NHGRI logo
Staff Clinician

Metabolic Medicine Branch


Skeletal Genomics Unit


M.D. National University of Asunción, 2006


Dr. Carlos Ferreira went to medical school at the National University of Asunción, completed an Internal Medicine residency at Rush University Medical Center in Chicago (2009-2012), a fellowship in Clinical Genetics at the NHGRI and Johns Hopkins Hospital Medical Genetics consortium (2012-2014), and a subspecialty in medical biochemical genetics at NHGRI (2015). From 2015 to 2018, he worked as an attending physician in the Division of Genetics and Metabolism at Children's National Medical Center. In 2019, he became an appointee of the Physician-Scientist Development Program at NHGRI.

Dr. Ferreira serves as an editor or board member for three biomedical journals, and participates as faculty in the prestigious annual course on skeletal dysplasias in Lausanne, Switzerland, and in the  Society for Inherited Metabolic Disorders North American Metabolic Academy (SIMD NAMA). He also teaches the MEDI 507 course on Inborn Errors of Metabolism offered by the Foundation for Advanced Education in the Sciences (FAES), and in 2019 was awarded  the Exceptional Didactic Teaching Award bestowed by genetics trainees. Dr. Ferreira serves as co-chair of the Skeletal Disorders Clinical Domain Working Group, and co-chair of the Skeletal Disorders Gene Curation Expert Panel of the Clinical Genome Resource (ClinGen), whose purpose is to create an authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research. He led a team of researchers that elucidated the molecular defect underlying Saul-Wilson syndrome, a rare skeletal dysplasia, and the genetic basis of Catel-Manzke-like syndrome, another rare constitutional disorder of bone development. In 2019, Dr. Ferreira received the Emmanuel Shapira Award bestowed to the best paper published in Molecular Genetics and Metabolism.

Scientific Summary

The Skeletal Genomics Unit focuses on using a translational research approach to understand the etiology, pathophysiology, diagnosis, and management of a select group of genetic skeletal disorders. My specific aims include clinical research to elucidate the phenotypic spectrum and genomic studies of the basis of selected skeletal dysplasias, the development of animal and cell models to understand the pathways and molecular mechanisms responsible for the abnormal skeletal phenotype, and the creation of targeted treatment approaches. My current research projects focus on three major areas: 1) Saul-Wilson syndrome; 2) disorders of FGF23 metabolism; and 3) disorders of osteocartilaginous overgrowth.

Saul-Wilson syndrome is a rare skeletal dysplasia characterized by profound short stature, distinctive craniofacial features, short distal phalanges, skeletal fragility and often clubfoot. Other findings can include hearing loss, lamellar cataracts, and neutropenia. In 2018, I led a group that identified a recurrent, heterozygous de novo variant in COG4 (p.Gly516Arg) as causative of the disease in 14 affected individuals. In the past year, my group delineated the natural history of Saul-Wilson syndrome and the growth pattern of individuals with this rare form of primordial dwarfism, including the establishment of growth references to aid in the follow-up of patients in clinic. My group has recently established a knock-in mouse model of Saul-Wilson syndrome, with the hope of improving our understanding of the pathophysiology of this rare disease. The experience gained in the study of Saul-Wilson syndrome will serve as a paradigm for research of other rare skeletal disorders.

Regarding disorders of FGF23 metabolism, my group currently studies ENPP1 deficiency, with an evolving interest in osteoglophonic dysplasia. ENPP1 deficiency is often fatal in early life due to cardiovascular involvement (Generalized Arterial Calcification of Infancy), whereas those who survive the disease (or those with milder forms of ENPP1 deficiency) manifest FGF23-mediated hypophosphatemic rickets or osteomalacia in later life (Autosomal Recessive Hypophosphatemic Rickets type 2). We enrolled 57 subjects with ENPP1 deficiency in a retrospective natural history study, assembling a total cohort of 127 patients in combination with a study site in Germany. This work represents the largest cohort of patients with this condition, and allowed us to establish the frequency and median age of onset for individual manifestations of the disease. Osteoglophonic dysplasia, caused by activating variants in the FGFR1 receptor, represents a rare skeletal dysplasia with associated short stature, non-ossifying fibromas, and FGF23 oversecretion. The cause of FGF23 elevation in both osteoglophonic dysplasia and ENPP1 deficiency remain poorly understood, so any insight would be innovative. My group is currently developing a knock-in model of osteoglophonic dysplasia to better understand the pathomechanism of FGF23 overproduction and the development of skeletal complications.

With respect to osteocartilaginous overgrowth, several disorders such as genochondromatosis, metachondromatosis (in some families), and Trevor disease (also known as dysplasia epiphysealis hemimelica) currently lack a known molecular basis. We have collected valuable samples from individuals and relatives with each of the aforementioned rare disorders, and are currently performing genomic studies to try to elucidate their genetic etiologies, the discovery of which might allow new understanding of the mechanisms governing bone and cartilage physiology.


Rios JJ, Denton K, Russell J, Kozlitina J, Ferreira CR, Lewanda A, Mayfield JE, Moresco E,Ludwig S, Tang M, Li X, Lyon S, Xie X, Khanshour A, Paria N, Khalid A, Li Y, Feng J, Xu Q, Lu Y, Hammer R, Wise CA, Beutler B. Germline saturation mutagenesis induces new skeletal phenotypes in mice. Journal of Bone and Mineral Research. 2021 April 27 (online ahead of print).

Ferreira CR, Kavanagh D, Oheim R, Zimmerman K, Stürznickel J, Li X, Stabach P, Luke RL, Calderone L, MacKichan C, Wang A, Hutchinson HA, Nelson T, Tommassini SM, Busse B, von Kroge S, Fiedler IAK, Moeckel GW, Carpenter TO, Levine MA, Horwowitz MC, Braddock DT. Response of the ENPP1-deficient skeletal phenotype to oral phosphate supplementation and/or enzyme replacement therapy; comparative studies in humans and mice. Journal of Bone and Mineral Research. 2021;36(5):942-95.

Ferreira CR, Hackbarth ME, Ziegler SG, Pan KS, Roberts MS, Rosing DR, Whelpley MS, Bryant JC, Macnamara EF, Wang S, Müller K, Hartley I, Chew EY, Corden TE, Jacobsen CM, Holm IA, Rutsch F, Dikoglu E, Chen MY, Mughal Z, Levine MA, Gafni RI, Gahl WA. Prospective phenotyping of long-term survivors of Generalized Arterial Calcification of Infancy (GACI). Genetics in Medicine. 2021;23(2):396-407.

Ziegler S, Gahl WA, Ferreira CR. Generalized Arterial Calcification of Infancy. 2020 Dec 30. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Boyce AM, Gafni RI, Ferreira CR. Generalized Arterial Calcification of Infancy: New insights, controversies, and approach to management. Current Osteoporosis Reports. 2020;18(3):232-41.

Cavalcanti DP, Fano V, Mellado C, Lacarrubba-Flores MDJ, Silveira C, Silveira KC, del Pino M, Moresco A, Caino S, Mejía RR, Bruce CG, Lay-Son GR, Ferreira CR. Skeletal dysplasias in Latin America. American Journal of Medical Genetics part C. 2020;184(4):986-995.

Ferreira CR, Niiler T, Duker AL, Jackson AP, Bober MB. Growth in individuals with Saul-Wilson syndrome. American Journal of Medical Genetics part A. 2020;182(9):2110-2116.

Ehmke N, Cusmano-Ozog K, Koenig R, Holtgrewe M, Nur B, Mihci E, Babcock H, Gonzaga-Jauregui C, Overton JD, Xiao J, Martinez A, Muenke M, Balzer A, Jochim J, El Choubassi N, Fischer-Zirnsak B, Huber C, Kornak U, Elsea S, Cormier-Daire V, Ferreira CR. Biallelic variants in KYNU cause a multisystemic syndrome with hand hyperphalangism. Bone. 2020;133:115219.

Florenzano P, Jimenez M, Ferreira CR, Nesterova G, Roberts MS, Harsha Tella S, Fernandez de Castro L, Gafni TI, Wolf M, Jüppner H, Gales B, Markovich D, Gahl WA, Salusky IB, Collins MT. Nephropathic cystinosis: a distinct form of CKD-mineral and bone disorder that provides novel insights into the regulation of FGF23. Journal of the American Society of Nephrology. 2020;31(9):2184-92 PMCID: PMC7461669

Ferreira CR, Zein WM, Huryn LA, Merker A, Berger SI, Wilson WG, Tiller GE, Wolfe LA, Merideth M, Carvalho DR, Duker AL, Bratke H, Haug MG, Rohena L, Hove HB, Xia ZJ, Ng BG, Freeze HH, Gabriel M, Russi AHS, Brick L, Kozenko M, Earl DL, Tham E, Nishimura G, Phillips JA 3rd, Gahl WA, Hamid R, Jackson AP, Grigelioniene G, Bober MB. Defining the clinical phenotype of Saul-Wilson syndrome. Genetics in Medicine. 2020;22(5):857-866 PMCID: PMC7205587.

Ferreira CR. Saul-Wilson syndrome 2020 Feb 20. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

Ferreira CR, Regier DS, Yoon R, Pan KS, Johnston JM, Yang S, Spranger JW, Tifft CJ. The skeletal phenotype of intermediate GM1 gangliosidosis: Clinical, radiographic and densitometric features, and implications for clinical monitoring and intervention. Bone. 2020;131:115142. PMCID: PMC6937522.

Knapp KM, Sullivan R, Murray J, Gimenez G, Arn P, D'Souza P, Gezdirici A, Wilson WG, Jackson AP, Ferreira CR, Bicknell LS. Linked-read genome sequencing identifies biallelic pathogenic variants in DONSON as a novel cause of Meier-Gorlin syndrome. Journal of Medical Genetics. 2020;57(3):195-202. PMCID: PMC7042968.

Ferreira CR, Xia ZJ, Clément A, Parry DA, Davids M, Taylan F, Sharma P, Turgeon CT, Blanco-Sánchez B, Ng BG, Logan CV, Wolfe LA, Solomon BD, Cho MT, Douglas G, Carvalho DR, Bratke H, Haug MG, Phillips JB, Wegner J, Tiemeyer M, Aoki K; Undiagnosed Diseases Network; Scottish Genome Partnership, Nordgren A, Hammarsjö A, Duker AL, Rohena L, Hove HB, Ek J, Adams D, Tifft CJ, Onyekweli T, Weixel T, Macnamara E, Radtke K, Powis Z, Earl D, Gabriel M, Russi AHS, Brick L, Kozenko M, Tham E, Raymond KM, Phillips JA 3rd, Tiller GE, Wilson WG, Hamid R, Malicdan MCV, Nishimura G, Grigelioniene G, Jackson A, Westerfield M, Bober MB, Gahl WA, Freeze HH. A recurrent de novo heterozygous COG4 substitution leads to Saul-Wilson syndrome, disrupted vesicular trafficking, and altered proteoglycan glycosylation. American Journal of Human Genetics. 2018;103(4):553-67. PMCID: PMC6174323.

Florenzano P, Ferreira CR, Nesterova G, Roberts MS, Tella SH, de Castro LF, Brown SM, Whitaker A, Pereira RC, Bulas D, Gafni RI, Salusky IB, Gahl WA, Collins MT. Skeletal consequences of nephropathic cystinosis. Journal of Bone and Mineral Research. 2018;33(10):1870-80.

Ziegler SG, Gahl WA, Ferreira CR. Chapter 32: Disorders and mechanisms of ectopic calcification. In: Thakker RV, editor. Genetics of Bone Biology and Skeletal Disease; Second Edition. Academic Press; 2018.

Ziegler SG, Ferreira CR, MacFarlane EG, Riddle RC, Tomlinson RE, Chew EY, Martin L, Ma CT, Sergienko E, Pinkerton AB, Millán JL, Gahl WA, Dietz HC. Ectopic calcification in pseudoxanthoma elasticum responds to inhibition of tissue-nonspecific alkaline phosphatase. Science Translational Medicine. 2017;9(393). PMCID: PMC5606141.

Ferreira CR, Ziegler SG, Gupta A, Groden C, Hsu KS, Gahl WA. Treatment of hypophosphatemic rickets in generalized arterial calcification of infancy (GACI) without worsening of vascular calcification. American Journal of Medical Genetics part A. 2016;170A(5):1308-11. PMCID: PMC4833596.

Skeletal Genomics Unit Staff

Jaya J. Jagadeesh
Jaya J. Jagadeesh
  • Lab Manager
  • Skeletal Genomics Unit
Holly Babcock
Holly Babcock, M.S, C.G.C.
  • Genetic Counselor
  • Skeletal Genetics Unit

Last updated: July 25, 2023