Novel lethal form of congenital hypopituitarism associated with the first recessive LHX4 mutation

L. C. Gregory, K. N. Humayun, J. P G Turton, M. J. McCabe, Simon Rhodes, M. T. Dattani

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: LHX4encodes a member of the LIM-homeodomain family of transcription factors that is required for normal development of the pituitary gland. To date, only incompletely penetrant heterozygous mutations in LHX4 have been described in patients with variable combined pituitary hormone deficiencies. Objective/Hypothesis: To report a unique family with a novel recessive variant in LHX4 associated with a lethal form of congenital hypopituitarism that was identified through screening a total of 97 patients. Method: We screened 97 unrelated patients with combined pituitary hormone deficiency, including 65% with an ectopic posterior pituitary, for variants in the LHX4 gene using Sanger sequencing. Control databases (1000 Genomes, dbSNP, Exome Variant Server, ExAC Browser) were consulted upon identification of variants. Results: We identified the first novel homozygous missense variant (c.377C>T, p.T126M) in two deceased male patients of Pakistani origin with severe panhypopituitarism associated with anterior pituitary aplasia and posterior pituitary ectopia. Both were born small for gestational age with a small phallus, undescended testes, and mid-facial hypoplasia. The parents' first-born child was a female with mid-facial hypoplasia (DNA was unavailable). Despite rapid commencement of hydrocortisone and T4 in the brothers, all three children died within the first week of life. The LHX4(p.T126M) variant is located within the LIM2 domain, in a highly conserved location. The absence of homozygosity for the variant in over 65 000 controls suggests that it is likely to be responsible for the phenotype. Conclusion: We report, for the first time to our knowledge, a novel homozygous mutation in LHX4 associated with a lethal phenotype, implying that recessive mutations in LHX4 may be incompatible with life.

Original languageEnglish (US)
Pages (from-to)2158-2164
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume100
Issue number6
DOIs
StatePublished - Jun 1 2015

Fingerprint

Hypopituitarism
Pituitary Hormones
Genes
Mutation
Hydrocortisone
Screening
Transcription Factors
Servers
Exome
Phenotype
Cryptorchidism
DNA
Pituitary Gland
Gestational Age
Siblings
Parents
Genome
Databases
Combined Pituitary Hormone Deficiency

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Novel lethal form of congenital hypopituitarism associated with the first recessive LHX4 mutation. / Gregory, L. C.; Humayun, K. N.; Turton, J. P G; McCabe, M. J.; Rhodes, Simon; Dattani, M. T.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 100, No. 6, 01.06.2015, p. 2158-2164.

Research output: Contribution to journalArticle

Gregory, L. C. ; Humayun, K. N. ; Turton, J. P G ; McCabe, M. J. ; Rhodes, Simon ; Dattani, M. T. / Novel lethal form of congenital hypopituitarism associated with the first recessive LHX4 mutation. In: Journal of Clinical Endocrinology and Metabolism. 2015 ; Vol. 100, No. 6. pp. 2158-2164.
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AU - Humayun, K. N.

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AU - Rhodes, Simon

AU - Dattani, M. T.

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AB - Background: LHX4encodes a member of the LIM-homeodomain family of transcription factors that is required for normal development of the pituitary gland. To date, only incompletely penetrant heterozygous mutations in LHX4 have been described in patients with variable combined pituitary hormone deficiencies. Objective/Hypothesis: To report a unique family with a novel recessive variant in LHX4 associated with a lethal form of congenital hypopituitarism that was identified through screening a total of 97 patients. Method: We screened 97 unrelated patients with combined pituitary hormone deficiency, including 65% with an ectopic posterior pituitary, for variants in the LHX4 gene using Sanger sequencing. Control databases (1000 Genomes, dbSNP, Exome Variant Server, ExAC Browser) were consulted upon identification of variants. Results: We identified the first novel homozygous missense variant (c.377C>T, p.T126M) in two deceased male patients of Pakistani origin with severe panhypopituitarism associated with anterior pituitary aplasia and posterior pituitary ectopia. Both were born small for gestational age with a small phallus, undescended testes, and mid-facial hypoplasia. The parents' first-born child was a female with mid-facial hypoplasia (DNA was unavailable). Despite rapid commencement of hydrocortisone and T4 in the brothers, all three children died within the first week of life. The LHX4(p.T126M) variant is located within the LIM2 domain, in a highly conserved location. The absence of homozygosity for the variant in over 65 000 controls suggests that it is likely to be responsible for the phenotype. Conclusion: We report, for the first time to our knowledge, a novel homozygous mutation in LHX4 associated with a lethal phenotype, implying that recessive mutations in LHX4 may be incompatible with life.

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