A Novel Dysfunctional LHX4 Mutation with High Phenotypical Variability in Patients with Hypopituitarism

Abstract

The present report describes three new exonic LHX4 allelic variants with at least one being responsible for congenital hypopituitarism. It also extends the phenotypical heterogeneity associated with LHX4 mutations, which includes variable anterior pituitary hormone deficits, as well as pituitary and extrapituitary abnormalities.

Pituitary stalk interruption syndrome in 83 patients: novel HESX1 mutation and severe hormonal prognosis in malformative forms

“…Concerning the two variants of unknown significance, whereas Gly to Ser amino acid substitution was not predicted to have significant physico-chemical effects, Thr90Met amino acid substitution affects the LIM domain and is likely associated with important physico-chemical changes. In our in vitro studies, these variants did not modify the DNA-binding and transactivation properties of the protein (17). Considering the limitations of functional studies, however, it cannot be ruled out that these variants may somehow be functionally relevant.…”

“…We also identified two LHX4 variants (c.1108GOA heterozygote, p.Gly370Ser and c.296 COT heterozygote, p.Thr90Met), with normal DNA-binding and transactivation properties in transfection studies as we reported (17). Moreover, 56.3% of patients presented the c.983GOA (p.Asn328Ser) LHX4 polymorphism in a heterozygous (40%) or homozygous (16.3%) way.…”

“…Their father carried the same heterozygous mutation. At age 28, he harbored a partial gonadotroph deficiency and a hyperplasic pituitary without pituitary stalk or posterior pituitary abnormalities on MRI (17).…”

“…HESX1 mutations are responsible for a wide spectrum of clinical features, from IGHD with no midline forebrain or optic defect to midline brain defects as part of septo-optic dysplasia (SOD) (13)(14)(15)(16). LHX4 mutations have been reported to cause CPHD with variable neuroradiological abnormalities: PSIS, sella turcica or pituitary hypoplasia, ectopic posterior lobe, and defect of the corpus callosum and hindbrain (17)(18)(19). OTX2 gene defects, first observed in association with eye malformations and later with variable pituitary disorders, were recently reported in three PSIS patients with no ocular abnormalities (20,21).…”

Vertical Transmission of Hypopituitarism: Critical Importance of Appropriate Interpretation of Thyroid Function Tests and Levothyroxine Therapy During Pregnancy

“…There is commercial testing available for both POU1F1 and PROP1, and research testing available at many academic institutions. Pediatric endocrinologists who treat patients with combined pituitary hormone deficiencies should strongly consider offering genetic testing, as the expanding reports of mutations may offer relevant clinical information.Mutations in the transcription factor LHX4 can be inherited in an autosomal fashion and result in variable anterior pituitary hormone deficiencies and preserved fertility (32,33). Endocrinologists who treat adult patients with idiopathic congenital hypopituitarism should also present the option of genetic testing to their patients, even in individuals in whom genetic mutations were not previously found, as novel mutations continue to be discovered.…”