ESPE Abstracts

Context: Kenny–Caffey syndrome (KCS) is a rare condition characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of the anterior fontanelle, ocular and dental anomalies, and variable hypocalcemia due to hypoparathyroidism. KCS is classified into two types according to its clinical features and inheritance pattern. KCS Type 2 (KCS2) is caused by mutations in FAM111A and is distinguished from KCS Type 1 by the absence of microcephaly and mental retardation.

Objective: To highlight the clinical characteristics and early genetic diagnosis of KCS2.

Methods: We present 8 new affected individuals with KCS2 from 6 families, including one family with three individuals found to be a father-to-daughter transmission, adding to the limited literature. We performed a review of genetically confirmed KCS2 cases in PubMed and MEDLINE.

Results:There were 6 females and 2 males in our cohort. All the patients present with short stature (100.0%). Facial dysmorphisms included prominent forehead, small eyes, depressed nasal bridge and micrognathia, consistent with the typical features of KCS2. Ocular defects included hypermetropia (5/8，62.5%), astigmatism (3/8, 37.5%), amblyopia (2/8, 25.0%) and pseudopapilledema (2/8, 25.0%). Dental problems included defective dentition (3/8, 37.5%) and dental caries (3/8, 37.5%). Skeletal and brain features included delayed closure of anterior fontanelle (6/8, 75.0%), cortical thickening (3/8, 37.5%) and medullary stenosis (4/8, 50.0%) of tubular bones, and cerebral calcification (3/8, 37.5%). Two patients suffered from hypocalcemic seizures. Endocrinologic abnormalities included hypoparathyroidism (5/8, 62.5%) and hypocalcemia (4/8, 50.0%). One male patient had micropenis and microorchidism. All cases harbored missense mutations of FAM111A, and nucleotides c.1706 arose as a mutational hotspot, with 7 individuals harboring a c.1706G>A (p.Arg569His) mutation and one child harboring a c.1531T>C (p.Tyr511His) mutation. Literature review yielded a total of 45 patients from 19 papers.

Conclusions: Our results indicates that there is a marked prevalence of short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of the anterior fontanelle, ocular and dental anomalies, hypoparathyroidism and hypocalcemia. This study provided strong evidence for the pathogenicity of missense mutations of FAM111A gene, refines the associated clinical phenotypes, and highlights implications for genetic counseling of affected individuals.