Table 3.

Genetic Disorders of Interest in the Differential Diagnosis of PROP1-Related Combined Pituitary Hormone Deficiency

GeneDisorderMOIClinical Characteristics
Combined pituitary hormone deficiency
GLI2 GLI2-related CPHD (OMIM 165230)ADCPHD or IGHD; ectopic posterior lobe, polydactyly, midline defects from hypotelorism to holoprosencephaly, cleft lip/palate
HESX1 HESX1-related CPHD (OMIM 182230)AD
AR		CPHD or isolated GH deficiency; midline defects, optic nerve hypoplasia, ectopic or normal posterior pituitary lobe & anterior lobe hypoplasia
LHX3 LHX3-related CPHD (OMIM 221750)ARCervical spine rigidity, vertebral abnormalities, sensorineural hearing loss. Pituitary is usually hypoplastic but may be normal & occasionally enlarged.
LHX4 LHX4-related CPHD (OMIM 262700)ADCerebellar defects (Chiari syndrome), small anterior pituitary, & ectopic posterior lobe (Biallelic pathogenic variants are assoc w/lethal phenotype w/hypopituitarism & respiratory distress.)
POU1F1 POU1F1-related isolated or
combined CPHD (OMIM 613038)		AR
AD		Deficiency of GH, PRL, & variable TSH, rarely IGHD. Hypothyroidism can be congenital & severe, or mild & later in onset; pituitary usually hypoplastic on imaging studies.
Isolated growth hormone deficiency
GH1IGHD1A (OMIM 262400)ARSevere growth failure; affected persons treated w/exogenous GH often develop anti-GH antibodies.
IGHD1B (OMIM 612781)ARGrowth failure is less severe than in IGHD1A & persons usually respond well to exogenous GH.
IGHD2 (OMIM 173100)ADClinical severity varies. Affected persons usually respond well to exogenous GH, may develop CPHD.
Isolated hypogonadotropic hypogonadism
Genes Disorder MOI Clinical characteristics
ANOS1, AXL, CCDC14, CHD7, DUSP6, FEZF1, FGF8, FGF17, FGFR1, FLRT3, GNRH1, GNRHR, HS6ST1, IGSF10 1, IL17RD, KISS1, KISS1R, NSMF, POLR3B, PROK2, PROKR2, SEMA3A, SEMA3E, SOX10, SPRY4, SRA1, TAC3, TACR3, WDR11Isolated GnRH hormone deficiency 2XL
AD
AR		Some genes generally assoc w/isolated hypogonadotropic hypogonadism can cause CPHD.

AD = autosomal dominant; AR = autosomal recessive; CPHD = combined pituitary hormone deficiency; GH = growth hormone; GnRH = gonadotropin-releasing hormone; IGHD = isolated growth hormone deficiency; MOI = mode of inheritance; PrL = prolactin; TSH = thyroid-stimulating hormone; XL = X-linked

1.
2.

Pathogenic variants in more than 30 genes account for about half of all isolated GnRH deficiency; the genetic cause is unknown in about 50% of persons with isolated GnRH deficiency.

From: PROP1-Related Combined Pituitary Hormone Deficiency

Cover of GeneReviews®
GeneReviews® [Internet].
Adam MP, Feldman J, Mirzaa GM, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-2024.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.