Approach to The Patient With Combined Pituitary Hormone Deficiency Due to a Novel Homozygous LHX3 Variant

Variants in LHX3, encoding a LIM-homeodomain transcription factor essential for pituitary and neuronal development, are a rare cause of combined pituitary hormone deficiency (CPHD). Affected patients typically exhibit deficiencies of growth hormone (GH), thyrotropin (TSH), prolactin (PRL), and gonadotropins, often accompanied by cervical spine rigidity or sensorineural hearing loss.

A 4.8-year-old boy presented with short stature and central hypothyroidism. Combined deficiencies of GH, TSH, and PRL were documented, while ACTH secretion remained intact. Cranial magnetic resonance imaging showed normal pituitary morphology. Neck mobility and audiological evaluation were unremarkable.

A targeted next-generation sequencing panel for panhypopituitarism was non-diagnostic. Whole-exome sequencing (WES) was performed at 10.5 years of age.

WES identified a novel homozygous LHX3 c.575 G > A, p.(Arg192His) variant located within the homeodomain. Segregation analysis confirmed parental heterozygosity. A younger sister carrying the same homozygous variant exhibited a similar endocrine phenotype. Growth velocity normalized on recombinant human GH replacement.

This case expands the phenotypic spectrum of LHX3-related CPHD by demonstrating that a homeodomain missense variant may produce isolated endocrine deficiencies without structural, auditory, or motor abnormalities, and underscores the value of serial genetic re-evaluation in unexplained CPHD.