Combined Pituitary Hormone
Deficiency (PROP1, POU1F1)

Combined pituitary hormone deficiency (CPHD), which has a prevalence of about 1:20,000 (1), is characterized by deficiencies in several anterior pituitary hormones. CPHD can be hereditary or result from pituitary trauma. Known monogenic causes of CPHD include loss-of-function mutations in the genes PROP1 or POU1F1 (2-6), which are estimated to account for 30-50% and 30%, respectively, of familial cases of CPHD (7-9). The two forms differ in the extent of the associated hormone deficiency and can show autosomal dominant or autosomal recessive inheritance, depending on the gene or even the exact sequence variant within the gene (10).

By identifying the underlying genetic cause, genetic testing for CPHD-associated mutations in PROP1 or POU1F1 can help establish a more precise disease prognosis and clarify the mode of inheritance. Genetic testing can also identify carriers of CPHD-associated mutations in PROP1 or POU1F1, allowing timely diagnosis and treatment of affected relatives.

Types and Causes of CPHD

Causes of CPHD include suppression of pituitary activity due to a depressed metabolic state or chronic illness, physical injury to the pituitary or the hypothalamus, or incomplete embryological development of the anterior pituitary. Physical injury to the pituitary or the hypothalamus may result from birth trauma, head injuries, tumors, surgery, or radiation treatment. Incomplete embryological development of the anterior pituitary has been linked to mutations in any one of a number of homeodomain transcription factors. These transcription factors are expressed in a defined temporal pattern and control formation of the anterior pituitary from its most primitive stage, an invagination of the oral ectoderm known as Rathke’s pouch, through terminal differentiation into five distinct cell lineages, the somatotroph, thyrotroph, lactotroph, gonadotroph, and corticotroph cells. In humans, six transcription factors have been shown to be associated with CPHD: PROP1, POU1F1, HESX1, PITX2, LHX3, and LHX4 (11). Of these, PROP1 and POU1F1 have been most often implicated in cases of familial CPHD (10).

The gene name PROP1 is an abbreviation for “Prophet of PIT1,” a term reflecting the fact that expression of PROP1 precedes and is necessary for that of PIT1 (later named POU1F1). PROP1 plays a role in the differentiation of pituitary precursor cells into the somatotroph, thyrotroph, lactotroph, and gonadotroph cell lineages of the anterior pituitary (10,11). Accordingly, loss-of-function mutations in PROP1 lead to deficiencies in growth hormone (GH), thyroid stimulating hormone (TSH), prolactin (PRL), luteinizing hormone (LH), and follicle stimulating hormone (FSH). In addition, loss-of-function mutations in PROP1 have been associated with late-onset deficiency in adrenocorticotropic hormone (ACTH) (12-15).

POU1F1 is required for terminal differentiation of somatotroph, thyrotroph, and lactotroph cells and for expression of the genes coding for GH, TSH, and PRL (10,11). Loss-of-function mutations in POU1F1 cause deficiencies in GH, TSH, and PRL, but do not appear to affect the function of gonadotroph or corticotroph cells.

Other genetic causes of CPHD include mutations in HESX1, PITX2, LHX3, or LHX4 (16-22). Mutations in these four genes do not seem to be frequent causes of familial CPHD and typically lead to extrapituitary symptoms in addition to CPHD (10,23).

Expression of HESX1 and PITX2 precedes expression of PROP1 and is important for the development of all cell lineages of the anterior pituitary. Mutations in HESX1 or PITX2 have been associated with varying degrees of CPHD, typically in conjunction with extrapituitary symptoms such as septo-optic dysplasia in the case of HESX1 and Rieger syndrome in the case of PITX2 (also known as RIEG) (16-20).

LHX3 and LHX4 are involved both in early anterior pituitary development and subsequent cell-line differentiation. Mutations in LHX3 have been associated with deficiencies in GH, TSH, PRL, LH, and FSH in combination with cervical spine rigidity (21). Mutations in LHX4 have been described in association with GH, TSH, and ACTH deficiencies accompanied by extrapituitary abnormalities (22).

CPHD due to mutations in PROP1 or POU1F1 typically presents in early childhood with severe short stature and failure to thrive due to GH deficiency. TSH deficiency most often appears next, or may, in a minority of cases, even precede GH deficiency (1,7, 24,25).

MRI scans of patients with PROP1-related CPHD show a normal posterior pituitary and pituitary stalk. The anterior pituitary may appear normal, hypoplastic, or hyperplastic (13,14). Any hyperplasia, however, seems to be transient and followed by involution and hypoplasia (15,26). PROP1-related CPHD typically leads to deficiencies in GH, TSH, PRL, LH, and FSH. While deficiencies usually appear in that order, the age at onset can be highly variable even within families (27). If onset of LH and FSH deficiencies is delayed, patients may enter puberty spontaneously (27). Typically, however, patients with PROP1-related CPHD remain sexually immature without treatment (13,14). ACTH deficiency does not occur in all cases, and onset is generally delayed into adulthood (12,13).

MRI scans of patients with POU1F1-related CPHD show a normal posterior pituitary and pituitary stalk, while the anterior pituitary may appear normal or hypoplastic (11). While POU1F1-related CPHD typically leads to deficiencies in GH, TSH, and prolactin, the age at onset of hormonal deficiencies can be highly variable even within families (28). Pubertal development is not affected.

Clinical diagnosis of CPHD is based on deficiencies in at least two anterior pituitary hormones. GH deficiency can be confirmed by demonstrating a lack of growth-hormone release in response to provocative stimuli such as insulin-induced hypoglycemia or administration of arginine, levodopa, clonidine, or glucagon. TSH deficiency is indicated by low serum levels of TSH associated with low total or free thyroxine (T4).

MRI is used to detect tumors and to reveal malformations of the pituitary. Since both PROP1-related and LHX3-related CPHD can be associated with transient pituitary hyperplasia, they may be difficult to distinguish from pituitary tumors such as craniopharyngiomas, which are predominantly observed in children.

Genetic testing can allow diagnosis of PROP1- and POU1F1-related CPHD and identify carriers of CPHD-associated mutations in PROP1 or POU1F1.

CPHD is treated with replacement of the deficient hormones. Treatment outcome is best if replacement of each hormone is initiated soon after the deficiency develops or becomes apparent. If a CPHD-associated mutation is detected in PROP1, surgery to correct pituitary hyperplasia is not indicated (26).

Both PROP1-related and POU1F1-related CPHD show autosomal inheritance, affecting males and females equally. Inheritance of PROP1-related CPHD is recessive, while inheritance of POU1F1-related CPHD can be either recessive or dominant, depending on the exact mutation in POU1F1 (10).

The Combined Pituitary Hormone Deficiency Evaluation detects mutations in PROP1 and POU1F1. By identifying a genetic cause for CPHD, the CPHD Evaluation can predict the types of hormone deficiencies likely to develop. Genetic testing can also clarify the mode of inheritance of familial CPHD and identify carriers of CPHD-associated mutations in PROP1 or POU1F1, allowing timely diagnosis of affected relatives. Early diagnosis alerts patients and physicians to the risk of other hormone deficiencies, helping to optimize the benefits of early treatment.

How Is Genetic Testing for Combined Pituitary Hormone Deficiency Performed?

DNA for sequencing is obtained from leukocytes present in a small blood sample. The coding sequences of PROP1 and POU1F1 are amplified in a highly specific manner through a polymerase chain reaction (PCR), and all PCR products are fully sequenced. Sequencing results are interpreted, and a detailed result report is sent to the patient’s physician.

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