PROP1 – Combined Pituitary Hormone Deficiency, Genetic Form

Combined pituitary hormone deficiency (CPHD; MONDO:0013099) is characterized by deficiencies in two or more anterior pituitary hormones, often leading to growth failure, hypothyroidism, and delayed puberty. PROP1, encoding a paired-like homeodomain transcription factor, is one of the most frequently mutated genes in the genetic form of CPHD. Biallelic loss-of-function variants in PROP1 disrupt pituitary cell lineage specification and hormonal output.

Genetic studies screened cohorts of CPHD patients and identified PROP1 defects in familial and sporadic cases. In one series of 23 patients, nine from eight unrelated kindreds harbored homozygous loss-of-function variants, including a recurrent AG deletion at codons 99/100/101 and point mutations p.Arg73Cys and p.Arg73His (PMID:11549703). Subsequent screening of 46 Portuguese CPHD cases confirmed PROP1 alterations in all seven familial kindreds, notably c.301_302delAG (p.Leu102fs) and c.2T>C (p.Met1Thr) (PMID:16984240). In a large international cohort of 195 patients, PROP1 mutations accounted for over 50% of familial cases and 13% of sporadic CPHD (PMID:16735499).

PROP1‐related CPHD follows an autosomal recessive inheritance pattern with documented segregation of homozygous and compound heterozygous variants in consanguineous and nonconsanguineous families. Affected relatives carrying pathogenic variants exhibit concordant hormone deficiencies, with at least 19 additional segregation events reported across multiple pedigrees. The most frequent variant c.295C>T (p.Arg99Ter) exemplifies frameshift‐induced haploinsufficiency.

Functional assays support a loss‐of‐function mechanism. Comparative genomics and cell culture experiments identified conserved regulatory elements in PROP1 intron 1 essential for proper spatial expression, and BAC transgenic rescue in Prop1-null mice restored pituitary development (PMID:17557180). Lineage‐tracing in Prop1-cre mice demonstrated that Prop1-expressing progenitors give rise to all anterior and intermediate lobe hormone‐secreting cells, linking PROP1 activity directly to cell fate decisions (PMID:26812162).

Clinically, PROP1 mutation carriers present with combined GH, TSH, LH/FSH deficiencies and frequently delayed ACTH loss, with variable pituitary imaging findings ranging from hypoplasia to transient hyperplasia. Early genetic diagnosis enables anticipatory monitoring for progressive hormone deficits and tailored hormone replacement, reducing morbidity and mortality.

In summary, compelling genetic and experimental data over two decades establish a definitive association between biallelic PROP1 variants and genetic CPHD. Routine PROP1 testing is recommended in familial CPHD, with implications for genetic counseling, early intervention, and improving long-term outcomes.

References

• The Journal of Clinical Endocrinology and Metabolism • 2001 • PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency PMID:11549703
• Clinical Endocrinology • 2006 • PROP1 gene analysis in Portuguese patients with combined pituitary hormone deficiency PMID:16984240
• The Journal of Clinical Endocrinology and Metabolism • 2006 • Genetic screening of combined pituitary hormone deficiency: experience in 195 patients PMID:16735499
• Mammalian Genome • 2007 • Comparative genomics reveals functional transcriptional control sequences in the Prop1 gene PMID:17557180
• Endocrinology • 2016 • All Hormone-Producing Cell Types of the Pituitary Intermediate and Anterior Lobes Derive From Prop1-Expressing Progenitors PMID:26812162

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