Kenny-Caffey syndrome type 2 (KCS2) is a very rare genetic disorder characterized by growth retardation and hypoparathyroidism, due to autosomal dominantly inherited pathogenic variants in the FAM111A gene. In this report, we presented a pediatric patient diagnosed as KCS2, with severe short stature and late-onset hypocalcemia. A 7-year-old male patient was referred to our clinic for growth retardation. His body weight, height, and body mass index were 13.1 kg [(-4.9) standard deviation (SD) score], 94.8 cm (-5.4 SD score), and 14.6 kg/m2 (-0.8 SD score), respectively. He had dysmorphic features including a triangular face, frontal bossing, low-set ears, and a bulbous nose. His height velocity was 3.97 cm/year (-1.1 SD score), and serum insulin-like growth factor-1 level was low. The peak growth hormone (GH) response during the GH stimulation tests was 8.5 ng/mL. Pituitary magnetic resonance imaging showed a partially empty sella and GH treatment was initiated. At the end of the first year of treatment, routine laboratory tests revealed hypocalcemia, hyperphosphatemia, and inappropriately low parathyroid hormone levels. His skeletal survey demonstrated cortical thickening and medullary stenosis of the long bones. Based on these findings, KCS2 was considered in the differential diagnosis, and genetic testing revealed a heterozygous pathogenic variant (c.1706G>A) in FAM111A. KCS2 should be considered in patients with severe growth retardation and hypoparathyroidism, particularly when cortical thickening and medullary narrowing of long bones are observed. Responses to the GH treatment may vary among those individuals, and hypocalcemia may occur in the form of transient episodes.

Kenny-Caffey syndrome type 2 (KCS2, #OMIM127000) is an extremely rare skeletal dysplasia characterized by characteristic facial features, relative macrocephaly, short stature, hypoparathyroidism, hypocalcemia, cortical thickening of tubular bones, and medullary stenosis. It is caused by the Family with Sequence Similarity 111 Member A (FAM111A) gene. Herein, we report a 7-year-old boy with microphthalmia, delayed anterior fontanelle closure, short stature, hypoparathyroidism, hypocalcemia, cortical thickening of tubular bones, and medullary stenosis. The presented patient had microcephaly, maculopathy, and craniosynostosis as rare distinct features. Microtia, lacunar skull appearance, and Arnold-Chiari malformation were present only in the reported patient. A diagnosis of KCS2 was considered with the clinical and radiological findings. Whole-exome sequencing identified a heterozygous pathogenic hotspot variant, c.1706G>A p.Arg569His (NM_001312909.2), in the FAM111A gene. Accurate diagnosis plays a critical role in enhancing clinical awareness, improving patient management, and offering appropriate genetic counseling for affected families.

Kenny-Caffey syndrome (KCS) is a rare genetic disorder characterized by extreme short stature, cortical thickening and medullary stenosis of tubular bones, facial dysmorphism, abnormal T cell function, and hypoparathyroidism. Biallelic loss-of-function variants in TBCE cause autosomal recessive type 1 KCS (KCS1). By contrast, heterozygous missense variants in a restricted region of the FAM111A gene have been identified in autosomal dominant type 2 KCS (KCS2) and a more severe lethal phenotype, osteocraniostenosis (OCS); these variants have recently been shown to confer a gain of function. In this study, we describe 2 unrelated children with KCS and OCS who were homozygous for different FAM111A variant alleles that result in replacement of the same residue, Tyr414 (c.1241A>G, p.Y414C and c.1240T>A, p.Y414N), in the mature FAM111A protein. Their heterozygous relatives are asymptomatic. Functional studies of recombinant FAM111AY414C demonstrated normal dimerization and a mild gain-of-function effect. This study provides evidence that both biallelic and monoallelic variants of FAM111A with varying degrees of activation can lead to dominant or recessive KCS2 and OCS.

Kenny-Caffey syndrome (KCS) is a rare syndrome characterized by short stature, hypoparathyroidism, eye abnormalities, and skeletal dysplasia. Two types of KCS result from pathogenic variants in the tubulin-specific chaperone E (TBCE) gene and the family with sequence similarity 111 member A (FAM111A) gene, respectively. In this study, we present 4 patients from three different families exhibiting facial dysmorphism, postnatal growth retardation, short stature, delayed bone age, cortical thickening and medullary stenosis of the bones, and hypoparathyroidism. Two of these cases were diagnosed with growth hormone (GH) deficiency and underwent GH therapy, highlighting the response to GH treatment in KCS. Three consanguineous cases of KCS type 1 possess a homozygous variant c.155_166del in the TBCE gene, and 1 patient with KCS type 2 has a de novo pathogenic variant c.1706G>A (p.Arg569His) in the FAM111 gene. Our findings suggest that prenatal and postnatal growth failure is a prominent characteristic of this syndrome, with KCS types 1 and 2 showing overlapping features.