Endocrine Abstracts

Background: Interstitial deletions of the long arm of chromosome 1 are rare and classified as proximal or intermediate, the intermediate spanning bands 1q24–1q32. This region contains several genes, including LHX4, a LIM-homeodomain transcription factor essential in the early steps of pituitary ontogenesis. Indeed, mutations in the LHX4 gene are related to combined pituitary hormone deficiency type 4 (CPHD4, OMIM 602146).

Aim: outline the impact of a deletion involving the 1q24–1q32 region in two unrelated boys followed in different Italian hospitals (b1: Rome, b2: Milan), enlightening the complex phenotype, including pituitary hormone deficiency.

Case reports: Both boys (b) were born at term, small for gestational age (b1: 2600 gr, –3.6 SDS; b2: 1800 gr –3.3 SDS), from non-consanguineous parents. At birth, common mild dysmorphic features such as very small feet and hands were evident. In both children brain MRI showed a poorly developed sella turcica, pituitary hypoplasia, thin pituitarystalk, ectopicneurohypophysis, and corpus callosum hypoplasia. Nonetheless, hormonal picture was different, showing b1 neonatal hypoglycaemia that led to diagnosis of GH deficiency and central hypoadrenalism, with central hypothyroidism defining the condition of CPHD and having b2 an uneventful neonatal period. In the latter, decreased linear growth was first observed at the age of 6 months. At that time, endocrine evaluation showed normal thyroid function, low GH, IGF-I and cortisol levels, suggesting GH deficiency and central hypoadrenalism. In both patients adequate replacement therapy was started. Due to the complex phenotype, in which CPHD and severe growth retardation were accompanied by mild neurodevelopmental delay, CGH-array was performed. Boys shared a quite similar genotype, with alteration involving the intermediate region of chromosome 1 (b1: del1q25.1q31.3, b2: arr1q24.3q31.1). During follow-up tocurrent age of 5.5 years, auxological and hormonal data were collected. CPHD was confirmed in b1, while in b2 a short synachten test performed at the age of 2 years showed a normal cortisol peak, narrowing the hormonal picture to isolated growth hormone deficiency.

Conclusion: diagnosis of hypopituitarism in neonatal period is extremely challenging. On this context, neuroradiological abnormalities are strongly supportive. Besides, in the era of precision medicine, accurate genotype characterization seems quite essential. However, as these reports show, even though CGH-Array allowed defining a common genetic condition likely causative of the clinical picture, follow-up revealed a different phenotype evolution.