Panhypopituitarism presenting as life-threatening heart failure caused by an inherited microdeletion in 1q25 including LHX4.
Clinical presentation of hypopituitarism in the neonate may be variable, ranging from absent to severe nonspecific symptoms and may be life-threatening in patients with adrenocorticotropic hormone deficiency. The LIM homeobox gene 4 (LHX4) transcription factor regulates early embryonic development of the anterior pituitary gland. Autosomal dominant mutations in LHX4 cause congenital hypopituitarism with variable combined pituitary hormone deficiency (CPHD). We report on a neonate with unexplained heart failure and minor physical anomalies, suggesting a midline defect. She was diagnosed with complete CPHD. Cardiac function was rescued by replacement with hydrocortisone and thyroxine; hypoglycaemia stopped under growth hormone therapy. Magnetic resonance imaging revealed a dysgenetic pituitary gland suggesting an early developmental defect. Array comparative genomic hybridization showed a maternally inherited 1.5-megabase microdeletion in 1q25.2q25.3, including the LHX4 gene. Haploinsufficiency of LHX4 likely explains the predominant pituitary phenotype in the proposita and we suggest variable intrafamilial penetrance of the inherited microdeletion. To the best of our knowledge, we are the first to report on heart failure as a rare nonspecific symptom of treatable CPHD in the newborn. Variably penetrant pituitary insufficiency, including this severe and atypical presentation, can be correlated with LHX4 insufficiency and highlights the role of LHX4 for pituitary development.
Division of Medical Genetics, University Children's Hospital and Department of Biomedicine, Burgfelderstrasse 101, Building J, CH- 4055 Basel, Switzerland. isabel.filges@unibas.ch
Isabel
I
Filges
Andrea
A
Bischof-Renner
Benno
B
Röthlisberger
Christian
C
Potthoff
René
R
Glanzmann
Joëlle
J
Günthard
Jacques
J
Schneider
Andreas R
AR
Huber
Urs
U
Zumsteg
Peter
P
Miny
Gabor
G
Szinnai
D000483:Alleles; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D006333:Heart Failure / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D020249:Hormone Replacement Therapy; D019382:Human Growth Hormone / Q000627:therapeutic use; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use; D007018:Hypopituitarism / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D060850:LIM-Homeodomain Proteins / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D009421:Nervous System Malformations / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D019683:Penetrance; D010641:Phenotype; D010902:Pituitary Gland / Q000002:abnormalities / Q000473:pathology; D013974:Thyroxine / Q000627:therapeutic use; D014157:Transcription Factors / Q000235:genetics*
C486362:LHX4 protein, human; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D019382:Human Growth Hormone; D013974:Thyroxine; D006854:Hydrocortisone