ESPE Abstracts

A new condition, unique to Irish Travellers, was first described clinically as autosomal recessive natural killer and glucocorticoid deficiency (AR-NKGCD) ORPHA:75391 in 2008 and was attributed to recessive founder variant in MCM4/PRKDC gene in 2012. Irish Travellers are an indigenous endogamous population numbering ~40,000 in the Republic of Ireland. AR-NKGCD is characterised by short stature, glucocorticoid and natural killer cell deficiency and is a disorder of DNA repair. Since first described, through monitoring cases our knowledge and experience of the condition has grown as more cases have been confirmed.

Objectives: To review the clinical presentation, diagnostic workup, and outcomes of known patients with AR-NKGCD attending our centre over the past 10 years. We compiled data from available medical, laboratory, genetic and radiology records on patients attending paediatric endocrinology and immunology services.

Results: Sequencing analysis of intron 1 of the MCM4/PRKDC gene in all patients (n=15) revealed the known homozygous variant c71-2A>G p.(Phe24Argfs). Those children for whom data was available (n=7), were all small for gestational age, birth weight between 0.4th-2nd centiles. Further endocrine data are outlined in Table 1.

Most children (n=14) had mild dysmorphic features. Feeding difficulties, failure to thrive (n=14) and recurrent infections such as respiratory tract (n=8) and herpes simplex labialis (n=6), were observed in infancy and young childhood. Tiredness (n=5), hyperpigmentation (n=8) and mild development delay (n=4) were also observed. All 15 had severe NK cell deficiency (NK cells represented just 0.1-4% of the peripheral blood lymphocytes). Nine patients (60%) required corticosteroid replacement (hydrocortisone doses range 9-15mg/m2), in others only emergency treatment was recommended. Mineralocorticoid secretion was not impaired. A serious adrenal crisis following infection occurred in two patients. Two patients developed haemophagocytic lymphohistiocytosis (HLH), one of which died.

Conclusions AR-NKGCD is a rare disorder affecting children from the Irish Traveller population with a variable phenotype. They have an increased risk of primary adrenal insufficiency, adrenal crisis, infection, malignancies and premature death. Input from endocrinology and immunology specialists is required.