Combined Pituitary Hormone Deficiency (CPHD) Panel

Combined pituitary hormone deficiency (CPHD) is a condition characterized by impaired production of growth hormone and at least one of the other 5 hormones produced by the anterior pituitary. The prevalence of CPHD is estimated to be 1 in 8,000 individuals, and approximately 5-30% of cases are familial (Baş et al. 2015. PubMed ID: 25500790). Most affected individuals are ascertained because of a failure to grow and short stature starting in infancy or early childhood. Patients with CPHD are associated with deficiencies of growth hormone (GH), thyroid-stimulating hormone (TSH), gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)), and occasionally adrenocorticotropic hormone (ACTH) (Otto et al. 2015. PubMed ID: 25315032). People with CPHD may have mild hypothyroidism which could cause poor weight gain and fatigue. Other features of CPHD include absent or delayed puberty and incomplete secondary sexual development with infertility, or more complex disorders such as septo-optic dysplasia (SOD) and holoprosencephaly (Giordano 2016. PubMed ID: 27974184; Fang et al. 2016. PubMed ID: 27828722).

CPHD is caused by both genetic and nonheritable factors such as trauma, tumor, and infections. Approximately 50-60% of familial CPHD has a genetic basis and pathogenic variants in a number of different genes are found to cause genetically determined CPHD (De Rienzo et al. 2015. PubMed ID: 26147833). GLI2, HESX1, LHX3, LHX4, OTX2, POU1F1, PROP1, SOX2, and SOX3 are the most studied ones (Fang et al. 2016. PubMed ID: 27828722). Of these, PROP1 pathogenic variants are the most common known cause of this disorder, accounting for approximately 50% of familiar cases, although the incidence in sporadic cases is much lower (de Graaff 2014 PubMed ID: 20301521). These genes all encode transcription factors that are expressed in the developing head, hypothalamus, and/or pituitary, and have been involved in the proper development of the pituitary gland and the specialization of its cell types (Fang et al. 2016. PubMed ID: 27828722). Pathogenic variants in these genes perturb ontogenesis of pituitary gonadotropes, somatotropes, lactotropes, and thyrotropes. These developmental defects result in deficiencies of LH, which is needed for normal growth; FSH and GH, which both play a role in sexual development and fertility; TSH, which helps with thyroid gland function; and ACTH, which influences energy production in the body and maintains normal blood sugar and blood pressure levels. CPHD can be inherited in X-linked (SOX3), autosomal dominant (GLI2, LHX4, HESX1, POU1F1, OTX2, SOX2), or autosomal recessive (HESX1, POU1F1, PROP1, LHX3) manner. See individual gene test descriptions for more information on molecular biology of gene products and mutation spectra.

This multi-gene panel analyzes 9 most common genes associated with combined pituitary hormone deficiency (CPHD). This test is predicted to detect pathogenic variants in PROP1, POU1F1, LHX4, LHX3 and HESX1 in ~ 63% of familial CPHD and ~11% of sporadic CPHD (De Rienzo et al. 2015. PubMed ID: 26147833). Clinical sensitivity for this NGS test is estimated to be 16-31% overall (Baş et al. 2015. PubMed ID: 25500790; Fang et al. 2016. PubMed ID: 27828722).

Complete deletion of PROP1 has been frequently reported in patients with CPHD, with ~35% familial cases and ~5% sporadic cases (Baş et al. 2015. PubMed ID: 25500790; Fang et al. 2016. PubMed ID: 27828722). Deletions or duplications of the other genes in this panel have also been identified in CPHD patients (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).