Combined Pituitary Hormone Deficiency-2 (CPHD2) via the PROP1 Gene

Combined pituitary hormone deficiency (CPHD) is a condition that characterized by a shortage of several hormones produced by anterior pituitary. PROP1-related CPHD2 is associated with deficiencies of growth hormone (GH), thyroid-stimulating hormone (TSH), gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)), prolactin (PrL), and occasionally adrenocorticotropic hormone (ACTH) ( de Graaff et al. 2014). The clinical phenotype of PROP1-related CPHD is highly variable both within and between pedigrees with respect to the degree of pituitary hormone deficiency and the age of onset of the deficiency. Most affected individuals are ascertained because of a failure to grow and short stature starting in infancy or early childhood. People with CPHD2 may have mild hypothyroidism which could cause poor weight gain and fatigue. Other features of CPHD2 include absent or delayed puberty and incomplete secondary sexual development with infertility. Untreated males usually present hypogonadism while females often lack breast development or menses. ACTH deficiency is less common and does not occur until adulthood (Flück et al. 1998; Bottner et al. 2004].

50% of CPHD has a genetic basis and pathogenic variants in at least eight genes are found to cause genetically determined CPHD. 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 et al. 2014). PROP1 is a pituitary-specific paired-like homeodomain transcription factor that plays a crucial role in the proper development of the pituitary gland and the specialization of its cell types (Duquesnoy et al. 1998). Pathogenic variants in PROP1 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 fetility; TSH, which helps with thyroid gland function; prolactin, which stimulates the production of breast milk; and ACTH, which influences energy production in the body and maintains normal blood sugar and blood pressure levels (Kelberman et al. 2009).

PROP1-related CPHD is inherited in an autosomal recessive manner. At least 34 pathogenic variants in the PROP1 gene have been found to cause CPHD (Human Gene Mutation Database). The most common pathogenic variant in which three AG repeats are reduced to two AG repeats (c.301_302del) deletes two DNA building blocks in the PROP1 gene and accounts for 55% of alleles in familial cases and 12% of alleles in sporadic cases of CPHD ( de Graaff et al. 2014).

This test is predicted to detect pathogenic variants in PROP1 in 50% of familial Combined Pituitary Hormone Deficiency and 1%-2% of sporadic CPHD (Bottner et al. 2004; Turton et al. 2005).

To date, 5 large deletions in the PROP1 gene have been reported in patients affected with CPHD (Abrão et al. 2006; Kelberman et al. 2009; Zhang et al. 2010).

This test provides full coverage of all coding exons of the PROP1 gene 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 full 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).