Defining the clinical phenotype of Saul-Wilson syndrome

doi:10.1038/s41436-019-0737-1

. 2020 May;22(5):857-866.

doi: 10.1038/s41436-019-0737-1. Epub 2020 Jan 17.

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
PMCID: PMC7205587
DOI: 10.1038/s41436-019-0737-1

Defining the clinical phenotype of Saul-Wilson syndrome

Carlos R Ferreira et al. Genet Med. 2020 May.

. 2020 May;22(5):857-866.

doi: 10.1038/s41436-019-0737-1. Epub 2020 Jan 17.

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
PMCID: PMC7205587
DOI: 10.1038/s41436-019-0737-1

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest:

The authors declare no conflict of interest.

Figures

**Figure 1.. Phenotypic traits of patients with Saul-Wilson syndrome.**
(A-D) Progeroid features seen in the first few months of life (A, P2.1; B, P5.1; C, P6.1; D, P7.1). In addition, wrist contractures can be seen in (A), blue sclerae in (A) and (D), and boots and bar treatment for clubfoot in (C). (E-H) Facial features seen during early childhood (E, P1.1; F, P5.1; G, P6.1; H, P10.1). Note prominent, round forehead with prominent scalp veins in all. (I-L) Facial features seen in late childhood (I, P7.1; J, P5.1; K, P6.1; L, P10.1). The forehead is still prominent, but mainly tall rather than round. (M-N) Facial features in adolescence (M, P2.1; N, P7.1). (O-P) Facial features in adulthood (O, P2.1; P, P7.1). (Q-T) Feet in P1.1 at 4 years old (Q), P9.1 at 9 years old (R), P7.1 at 27 years old (S), and P2.1 at 29 years old (T). Note short distal phalanges in all, and metatarsus varus in (Q). (U-X) Hands in P1.1 at 4 years old (U), P4.1 at 5 years old (V), P9.1 at 9 years old (W), and P7.1 at 27 years old (X). Note short distal phalanges of variable degree in all.

**Figure 2.. Ophthalmologic findings.**
Clinical imaging of the ocular fundus, psychophysical testing, and electroretinography in individuals with Saul-Wilson Syndrome. (A) Color fundus photography (CFP) of left eye of P1.1 obtained under anesthesia using a portable device (RetCam3) and showing mottling of the retinal pigment epithelium (yellow arrows) and an elevated lesion inferior to the optic nerve head (white arrow). Image clarity is reduced by the presence of lamellar cataract. (B) Bioptigen optical coherence tomography indicates preserved central retina including absence of macular cystic changes and normal ellipsoid zone (EZ) layer in P1.1. (C, F) CFP of the right and (I) left eye of affected individuals showing characteristic features of rod-cone dystrophies including attenuated retinal vessels, waxy pallor of optic nerve head, and midperipheral bony spicules (yellow arrowheads) (C, P2.1; F: P7.1; I: P10.1). (D, G) Fundus autofluorescence (FAF) images of the right eye and (J) left eye of affected individuals showing pigment deposition as hypoautofluorescence (yellow arrowheads) and a characteristic hyperautofluorescence ring (white arrowheads) typically seen in rod-cone dystrophies (D: P2.1; G: P:7.1; J: P10.1). (E, H) Cirrus optical coherence tomography scans of the right eye and (K) left eye of affected individuals ranging from an almost normal scan in (E) to loss of ellipsoid zone EZ-band (yellow arrowheads) in (H) as well as presence of macular cystic changes in (H, K) (white arrowheads) (E: P2.1; H: P7.1; K: P10.1). (L, M) Kinetic perimetry of P2.1 and P7.1, respectively, showing different degrees of constriction and midperipheral scotomata. (N) Representative electroretinography (ERG) from P2.1 showing a reduction and delay of the scotopic responses to a greater degree than the photopic ones, confirming the presence of a rod-cone dystrophy.

**Figure 3.. Length/height expressed as standard deviation scores.**
Note a sharp decline in SD scores during the first few months of life, with an eventual plateau around −4 to −8.5 SD scores. Growth is near or below the mean stature for achondroplasia (dashed line).

**Figure 4.. Radiographs depicting skeletal features of individuals with Saul-Wilson syndrome.**
(A-E) Radiographs of lateral cervical spine in P4.1 at 8 months (A), P5.2 at 1 year 11 months (B), P3.1 at 2 years 6 months (C), P5.1 at 6 years 1 month (D), and P7.1 at 11 years 6 months (E). Note hypoplasia of the odontoid process in all (arrows). (F-J) Radiographs of lateral lumbar spine in P4.1 at 3 months old (F), P6.1 at 5 years 10 months (G), P5.1 at 6 years 7 months (H), P10.1 at 9 years 3 months (I), and P9.1 at 12 years 5 months (J). The vertebral bodies become taller and more irregular with age. Note hypoplasia of L1 in (G, H, I). (K-O) Radiographs of lower extremities in P7.1 at 23 days (K), P10.1 at 9 weeks (L), P8.1 at 6 months (M), P5.2 at 3 years 10 months (N), and P9.1 at 12 years 5 months (O). Note proximal femoral lucencies in the first few months of life (arrows), as well as overtubulation of the long bones with slender diaphyses and metaphyseal flaring in all. (P-T) Radiographs of hands in P4.1 at 3 months (P), P13.1 at 13 months (Q), P6.1 at 6 years 9 months (R), P9.1 at 9 years 8 months (S), and P6.1 at 10 years (T). Note shortening of metacarpals and phalanges and cone-shaped epiphyses of the phalanges in all, accessory ossification centers of the proximal metacarpals (Q, R, T), and the development of squared-off ivory epiphyses (arrows) in late childhood (S, T).

**Figure 5.. Relative frequency of clinical and radiographic findings in Saul-Wilson syndrome.**
AF, anterior fontanelle; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

See this image and copyright information in PMC

Cited by

COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay.
Marom R, Burrage LC, Venditti R, Clément A, Blanco-Sánchez B, Jain M, Scott DA, Rosenfeld JA, Sutton VR, Shinawi M, Mirzaa G, DeVile C, Roberts R, Calder AD, Allgrove J, Grafe I, Lanza DG, Li X, Joeng KS, Lee YC, Song IW, Sliepka JM, Batkovskyte D, Washington M, Dawson BC, Jin Z, Jiang MM, Chen S, Chen Y, Tran AA, Emrick LT, Murdock DR, Hanchard NA, Zapata GE, Mehta NR, Weis MA, Scott AA, Tremp BA, Phillips JB, Wegner J, Taylor-Miller T, Gibbs RA, Muzny DM, Jhangiani SN, Hicks J, Stottmann RW, Dickinson ME, Seavitt JR, Heaney JD, Eyre DR; Undiagnosed Diseases Network; Westerfield M, De Matteis MA, Lee B. Marom R, et al. Am J Hum Genet. 2021 Sep 2;108(9):1710-1724. doi: 10.1016/j.ajhg.2021.08.002. Epub 2021 Aug 26. Am J Hum Genet. 2021. PMID: 34450031 Free PMC article.
Sequenced-based GWAS for linear classification traits in Belgian Blue beef cattle reveals new coding variants in genes regulating body size in mammals.
Gualdrón Duarte JL, Yuan C, Gori AS, Moreira GCM, Takeda H, Coppieters W, Charlier C, Georges M, Druet T. Gualdrón Duarte JL, et al. Genet Sel Evol. 2023 Nov 28;55(1):83. doi: 10.1186/s12711-023-00857-4. Genet Sel Evol. 2023. PMID: 38017417 Free PMC article.
COG4 mutation in Saul-Wilson syndrome selectively affects secretion of proteins involved in chondrogenesis in chondrocyte-like cells.
Xia ZJ, Mahajan S, Paul Daniel EJ, Ng BG, Saraswat M, Campos AR, Murad R, He M, Freeze HH. Xia ZJ, et al. Front Cell Dev Biol. 2022 Oct 28;10:979096. doi: 10.3389/fcell.2022.979096. eCollection 2022. Front Cell Dev Biol. 2022. PMID: 36393834 Free PMC article.
Clinical and biochemical footprints of congenital disorders of glycosylation: Proposed nosology.
Ng BG, Freeze HH, Himmelreich N, Blau N, Ferreira CR. Ng BG, et al. Mol Genet Metab. 2024 May;142(1):108476. doi: 10.1016/j.ymgme.2024.108476. Epub 2024 Apr 10. Mol Genet Metab. 2024. PMID: 38653092 Free PMC article. Review.
Craniofacial disorders and dysplasias: Molecular, clinical, and management perspectives.
Akintoye SO, Adisa AO, Okwuosa CU, Mupparapu M. Akintoye SO, et al. Bone Rep. 2024 Mar 1;20:101747. doi: 10.1016/j.bonr.2024.101747. eCollection 2024 Mar. Bone Rep. 2024. PMID: 38566929 Free PMC article. Review.

See all "Cited by" articles

References

1. Saul RA. Unknown cases. Proceedings of the Greenwood Genetic Center. 1982;1(1):102–105.
1. Saul RA, Wilson WG. A “new” skeletal dysplasia in two unrelated boys. Am J Med Genet. 1990;35(3):388–393. - PubMed
1. Saul RA, Wilson WG. COMMENTARY-The Saul-Wilson syndrome from its early days until now. Am J Med Genet A. December 2018. doi:10.1002/ajmg.a.8 - DOI - PubMed
1. Hersh JH, Joyce MR, Spranger J, et al. Microcephalic osteodysplastic dysplasia. Am J Med Genet. 1994;51(3):194–199. - PubMed
1. Ferreira CR, Xia Z-J, Clément A, et al. A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation. Am J Hum Genet. 2018;103(4):553–567. doi:10.1016/j.ajhg.2018.09.003 - DOI - PMC - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information

[1] Saul RA. Unknown cases. Proceedings of the Greenwood Genetic Center. 1982;1(1):102–105.

[2] Saul RA. Unknown cases. Proceedings of the Greenwood Genetic Center. 1982;1(1):102–105.

[3] Saul RA, Wilson WG. A “new” skeletal dysplasia in two unrelated boys. Am J Med Genet. 1990;35(3):388–393. - PubMed

[4] Saul RA, Wilson WG. A “new” skeletal dysplasia in two unrelated boys. Am J Med Genet. 1990;35(3):388–393. - PubMed

[5] Saul RA, Wilson WG. COMMENTARY-The Saul-Wilson syndrome from its early days until now. Am J Med Genet A. December 2018. doi:10.1002/ajmg.a.8 - DOI - PubMed

[6] Saul RA, Wilson WG. COMMENTARY-The Saul-Wilson syndrome from its early days until now. Am J Med Genet A. December 2018. doi:10.1002/ajmg.a.8 - DOI - PubMed

[7] Hersh JH, Joyce MR, Spranger J, et al. Microcephalic osteodysplastic dysplasia. Am J Med Genet. 1994;51(3):194–199. - PubMed

[8] Hersh JH, Joyce MR, Spranger J, et al. Microcephalic osteodysplastic dysplasia. Am J Med Genet. 1994;51(3):194–199. - PubMed

[9] Ferreira CR, Xia Z-J, Clément A, et al. A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation. Am J Hum Genet. 2018;103(4):553–567. doi:10.1016/j.ajhg.2018.09.003 - DOI - PMC - PubMed

[10] Ferreira CR, Xia Z-J, Clément A, et al. A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation. Am J Hum Genet. 2018;103(4):553–567. doi:10.1016/j.ajhg.2018.09.003 - DOI - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Defining the clinical phenotype of Saul-Wilson syndrome

Affiliations

Defining the clinical phenotype of Saul-Wilson syndrome

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical