PROP1-Related Combined Pituitary Hormone Deficiency

Clinical characteristics: PROP1-related combined pituitary hormone deficiency (CPHD) is associated with deficiencies of: growth hormone (GH); thyroid-stimulating hormone (TSH); the two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH); prolactin (PrL); and occasionally adrenocorticotropic hormone (ACTH). At birth, in contrast to individuals with congenital CPHD of other etiologies, neonates with PROP1-related CPHD lack perinatal signs of hypopituitarism. Mean birth weights and lengths are usually within the normal range and neonatal hypoglycemia and prolonged neonatal jaundice are not prevalent findings.

Most affected individuals are ascertained because of short stature during childhood. Although TSH deficiency can present shortly after birth, TSH deficiency usually occurs with or after the onset of GH deficiency. Hypothyroidism is usually mild. FSH and LH deficiencies are typically identified at the age of onset of puberty. Affected individuals can have absent or delayed and incomplete secondary sexual development with infertility. Untreated males usually have a small penis and small testes. Some females experience menarche but subsequently require hormone replacement therapy. ACTH deficiency is less common and, when present, usually occurs in adolescence or adulthood. Neuroimaging of hypothalamic-pituitary region usually demonstrates a hypoplastic or normal anterior pituitary lobe and a normal posterior pituitary lobe.

Diagnosis/testing: The diagnosis of PROP1-related CPHD is established in a proband with suggestive findings and biallelic pathogenic variants in PROP1 identified by molecular genetic testing.

Management: Treatment of manifestations: GH deficiency is treated with injection of biosynthetic growth hormone. TSH deficiency is treated by thyroid hormone replacement in the form of oral L-thyroxine. In male infants with LH and FSH deficiency, micropenis is treated with a limited course of testosterone. Hormone replacement to induce secondary sex characteristics can be initiated in males at age 12 to 13 years with monthly injections of testosterone enanthate and in females at age 11 to 12 years with 17 beta-estradiol or estradiol valerate and later by cycling with progesterone. Fertility in both sexes is possible with administration of gonadotropins. ACTH deficiency is treated with hydrocortisone, with dose adjustments as needed for illness and/or surgeries.

Surveillance: IGF1, total T4, free T4, estradiol (in females) or testosterone (in males), and cortisol levels every three to four months; measure PrL at diagnosis.

Agents/circumstances to avoid: Thyroid hormone replacement in those with untreated adrenal insufficiency; for individuals with GH deficiency, the lowest safe dose of hydrocortisone is used to avoid interfering with the growth response to growth hormone therapy.

Evaluation of relatives at risk: In younger sibs, perform molecular genetic testing to enable early diagnosis and treatment; otherwise monitor growth for evidence of growth failure.

Genetic counseling: PROP1-related CPHD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PROP1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial PROP1 pathogenic variants. Once the PROP1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.