Peter, Giraud, A, Judd, L, Arte, S, Brueton, LA, Wall, SA, Mathijssen, Irene, Maher, ER, Wilkie, AOM, Kreiborg, S, and Thesleff, I
Abstract: Craniosynostosis and supernumerary teeth most often occur as isolated developmental anomalies, but they are also separately manifested in several malformation syndromes. Here, we describe a human syndrome featuring craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth. We performed homozygosity mapping in three unrelated consanguineous Pakistani families and localized the syndrome to a region in chromosome 9. Mutational analysis of candidate genes in the region revealed that all affected children harbored homozygous missense mutations (c.662C>G [p.Pro221Arg], c.734C>G [p.Ser245Cys] or c.886C>T [p.Arg296Trp]) in IL11RA (encoding interleukin 11 receptor, alpha) on chromosome 9p13.3. In addition, a homozygous nonsense mutation, c.475C>T (p.Gln159X), and a homozygous duplication, c.916_924dup (p.Thr306_Ser308dup), were observed in two north European families. In cell-transfection experiments, the p.Arg296Trp mutation rendered the receptor unable to mediate the IL11 signal, indicating that the mutation causes loss of IL11RA function. We also observed disturbed cranial growth and suture activity in the IL11ra null mutant mice, in which reduced size and remodeling of limb bones has been previously described. We conclude that IL11 signaling is essential for the normal development of craniofacial bones and teeth and that its function is to restrict suture fusion and tooth number. The results open up the possibility of modulation of IL11 signaling for the treatment of craniosynostosis.
Published: 2011

24. Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome

Author: UCL - Autre, Glaser, RL, Jiang, W, Boyadjiev, SA, Tran, AK, Zachary, AA, Van Maldergem, L., Johnson, M, Walsh, S, Oldridge, M, Wall, SA, Wilkie, AOM, Jabs, EW, 49th Annual Meeting of the American-Society-of-Human-Genetics, UCL - Autre, Glaser, RL, Jiang, W, Boyadjiev, SA, Tran, AK, Zachary, AA, Van Maldergem, L., Johnson, M, Walsh, S, Oldridge, M, Wall, SA, Wilkie, AOM, Jabs, EW, and 49th Annual Meeting of the American-Society-of-Human-Genetics
Abstract: Crouzon syndrome and Pfeiffer syndrome are both autosomal dominant craniosynostotic disorders that can be caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. To determine the parental origin of these FGFR2 mutations, the amplification refractory mutation system (ARMS) was used, ARMS IS PCR primers were developed to recognize polymorphisms that could distinguish maternal and paternal alleles, A total of 4,374 bases between introns IIIa and 11 of the FGFR2 gene were sequenced and were assayed by heteroduplex analysis, to identify polymorphisms. Two polymorphisms (1333TA/TATA and 2710 C/T) were found and were used with two previously described polymorphisms, to screen a total of 41 families, Twenty-two of these families were shown to be informative (11 for Crouzon syndrome and 11 for Pfeiffer syndrome), Eleven different mutations in the 22 families mere detected by either restriction digest or allele-specific oligonucleotide hybridization of ARMS PCR products. We molecularly proved the origin of these different mutations to be paternal for all informative cases analyzed (P = 2.4 x 10(-7); 95% confidence limits 87%-100%). Advanced paternal age was noted for the fathers of patients with Crouzon syndrome or Pfeiffer syndrome, compared with the fathers of control individuals (34.50 +/- 7.65 years vs. 30.45 +/- 1.28 years, P < .01), Our data on advanced paternal age corroborates and extends previous clinical evidence based on statistical analyses as well as additional reports of advanced paternal age associated with paternal origin of three sporadic mutations causing Apert syndrome (FGFR2) and achondroplasia (FGFR3). Our results suggest that older men either have accumulated or are more susceptible to a variety of germline mutations.
Published: 2000

25. A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis

Author: Schwerd, T, Twigg, SRF, Aschenbrenner, D, Manrique, S, Miller, KA, Taylor, IB, Capitani, M, McGowan, SJ, Sweeney, E, Weber, A, Chen, L, Bowness, P, Riordan, A, Cant, A, Freeman, AF, Milner, JD, Holland, SM, Frede, N, Müller, M, Schmidt-Arras, D, Grimbache, B, Wall, SA, Jones, EY, Wilkie, AOM, and Uhlig, HH
Abstract: Multiple cytokines, including interleukin 6 (IL-6), IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF), signal via the common GP130 cytokine receptor subunit. In this study, we describe a patient with a homozygous mutation of IL6ST (encoding GP130 p.N404Y) who presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis. The p.N404Y missense substitution is associated with loss of IL-6, IL-11, IL-27, and OSM signaling but a largely intact LIF response. This study identifies a novel immunodeficiency with phenotypic similarities to STAT3 hyper-IgE syndrome caused by loss of function of GP130.

26. Apparently synonymous substitutions in FGFR2affect splicing and result in mild Crouzon syndrome

Author: Fenwick, A, Goos, J, Rankin, J, Lord, H, Lester, T, Hoogeboom, A, Van Den Ouweland, A, Wall, SA, Mathijssen, I, Wilkie, A, Plastic and Reconstructive Surgery and Hand Surgery, and Clinical Genetics
Subjects: Male, musculoskeletal diseases, Heterozygote, congenital, hereditary, and neonatal diseases and abnormalities, Craniofacial Dysostosis, RNA Splicing, Mutation, Missense, Case Report, Penetrance, Exons, Splicing, Crouzon syndrome, Pedigree, Craniosynostoses, Amino Acid Substitution, Craniosynostosis, FGFR2, Genetics, Expressivity, Humans, Female, Genetics(clinical), Synonymous substitution, Receptor, Fibroblast Growth Factor, Type 2
Abstract: Background: Mutations of fibroblast growth factor receptor 2 (FGFR2) account for a higher proportion of genetic cases of craniosynostosis than any other gene, and are associated with a wide spectrum of severity of clinical problems. Many of these mutations are highly recurrent and their associated features well documented. Crouzon syndrome is typically caused by heterozygous missense mutations in the third immunoglobulin domain of FGFR2. Case presentation: Here we describe two families, each segregating a different, previously unreported FGFR2 mutation of the same nucleotide, c.1083A>G and c.1083A>T, both of which encode an apparently synonymous change at the Pro361 codon. We provide experimental evidence that these mutations affect normal FGFR2 splicing and document the clinical consequences, which include a mild Crouzon syndrome phenotype and reduced penetrance of craniosynostosis. Conclusions: These observations add to a growing list of FGFR2 mutations that affect splicing and provide important clinical information for genetic counselling of families affected by these specific mutations.
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27. Glucarpidase for Treatment of High-Dose Methotrexate Toxicity.

Author: Gupta S, Kaunfer SA, Chen KL, Dias JA, Vijayan A, Rajasekaran A, Prosek J, Truong HL, Wood A, Bassil C, Renaghan AD, Shah CV, Zhang J, Glezerman I, Carlos C, Kelly K, Passero CJ, Drappatz J, Abudayyeh A, Shin D, Sperati CJ, Yelvington BJ, Kanduri SR, Neyra JA, Edmonston D, Shirali AC, Bansal A, Geara A, Mithani Z, Ziolkowski SL, Rashidi A, Jakubowski J, Pujari A, Bond DA, Dotson EK, Wall SA, Patton JT, Barreto JN, Herrmann SM, Sheikh MS, Baz RC, Lee JH, Lucchesi N, Kolman M, Rasheed MA, Afzal A, Kang D, Mahesh A, Hsu R, Nicolaysen A, Tefera K, Schretlen C, Miller RM, Velez JCQ, Flannery AH, Aklilu AM, Anand S, Chandrasekhara S, Donley V, Patel A, Ni J, Krishnamurthy S, Ali R, Yilmam OA, Wells SL, Ortega JL, Green-Lingren OL, Leaf RK, Sise ME, Nayak L, LaCasce AS, Leung N, and Leaf DE
Abstract: High-dose methotrexate (MTX) results in high rates of acute kidney injury (AKI), neutropenia, and hepatotoxicity. Glucarpidase is a recombinant enzyme that cleaves MTX, but clinical data supporting its use are scarce. We examined the association between glucarpidase administration and outcomes in adults with MTX-AKI from 28 cancer centers across the U.S using a sequential target trial emulation framework. The primary end point was kidney recovery at hospital discharge, defined as survival to discharge with serum creatinine <1.5-fold baseline and without dialysis-dependence. Key secondary end points were time-to-kidney recovery, neutropenia and transaminitis on day 7, and time-to-death. Using multivariable logistic and Cox regression models, we compared outcomes in patients who received glucarpidase within 4 days following MTX initiation with those in patients who did not. Among 708 patients with MTX-AKI, 209 (29.5%) received glucarpidase. Overall, 183 (25.8%) had a primary end point event. Glucarpidase receipt was associated with a 2.70-fold higher adjusted odds of kidney recovery (95% CI, 1.69-4.31) compared to no glucarpidase receipt. Patients treated with glucarpidase also had faster time-to-kidney recovery (adjusted hazard ratio [aHR], 1.88, 95% CI, 1.18-3.33) and lower risks of grade ≥2 neutropenia (adjusted odds ratio [aOR], 0.50, 95% CI, 0.28-0.91) and grade ≥2 transaminitis (aOR, 0.50, 95% CI, 0.28-0.91) on day 7. There was no difference in time-to-death (aHR, 0.76; 95 CI, 0.49-1.18). These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI., (Copyright © 2025 American Society of Hematology.)
Published: 2025
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28. Predictive ability of the Cancer and Aging Research Group chemotherapy toxicity calculator in hematologic malignancy.

Author: Rosko AE, Huang Y, Wall SA, Mims A, Woyach J, Presley C, Williams NO, Stevens E, Han CJ, Von Ah D, Islam N, Krok-Schoen JL, Burd CE, and Naughton MJ
Subjects: Humans, Aged, Male, Female, Middle Aged, Aged, 80 and over, Pilot Projects, Prospective Studies, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Predictive Value of Tests, Physical Functional Performance, Hematologic Neoplasms drug therapy, Geriatric Assessment methods, Quality of Life
Abstract: Introduction: Chemotherapy toxicity tools are rarely studied in patients with hematologic malignancy (HM). The primary aim of this pilot study was to determine the predictive ability of the Cancer and Aging Research Group (CARG) chemo-toxicity calculator in estimating grade 3-5 toxicity in patients with HM., Materials and Methods: Patients 60 years and older with HM were prospectively evaluated using the CARG chemo-toxicity calculator. Discrimination and calibration were checked by applying the published model in our data. Additionally, a full geriatric assessment (GA), the Short Physical Performance Battery (SPPB), and health related quality of life (HRQoL) were captured longitudinally at the start of treatment and at end of study. Secondary aims explored the association of GA metrics with chemo-related toxicities and survival., Results: One hundred forty-five patients were approached, 118 patients consented, and 97 patients were evaluable. Most patients were newly diagnosed (n = 91). The median CARG score was 9 (range 4-18). The CARG score was not validated in our cohort of older patients with HM, with area under the receiver operation characteristic curve being 0.53 (95 % CI: 0.41-0.65). In multivariable analysis, after controlling for disease type, risk factors associated with grade 3-5 toxicity included living alone (hazard ratio [HR] 4.24, 95 %CI: 2.07-8.68, p < 0.001), increase in body mass index (HR 1.06, 95 %CI: 1.01-1.12, p = 0.03) and a higher social activities score (HR 1.27, 95 %CI: 1.06-1.51, p = 0.01). In multivariable analysis of overall survival, the only prognostic factor was an objective marker of physical function (SPPB score HR = 0.85, 95 %CI:0.78-0.93, p < 0.001)., Discussion: The CARG chemo-toxicity calculator was not predictive of grade 3-5 toxicity in patients with hematologic malignancy. The SPPB was associated with overall survival in multivariable analysis, suggesting future use as an objective biomarker in HM. We also report a comprehensive trajectory of function, QoL, psychosocial well-being, and cognition among older adults with HM. The predictive accuracy of the CARG chemo-toxicity calculator may be affected by the diverse range of HM treatment options that are not traditional chemotherapy., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Published: 2025
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29. Reassessing the association: Evaluation of a polyalanine deletion variant of RUNX2 in non-syndromic sagittal and metopic craniosynostosis.

Author: Walton IS, McCann E, Weber A, Morton JEV, Noons P, Wilson LC, Ching RC, Cilliers D, Johnson D, Phipps JM, Shears DJ, Thomas GPL, Wall SA, Twigg SRF, and Wilkie AOM
Subjects: Humans, Peptides genetics, Sequence Deletion, Gene Frequency genetics, Male, Core Binding Factor Alpha 1 Subunit genetics, Craniosynostoses genetics
Abstract: The RUNT-related transcription factor RUNX2 plays a critical role in osteoblast differentiation, and alterations to gene dosage cause distinct craniofacial anomalies. Uniquely amongst the RUNT-related family, vertebrate RUNX2 encodes a polyglutamine/polyalanine repeat (Gln 23 -Glu-Ala 17 in humans), with the length of the polyalanine component completely conserved in great apes. Surprisingly, a frequent 6-amino acid deletion polymorphism, p.(Ala84_Ala89)del, occurs in humans (termed 11A allele), and a previous association study (Cuellar et al. Bone 137:115395;2020) reported that the 11A variant was significantly more frequent in non-syndromic sagittal craniosynostosis (nsSag; allele frequency [AF] = 0.156; 95% confidence interval [CI] 0.126-0.189) compared to non-syndromic metopic craniosynostosis (nsMet; AF = 0.068; 95% CI 0.045-0.098). However, the gnomAD v.2.1.1 control population used by Cuellar et al. did not display Hardy-Weinberg equilibrium, hampering interpretation. To re-examine this association, we genotyped the RUNX2 11A polymorphism in 225 individuals with sporadic nsSag as parent-child trios and 164 singletons with sporadic nsMet, restricting our analysis to individuals of European ancestry. We compared observed allele frequencies to the non-transmitted alleles in the parent-child trios, and to the genome sequencing data from gnomAD v.4, which display Hardy-Weinberg equilibrium. Observed AFs (and 95% CI) were 0.076 (0.053-0.104) in nsSag and 0.082 (0.055-0.118) in nsMet, compared with 0.062 (0.042-0.089) in non-transmitted parental alleles and 0.065 (0.063-0.067) in gnomAD v.4.0.0 non-Finnish European control genomes. In summary, we observed a non-significant excess, compared to gnomAD data, of 11A alleles in both nsSag (relative risk 1.18, 95% CI 0.83-1.67) and nsMet (relative risk 1.29, 95% CI 0.87-1.92), but we did not replicate the much higher excess of RUNX2 11A alleles in nsSag previously reported (p = 0.0001)., (© 2024 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)
Published: 2024
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30. A European Multicenter Outcome Study of Perioperative Airway Management Policies following Midface Surgery in Syndromic Craniosynostosis.

Author: Cuperus IE, Mathijssen IMJ, van Veelen MC, Bouzariouh A, Stubelius I, Kölby L, Lundborg C, Das S, Johnson D, Wall SA, Larysz DF, Dowgierd K, Koszowska M, Schulz M, Gratopp A, Thomale UW, Zafra Vallejo V, Redondo Alamillos M, Ferreras Vega R, Apolito M, Vergnaud E, Paternoster G, and Khonsari RH
Subjects: Humans, Retrospective Studies, Male, Female, Child, Preschool, Europe, Child, Infant, Perioperative Care methods, Treatment Outcome, Craniofacial Dysostosis surgery, Osteotomy, Le Fort methods, Osteotomy, Le Fort adverse effects, Craniosynostoses surgery, Tracheostomy adverse effects, Tracheostomy methods, Acrocephalosyndactylia surgery, Facial Bones surgery, Airway Extubation adverse effects, Airway Management methods, Postoperative Complications etiology, Postoperative Complications prevention & control, Postoperative Complications epidemiology
Abstract: Background: Perioperative airway management following midface advancements in children with Apert and Crouzon-Pfeiffer syndromes can be challenging, and protocols often differ. This study examined airway management following midface advancements and postoperative respiratory complications., Methods: A multicenter, retrospective cohort study was performed to obtain information about the timing of extubation, perioperative airway management, and respiratory complications after monobloc or Le Fort III procedures., Results: A total of 275 patients (monobloc surgery, n = 129; Le Fort III surgery, n = 146) were included. Sixty-two patients received immediate extubation and 162 received delayed extubation; 42 had long-term tracheostomies, and 9 had perioperative short-term tracheostomies. In most centers, short-term tracheostomies were reserved for selected cases. Patients with delayed extubation remained intubated for 3 days (interquartile range, 2 to 5 days). The rate of no or only oxygen support after extubation was comparable between immediate and delayed extubation groups (58 of 62 patients [94%] and 137 of 162 patients [85%], respectively). However, the immediate extubation group developed fewer cases of postoperative pneumonia than did the delayed group (0 of 62 [0%] versus 24 of 161 [15%]; P = 0.001). Immediate extubation also appeared safe in moderate to severe obstructive sleep apnea, as 19 of 20 patients (95%) required either no or only oxygen support after extubation. The odds of developing intubation-related complications increased by 21% with every extra day of intubation., Conclusions: Immediate extubation following midface advancements was found to be a safe option, as it was not associated with respiratory insufficiency but did lead to fewer complications. Immediate extubation should be considered routine management in patients with no or mild obstructive sleep apnea, and should be the aim in moderate to severe obstructive sleep apnea cases after careful assessment., Clinical Question/level of Evidence: Therapeutic, III., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons.)
Published: 2024
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31. Myeloid neoplasm with histiocytosis and spleen tyrosine kinase fusion responds to fostamatinib.

Author: Risch Z, Kaffenberger BH, Chung CG, Samorodnitsky E, Hoskins EL, Dao T, Smith A, Wall SA, Brammer J, Reeser JW, Wing MR, Hopkins JF, Albacker LA, Abruzzo LV, Eisele CD, Freud AG, Roychowdhury S, and Walsh KE
Published: 2024
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32. Exploring the Perspectives of Unhoused Adults and Providers Across the HCV Care Continuum.

Author: Salem BE, Almeida H, Wall SA, Yadav K, Chang AH, Gelberg L, and Nyamathi A
Subjects: Humans, Female, Middle Aged, Male, Adult, Los Angeles, Aged, Community-Based Participatory Research, Qualitative Research, Focus Groups, Ill-Housed Persons psychology, Hepatitis C psychology, Hepatitis C therapy, Continuity of Patient Care
Abstract: Hepatitis C virus (HCV), the most common blood-borne infection, disproportionately affects people experiencing homelessness (PEH); however, HCV interventions tailored for PEH are scarce. This study utilized a community-based participatory approach to assess perceptions of HCV treatment experiences among HCV-positive PEH, and homeless service providers (HSP) to develop and tailor the "I am HCV Free" intervention which integrates primary, secondary, and tertiary care to attain and maintain HCV cure. Four focus groups were conducted with PEH ( N = 30, M age = 51.76, standard deviation 11.49, range 22-69) and HSPs ( n = 10) in Central City East (Skid Row) in Los Angeles, California. An iterative, thematic approach was used to ensure the trustworthiness of the data. Barriers and facilitators emerged from the data which have the potential to impact initiating HCV treatment and completion across the HCV care continuum. Understanding and addressing barriers and strengthening facilitators to HCV treatment will aid in HCV treatment completion and cure for PEH., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Published: 2024
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33. Regulatory elements in SEM1-DLX5-DLX6 (7q21.3) locus contribute to genetic control of coronal nonsyndromic craniosynostosis and bone density-related traits.

Author: Nicoletti P, Zafer S, Matok L, Irron I, Patrick M, Haklai R, Evangelista JE, Marino GB, Ma'ayan A, Sewda A, Holmes G, Britton SR, Lee WJ, Wu M, Ru Y, Arnaud E, Botto L, Brody LC, Byren JC, Caggana M, Carmichael SL, Cilliers D, Conway K, Crawford K, Cuellar A, Di Rocco F, Engel M, Fearon J, Feldkamp ML, Finnell R, Fisher S, Freudlsperger C, Garcia-Fructuoso G, Hagge R, Heuzé Y, Harshbarger RJ, Hobbs C, Howley M, Jenkins MM, Johnson D, Justice CM, Kane A, Kay D, Gosain AK, Langlois P, Legal-Mallet L, Lin AE, Mills JL, Morton JEV, Noons P, Olshan A, Persing J, Phipps JM, Redett R, Reefhuis J, Rizk E, Samson TD, Shaw GM, Sicko R, Smith N, Staffenberg D, Stoler J, Sweeney E, Taub PJ, Timberlake AT, Topczewska J, Wall SA, Wilson AF, Wilson LC, Boyadjiev SA, Wilkie AOM, Richtsmeier JT, Jabs EW, Romitti PA, Karasik D, Birnbaum RY, and Peter I
Abstract: Purpose: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown., Methods: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model., Results: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E-12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence., Conclusion: Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health., Competing Interests: Conflict of Interest The authors declare no competing interests in relation to the work described.
Published: 2024
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34. Haploidentical donor hematopoietic cell transplantation for myelodysplastic/myeloproliferative overlap neoplasms: results from a North American collaboration.

Author: Jain T, Tsai HL, Elmariah H, Vachhani P, Karantanos T, Wall SA, Gondek LP, Bashey A, Keyzner A, Tamari R, Grunwald MR, Abedin S, Nadiminti KV, Iqbal M, Gerds AT, Viswabandya A, McCurdy SR, Al Malki MM, Varadhan R, Ali H, Gupta V, Jones RJ, and Otoukesh S
Subjects: Humans, Middle Aged, Retrospective Studies, Splenomegaly, Cyclophosphamide, Unrelated Donors, Acute Disease, Recurrence, North America, Transplantation Conditioning methods, Hematopoietic Stem Cell Transplantation methods, Myelodysplastic-Myeloproliferative Diseases genetics, Myelodysplastic-Myeloproliferative Diseases therapy, Graft vs Host Disease, Neoplasms
Abstract: Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and post-transplantation cyclophosphamide (PTCy) in myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in seven of 120 (6%) patients. At 3 years, nonrelapse mortality (NRM) was 25% (95% confidence interval [CI]: 17-34), relapse 27% (95% CI: 18-36), grade 3-4 acute graftversus- host disease 12% (95% CI: 6-18), chronic graft-versus-host disease requiring systemic immunosuppression 14% (95% CI: 7-20), progression-free survival (PFS) 48% (95% CI: 39-59), and overall survival (OS) 56% (95% CI: 47-67). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, subdistribution hazard ratio [sdHR] =3.28; 95% CI: 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR=2.61; 95% CI: 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR=1.98, 95% CI: 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR=2.01; 95% CI: 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR=2.20; 95% CI: 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.
Published: 2023
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35. The Transplantation Ecosystem: A New Concept to Improve Access and Outcomes for Older Allogeneic Hematopoietic Cell Transplantation Patients.

Author: Wall SA, Olin R, Bhatt V, Chhabra S, Munshi P, Hacker E, Hashmi S, Hassel H, Howard D, Jayani R, Lin R, McCurdy S, Mishra A, Murthy H, Popat U, Wood W, Rosko AE, and Artz A
Subjects: Humans, Aged, Quality of Life, Ecosystem, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation, Hematologic Neoplasms therapy
Abstract: Allogeneic hematopoietic cell transplantation (HCT) is increasingly offered to older adults with hematologic malignancies, even though nonrelapse mortality remains a major concern in older patients owing to more comorbidities and greater frailty compared with their younger counterparts. The importance of patient fitness, a well-matched donor, and disease control to the success of allogeneic HCT have been well documented; however, these factors fail to account for the impact of the complex transplantation ecosystem (TE) that older adult HCT candidates must navigate. We propose a definition of the TE modeled after the social determinants of health. Furthermore, we outline a research agenda aimed at increasing understanding of the roles of individual social determinants of transplantation health in the larger ecosystem and how they may benefit or harm older adult HCT candidates. Herein we define the TE and its individual tenets, the social determinants of transplantation health. We review the available literature while incorporating the expertise of the membership of the American Society for Transplantation and Cellular Therapy (ASTCT) Special Interest Group for Aging. The membership of the ASTCT Special Interest Group for Aging identify knowledge gaps and strategies to address them for each of the described social determinants of transplantation health. The ecosystem is an essential but underappreciated pillar for transplant access and success. We put forth this novel research agenda seeking to gain a better understanding of the complexity of HCT in older adults and develop strategies to improve access to HCT, survival, and quality of life., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
Published: 2023
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36. Neoforehead Remodelling Techniques for Fronto-Orbital Advancement and Remodelling in the Oxford Craniofacial Unit: Lateral Remodelling and a Novel Central Self-Stabilizing S-Osteotomy Technique.

Author: Ching RC, Wall SA, and Johnson D
Subjects: Humans, Infant, Frontal Bone surgery, Retrospective Studies, Osteotomy methods, Forehead surgery, Orbit surgery, Plastic Surgery Procedures, Craniosynostoses surgery
Abstract: Fronto-orbital advancement and remodelling (FOAR) has undergone many modifications over the years, aimed at improving outcomes and reducing risks for patients. This work describes 2 techniques for remodelling the neoforehead used by the Oxford Craniofacial Unit since 1995: lateral remodelling and a central S-Osteotomy. Both methods adopt bone from the vertex as a neoforehead, but they differ in their techniques to adapt its shape to that of the newly remodelled orbital bandeau. The novel S-Osteotomy technique can be successfully applied to all FOAR procedures, irrespective of underlying synostosis and calvarial symmetry. It was originally developed for when 2 separate bony panels were required to create a neoforehead in asymmetrical cases, but was adopted for single panel neoforehead designs in metopic synostosis with the idea it may reduce temporal hollowing. An investigation of temporal hollowing in these patients who underwent either of the described methods was undertaken to assess this hypothesis with no statistically significant difference seen ( P =0.1111). Both techniques on average resulted in minimal hollowing that was not felt to require any revision, supporting the belief that temporal hollowing is a multifactorial issue. This work describes 2 successful methods of neoforehead remodelling and introduces the S-Osteotomy technique that can be applied in all FOAR procedures., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by Mutaz B. Habal, MD.)
Published: 2023
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37. Cognitive, Behavioural, Speech, Language and Developmental Outcomes Associated with Pathogenic Variants in the ERF Gene.

Author: Care H, Luscombe C, Wall SA, Dalton L, Johnson D, and Wilkie AOM
Subjects: Behavior, Child, Cognition, Humans, Language, Repressor Proteins genetics, Speech, Speech Disorders genetics, Communication Disorders, Craniosynostoses genetics
Abstract: Abstract: Pathogenic variants of the ERF gene were previously associated with craniosynostosis, craniofacial dysmorphism and Chiari malformation. This study investigates cognitive, behavioural, speech, language, and developmental outcomes in the first 5 children identified at the Oxford Craniofacial Unit as having ERF- related craniosynostosis, together with three of their carrier parents.There were no consistent findings related to overall intelligence. However, a pattern of cognitive difficulties is described, which includes poor attention, impulsivity and difficulties with functional fine motor skills, such as handwriting. A high frequency of speech, language and communication difficulties was evident, which was most often related to early language difficulties, speech sound difficulties, hyponasal resonance and concern regarding social communication skills and emotional immaturity.It was common for these children to have needed input from ear, nose and throat services. Problems with tonsils and/or adenoids and/ or fluctuating conductive hearing loss were found which may be contributors to early speech, language and communication difficulties.The authors make recommendations regarding the need for formal assessment of a range of developmental aspects upon diagnosis of a pathogenic variant in the ERF gene. The aim of this report is to give clinical guidance to anyone who may have care of patients with the ERF -related mutation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by Mutaz B. Habal, MD.)
Published: 2022
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38. Nurse-led intervention to decrease drug use among LTBI positive homeless adults.

Author: Nyamathi A, Morisky D, Wall SA, Yadav K, Shin S, Hall E, Chang AH, White K, Arce N, Parsa T, and Salem BE
Subjects: Adult, Humans, Nurse's Role, Pilot Projects, Ill-Housed Persons, Latent Tuberculosis epidemiology, Substance-Related Disorders prevention & control
Abstract: Background: People experiencing homelessness (PEH) are disproportionately diagnosed with active tuberculosis. While promoting latent tuberculosis infection (LTBI) treatment has been a call to action, PEH engaging in substance use often experience challenges in completing LTBI treatment., Methods: In this non-randomized single arm study, we tested an innovative, community-based, nurse-led community health worker (RN-CHW) model, on reducing drug use among 50 PEH, residing in homeless shelters or living on the streets in Los Angeles. Follow-up was at 3- and 6- months., Results: Findings revealed significant and ongoing decrease in any drug use (odds ratio [OR] = 0.30; 95% confidence interval [CI] = 0.14-0.68); p = .004), amphetamine use (OR = 0.14; 95% CI = 0.02-0.81; p = .029), cannabis use (OR = 0.26; 95% CI = 0.12-0.57; p = .001) and methamphetamine use (OR = 0.30; 95% CI = 0.10-0.90; p = .031) at 6-month follow-up., Conclusions: To our knowledge, this pilot study is the first to evaluate the impact a RN-CHW delivered intervention on reduction in drug use among PEH enrolled in a LTBI intervention. LTBI interventions may serve as an entryway into reduction in drug use among this underserved population., (© 2022 Wiley Periodicals LLC.)
Published: 2022
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39. Diagnostic utility of bronchoscopy in newly diagnosed acute leukemia patients.

Author: Koenig KL, Curley TP, Mani S, Keiter A, Zhao Q, Behbehani GK, Bhatnagar B, Blachly JS, Haque TZ, Larkin KTM, Long M, Mims AS, Vasu S, Wall SA, Byrd JC, Lustberg M, Walker AR, and Grieselhuber NR
Subjects: Female, Humans, Male, Middle Aged, Retrospective Studies, Bronchoscopy, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Lung Diseases diagnosis, Lung Diseases microbiology
Published: 2022
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40. Multidisciplinary Approach to Older Adults with Hematologic Malignancies-a Paradigm Shift.

Author: Wall SA, Stevens E, Vaughn J, Bumma N, Rosko AE, and Borate U
Subjects: Aged, Aging, Humans, Medical Oncology, Hematologic Neoplasms diagnosis, Hematologic Neoplasms epidemiology, Hematologic Neoplasms therapy, Neoplasms
Abstract: Hematologic malignancies are most likely to present in the seventh and eighth decades of life. Continued population growth will lead to increasing numbers of older adults with hematologic malignancies. Oncology care for older adults is complex and must account for the effect of aging on disease biology and treatment tolerance. Multidisciplinary oncology care has been utilized in solid tumor oncology for decades, initially driven by the need for multi-modality treatment. In this review, we make the case for multidisciplinary oncogeriatric care for older adults with hematologic malignancies in order to best navigate the intersection of aging and blood cancer., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Published: 2022
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41. Unexpected role of SIX1 variants in craniosynostosis: expanding the phenotype of SIX1 -related disorders.

Author: Calpena E, Wurmser M, McGowan SJ, Atique R, Bertola DR, Cunningham ML, Gustafson JA, Johnson D, Morton JEV, Passos-Bueno MR, Timberlake AT, Lifton RP, Wall SA, Twigg SRF, Maire P, and Wilkie AOM
Subjects: Animals, Child, Preschool, Cohort Studies, Cranial Sutures embryology, Cranial Sutures pathology, Craniosynostoses complications, Craniosynostoses embryology, DNA Mutational Analysis, Genetic Association Studies, Homeodomain Proteins physiology, Humans, Infant, Mice, Pedigree, Phenotype, RNA-Seq, Whole Genome Sequencing, Craniosynostoses genetics, Homeodomain Proteins genetics
Abstract: Background: Pathogenic heterozygous SIX1 variants (predominantly missense) occur in branchio-otic syndrome (BOS), but an association with craniosynostosis has not been reported., Methods: We investigated probands with craniosynostosis of unknown cause using whole exome/genome (n=628) or RNA (n=386) sequencing, and performed targeted resequencing of SIX1 in 615 additional patients. Expression of SIX1 protein in embryonic cranial sutures was examined in the Six1 nLacZ/+ reporter mouse., Results: From 1629 unrelated cases with craniosynostosis we identified seven different SIX1 variants (three missense, including two de novo mutations, and four nonsense, one of which was also present in an affected twin). Compared with population data, enrichment of SIX1 loss-of-function variants was highly significant (p=0.00003). All individuals with craniosynostosis had sagittal suture fusion; additionally four had bilambdoid synostosis. Associated BOS features were often attenuated; some carrier relatives appeared non-penetrant. SIX1 is expressed in a layer basal to the calvaria, likely corresponding to the dura mater, and in the mid-sagittal mesenchyme., Conclusion: Craniosynostosis is associated with heterozygous SIX1 variants, with possible enrichment of loss-of-function variants compared with classical BOS. We recommend screening of SIX1 in craniosynostosis, particularly when sagittal±lambdoid synostosis and/or any BOS phenotypes are present. These findings highlight the role of SIX1 in cranial suture homeostasis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
Published: 2022
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42. Integration of a Geriatric Assessment With Intervention in the Care of Older Adults With Hematologic Malignancies.

Author: Wall SA, Huang Y, Keiter A, Funderburg A, Kloock C, Yuhasz N, Gure TR, Folefac E, Stevens E, Presley CJ, Williams NO, Krok-Schoen JL, Naughton MJ, and Rosko AE
Abstract: The incidence of hematologic malignancies (HMs) is highest in the seventh decade of life and coincides with increasing occult, age-related vulnerabilities. Identification of frailty is useful in prognostication and treatment decision-making for older adults with HMs. This real-world analysis describes 311 older adults with HMs evaluated in a multidisciplinary oncogeriatric clinic. The accumulation of geriatric conditions [1-unit increase, hazards ratio (HR) = 1.13, 95% CI 1.00-1.27, p = 0.04] and frailty assessed by the Rockwood Clinical Frailty Scale (CFS, mild/moderate/severe frailty vs. very fit/well, HR = 2.59, 95% CI 1.41-4.78, p = 0.002) were predictive of worse overall survival. In multivariate analysis, HM type [acute leukemia, HR = 3.84, 95% CI 1.60-9.22, p = 0.003; myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN)/bone marrow failure, HR = 2.65, 95% CI 1.10-6.35, p = 0.03], age (per 5-year increase, HR = 1.46, 95% CI 1.21-1.76, p < 0.001), hemoglobin (per 1 g/dl decrease, HR = 1.21, 95% CI 1.05-1.40, p = 0.009), deficit in activities of daily living (HR = 2.20, 95% CI 1.11-4.34, p = 0.02), and Mini Nutrition Assessment score (at-risk of malnutrition vs. normal, HR = 2.00, 95% CI 1.07-3.73, p = 0.03) were independently associated with risk of death. The most commonly prescribed geriatric interventions were in the domains of audiology (56%) and pharmacy (54%). The Rockwood CFS correlated with prescribed interventions in nutrition (p = 0.01) and physical function (p < 0.001) domains. Geriatric assessment with geriatric intervention can be practically integrated into the routine care of older adults with HMs., Competing Interests: MN receives funding from the Merck Foundation. TG has received funding from the National Institute on Aging, and National Institute of Heart, Lung, & Blood. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wall, Huang, Keiter, Funderburg, Kloock, Yuhasz, Gure, Folefac, Stevens, Presley, Williams, Krok-Schoen, Naughton and Rosko.)
Published: 2021
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43. Rapid test to assess the escape of SARS-CoV-2 variants of concern.

Author: Heggestad JT, Britton RJ, Kinnamon DS, Wall SA, Joh DY, Hucknall AM, Olson LB, Anderson JG, Mazur A, Wolfe CR, Oguin TH 3rd, Sullenger BA, Burke TW, Kraft BD, Sempowski GD, Woods CW, and Chilkoti A
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are concerning in the ongoing coronavirus disease 2019 (COVID-19) pandemic. Here, we developed a rapid test, termed CoVariant-SCAN, that detects neutralizing antibodies (nAbs) capable of blocking interactions between the angiotensin-converting enzyme 2 receptor and the spike protein of wild-type (WT) SARS-CoV-2 and three other variants: B.1.1.7, B.1.351, and P.1. Using CoVariant-SCAN, we assessed neutralization/blocking of monoclonal antibodies and plasma from COVID-19–positive and vaccinated individuals. For several monoclonal antibodies and most plasma samples, neutralization against B.1.351 and P.1 variants is diminished relative to WT, while B.1.1.7 is largely cross-neutralized. We also showed that we can rapidly adapt the platform to detect nAbs against an additional variant—B.1.617.2 (Delta)—without reengineering or reoptimizing the assay. Results using CoVariant-SCAN are consistent with live virus neutralization assays and demonstrate that this easy-to-deploy test could be used to rapidly assess nAb response against multiple SARS-CoV-2 variants.
Published: 2021
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44. Author Correction: Cellphone enabled point-of-care assessment of breast tumor cytology and molecular HER2 expression from fine-needle aspirates.

Author: Joh DY, Heggestad JT, Zhang S, Anderson GR, Bhattacharyya J, Wardell SE, Wall SA, Cheng AB, Albarghouthi F, Liu J, Oshima S, Hucknall AM, Hyslop T, Hall AHS, Wood KC, Shelley Hwang E, Strickland KC, Wei Q, and Chilkoti A
Published: 2021
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45. Engaging the Community in Designing a Hepatitis C Virus Treatment Program for Adults Experiencing Homelessness.

Author: Nyamathi AM, Wall SA, Yadav K, Shin SS, Chang A, Arce N, Cuellar H, Fernando S, White K, Gelberg L, and Salem BE
Subjects: Adult, Community Health Workers, Hepacivirus, Humans, Motivation, Hepatitis C therapy, Ill-Housed Persons
Abstract: Despite the availability of cure for hepatitis C virus (HCV), people experiencing homelessness (PEH) are challenged with initiating and completing HCV treatment. The design of culturally sensitive HCV treatment programs is lacking. The objective was to employ community-based participatory research methods to understand perceptions of HCV-positive PEH, and providers, on the design and delivery of a culturally sensitive, nurse-led community health worker (RN/CHW) HCV initiation and completion program. Four focus group sessions were conducted with HCV-positive PEH ( n = 30) as well as homeless service providers (HSP; n = 7) in Skid Row, Los Angeles. An iterative, thematic approach provided the themes of essentials of successful participant engagement and retention: Role of nurse-Led CHW in promotin g: (a) tangible and emotional support; (b) cognitive and behavioral support; and (c) financial and structural resources. The goal of this study is to provide the groundwork for future research of HCV program design to support HCV cure among homeless populations.
Published: 2021
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46. Clinical signs, interventions, and treatment course of three different treatment protocols in patients with Crouzon syndrome with acanthosis nigricans.

Author: de Planque CA, Wall SA, Dalton L, Paternoster G, Arnaud É, van Veelen MC, Versnel SL, Johnson D, Jayamohan J, and Mathijssen IMJ
Subjects: Acanthosis Nigricans complications, Acanthosis Nigricans genetics, Brain diagnostic imaging, Child, Child, Preschool, Clinical Protocols, Cohort Studies, Craniofacial Abnormalities surgery, Craniofacial Dysostosis complications, Craniofacial Dysostosis genetics, Decompression, Surgical, Female, Foramen Magnum surgery, France, Humans, Infant, Magnetic Resonance Imaging, Male, Mutation genetics, Netherlands, Receptor, Fibroblast Growth Factor, Type 3 genetics, Tomography, X-Ray Computed, Treatment Outcome, United Kingdom, Ventriculostomy, Acanthosis Nigricans surgery, Craniofacial Dysostosis surgery
Abstract: Objective: Crouzon syndrome with acanthosis nigricans (CAN) is a rare and clinically complex subtype of Crouzon syndrome. At three craniofacial centers, this multicenter study was undertaken to assess clinical signs in relation to the required interventions and treatment course in patients with CAN., Methods: A retrospective cohort study of CAN was performed to obtain information about the clinical treatment course of these patients. Three centers participated: Erasmus Medical Centre, Rotterdam, the Netherlands; John Radcliffe Hospital, Oxford, United Kingdom; and Hôpital Necker-Enfants Malades, Paris, France., Results: Nineteen patients (5 males, 14 females) were included in the study. All children were operated on, with a mean of 2.2 surgeries per patient (range 1-6). Overall, the following procedures were performed: 23 vault expansions, 10 monobloc corrections, 6 midface surgeries, 11 foramen magnum decompressions, 29 CSF-diverting surgeries, 23 shunt-related interventions, and 6 endoscopic third ventriculostomies, 3 of which subsequently required a shunt., Conclusions: This study demonstrates that patients with the mutation c.1172C>A (p.Ala391Glu) in the FGFR3 gene have a severe disease trajectory, requiring multiple surgical procedures. The timing and order of interventions have changed among patients and centers. It was not possible to differentiate the effect of a more severe clinical presentation from the effect of treatment order on outcome.
Published: 2021
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47. Cellphone enabled point-of-care assessment of breast tumor cytology and molecular HER2 expression from fine-needle aspirates.

Author: Joh DY, Heggestad JT, Zhang S, Anderson GR, Bhattacharyya J, Wardell SE, Wall SA, Cheng AB, Albarghouthi F, Liu J, Oshima S, Hucknall AM, Hyslop T, Hall AHS, Wood KC, Shelley Hwang E, Strickland KC, Wei Q, and Chilkoti A
Abstract: Management of breast cancer in limited-resource settings is hindered by a lack of low-cost, logistically sustainable approaches toward molecular and cellular diagnostic pathology services that are needed to guide therapy. To address these limitations, we have developed a multimodal cellphone-based platform-the EpiView-D4-that can evaluate both cellular morphology and molecular expression of clinically relevant biomarkers directly from fine-needle aspiration (FNA) of breast tissue specimens within 1 h. The EpiView-D4 is comprised of two components: (1) an immunodiagnostic chip built upon a "non-fouling" polymer brush-coating (the "D4") which quantifies expression of protein biomarkers directly from crude cell lysates, and (2) a custom cellphone-based optical microscope ("EpiView") designed for imaging cytology preparations and D4 assay readout. As a proof-of-concept, we used the EpiView-D4 for assessment of human epidermal growth factor receptor-2 (HER2) expression and validated the performance using cancer cell lines, animal models, and human tissue specimens. We found that FNA cytology specimens (prepared in less than 5 min with rapid staining kits) imaged by the EpiView-D4 were adequate for assessment of lesional cellularity and tumor content. We also found our device could reliably distinguish between HER2 expression levels across multiple different cell lines and animal xenografts. In a pilot study with human tissue (n = 19), we were able to accurately categorize HER2-negative and HER2-positve tumors from FNA specimens. Taken together, the EpiView-D4 offers a promising alternative to invasive-and often unavailable-pathology services and may enable the democratization of effective breast cancer management in limited-resource settings.
Published: 2021
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48. Multiplexed, quantitative serological profiling of COVID-19 from blood by a point-of-care test.

Author: Heggestad JT, Kinnamon DS, Olson LB, Liu J, Kelly G, Wall SA, Oshabaheebwa S, Quinn Z, Fontes CM, Joh DY, Hucknall AM, Pieper C, Anderson JG, Naqvi IA, Chen L, Que LG, Oguin T 3rd, Nair SK, Sullenger BA, Woods CW, Burke TW, Sempowski GD, Kraft BD, and Chilkoti A
Subjects: Antibodies, Viral blood, Antibodies, Viral immunology, COVID-19 blood, COVID-19 virology, COVID-19 Serological Testing instrumentation, Humans, Reproducibility of Results, SARS-CoV-2 metabolism, SARS-CoV-2 physiology, Sensitivity and Specificity, Spike Glycoprotein, Coronavirus immunology, Spike Glycoprotein, Coronavirus metabolism, COVID-19 diagnosis, COVID-19 Serological Testing methods, Point-of-Care Testing, SARS-CoV-2 immunology
Abstract: Highly sensitive, specific, and point-of-care (POC) serological assays are an essential tool to manage coronavirus disease 2019 (COVID-19). Here, we report on a microfluidic POC test that can profile the antibody response against multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens-spike S1 (S1), nucleocapsid (N), and the receptor binding domain (RBD)-simultaneously from 60 μl of blood, plasma, or serum. We assessed the levels of antibodies in plasma samples from 31 individuals (with longitudinal sampling) with severe COVID-19, 41 healthy individuals, and 18 individuals with seasonal coronavirus infections. This POC assay achieved high sensitivity and specificity, tracked seroconversion, and showed good concordance with a live virus microneutralization assay. We can also detect a prognostic biomarker of severity, IP-10 (interferon-γ-induced protein 10), on the same chip. Because our test requires minimal user intervention and is read by a handheld detector, it can be globally deployed to combat COVID-19., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
Published: 2021
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49. Discharge Disposition Following Hematopoietic Cell Transplantation: Predicting the Need for Rehabilitation and Association with Survival.

Author: Wall SA, Zhao Q, Vasu S, and Rosko A
Subjects: Case-Control Studies, Female, Humans, Retrospective Studies, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation, Patient Discharge
Abstract: Many hematopoietic cell transplantation (HCT) recipients require rehabilitation due to deconditioning following intensive conditioning regimens and immune reconstitution. HCT recipients are preferentially discharged to home to avoid the risk of exposure to healthcare-associated infection in a rehabilitation facility (RF), with a caregiver who has been provided specific education about the complexity of post-HCT care. This study was conducted to determine the incidence of discharge to an RF following HCT, identify pre-HCT and peri-HCT risk factors for discharge to an RF, and estimate the effect of discharge disposition on overall survival (OS). This retrospective, matched 1:4 case-control study included 56 cases over a 10-year period from a single institution. Controls were matched by transplantation type (autologous versus allogeneic) and date of transplantation. The incidence of discharge to an RF was 2.2%. Controlling for disease, increasing age (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.04 to 1.15; P < .001), female sex (OR, 3.11; 95% CI, 1.32 to 7.32; P = .01), high-risk HCT Comorbidity Index (HCT-CI) score (≥3) (OR, 3.44; 95% CI, 1.39 to 8.52; P = .008), decreasing pre-HCT serum albumin (OR, 2.60; 95% CI, 1.07 to 6.38; P = .037), and development of acute kidney injury during HCT (OR, 4.10; 95% CI, 1.36 to 12.40; P = .012) were associated with discharge to an RF. Discharge to an RF was associated with worse OS and higher nonrelapse mortality (NRM) compared with discharge to home (1-year OS, 70.5% [95% CI, 55.8% to 81.1%] versus 88.8% [95% CI, 83.6% to 92.4%], P < .001; 100-day NRM: 9.5% [95% CI, 3.5% to 19.2%] versus 1.8% [95% CI, 0.6% to 4.3%]; P = .03). Discharge to an RF following HCT is a rare event but associated with poor OS. Modifiable risk factors for discharge to an RF, including serum albumin as a measure of nutrition and reversible HCT-CI components, should be prospectively studied to determine the effect of mitigation on discharge disposition and survival., (Copyright © 2020 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
Published: 2021
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50. Comparison of fixed dose reduced-intensity conditioning with fludarabine and busulfan to PK-guided busulfan AUC (FluBu4K) in hematopoietic stem cell transplant for AML/MDS.

Author: Rasor B, Dickerson T, Zhao Q, Elder P, Brammer JE, Larkin K, Jaglowski S, Mims A, Penza S, Vasu S, Wall SA, William B, Saad A, Roddy JVF, Choe H, and Puto M
Subjects: Adult, Area Under Curve, Busulfan, Humans, Neoplasm Recurrence, Local, Retrospective Studies, Transplantation Conditioning, Transplantation, Homologous, Vidarabine analogs & derivatives, Graft vs Host Disease epidemiology, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute therapy
Abstract: A retrospective cohort study was conducted to assess differences in efficacy and tolerability between a busulfan AUC target of 16.4 mg × Hr/L per day (FluBu4K) and a conventional RIC regimen (FluBu2). Adult patients with a diagnosis of AML or MDS who received fludarabine + busulfan conditioning with or without antithymocyte globulin between 2015 and 2018 were included. The primary outcome was relapse free survival. Overall, 74 patients received conditioning with either FluBu4K or FluBu2. At 18 months, relapse-free survival was not significantly different, at 63.9% with FluBu4k compared to 57.5% with FluBu2 ( p = 0.49). There was a statistically significant difference in the cumulative incidence of relapse at 18 months in favor of the FluBu4K regimen, at 12.0% vs 32.5% ( p = 0.047). The results of this study indicate that for select patients, there may be benefit in choosing targeted FluBu4K over FluBu2. Adverse effects other than mucositis were not significantly different.
Published: 2021
Full Text: View/download PDF

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