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A Novel LHX3 Mutation Presenting as Combined Pituitary Hormonal Deficiency

Pediatric Endocrinology Division (A.P.S.B., S.T.) and Pediatric Neurology Division (S.P.), Infant’s and Children’s Hospital of Brooklyn at Maimonides, Brooklyn, New York 11219; Department of Biology (C.S.H., J.J.S.), Indiana University-Purdue University, Indianapolis, Indiana 46202; Pediatric Endocrinology Division (H.A.), Saint Barnabas Medical Center, Livingston, New Jersey 07039; and Department of Pediatrics (E.C.W.), Section of Endocrinology and Diabetology, and Department of Cellular and Integrative Physiology (S.J.R.), Indiana University School of Medicine, Indianapolis, Indiana 46202

Address all correspondence and requests for reprints to: Svetlana Ten, M.D., 977 48th Street, Brooklyn, New York 11219. E-mail: tenlana{at}aol.com.

Context: LHX3 encodes LIM homeodomain class transcription factors with important roles in pituitary and nervous system development. The only previous report of LHX3 mutations described patients with two types of recessive mutations displaying combined pituitary hormone deficiency coupled with neck rigidity.

Objective: We report a patient presenting a unique phenotype associated with a novel mutation in the LHX3 gene.

Patient: We report a 6-yr, 9-month-old boy born from a consanguineous relationship who presented shortly after birth with cyanosis, feeding difficulty, persistent jaundice, micropenis, and poor weight gain and growth rate. Laboratory data, including an undetectable TSH, low free T₄, low IGF-I and IGF binding protein-3, prolactin deficiency, and LH and FSH deficiency were consistent with hypopituitarism. A rigid cervical spine leading to limited head rotation was noticed on follow-up examination. Magnetic resonance imaging revealed an apparently structurally normal cervical spine and a postcontrast hypointense lesion in the anterior pituitary.

Results: Analysis of the LHX3 gene revealed homozygosity for a novel single-base-pair deletion in exon 2. This mutation leads to a frame shift predicted to result in the production of short, inactive LHX3 proteins. The results of in vitro translation experiments are consistent with this prediction. The parents of the patients are heterozygotes, indicating a recessive mode of action for the deletion allele.

Conclusions: The presence of a hypointense pituitary lesion and other clinical findings broadens the phenotype associated with LHX3 gene mutation.

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