2020 Jan 17[Online ahead of print]

Defining the Clinical Phenotype of Saul-Wilson Syndrome

Carlos R Ferreira¹, Wadih M Zein², Laryssa A Huryn², Andrea Merker³, Seth I Berger⁴, William G Wilson⁵, George E Tiller⁶, Lynne A Wolfe⁷, Melissa Merideth⁷, Daniel R Carvalho⁸, Angela L Duker⁹, Heiko Bratke¹⁰, Marte Gjøl Haug¹¹, Luis Rohena^{12

13}, Hanne B Hove¹⁴, Zhi-Jie Xia¹⁵, Bobby G Ng¹⁵, Hudson H Freeze¹⁵, Melissa Gabriel¹⁶, Alvaro H Serrano Russi¹⁶, Lauren Brick¹⁷, Mariya Kozenko¹⁷, Dawn L Earl¹⁸, Emma Tham^{19

20}, Gen Nishimura²¹, John A Phillips 3rd²², William A Gahl⁷, Rizwan Hamid²², Andrew P Jackson²³, Giedre Grigelioniene^{19

20}, Michael B Bober⁹

Affiliations

¹ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. carlos.ferreira@nih.gov.
² Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
³ Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
⁴ Center for Genetic Medicine and Research, Children's National Hospital, Washington, DC, USA.
⁵ Department of Pediatrics, University of Virginia Health System, Charlottesville, VA, USA.
⁶ Department of Genetics, Kaiser Permanente, Los Angeles, CA, USA.
⁷ Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Genetic Unit, SARAH Network of Rehabilitation Hospitals, Brasília-DF, Brazil.
⁹ Division of Orthogenetics, Nemours/A.I. duPont Hospital for Children, Wilmington, DE, USA.
¹⁰ Department of Internal Medicine, Section of Paediatrics, Haugesund District Hospital, Fonna Health Trust, Haugesund, Norway.
¹¹ Department of Medical Genetics, St. Olav's Hospital, Trondheim, Norway.
¹² Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, TX, USA.
¹³ Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX, USA.
¹⁴ Section of Rare Disorders, Department of Pediatrics, Rigshospitalet, Copenhagen, Denmark.
¹⁵ Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
¹⁶ Division of Medical Genetics, Children's Hospital of Los Angeles, University of Southern California, Los Angeles, CA, USA.
¹⁷ Division of Genetics, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, ON, Canada.
¹⁸ Division of Genetic Medicine, Seattle Children's, Seattle, WA, USA.
¹⁹ Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
²⁰ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
²¹ Center for Intractable Diseases, Saitama Medical University Hospital, Saitama, Japan.
²² Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
²³ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

PMID: 31949312
DOI: 10.1038/s41436-019-0737-1

Defining the Clinical Phenotype of Saul-Wilson Syndrome

Carlos R Ferreira et al. Genet Med. 2020

Authors

Affiliations

¹ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. carlos.ferreira@nih.gov.
² Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
³ Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
⁴ Center for Genetic Medicine and Research, Children's National Hospital, Washington, DC, USA.
⁵ Department of Pediatrics, University of Virginia Health System, Charlottesville, VA, USA.
⁶ Department of Genetics, Kaiser Permanente, Los Angeles, CA, USA.
⁷ Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Genetic Unit, SARAH Network of Rehabilitation Hospitals, Brasília-DF, Brazil.
⁹ Division of Orthogenetics, Nemours/A.I. duPont Hospital for Children, Wilmington, DE, USA.
¹⁰ Department of Internal Medicine, Section of Paediatrics, Haugesund District Hospital, Fonna Health Trust, Haugesund, Norway.
¹¹ Department of Medical Genetics, St. Olav's Hospital, Trondheim, Norway.
¹² Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, TX, USA.
¹³ Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX, USA.
¹⁴ Section of Rare Disorders, Department of Pediatrics, Rigshospitalet, Copenhagen, Denmark.
¹⁵ Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
¹⁶ Division of Medical Genetics, Children's Hospital of Los Angeles, University of Southern California, Los Angeles, CA, USA.
¹⁷ Division of Genetics, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, ON, Canada.
¹⁸ Division of Genetic Medicine, Seattle Children's, Seattle, WA, USA.
¹⁹ Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
²⁰ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
²¹ Center for Intractable Diseases, Saitama Medical University Hospital, Saitama, Japan.
²² Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
²³ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

PMID: 31949312
DOI: 10.1038/s41436-019-0737-1

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Abstract

Purpose: Four patients with Saul-Wilson syndrome were reported between 1982 and 1994, but no additional individuals were described until 2018, when the molecular etiology of the disease was elucidated. Hence, the clinical phenotype of the disease remains poorly defined. We address this shortcoming by providing a detailed characterization of its phenotype.

Methods: Retrospective chart reviews were performed and primary radiographs assessed for all 14 individuals. Four individuals underwent detailed ophthalmologic examination by the same physician. Two individuals underwent gynecologic evaluation. Z-scores for height, weight, head circumference and body mass index were calculated at different ages.

Results: All patients exhibited short stature, with sharp decline from the mean within the first months of life, and a final height Z-score between -4 and -8.5 standard deviations. The facial and radiographic features evolved over time. Intermittent neutropenia was frequently observed. Novel findings included elevation of liver transaminases, skeletal fragility, rod-cone dystrophy, and cystic macular changes.

Conclusions: Saul-Wilson syndrome presents a remarkably uniform phenotype, and the comprehensive description of our cohort allows for improved understanding of the long-term morbidity of the condition, establishment of follow-up recommendations for affected individuals, and documentation of the natural history into adulthood for comparison with treated patients, when therapeutics become available.

Keywords: COG4; G516R; Saul–Wilson syndrome; phenotype.

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Defining the Clinical Phenotype of Saul-Wilson Syndrome

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Defining the Clinical Phenotype of Saul-Wilson Syndrome

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