ESPE Abstracts

Background: Kenny–Caffey syndrome 2 (KCS 2) is a rare cause of hypoparathyroidism, characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular long bones, delayed closure of anterior fontanel and eye abnormalities.

Objective: We report the case of a 4-years’-old boy, who presented with the characteristic, and newly identified clinical, biochemical, radiological and genetic abnormalities of the syndrome.

Results: The toddler presented for short stature investigation. He is the second child of the family, born after an otherwise full-term uneventful pregnancy. On the third day of life, he presented with respiratory distress, attributed to birth asphyxia. On revisiting his personal history several episodes of hypocalcemia were reported, requiring repeated hospital admissions. He firstly presented with an episode of neonatal seizures, attributed to central nervous system (CNS) infection, with concurrent hypomagnesemia, and hypocalcemia. Normocalcemia was achieved with parenteral calcium gluconate, and maintained with oral elemental calcium and cholecalciferol, or alfacalcidol. Parents are clinically unaffected, and there is no family history of short stature or hypoparathyroidism. On examination his height and weight were below the 3rd centile (89,5cm;-4.11SD, 15,7kg;-3SD, respectively). He had noticeable dysmorphic features, including prominent forehead, small palpebral fissures, low set ears, long philtrum, thin upper lip, pectus excavatum, and genu valgus. Although the closure of anterior fontanel was delayed until the age of 2-years, developmental milestones were achieved at expected ages. Skeletal survey revealed cortical thickening, and medullary stenosis of the long bones. The biochemical evaluation showed hypocalcemia (7.9mg/dl), high normal phosphorous (5.4mg/dl) and inappropriately low normal parathyroid hormone (PTH) (20.4pg/ml). To rule out other causes of short stature, routine investigations were performed, revealing on CNS MRI small pituitary gland and empty sella, and low IGF-1. Nocturnal levels of growth hormone were normal (21.2ng/ml). Cortisol, and thyroid function tests were within normal range. Comprehensive cardiovascular, and ophthalmological evaluation was negative for any pathology. Based on the aforementioned clinical, biochemical and radiological features KCS2 was suspected.

Molecular analysis: Molecular genetic analysis was carried out employing Whole Exome Sequencing, followed by Sanger sequencing of the pathogenic variant detected. Genetic testing revealed heterozygosity for the FAM111A gene with de novo pathogenic variant c.1706G>A, p.Arg569His. This variant has been reported in KCS2. Pathogenic variants related to patient’s pituitary morphology were not identified.

Conclusion: To our knowledge this is the first time KCS2 is associated with low levels of IGF-1, and pituitary abnormalities on the MRI of the hypothalamic-pituitary region.