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.

Suggestive Findings

PROP1-related combined pituitary hormone deficiency (CPHD) should be suspected in individuals with the following clinical, laboratory, imaging, and family history features.

CPHD is defined as growth hormone (GH) deficiency AND deficiency of at least one of the following other pituitary hormones:

• Thyroid-stimulating hormone (TSH)
• The two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
• Prolactin (PrL)
• Adrenocorticotropic hormone (ACTH) (Deficiency develops in ~50% of individuals.)

Clinical features

• GH deficiency. Proportionate moderate-to-severe short stature with growth deceleration
• TSH deficiency. Although TSH deficiency can present shortly after birth, it usually occurs with or following the onset of GH deficiency. Hypothyroidism is usually mild, without clinical features of congenital hypothyroidism, but likely contributes to impaired growth velocity.
• LH and FSH deficiency. Newborn males with micropenis (stretched penile length <2.5 cm in a term infant), with or without cryptorchidism; adolescent males with onset of puberty after age 14 years or impaired secondary sexual development; adolescent females with lack of breast development or menses by age 13 years
• PrL deficiency. Adult females with impaired lactation
• ACTH deficiency. Features of chronic ACTH deficiency in children and adults include persistent weakness, abdominal pain, anorexia, and weight loss. Note: Features of acute ACTH deficiency including acute hypotension, dehydration, and shock are not reported.

Laboratory features

• GH deficiency. Low basal IGF1 levels; serum GH <7 ng/dL on two provocative tests. Stimuli used for provocative testing for GH deficiency include arginine, clonidine, insulin, insulin-arginine, and glucagon.
• TSH deficiency can be present in individuals with apparently normal TSH-T4 axis. Basal serum free T4 is low or repeatedly low-normal and T4 concentration 1.0 µg/dL below normal for age with a low-normal serum TSH (normal: 0.1 mIU/L to 4.5-5.5 mIU/L). Most individuals are diagnosed based on insufficient responses in thyrotropin-releasing hormone (TRH) stimulation tests.
• LH and FSH deficiency. Low serum LH and FSH and low serum testosterone in males; low serum estradiol (and/or the lack of progestin-induced withdrawal bleeding) in females age 13 years or older. LH and FSH deficiency are confirmed by subnormal increase in serum LH and FSH following infusion of GnRH in an individual age 13-14 years or older.
• PrL deficiency. Serum PrL low or normal
• ACTH deficiency. Hyponatremia, hyperkalemia, and hypoglycemia in an acutely ill untreated individual; serum ACTH is inappropriately low in the presence of a low serum concentration of cortisol; normal renin-aldosterone axis. ACTH deficiency is confirmed by subnormal increase in serum ACTH in response to hypoglycemia or corticotropin-releasing hormone, suggesting a pituitary etiology of ACTH deficiency.

Imaging features

• Delayed bone maturation on x-ray examination
• On head MRI, normal pituitary stalk and normal position of posterior lobe; anterior lobe may appear hypoplastic, normal, or diffusely enlarged [Correa et al 2019]. The sella turcica may be normal in size, enlarged, or may appear empty; pituitary imaging findings may mimic those seen in pseudotumor, non-functioning adenoma, craniopharyngioma, or Rathke's pouch cyst. The pituitary may initially be enlarged in childhood, wax and wane in size before reducing in size in adolescence or adulthood, and then undergo complete involution.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of PROP1-related CPHD is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in PROP1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic PROP1 variants of uncertain significance (or identification of one known PROP1 pathogenic variant and one PROP1 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1). Those with a phenotype indistinguishable from other causes of CPHD are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

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 adrenocorticotropic hormone (ACTH). The secretion of all these pituitary-derived hormones declines gradually with age; often the order of appearance of hormone deficiency is GH, LH and FSH, TSH, and then ACTH. The degree of hormone deficiency and the age of onset of the deficiency are variable even within the same family. To date, hundreds of individuals have been identified with PROP1-related CPHD [Baş et al 2015, Fritez et al 2015, Rohayem et al 2016, Madeira et al 2017, Gorar et al 2018, Bajuk Studen et al 2019, Correa et al 2019, Bulut et al 2020]. The following description of the phenotypic features associated with this condition is based on reports that included affected adults to account for the later onset of gonadotropin and ACTH deficiency.

GH deficiency. In general, short stature is the first symptom reported in individuals with PROP1-related CPHD. Most affected children have normal birth weight and birth length and an uncomplicated perinatal period. Hypoglycemia in newborns with PROP1-related CPHD may rarely occur. Growth deficiency with moderate-to-severe growth deceleration usually develops within the first year of life (height -1.5±0.9 SDs at age 1.5 years) and becomes more prominent later in infancy and early childhood, mainly between ages 1.5 and 3 years (-3.6±1.3 SDs at age 3 years), when parents seek medical assistance. At diagnosis, bone age is usually severely delayed (-4.0 SDs at age 2.5 years) and hands and feet are proportionately small.

Clinical response to exogenous GH usually depends on the severity of GH deficiency, deficiencies of other pituitary hormones, age of onset of growth failure, the time interval between the onset of growth failure and the onset of GH therapy, duration of replacement therapy, and the sex of the affected individual.

If treatment is started early in life, GH therapy is very effective for linear growth to achieve familial expected height. GH therapy has also improved body composition and quality of life in older individuals [Doknic et al 2020].

TSH deficiency. Rarely, hypothyroidism is the presenting finding. Hypothyroidism is usually mild and occurs in later infancy and childhood. Since it is usually not congenital or severe, it is not associated with intellectual disability or other physical findings of congenital hypothyroidism. TSH deficiency can be present in individuals with apparently normal TSH-T4 axis.

FSH and LH deficiency. Newborn males with early-onset gonadotropin deficiency can present with micropenis (stretched penile length <2.5 cm in a term infant) with or without cryptorchidism.

Affected individuals with later onset can have absent or delayed and incomplete secondary sexual development and infertility. Adolescent males may present with small penis, small testes, onset of puberty after age 14 years, and/or cessation of secondary sexual development. Adolescent females may present with lack of breast development or delayed menarche. Some females experience menarche before requiring hormone replacement therapy [Flück et al 1998]. Gonadotropic function can also progressively decline and present as primary or secondary lack of reproductive function. There are reports of spontaneous puberty with decline of gonadotropic function in individuals with p.Arg120Cys, p.Phe88Ser, and c.150delA PROP1 variants. Impaired gonadotropic function occurs in all individuals with the most common PROP1 variant, c.301_302delAG.

Gonadotropin deficiency can be the presenting feature, with GH deficiency and TSH deficiency developing later in adulthood [Reynaud et al 2005].

Prolactin (PrL) deficiency generally causes few symptoms, aside from impaired lactation in adult women [Voutetakis et al 2004].

ACTH deficiency most often occurs in adolescence or adulthood. The range of onset of ACTH deficiency is age 11 years to 63 years. Individuals may present with persistent weakness, abdominal pain, anorexia, and weight loss. Neonatal presentation and signs of acute ACTH deficiency have not been described. It appears unlikely that deficiency of the PROP1 transcription factor causes ACTH deficiency directly, but PROP1 may have some role in differentiation or viability of corticotrophs [Araujo et al 2013]. Surveillance is extremely important in all individuals with PROP1-related CPHD because adrenal function gradually declines over time, even after more than four decades. Furthermore, as GH replacement can increase cortisol metabolism, it is necessary to be aware of the signs of an unveiled adrenal insufficiency.

Intelligence is usually normal.

Other findings

• Facies are characterized as "immature," with a depressed nasal bridge and relative decrease in the vertical dimensions of the face [Pirinen et al 1994].
• Obesity, rare in childhood, is more common in adulthood.

Genotype-Phenotype Correlations

Limited genotype-phenotype correlations have been identified. Phenotypic variability was observed among individuals with the same pathogenic variants, particularly the presence and age of onset of hypocortisolism, the levels of prolactin, and the results of pituitary imaging [Lemos et al 2006].

• There are reports of spontaneous puberty with decline of gonadotropic function in individuals with PROP1 variants p.Arg120Cys, p.Phe88Ser, and c.150delA [Flück et al 1998].
• Impaired gonadotropic function occurs in all individuals with the most common PROP1 variant, c.301_302delAG [Madeira et al 2017].

Prevalence

The prevalence of PROP1-related CHPD is estimated at fewer than 1:30,000 individuals, and PROP1 pathogenic variants are the most common cause of CPHD worldwide. PROP1 pathogenic variants were found in 6.7% of simplex cases and 48.5% of individuals with familial CPHD [De Rienzo et al 2015]. Incidence of PROP1 variants in individuals with CHPD varies widely by ethnicity: 70.1% in Lithuania (47/67 individuals with CPHD were found to have biallelic PROP1 pathogenic variants); approximately 53% in the Brazilian population (16/30 individuals tested), 50.8% in Poland (32/63); 0% in the Netherlands (0/50), the United Kingdom (0/27), Japan (0/71), Korea (0/12), and Australia (0/33).

PROP1-related CHPD may be more common in populations with reported founder variants (see Table 7).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in each individual with newly diagnosed PROP1-related combined pituitary hormone deficiency (CPHD), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The main principle of treatment in PROP1-related CPHD is replacement hormone therapy under the guidance of endocrinology.

Surveillance

Agents/Circumstances to Avoid

Thyroid hormone replacement should not be initiated until adrenal function has been assessed and adrenal insufficiency is treated if present.

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

It is appropriate to clarify the genetic status of younger sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of hormone replacement therapy and surveillance.

For younger sibs who have not undergone molecular genetic testing, monitoring growth for evidence of growth failure is appropriate. Of note, affected sibs usually have extreme short stature because of thyroid hormone deficiency and GH deficiency.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Long-acting GH preparations are being developed to improve adherence by decreasing the frequency of GH injections from daily to weekly, biweekly, or monthly. However, several questions need to be addressed including the methods of dose adjustment, the timing of IGF1 monitoring, safety, efficacy, and cost effectiveness [Miller et al 2020].

Newer glucocorticoid replacement alternatives are under development. Medications with a modified release (Chonocort^®) and dual release (Plenadren^®) of hydrocortisone have been studied. Their pharmacokinetics promote corticoid bioavailability closer to circadian production [Paragliola & Corsello 2018, Garmes et al 2021].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

PROP1-related combined pituitary hormone deficiency (CPHD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a PROP1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a PROP1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• 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.
• Intrafamilial clinical variability may be observed between sibs with the same pathogenic variants [Lemos et al 2006, Madeira et al 2017].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• Fertility in both females and males with PROP1-related CPHD is possible with administration of gonadotropins. Two females with PROP1 pathogenic variants had ovulation induction and successful pregnancy outcome without GH replacement. They were not able to lactate [Voutetakis et al 2004].
• The offspring of an individual with PROP1-related CPHD are obligate heterozygotes (carriers) for a pathogenic variant in PROP1.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a PROP1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the PROP1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the PROP1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

PROP1 encodes the homeobox protein prophet of PIT-1, which has DNA binding and transcriptional activation ability. Expression of homeobox protein prophet of PIT-1 is required for the ontogenesis of pituitary gonadotropes, somatotropes, lactotropes, and thyrotropes needed for the normal production of growth hormone (GH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (PrL). Two conserved basic regions within the homeodomain are important for localization to the nucleus, DNA binding, and target gene activation. Missense variants in these two regions of PROP1 result in CPHD, indicating the importance of these conserved sequences [Guy et al 2004].

Mechanism of disease causation. Loss of function with reduced or absent DNA binding and transcriptional activation ability

Author Notes

www.endocrinologiausp.com.br
Instagram: @disciplinaendocrinologia
deficienciaghusp.com

Acknowledgments

Fundação de amparo a Pesquisa do Estado de São Paulo (Fapesp)
Conselho nacional de apoio à Pesquisa (CNPq)

Author History

Ivo Jorge Prado Arnhold, MD (2022-present)
Fernanda Azevedo Correa, MD (2022-present)
Berenice B Mendonca, MD (2022-present)
Luciani Renata Carvalho, MD, PhD (2022-present)
Laura CG de Graaff, MD, PhD; Erasmus Medical Center (2011-2022)
Lawrence C Layman, MD; Medical College of Georgia (1999-2011)
Juliana Moreira Marques, PhD (2022-present)
Mirian Yumie Nishi, MD, PhD (2022-present)
John A Phillips III, MD; Vanderbilt University Medical Center (1999-2011)
Cindy Vnencak-Jones, PhD; Vanderbilt University Medical Center (1999-2011)

Revision History

• 24 February 2022 (sw) Comprehensive update posted live
• 7 August 2014 (me) Comprehensive update posted live
• 6 October 2011 (me) Comprehensive update posted live
• 21 November 2005 (me) Comprehensive update posted live
• 16 June 2003 (ca) Comprehensive update posted live
• 7 December 2000 (me) Review posted live
• 18 October 1999 (jp) Original submission

Published Guidelines / Consensus Statements

• Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab. Available online. 2000. Accessed 11-15-22.
• Ho KK, et al. GH Deficiency Consensus Workshop Participants. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Available online. 2007. Accessed 11-15-22.

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