A novel mutation of LHX3 is associated with combined pituitary hormone deficiency including ACTH deficiency, sensorineural hearing loss, and short neck-a case report and review of the literature.
The LHX3 LIM-homeodomain transcription factor gene is required for normal pituitary and motoneuron development. LHX3 mutations are associated with growth hormone, prolactin, gonadotropin, and TSH deficiency; abnormal pituitary morphology; and may be accompanied with limited neck rotation and sensorineural hearing loss. We report on a boy, who presented with hypoglycemia in the newborn period. He is the second child of healthy unrelated parents. Short neck, growth hormone deficiency, and central hypothyroidism were diagnosed at a general pediatric hospital. Growth hormone and levothyroxine treatment were started, and blood sugar normalized with this treatment. On cerebral MRI, the anterior pituitary gland was hypoplastic. Sensorineural hearing loss was diagnosed by auditory testing. During follow-up, six repeatedly low morning cortisol levels (<1 μg/dl) and low ACTH levels (<10 pg/ml) were documented, so ACTH deficiency had developed over time and therefore hydrocortisone replacement was started at 1.5 years of age. Mutation analysis of the LHX3 gene revealed a homozygous stop mutation in exon 2: c.229C>T (CGA > TGA), Arg77stop (R77X). A complete loss of function is assumed with this homozygous stop mutation. We report a novel LHX3 mutation, which is associated with combined pituitary hormone deficiency including ACTH deficiency, short neck, and sensorineural hearing loss. All patients with LHX3 defects should undergo longitudinal screening for ACTH deficiency, since corticotrope function may decline over time. All patients should have auditory testing to allow for regular speech development.
Kinderklinik und Kinderpoliklinik Schwabing Department of Pediatric Endocrinology, Technische Universität München, Kölner Platz 1, 80804, München, Germany. Walter.Bonfig@lrz.tum.de
Walter
W
Bonfig
Heiko
H
Krude
Heinrich
H
Schmidt
D000015:Abnormalities, Multiple / Q000235:genetics*; D000324:Adrenocorticotropic Hormone / Q000172:deficiency; D003409:Congenital Hypothyroidism / Q000175:diagnosis / Q000235:genetics; D006319:Hearing Loss, Sensorineural / Q000151:congenital / Q000175:diagnosis / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007018:Hypopituitarism / Q000151:congenital / Q000175:diagnosis / Q000235:genetics*; D007223:Infant; D060850:LIM-Homeodomain Proteins / Q000235:genetics*; D008297:Male; D009333:Neck / Q000002:abnormalities*; D010907:Pituitary Hormones / Q000172:deficiency*; D017354:Point Mutation; D014157:Transcription Factors / Q000235:genetics*
D060850:LIM-Homeodomain Proteins; C094898:Lhx3 protein; D010907:Pituitary Hormones; D014157:Transcription Factors; D000324:Adrenocorticotropic Hormone
Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2720-4
7708713
J Clin Endocrinol Metab. 2000 Aug;85(8):2701-8
10946868
Pituitary. 2002;5(3):163-8
12812307
Cell. 1994 Dec 16;79(6):957-70
7528105
J Clin Endocrinol Metab. 2007 May;92(5):1909-19
17327381
Ann Med. 2006;38(8):560-77
17438671
J Clin Endocrinol Metab. 2000 Dec;85(12):4556-61
11134108
DNA Cell Biol. 1994 Dec;13(12):1163-80
7811383
J Clin Endocrinol Metab. 2004 Oct;89(10):5256-65
15472232
J Clin Endocrinol Metab. 2006 Mar;91(3):747-53
16394081
J Clin Endocrinol Metab. 2009 Apr;94(4):1154-61
19126629
Hum Mol Genet. 2008 Jul 15;17(14):2150-9
18407919
Nat Genet. 2000 Jun;25(2):182-6
10835633