Expanding the Phenotypic Spectrum of Kenny-Caffey Syndrome.

Heidi Schigt, Martin Bald, Bram C J van der Eerden, Lars Gal, Barnabas P Ilenwabor, Martin Konrad, Michael A Levine, Dong Li, Christoph J Mache, Sharon Mackin, Colin Perry, Francisco J Rios, Karl Peter Schlingmann, Ben Storey, Christine M Trapp, Annemieke J M H Verkerk, M Carola Zillikens, Rhian M Touyz, Ewout J Hoorn, Joost G J Hoenderop, Jeroen H F de Baaij

Journal: The Journal of clinical endocrinology and metabolism 2023;108(9):e754-e768

PMID: 36916904

Free Full Text on PubMed Central View on PubMed

Abstract

CONTEXT

Kenny-Caffey syndrome (KCS) is a rare hereditary disorder characterized by short stature, hypoparathyroidism, and electrolyte disturbances. KCS1 and KCS2 are caused by pathogenic variants in TBCE and FAM111A, respectively. Clinically the phenotypes are difficult to distinguish.

OBJECTIVE

The objective was to determine and expand the phenotypic spectrum of KCS1 and KCS2 in order to anticipate complications that may arise in these disorders.

METHODS

We clinically and genetically analyzed 10 KCS2 patients from 7 families. Because we found unusual phenotypes in our cohort, we performed a systematic review of genetically confirmed KCS cases using PubMed and Scopus. Evaluation by 3 researchers led to the inclusion of 26 papers for KCS1 and 16 for KCS2, totaling 205 patients. Data were extracted following the Cochrane guidelines and assessed by 2 independent researchers.

RESULTS

Several patients in our KCS2 cohort presented with intellectual disability (3/10) and chronic kidney disease (6/10), which are not considered common findings in KCS2. Systematic review of all reported KCS cases showed that the phenotypes of KCS1 and KCS2 overlap for postnatal growth retardation (KCS1: 52/52, KCS2: 23/23), low parathyroid hormone levels (121/121, 16/20), electrolyte disturbances (139/139, 24/27), dental abnormalities (47/50, 15/16), ocular abnormalities (57/60, 22/23), and seizures/spasms (103/115, 13/16). Symptoms more prevalent in KCS1 included intellectual disability (74/80, 5/24), whereas in KCS2 bone cortical thickening (1/18, 16/20) and medullary stenosis (7/46, 27/28) were more common.

CONCLUSION

Our case series established chronic kidney disease as a new feature of KCS2. In the literature, we found substantial overlap in the phenotypic spectra of KCS1 and KCS2, but identified intellectual disability and the abnormal bone phenotype as the most distinguishing features.

Address: Department of Medical BioSciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.; Department of Pediatric Nephrology, Olga Hospital, Clinics of Stuttgart, 70174 Stuttgart, Germany.; Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.; Pediatric Nephrology, Department of General Pediatrics, University Children's Hospital Münster, 48149 Münster, Germany.; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.; Division of Endocrinology and Diabetes and Center for Bone Health, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.; Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Pediatric Nephrology, Department of Pediatrics, Medical University Graz, 8036 Graz, Austria.; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.; Department of Endocrinology, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.; Department of Endocrinology, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.; Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec H3H 2R9, Canada.; Oxford Kidney Unit, Oxford University Hospitals, Oxford OX3 7LE, UK.; Trapp-Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT 06032, USA.; Division of Endocrinology, Connecticut Children's Medical Center, Hartford, CT 06106, USA.; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.; Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec H3H 2R9, Canada.

DOI: 10.1210/clinem/dgad147

Link outs

Free resources

Full Text Sources:

Subscription / membership required

Full Text Sources:

MeSH Terms: Humans, Intellectual Disability, Hyperostosis, Cortical, Congenital, Phenotype, Electrolytes, Hypoparathyroidism