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Background/Objectives: Kenny–Caffey syndrome 2 (KCS2) is a rare cause of hypoparathyroidism, inherited in an autosomal dominant mode, resulting from pathogenic variants of the FAM111A gene, which is implicated in intracellular pathways regulating parathormone (PTH) synthesis and skeletal and parathyroid gland development. Methods: The case of a boy is reported, presenting with the characteristic and newly identified clinical, biochemical, radiological, and genetic abnormalities of KCS2. Results: The proband had noticeable dysmorphic features, and the closure of the anterior fontanel was delayed until the age of 4 years. Biochemical evaluation at several ages revealed persistent hypocalcemia, high normal phosphorous, and inappropriately low normal PTH. To exclude other causes of short stature, the diagnostic approach revealed low levels of IGF-1, and on CNS MRI, small pituitary gland and empty sella. Nocturnal levels of growth hormone were normal. MRI also revealed bilateral symmetrical microphthalmia and torturous optic nerves. Skeletal survey was compatible with cortical thickening and medullary stenosis of the long bones. Genomic data analysis revealed a well-known pathogenic variant of the FAM111A gene (c.1706G>A, p. R569H), which is linked with KCS2 or nanophthalmos. Conclusions: KCS2, although a rare disease, should be included in the differential diagnosis of hypoparathyroidism and short stature. Understanding the association of pathogenic variants with KCS2 phenotypic variability will allow the advancement of clinical genetics and personalized long-term follow-up and will offer insights into the role of the FAM111A gene in the disease pathogenesis and normal embryogenesis of implicated tissues and organs. Full article

Osteocraniostenosis (OCS, OMIM #602361) is a severe, usually lethal condition characterized by gracile bones with thin diaphyses, a cloverleaf-shaped skull and splenic hypo/aplasia. The condition is caused by heterozygous mutations in the FAM111A gene and is allelic to the non-lethal, dominant disorder Kenny-Caffey syndrome (KCS, OMIM #127000). Here we report two new cases of OCS, including one with a detailed pathological examination. We review the main diagnostic signs of OCS both before and after birth based on our observations and on the literature. We then review the current knowledge on the mutational spectrum of FAM111A associated with either OCS or KCS, including three novel variants, both from one of the OCS fetuses described here, and from further cases diagnosed at our centers. This report refines the previous knowledge on OCS and expands the mutational spectrum that results in either OCS or KCS. Full article