Endocrine Abstracts

Background: Growth is a multifactorial trait, in which about 80% are determined by genetic factors. The pituitary plays a central role and some of the transcription factors can be involved in isolated or combined deficits: they orchestrate the ontogeny of the gland, maintain the differentiated state and mediate the coordinated expression of specific cell type. Among them, LHX4 mutations can manifest as a combined pituitary hormone deficiency and are associated with an ectopic posterior pituitary and/or a sella turcica defect. Its mutations are associated with variable expressivity and incomplete penetrance.

Case presentation: We describe a patient with growth failure. Regular pregnancy without problems reported at prenatal ultrasounds. Term-born: weight 3040g (-1.1 SDS), length 48 cm (-1.5 SDS), head circumference 33 cm (-1.5 SDS). No dysmorphisms. At the age of three, sleep apneas are reported with an obstructive sleep apnea syndrome (OSAS) with central predominant component of mild degree at the polysomnography. At the age of four, we evidenced a growth slowdown (height -2.7 SDS, with TH -1, 2 SDS). We excluded celiac disease, hypothyroidism, GH deficiency (GHD), chromosomopathy and SHOX gene alteration. Bone age was delayed by about 1 year. Due to persistence of growth failure, we performed a genetic analysis that revealed a mutation in the LHX4 gene c.250C>T p.(Arg84Cys), which was subsequently detected in the father (final height 168 cm). No other deficits in pituitary hormone function were found. The brain MRI showed no abnormalities in the hypothalamic-pituitary region nor other encephalic defects were detected. At the age of 6, 8, we started a trial therapy with rhGH 27 mg/kg/day, but due to behavior disorder (anger outbursts) and the lack of improvement in growth rate with the therapy the treatment was suspended after 6 months.

Conclusions: Our patient has a mutation that is already described as putative, but he doesn’t present the typical clinical features: he doesn’t have any pituitary deficit nor any alteration at the brain MRI. His short stature can’t be explained by a GHD, moreover the trial treatment with rhGH didn’t work. Further studies are needed to elucidate the relationship between short stature and the LHX4 mutation. The central OSAS could be related to the LHX4 mutation since studies on mice demonstrated a ventral motor neuron defect that impair respiratory movements, associated whit lung hypoplasia. This could be a possible manifestation in humans which let us widen the clinical manifestation associated with such mutation.