• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

PROP1-Related Combined Pituitary Hormone Deficiency

Synonym: PROP1-Related CPHD
, MD, PhD
Erasmus Medical Center
Rotterdam, The Netherlands

Initial Posting: ; Last Update: October 6, 2011.

Summary

Disease 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). Most affected individuals are ascertained because of growth failure and failure to thrive starting in infancy or early childhood (age range: ~9 months to ~8 years). Hypothyroidism is usually mild and occurs in later infancy and childhood. 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.

Diagnosis/testing. Testing for deficient secretion of GH, TSH, LH, FSH, PrL, and ACTH establishes the diagnosis of CPHD. PROP1 is the only gene in which mutation is known to cause PROP1-related CPHD.

Management. Treatment of manifestations: GH deficiency is treated with injection of biosynthetic growth hormone from the time of diagnosis until approximately age 17 years. TSH deficiency is treated by thyroid hormone replacement in the form of oral L-thyroxine. Infants with micropenis are treated with 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 conjugated estrogens or ethinyl estradiol and later by cycling with estrogen and progesterone. Fertility in both sexes is possible with administration of gonadotropins. ACTH deficiency is treated with oral hydrocortisone.

Surveillance: Regular follow up for all affected individuals to monitor for effectiveness and/or complications of hormone replacement therapy and for evidence of other hormone deficiencies.

Evaluation of relatives at risk: For younger sibs: if both (paternal and maternal) PROP1 mutations are known 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. At conception, the sibs of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible when both paternal and maternal disease-causing PROP1 mutations are known.

Diagnosis

Clinical Diagnosis

The diagnosis of combined pituitary hormone deficiency (CPHD) requires the presence of 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)
  • Less frequently, adrenocorticotropic hormone (ACTH)

The diagnosis of PROP1-related combined pituitary hormone deficiency, the focus of this GeneReview, requires the diagnosis of CPHD and identification at least one PROP1 mutation.

Growth hormone (GH) deficiency is suspected in children with:

  • Neonatal hypoglycemia

    AND/OR
  • Proportionate short stature and delayed bone maturation (in the absence of an inherited bone dysplasia or chronic disease) with the following growth patterns [Rosenfeld 1996]:
    • Severe short stature with height more than three standard deviations (SD) below the mean for age

      OR
    • Moderate short stature with height 2-3 SD below the mean for age and growth deceleration with height velocity less than 25th percentile for age

      OR
    • Severe growth deceleration with height velocity less than fifth percentile for age

Thyroid-stimulating hormone (TSH) deficiency is suspected in the following:

  • Infants over age one month with large posterior fontanelle (diameter >1 cm), jaundice that lasts for more than one week after birth, macroglossia, hoarse cry, distended abdomen, umbilical hernia, excessive sleeping, and hypotonia. Note: Infants with congenital hypothyroidism may show no signs in the first month of life.
  • Children with growth failure, poor weight gain, and delayed bone maturation

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deficiency is suspected in the following:

  • Newborn males with micropenis (stretched penile length <2.5 cm in a term infant) without hypospadias, with or without cryptorchidism
  • Adolescent males with onset of puberty after age 14 years or cessation of secondary sexual development
  • Adolescent females with lack of breast development or menses by age 14 years

Prolactin (PrL) deficiency is suspected in females with impaired lactation.

Adrenocorticotropic hormone (ACTH) deficiency is suspected in children and adults with persistent weakness, fever, abdominal pain, anorexia, and weight loss. Signs of acute ACTH deficiency include acute hypotension, dehydration, and shock accompanied by hyponatremia, hyperkalemia, and hypoglycemia.

Testing

Testing concomitantly for deficient secretion of GH, TSH, LH, FSH, PrL, and ACTH should be performed for diagnosis and management [Phillips 1995, Rimoin & Phillips 1997].

Deficiencies of all pituitary hormones may be assessed simultaneously using a triple test comprising the following:

  • Insulin-induced hypoglycemia (with a blood sugar <40 mg/dL or half the baseline value) which should increase the serum concentration of growth hormone, prolactin, and cortisol
  • TRH (thyrotropin-releasing hormone) which should increase serum concentrations of TSH and PrL
  • Exogenous GnRH (gonadotropin-releasing hormone) which should increase serum concentrations of LH and FSH

Growth hormone (GH) deficiency. Note: (1) Even in the appropriate clinical setting, the diagnosis of GH deficiency remains problematic because of the difficulty in measuring physiologic GH secretion. (2) Provocative tests of GH secretion are widely used in the diagnosis of GH deficiency, although they are associated with a high false positive rate.

Stimuli used for provocative testing for GH deficiency include exercise, arginine, L-dopa, clonidine, insulin, insulin-arginine, glucagon, and propranolol.

  • Confirmatory finding. Serum concentration of GH less than 7-10 ng/dL on two provocative tests
    Note: A peak serum concentration of GH greater than 7-10 ng/mL on one test rules out the diagnosis of GH deficiency.

Thyroid-stimulating hormone (TSH) deficiency

  • Suggestive finding. Serum T4 concentration 1.0 µg/dL below normal for age with a low serum TSH concentration (normal: 0.1 mU/L to 4.5-5.5 mU/L)
  • Confirmatory finding. Subnormal increase in serum concentration of TSH 30 minutes after infusion of TRH

Note: All newborn screening programs for congenital hypothyroidism screen for elevated TSH. Persons with central hypothyroidism normally have low thyroid hormone concentrations associated with inappropriately low/normal TSH levels. Note: In countries in which the neonatal screening program is based on TSH levels only, such individuals are not detected.

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deficiency

  • Suggestive finding. Low serum concentrations of LH and FSH and low serum testosterone concentration in males; low serum estradiol concentration (and/or the lack of progestin-induced withdrawal bleeding) in females age 14 years or older
  • Confirmatory finding. Subnormal increase in serum concentration of LH and FSH following infusion of GnRH in an individual age 14 years or older
    Note: No absolute cutoff values have been established.

Prolactin (PrL) deficiency

  • Suggestive finding. Very low or undetectable baseline prolactin
  • Confirmatory finding. Absent response to TRH stimulation

Adrenocorticotropic hormone (ACTH) deficiency

  • Suggestive findings
    • Low serum concentration of sodium and glucose and elevated serum concentration of potassium in an acutely ill individual
    • Serum ACTH concentration that is inappropriately low in the face of a low serum concentration of cortisol (Note: Blood sample for the ACTH assay needs to be collected properly and processed rapidly.)
    • Normal renin-aldosterone axis
  • Confirmatory finding. Subnormal increase in serum ACTH concentration in response to CRH (corticotropin releasing hormone) suggests a pituitary etiology of ACTH deficiency. Note: Insulin-induced hypoglycemia may also be used, but a subnormal response could indicate a hypothalamic or a pituitary cause.

Molecular Genetic Testing

Gene. PROP1 is the only gene in which mutations cause PROP1-related CPHD.

Note: The proportion of CPHD caused by mutations in PROP1 varies by study suggesting either bias in ascertainment in some studies or variation in the frequency of PROP1 mutations between populations of different ethnic origins [reviewed in de Graaff et al 2010]. See Table 2.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in PROP1-Related Combined Pituitary Hormone Deficiency

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 1
PROP1Sequence analysis 4Sequence variants 5>98%
Deletion/duplication analysis 6(Multi)exonic or whole-gene deletionSee footnote 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene in a person who meets diagnostic criteria for PROP1-related CPHD.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. The common recurring PROP1 deletion in which three AG repeats are reduced to two AG repeats (c.301_302delAG) accounts for 55% of alleles in familial cases and 12% of alleles in simplex cases of CPHD (i.e., single occurrence in a family).

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Abrão et al [2006] reported complete deletion of PROP1 in two sibs with GH deficiency associated with other pituitary hormone deficiencies (TSH, PRL and gonadotropins). One of the sibs also had an evolving cortisol deficiency. Kelberman et al [2009] identified a homozygous deletion of PROP1 in two individuals with CPHD born to consanguineous parents. Zhang et al [2010] reported in two pedigrees with CPHD a deletion of a segment of about 53.2 kb encompassing PROP1 and adjacent sequences.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Growth hormone (GH) deficiency must be present.
  • The order in which TSH, LH, FSH, PrL, and ACTH secretion is assessed depends on the findings in the individual.
  • In individuals with GH deficiency and at least one other pituitary hormone deficiency, molecular genetic testing of PROP1 (first by sequence analysis followed by deletion/duplication analysis if no or only one PROP1 mutation is identified) is indicated to establish the diagnosis of PROP1-related CPHD.

    The likelihood of CPHD being PROP1-related CPHD varies by study suggesting either bias in ascertainment in some studies or variation in the frequency of PROP1 mutations between populations of different ethnic origins. In several international centers (UK, India, and Poland), PROP1 mutations were identified in almost 30% of familial cases and only 1%-2% of simplex cases [Turton et al 2005]. Table 2 summarizes the PROP1 mutation frequencies in persons with CPHD from several published articles.
  • For individuals with CPHD in whom no PROP1 mutation is identified, consider testing other genes in which mutations are known to cause CPHD (see Differential Diagnosis).

Table 2. PROP1 Mutation Detection Frequency in Cohorts with CPHD

ReferenceSimplex / Familial CasesN PatientsN FamiliesN Mutations/
N Tested
Origin
Dateki et al [2010]Unknown71NA0Japanese
Diaczok et al [2008]Unknown19NA0Unknown
De Graaff et al [2010] Mostly simplex 78760Dutch
McLennan et al [2003]Simplex 3300Australian
Kim et al [2003]Simplex1200Korean
Rainbow et al [2005]Mostly simplex 27260UK
Fernandez-Rodriguez et al [2011]Mixed simplex and familial23NA2/23Spanish
Turton et al [2005]Mixed simplex and familial153NA15Various
Osorio et al [2002]Mostly simplex 76745/43Brazilian
Nyström et al [2011]Mixed 25232/17Unknown
Reynaud et al [2006]Mixed 19516520/109Various
Lebl et al [2005]Mostly simplex 74NA 118/74Czech
Zimmermann et al [2007]Mixed simplex and familial17NA5/17Unknown
Vieira et al [2007]Mixed 40369/26Brazilian
Vallette-Kasic et al [2001]Mostly simplex 23209/23 2Various
Lemos et al [2006]Mixed 46Footnote 319Portuguese
Halász et al [2006]Unknown35NA15/35Hungarian
Deladoëy et al [1999]Familial 733635/73 2Unknown
Fofanova et al [1998]Mixed 14Footnote 48/14Russian

PROP1 mutation frequencies reported in CPHD populations (Studies that investigated cohorts mixed isolated growth hormone deficiency (IGHD) and CPHD are not included.)

1. Including 4 sib pairs

2. Same mutation found in more than one individual from a given family

3. 17 familial cases from seven families; 29 simplex cases

4. Seven familial cases from four families; seven simplex cases

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

PROP1 mutations are associated with deficiencies of growth hormone (GH), thyroid-stimulating hormone (TSH), gonadotropins (FSH and LH), 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 ACTH.

The degree of hormone deficiency and the age of onset of the deficiency are variable even within the same family. In a follow-up study of nine individuals with PROP1 mutations, all seven who had reached the age of puberty required sex hormone replacement therapy (HRT). Repeated testing of pituitary function indicated a decline over time; all individuals developed some degree of adrenal insufficiency [Bottner et al 2004].

GH deficiency. Children with PROP1-related CPHD are often ascertained because of short stature. Most affected children have normal birth weight and birth length and an uncomplicated perinatal period. Growth failure and failure to thrive begin in infancy or early childhood (range: ~9 months to ~8 years).

Individuals with PROP1-related CPHD who have untreated growth hormone deficiency have proportional short stature (i.e., <4 cm difference between length of arm span and height) with proportionately small hands and feet. Height is usually profoundly reduced, with SD scores of more than -3.7 [Bottner et al 2004, Reynaud et al 2004a].

In newborn infants, the primary manifestation may be hypoglycemia.

TSH deficiency. Rarely, hypothyroidism is the presenting finding [Flück et al 1998]. 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.

FSH and LH deficiency. 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 before requiring hormone replacement therapy [Flück et al 1998].

In some individuals, apparently isolated gonadotropin deficiency may be the presenting finding: in one family two brothers were thought to have isolated hypogonadotropic hypogonadism until they developed GH deficiency and TSH deficiency after age 30 years; at that time CPHD was diagnosed [Reynaud et al 2005].

PrL deficiency. Prolactin deficiency generally causes few symptoms, as prolactin is only required at the time of breastfeeding.

ACTH deficiency. It was initially thought that ACTH deficiency was uncommon and, when present, usually occurred in adolescence or adulthood; however, longer follow up has shown that some degree of adrenal failure may occur in most individuals with PROP1 mutations [Bottner et al 2004].

CPHD. Severe deficiency of GH and insulin-like growth factor 1 (IGF-1), especially when combined with hypothyroidism and absence of secondary sexual development, are associated with significant growth failure. In one Brazilian family in which eight individuals had this combination of findings; adult heights ranged from 5.9 to 9.6 SD below the mean [Pernasetti et al 2000].

Other findings

  • An 8° to 20° limitation of extension of the elbows that increases with age has been observed.
  • 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.
  • Intelligence is usually normal.

Imaging studies. The pituitary may initially appear diffusely enlarged in childhood and then reduced in size in adolescence or adulthood [Mendonca et al 1999, Riepe et al 2001, Reynaud et al 2004a, Tatsumi et al 2004, Voutetakis et al 2004a, Voutetakis et al 2004b].

The sella turcica may be normal in size or enlarged, or may appear "empty."

Genotype-Phenotype Correlations

No correlation has been observed between the different PROP1 mutations and the phenotype of the affected individual.

Penetrance

The clinical phenotype of PROP1-related CPHD is variable, even among individuals with the same mutations. Variation is observed in the age at diagnosis and the severity of findings resulting from deficiencies of GH, TSH, LH, FSH, and PrL [Flück et al 1998].

Anterior pituitary function including adrenal function can deteriorate over time such that penetrance is age dependent.

Prevalence

The frequency of pituitary dwarfism is estimated at 1:4000 in England and the US. The proportion of individuals with pituitary dwarfism who have CPHD ranges from 43% to 63%, suggesting that the frequency of CPHD is approximately 1:8000.

Differential Diagnosis

While short stature, delayed growth velocity, and delayed skeletal maturation are all seen with GH deficiency, none of these manifestations is specific for GH deficiency; therefore, individuals with these findings should be evaluated for other, systemic diseases associated with short stature before doing provocative tests to document GH deficiency.

Combined Pituitary Hormone Deficiencies (CPHD)

Whereas many individuals with pituitary dwarfism have a craniopharyngioma or other non-genetic cause, 7% to 12% of individuals have an affected first-degree relative, suggesting that many cases are the result of genetic factors [Phillips 1995].

Familial CPHD can be inherited in an autosomal recessive, autosomal dominant, or X-linked recessive manner. To date, PROP1, POU1F1 (formerly PIT1), HESX1, LHX3, and LHX4 have been associated with familial CPHD [Dattani et al 1998, Dattani 2003, Kim et al 2003, McLennan et al 2003, Reynaud et al 2004b].

Although genetic aberrations of a specific gene are associated with a ‘typical’ phenotype, variability in the onset and extent of clinical manifestations can be observed. Depending on the gene involved, pituitary manifestations may range from normal pituitary function to complete pan-hypopituitarism and from normal height to severe growth retardation.

For the clinician this means that continuous monitoring of the hormonal state of the patient until adulthood is mandatory to avoid late-onset complications. For the geneticist it means that the type of hormone deficiencies, the extra-pituitary manifestations and the family history give valuable information for a specific genetic workup, but that additional ‘atypical’ genes have to be considered if the initial analysis fails to detect a mutation in the ‘first-choice’ candidate genes [Pfäffle & Klammt 2011].

PROP1. Bottner et al [2004] concluded that 50% of CPHD has a genetic basis and that half of familial cases are caused by PROP1 mutations; however, more recent data demonstrate that this is not the situation for simplex cases (see Table 2).

POU1F1 (formerly PIT1). Mutations of POU1F1 causing CPHD can be inherited in either an autosomal recessive or autosomal dominant manner. POU1F1 mutations are associated with deficiencies of growth hormone and prolactin and variable deficiency of the ß subunit of TSH. Of note, POU1F1 mutations are also associated with isolated growth hormone deficiency [Dattani 2003].

Most affected individuals have normal birth weight and birth length and an uncomplicated perinatal course. Growth hormone deficiency is usually severe and most individuals have growth failure in early infancy.

Hypothyroidism can be congenital, or mild and later in onset; progressive loss of TSH occurs over time.

Affected individuals have proportional short stature and distinctive facies characterized by prominent forehead, marked midface hypoplasia with depressed nasal bridge, deep-set eyes, and short nose with anteverted nostrils [Aarskog et al 1997].

The pituitary usually appears hypoplastic on imaging studies.

HESX1. Mutations in HESX1 have been identified with both autosomal dominant and autosomal recessive inheritance of CPHD [Cohen et al 2003], sometimes combined with septo-optic dysplasia (SOD). Affected individuals may present with isolated growth hormone deficiency (IGHD) [Vivenza et al 2011].

At present, eleven HESX1 mutations have been described. Affected individuals had midline defects, optic nerve hypoplasia, neuro-pituitary ectopia, and pituitary hypoplasia associated with hormonal deficiencies [McNay et al 2007].

HESX1 is expressed in the thickened layer of oral ectoderm that gives rise to the Rathke pouch, the primordium of the anterior pituitary. Down-regulation of HESX1 coincides with the differentiation of pituitary-specific cell types.

LHX3 and LHX4. LHX3 and LHX4 are members of the LIM-homeodomain family of transcription factors. Together, they regulate proliferation and differentiation of pituitary-specific cell lineages.

LHX3, comprising seven coding exons and six introns that span 8.7 kilobases, is located in the subtelomeric region of chromosome 9. To date, ten recessive mutations in LHX3 have been detected in persons with CPHD.

  • Netchine et al [2000] identified homozygosity for two different LHX3 mutations in affected members of two unrelated consanguineous families with rigidity of the cervical spine and CPHD that involved all the anterior pituitary hormones except ACTH: one was a nonsense mutation (p.Tyr111Cys) and one a 23-bp intragenic deletion.
  • Bhangoo et al [2006] identified a homozygous 1-bp LHX3 deletion (g.159delT) in a boy with CPHD and rigid cervical spine.
  • Pfaeffle et al [2007] identified the LHX3 mutations p.Glu173Ter, p.Ala210Val, LHX3 -/-, and p.Trp224Ter in seven affected individuals from four families in a cohort of 366 persons from 342 families with CPHD. They concluded that LHX3 mutations are a rare cause of CPHD and that they are associated with mild or severe deficiencies of GH, PRL, TSH, and LH/FSH in all cases. They noted that limited neck rotation was not present in three sibs with CPHD who had an LHX3 nonsense mutation.
  • Rajab et al [2008] identified a homozygous large intragenic deletion (3088-bp del) and a homozygous nonsense mutation (p.Lys50Ter) in four persons from two unrelated consanguineous families with CPHD and neonatal hypoglycemia, short neck with limited rotation, and mild sensorineural hearing loss. Based on the observations that sensorineural hearing loss was found when three of the mutation-positive individuals studied by Netchine et al [2000] were reexamined and that ACTH deficiency was present in one of the persons reported by Rajab et al [2008], they proposed that the phenotypic spectrum of LHX3 mutations includes CPHD (with or without ACTH deficiency) with limited neck rotation and mild sensorineural hearing loss.
  • Kriström et al [2009] found a novel, recessive, A-G splice-acceptor site mutation in exon 3, resulting in deletion of the homeodomain and the C-terminus. Like the individuals reported by Rajab et al [2008], the individuals reported by Kriström et al [2009] had CPHD, restricted neck rotation, and a severe hearing defect.

LHX4 extends over approximately 45 kb on chromosome 1. Heterozygous mutations in LHX4 are associated with CPHD along with congenital defects in the cerebellum and sella turcica. To date six LHX4 mutations have been described.

  • In a French family with CPHD, pituitary and cerebellar defects, and abnormalities of the sella turcica, Machinis et al [2001] identified a G-to-C transversion (IVS4, G-C, -1) in four affected members.
  • Pfaeffle et al [2008] identified three heterozygous missense LHX4 mutations (p.Arg84Cys, p.Ala210Pro, and p.Leu190Arg) in five persons out of 253 individuals from 245 families with CPHD. In structural models and functional studies the p.Ala210Pro and p.Leu190Arg mutant proteins showed impaired DNA binding and impaired gene activation, causing the protein to be inactive. The p.Arg84Cys mutant protein showed only reduced activity.
  • Castinetti et al [2008] found a new mutation in the protein sequence of LHX4 (Thr99fs) in one of 136 individuals with CPHD and malformations of the brain, pituitary stalk, or posterior pituitary gland [Castinetti et al 2008].
  • Tajima et al [2007] found a de novo heterozygous Pro366-to-Thr (p.Pro366Thr) substitution in a conserved residue in the C terminus in a 16-month-old Japanese girl with severe CPHD, pituitary defects, small sella turcica, and Chiari malformation. The mutation was not found in 80 Japanese controls [Tajima et al 2007].

Isolated Growth Hormone Deficiency

CPHD needs to be differentiated from isolated growth hormone deficiency (IGHD).

GH1-related IGHD

  • IGHD IA and IB are inherited in an autosomal recessive manner.
    • In IGHD 1A, GH1 deletions, frameshifts, and nonsense mutations lead to GH deficiency with severe growth failure; affected individuals often develop anti-GH antibodies when given exogenous GH.
    • In IGHD IB, GH1 splice site mutations are responsible for low (but detectable) levels of GH. Growth failure is less severe than in IGHD IA, and individuals usually respond well to exogenous GH.
  • IGHD II is inherited in an autosomal dominant manner. Splice site or missense GH1 mutations have a dominant-negative effect. The clinical severity of IGHD II varies across kindreds. Affected individuals usually respond well to exogenous GH.

Isolated Hypogonadotropic Hypogonadism

In one family two brothers with PROP1-related CPHD were thought to have hypogonadotropic hypogonadism until they developed GH deficiency and TSH deficiency after age 30 years [Reynaud et al 2005]. Their findings demonstrate that PROP1 mutations should also be considered among possible genetic causes of apparently isolated hypogonadotropic hypogonadism.

Syndromes that Include Hypopituitarism

Recently, mutations in the following genes have been studied in syndromes that include hypopituitarism [Roessler et al 2003, Kelberman & Dattani 2007, Ashkenazi-Hoffnung et al 2010]:

  • SOX2 mutations observed with hypogonadotropic hypogonadism; anterior pituitary hypoplasia; bilateral anophthalmia/microphthalmia; abnormal corpus callosum; learning difficulties; esophageal atresia, and/or sensorineural hearing loss (See Anophthalmia/Microphthalmia Overview, SOX2-Related Eye Disorders.)
  • SOX3 mutations observed with X-linked anterior pituitary hypoplasia with IGHD or panhypopituitarism; infundibular hypoplasia and/or ectopic posterior pituitary; intellectual disability [Solomon et al 2004, Woods et al 2005]
  • OTX2 mutations observed with isolated growth hormone deficiency (IGHD) with small anterior pituitary gland, invisible stalk, ectopic posterior lobe, and anophthalmia [Diaczok et al 2008]
  • GLI2 mutations observed with holoprosencephaly, abnormal pituitary gland function, and variable craniofacial abnormalities. Other features included postaxial polydactyly, single nares, single central incisor, and partial agenesis of the corpus callosum [Roessler et al 2003].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in each individual with newly diagnosed PROP1-related combined pituitary hormone deficiency (CPHD), it is important to evaluate for deficiencies of GH, TSH, LH, FSH, PRL, and ACTH because treatment of one hormone deficiency can precipitate symptoms of another hormone deficiency.

  • A total T4 assay can be used to evaluate thyroid hormone production.
  • Evaluation of LH and FSH production is more relevant in postpubertal individuals, particularly if sexual development is incomplete or if women display hypoestrogenic amenorrhea.
  • AM cortisol can be used to evaluate adrenal hormone production.

Treatment of Manifestations

The main principle of treatment in CPHD is replacement therapy with the appropriate hormones [Mehta et al 2009].

  • Growth hormone. GH deficiency is treated by subcutaneous injection of biosynthetic (i.e., recombinant) GH. To obtain an optimal outcome, replacement therapy should be started as soon as the diagnosis of GH deficiency is established. The initial dose of recombinant human GH (rhGH) is based on body weight, but the exact dose and the frequency of administration vary by protocol. The dose increases with increasing body weight to a maximum during puberty and is usually discontinued when final height has been reached, at approximately age 17 years [Ranke 1995, Rosén et al 1995, Growth Hormone Research Society 2000 (full text)].

    There is increasing support for the use of rhGH treatment in young adults with GHD as well because of the possible effects on fat metabolism, lean body mass, and bone mineral density [Ho 2007 (full text)].

    Clinical response to exogenous GH usually depends on the etiology and severity of the 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 [Blethen et al 1997]. De Ridder et al [2007] developed a model that accurately predicts the adult height that will be achieved by GH therapy.
  • TSH. TSH deficiency is treated by thyroid hormone replacement in the form of L-thyroxine at a dose of approximately 1-3 µg/kg/day given orally. Of note, thyroid hormone replacement should not be initiated until adrenal function has been assessed and adrenal insufficiency is treated if present.
  • LH and FSH
    • Male infants with micropenis are treated with 50 mg testosterone enanthate intramuscularly every four weeks for a total of three to four doses.
    • If GH deficiency is present and if the child's growth normalizes before adolescence, it is appropriate to begin sex steroid replacement to induce secondary sex characteristics.
      • In males, this can be initiated at age 12 to 13 years with monthly injections of 100 mg testosterone enanthate, gradually increasing by 50 mg every six months to a dose of 200 to 300 mg per month.
      • In females, this can be initiated at age 11 to 12 years with conjugated estrogens or ethinyl estradiol, eventually cycling with estrogen and progesterone.
    • If the child has untreated growth hormone deficiency, the sex hormone replacement is given in lower doses and started at a later age to ensure maximal growth before epiphyseal closure.
    • Usually sex steroids are used to maintain secondary sex characteristics.
    • Fertility in both females and males is possible with administration of gonadotropins [Voutetakis et al 2004c]. Note: Because infertility in individuals with PROP1-related CPHD is secondary to hypogonadotropic hypogonadism, appropriate treatment consists of gonadotropin replacement rather than the use of clomiphene citrate, which requires an intact pituitary gland.
  • ACTH. Long-term management is usually 10-15 mg/M2 oral hydrocortisone per 24 hours divided into three doses.
    • For individuals with GH deficiency, the lowest safe dose of hydrocortisone is used to avoid interfering with the growth response to growth hormone therapy.
    • For minor stress such as fever or minor illness, the dose of hydrocortisone is doubled or tripled until the illness has resolved.
    • For major stress, such as surgery or significant illness, hydrocortisone is increased to 40 to 100 mg/M2 and administered parenterally.

Surveillance

Growth should be carefully monitored; if growth velocity is low, evaluation for GH deficiency should be undertaken.

In persons with PROP1 mutations without known ACTH deficiency, cortisol levels should be monitored because ACTH deficiency may develop at a later time.

Evaluation of Relatives at Risk

If both (paternal and maternal) PROP1 mutations are identified in a proband, it is appropriate to perform molecular genetic testing on younger sibs to enable early diagnosis and treatment.

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 growth hormone deficiency.

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

Therapies Under Investigation

Search ClinicalTrials.gov 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

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

Carrier Detection

Carrier testing is possible if the disease-causing PROP1 mutations have been identified 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, clarification of carrier status, and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like PROP1-related combined pituitary hormone deficiency) do not affect intellect and are associated with a good prognosis with early treatment are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
    Email: hgf1@hgfound.org
  • MAGIC Foundation
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
    Fax: 708-383-0899
    Email: info@magicfoundation.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. PROP1-Related Combined Pituitary Hormone Deficiency: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
PROP15q35​.3Homeobox protein prophet of Pit-1PROP1 homepage - Mendelian genesPROP1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for PROP1-Related Combined Pituitary Hormone Deficiency (View All in OMIM)

262600PITUITARY HORMONE DEFICIENCY, COMBINED, 2; CPHD2
601538PROP PAIRED-LIKE HOMEOBOX 1; PROP1

Gene structure. PROP1 comprises three exons of 418, 233, and 339 bp and spans 3.54 kb. Transcripts are 1464 nucleotides long. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. (See Table 3, Table 4 [pdf].)

  • Wu et al [1998] reported five families in which CPHD was caused by homozygosity or compound heterozygosity for inactivating mutations of PROP1; these mutations result in PROP1 products with reduced DNA binding and transcriptional activation. The mutation c.301_302delAG was detected on different haplotypes in families with CPHD from different countries. These data strongly suggest that the c.301_302delAG is a recurrent mutation, possible resulting from DNA slippage repair defects.
  • Paracchini et al [2003] described two sibs with compound heterozygosity p.[Arg71Cys]+[Arg71His] in the first alpha helix of the PROP1 homeodomain (no in vitro analysis was performed). Both had GH and TSH deficiency and short stature. One sib, who was of pubertal age, lacked breast development.
  • Reynaud et al [2004a] described a homozygous c.217C>T mutation in a large, consanguineous kindred. All 12 individuals studied had complete GH deficiency. Eleven of 12 had TSH deficiency and eight of ten had ACTH deficiency. Only two females had spontaneous puberty. In vitro studies revealed that the mutant protein had 11.5% of transactivation capacity of wild type PROP1 and was unable to bind a high-affinity DNA sequence.
  • Tatsumi et al [2004] reported the first instance of PROP1 mutations causing CPHD in Japanese individuals. Two sibs presenting with early-onset growth deficiency and deficiencies of GH, TSH, PRL, and gonadotropins were homozygous for c.157delA. The protein, if translated, predicts the absence of the DNA binding domain.
  • Voutetakis et al [2004b] reported compound heterozygosity for p.Leu102CysfsTer8 (c.300_301 delGA) and a nonsense mutation p.Gln83Ter (in a neonate with jaundice and congenital hypothyroidism.
  • Voutetakis et al [2004a] reported 15 individuals (age 2.5-45 years) with a variety of different PROP1 genotypes including
    • Homozygosity for c.300_301delGA (7 individuals);
    • Homozygosity for c.150delA (5 individuals);
    • Compound heterozygosity for c.[300_301delGA]+[150delA] (2 individuals);
    • Compound heterozygosity for c.[300_301delGA]+[218G>A] (1 individual).
  • Böttner et al [2004] reported a progressive decline with age in peak levels of GH, TSH, prolactin, and LH/FSH in nine individuals with the mutations c.300_301delGA, c.150delA, and/or c.109+1G>T. Although PROP1 mutations are usually not associated with ACTH deficiency, all patients developed at least partial adrenal insufficiency, with a gradual decline of the function of the pituitary adrenal axis, and eventually required treatment with hydrocortisone.
  • Reynaud et al [2005] reported three brothers with hypogonadotropic hypogonadism as a result of homozygosity for the nonsense mutation c.582G>A (p.Trp194Ter) causing premature truncation of the protein in the transactivation domain. The brothers reached normal adult height but developed GH and TSH deficiencies after age 30 years. In vitro studies revealed that the transactivation capacity of the protein was 34.4% of wild type and suggested that the C-terminal end of the protein plays a role in protein-DNA binding.
  • Turton et al [2005] described considerable phenotypic variability in siblings with CPHD, suggesting that modifying environmental or genetic factors play a role in phenotypic expression of disease. In addition, they report the mutation c.112_124del as a possible founder mutation from the Indian subcontinent, having identified the mutation in eight individuals from five different families.
  • Nose et al [2006] described an insertion, c.467_468insT, located in the transcription-activating region of PROP1 in two sisters with slight pituitary hypoplasia and deficiencies of growth hormone, thyroid stimulating hormone, prolactin, and gonadotropins; adrenocorticotropin secretion appeared adequate.
  • Lemos et al [2006] described a novel initiation codon mutation (c.2T>C), the first mutation reported in exon 1, which appears to lead to a null allele that abolishes the translation of the PROP1 protein.
  • Abrão et al [2006] reported a complete deletion of PROP1 in two siblings with GH deficiency associated with other pituitary hormone deficiencies (TSH, PRL, and gonadotropins). One of the siblings also had an evolving cortisol deficiency.
  • Kelberman et al [2009] reported compound heterozygosity for the c.373C>T and c.310delC mutations associated with CPHD including ACTH deficiency. Two individuals harboring a complete PROP1 deletion had normal cortisol secretion.

    Kelberman et al [2009] also reported an intronic c.343-11C>G mutation associated with CPHD, which disrupts correct splicing resulting in the loss of exon 3 from the PROP1 transcript.
  • Zhang et al [2010] reported a deletion of a segment of about 53.2 kb encompassing PROP1 and adjacent sequences in two pedigrees with CPHD.

No autosomal dominant PROP1 mutations have been reported to date. (For more information see Table A.)

Table 3. Selected PROP1 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.2T>C(null allele)
c.109+1G>T
(IVS1+1G>T)
NM_006261​.4
NP_006252​.3
c.112_124delp.Ser38ProfsTer123
c.150delAp.Arg53AspfsTer112
c.157delAp.Arg53AspfsTer112
c.211C>Tp.Arg71Cys
c.212G>A p.Arg71His
c.217C>Tp.Arg73Cys
c.218G>Ap.Arg73His
c.247C>Tp.Gln83Ter
c.300_301delGA
(GA296deletion)
p.Leu102CysfsTer8
c.301_302delAGp.Leu102CysfsTer8
c.310delCp.Arg104GlyfsTer61
c.343-11C>G--
c.373C>Tp.Arg125Trp
c.467_468insT
(467insT)
p.Tyr157LeufsTer36
c.582G>Ap.Trp194Ter

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. The product of PROP1, homeobox protein prophet of PIT-1, 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 FSH, LH, GH, PrL, and TSH. Two conserved basic regions within the homeodomain are important for localization to the nucleus, DNA binding, and target gene activation. Missense mutations in these two regions of PROP1 result in CPHD, indicating the importance of these conserved sequences [Guy et al 2004].

Abnormal gene product. Products of mutant PROP1 alleles have reduced or absent DNA-binding and transcriptional activation ability.

References

Published Guidelines/Consensus Statements

  1. 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. Available online. 2000. Accessed 5-8-14. [PubMed: 11095419]
  2. Ho KK. 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 5-8-14. [PubMed: 18057375]

Literature Cited

  1. Aarskog D, Eiken HG, Bjerknes R, Myking OL. Pituitary dwarfism in the R271W Pit-1 gene mutation. Eur J Pediatr. 1997;156:829–34. [PubMed: 9392392]
  2. Abrão MG, Leite MV, Carvalho LR, Billerbeck AE, Nishi MY, Barbosa AS, Martin RM, Arnhold IJ, Mendonca BB. Combined pituitary hormone deficiency (CPHD) due to a complete PROP1 deletion. Clin Endocrinol (Oxf). 2006;65:294–300. [PubMed: 16918947]
  3. Ashkenazi-Hoffnung L, Lebenthal Y, Wyatt AW, Ragge NK, Dateki S, Fukami M, Ogata T, Phillip M, Gat-Yablonski G. A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency. Hum Genet. 2010;127:721–9. [PubMed: 20396904]
  4. Bhangoo AP, Hunter CS, Savage JJ, Anhalt H, Pavlakis S, Walvoord EC, Ten S, Rhodes SJ. Clinical case seminar: a novel LHX3 mutation presenting as combined pituitary hormonal deficiency. J Clin Endocrinol Metab. 2006;91:747–53. [PubMed: 16394081]
  5. Blethen SL, Baptista J, Kuntze J, Foley T, LaFranchi S, Johanson A. Adult height in growth hormone (GH)-deficient children treated with biosynthetic GH. The Genentech Growth Study Group. J Clin Endocrinol Metab. 1997;82:418–20. [PubMed: 9024229]
  6. Bottner A, Keller E, Kratzsch J, Stobbe H, Weigel JF, Keller A, Hirsch W, Kiess W, Blum WF, Pfaffle RW. PROP1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis. J Clin Endocrinol Metab. 2004;89:5256–65. [PubMed: 15472232]
  7. Brickman JM, Clements M, Tyrell R, McNay D, Woods K, Warner J, Stewart A, Beddington RS, Dattani M. Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders. Development. 2001;128:5189–99. [PubMed: 11748154]
  8. Castinetti F, Saveanu A, Reynaud R, Quentien MH, Buffin A, Brauner R, Kaffel N, Albarel F, Guedj AM, El Kholy M, Amin M, Enjalbert A, Barlier A, Brue T. A novel dysfunctional LHX4 mutation with high phenotypical variability in patients with hypopituitarism. J Clin Endocrinol Metab. 2008;93:2790–9. [PubMed: 18445675]
  9. Cohen RN, Cohen LE, Botero D, Yu C, Sagar A, Jurkiewicz M, Radovick S. Enhanced repression by HESX1 as a cause of hypopituitarism and septooptic dysplasia. J Clin Endocrinol Metab. 2003;88:4832–9. [PubMed: 14557462]
  10. Dateki S, Fukami M, Uematsu A, Kaji M, Iso M, Ono M, Mizota M, Yokoya S, Motomura K, Kinoshita E, Moriuchi H, Ogata T. Mutation and gene copy number analyses of six pituitary transcription factor genes in 71 patients with combined pituitary hormone deficiency: identification of a single patient with LHX4 deletion. J Clin Endocrinol Metab. 2010;95:4043–7. [PubMed: 20534763]
  11. Dattani MT (2003) DNA testing in patients with GH deficiency at the time of transition. Growth Horm IGF Res. 13 Suppl A:S122-9. [PubMed: 12914740]
  12. Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM, Gupta R, Martensson IL, Toresson H, Fox M, Wales JK, Hindmarsh PC, Krauss S, Beddington RS, Robinson IC. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet. 1998;19:125–33. [PubMed: 9620767]
  13. de Graaff LC, Argente J, Veenma DC, Drent ML, Uitterlinden AG, Hokken-Koelega AC. PROP1, HESX1, POU1F1, LHX3 and LHX4 mutation and deletion screening and GH1 P89L and IVS3+1/+2 mutation screening in a Dutch nationwide cohort of patients with combined pituitary hormone deficiency. Horm Res Paediatr. 2010;73:363–71. [PubMed: 20389107]
  14. de Ridder MA, Stijnen T, Hokken-Koelega AC. Prediction of adult height in growth-hormone-treated children with growth hormone deficiency. J Clin Endocrinol Metab. 2007;92:925–31. [PubMed: 17179199]
  15. Deladoëy J, Flück C, Büyükgebiz A, Kuhlmann BV, Eblé A, Hindmarsh PC, Wu W, Mullis PE. "Hot spot" in the PROP1 gene responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab. 1999;84:1645–50. [PubMed: 10323394]
  16. Diaczok D, Romero C, Zunich J, Marshall I, Radovick S. A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency. J Clin Endocrinol Metab. 2008;93:4351–9. [PMC free article: PMC2582563] [PubMed: 18728160]
  17. Diaczok D, Romero C, Zunich J, Marshall I, Radovick S. A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency. J Clin Endocrinol Metab. 2008;93:4351–9. [PMC free article: PMC2582563] [PubMed: 18728160]
  18. Fernandez-Rodriguez E, Quinteiro C, Barreiro J, Marazuela M, Pereiro I, Peinó R, Cabezas-Agrícola JM, Dominguez F, Casanueva FF, Bernabeu I. Pituitary stalk dysgenesis-induced hypopituitarism in adult patients: prevalence, evolution of hormone dysfunction and genetic analysis. Neuroendocrinology. 2011;93:181–8. [PubMed: 21304225]
  19. Flück C, Deladoey J, Rutishauser K, Eblé A, Marti U, Wu W, Mullis PE. Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg-->Cys at codon 120 (R120C). J Clin Endocrinol Metab. 1998;83:3727–34. [PubMed: 9768691]
  20. Fofanova OV, Takamura N, Kinoshita E, Parks JS, Brown MR, Peterkova VA, Evgrafov OV, Goncharov NP, Bulatov AA, Dedov II, Yamashita S. A mutational hot spot in the Prop-1 gene in Russian children with combined pituitary hormone deficiency. Pituitary. 1998;1:45–9. [PubMed: 11081182]
  21. 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. GH Research Society. J Clin Endocrinol Metab. 2000;85:3990–3. [PubMed: 11095419]
  22. Guy JC, Hunter CS, Showalter AD, Smith TP, Charoonpatrapong K, Sloop KW, Bidwell JP, Rhodes SJ. Conserved amino acid sequences confer nuclear localization upon the Prophet of Pit-1 pituitary transcription factor protein. Gene. 2004;336:263–73. [PubMed: 15246537]
  23. Halász Z, Toke J, Patócs A, Bertalan R, Tömböl Z, Sallai A, Hosszú E, Muzsnai A, Kovács L, Sólyom J, Fekete G, Rácz K. High prevalence of PROP1 gene mutations in Hungarian patients with childhood-onset combined anterior pituitary hormone deficiency. Endocrine. 2006;30:255–60. [PubMed: 17526936]
  24. Ho KK. 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. Eur J Endocrinol. 2007;157:695–700. [PubMed: 18057375]
  25. Kelberman D, Dattani MT. Hypothalamic and pituitary development: novel insights into the aetiology. Eur J Endocrinol. 2007;157 Suppl 1:S3–14. [PubMed: 17785694]
  26. Kelberman D, Turton JP, Woods KS, Mehta A, Al-Khawari M, Greening J, Swift PG, Otonkoski T, Rhodes SJ, Dattani MT. Molecular analysis of novel PROP1 mutations associated with combined pituitary hormone deficiency (CPHD). Clin Endocrinol (Oxf). 2009;70:96–103. [PubMed: 19128366]
  27. Kim SS, Kim Y, Shin YL, Kim GH, Kim TU, Yoo HW. Clinical characteristics and molecular analysis of PIT1, PROP1,LHX3, and HESX1 in combined pituitary hormone deficiency patients with abnormal pituitary MR imaging. Horm Res. 2003;60:277–83. [PubMed: 14646405]
  28. Kriström B, Zdunek AM, Rydh A, Jonsson H, Sehlin P, Escher SA. A novel mutation in the LIM homeobox 3 gene is responsible for combined pituitary hormone deficiency, hearing impairment, and vertebral malformations. J Clin Endocrinol Metab. 2009;94:1154–61. [PubMed: 19126629]
  29. Lebl J, Vosáhlo J, Pfaeffle RW, Stobbe H, Cerná J, Novotná D, Zapletalová J, Kalvachová B, Hána V, Weiss V, Blum WF. Auxological and endocrine phenotype in a population-based cohort of patients with PROP1 gene defects. Eur J Endocrinol. 2005;153:389–96. [PubMed: 16131601]
  30. Lemos MC, Gomes L, Bastos M, Leite V, Limbert E, Carvalho D, Bacelar C, Monteiro M, Fonseca F, Agapito A, Castro JJ, Regateiro FJ, Carvalheiro M. PROP1 gene analysis in Portuguese patients with combined pituitary hormone deficiency. Clin Endocrinol (Oxf). 2006;65:479–85. [PubMed: 16984240]
  31. Machinis K, Pantel J, Netchine I, Léger J, Camand OJ, Sobrier ML, Dastot-Le Moal F, Duquesnoy P, Abitbol M, Czernichow P, Amselem S. Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4. Am J Hum Genet. 2001;69:961–8. [PMC free article: PMC1274372] [PubMed: 11567216]
  32. McLennan K, Jeske Y, Cotterill A, Cowley D, Penfold J, Jones T, Howard N, Thomsett M, Choong C. Combined pituitary hormone deficiency in Australian children: clinical and genetic correlates. Clin Endocrinol (Oxf). 2003;58:785–94. [PubMed: 12780757]
  33. McNay DE, Turton JP, Kelberman D, Woods KS, Brauner R, Papadimitriou A, Keller E, Keller A, Haufs N, Krude H, Shalet SM, Dattani MT. HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. J Clin Endocrinol Metab. 2007;92:691–7. [PubMed: 17148560]
  34. Mehta A, Gevers EF, Dattani MT. Congenital disorders of the hypothalamo-pituitary-somatotrope axis. Chap 4. In: Brook CDG, Clayton PE, Brown RS, eds. Brook’s Clinical Pediatric Endocrinology. 6 ed. Wiley-Blackwell; 2009:82.
  35. Mendonca BB, Osorio MG, Latronico AC, Estefan V, Lo LS, Arnhold IJ. Longitudinal hormonal and pituitary imaging changes in two females with combined pituitary hormone deficiency due to deletion of A301,G302 in the PROP1 gene. J Clin Endocrinol Metab. 1999;84:942–5. [PubMed: 10084575]
  36. Netchine I, Sobrier ML, Krude H, Schnabel D, Maghnie M, Marcos E, Duriez B, Cacheux V, Moers A, Goossens M, Grüters A, Amselem S. Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet. 2000;25:182–6. [PubMed: 10835633]
  37. Nose O, Tatsumi K, Nakano Y, Amino N. Congenital combined pituitary hormone deficiency attributable to a novel PROP1 mutation (467insT). J Pediatr Endocrinol Metab. 2006;19:491–8. [PubMed: 16759034]
  38. Nyström HF, Saveanu A, Barbosa EJ, Barlier A, Enjalbert A, Glad C, Palming J, Johannsson G, Brue T. Detection of genetic hypopituitarism in an adult population of idiopathic pituitary insufficiency patients with growth hormone deficiency. Pituitary. 2011;14:208–16. [PubMed: 21132537]
  39. Osorio MG, Marui S, Jorge AA, Latronico AC, Lo LS, Leite CC, Estefan V, Mendonca BB, Arnhold IJ. Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRH-R, GH-1, or PROP-1 genes. J Clin Endocrinol Metab. 2002;87:5076–84. [PubMed: 12414875]
  40. Paracchini R, Giordano M, Corrias A, Mellone S, Matarazzo P, Bellone J, Momigliano-Richiardi P, Bona G. Two new PROP1 gene mutations responsible for compound pituitary hormone deficiency. Clin Genet. 2003;64:142–7. [PubMed: 12859410]
  41. Pernasetti F, Toledo SP, Vasilyev VV, Hayashida CY, Cogan JD, Ferrari C, Lourenço DM, Mellon PL. Impaired adrenocorticotropin-adrenal axis in combined pituitary hormone deficiency caused by a two-base pair deletion (301-302delAG) in the prophet of Pit-1 gene. J Clin Endocrinol Metab. 2000;85:390–7. [PubMed: 10634415]
  42. Pfaeffle RW, Hunter CS, Savage JJ, Duran-Prado M, Mullen RD, Neeb ZP, Eiholzer U, Hesse V, Haddad NG, Stobbe HM, Blum WF, Weigel JF, Rhodes SJ. Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies. J Clin Endocrinol Metab. 2008;93:1062–71. [PMC free article: PMC2266965] [PubMed: 18073311]
  43. Pfaeffle RW, Savage JJ, Hunter CS, Palme C, Ahlmann M, Kumar P, Bellone J, Schoenau E, Korsch E, Brämswig JH, Stobbe HM, Blum WF, Rhodes SJ. Four novel mutations of the LHX3 gene cause combined pituitary hormone deficiencies with or without limited neck rotation. J Clin Endocrinol Metab. 2007;92:1909–19. [PubMed: 17327381]
  44. Pfäffle R, Klammt J. Pituitary transcription factors in the aetiology of combined pituitary hormone deficiency. Best Pract Res Clin Endocrinol Metab. 2011;25:43–60. [PubMed: 21396574]
  45. Phillips JA III. Inherited defects in growth hormone synthesis and action. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease, 6 ed. New York, NY: McGraw-Hill; 1995:3023-44.
  46. Pirinen S, Majurin A, Lenko HL, Koski K. Craniofacial features in patients with deficient and excessive growth hormone. J Craniofac Genet Dev Biol. 1994;14:144–52. [PubMed: 7852543]
  47. Rainbow LA, Rees SA, Shaikh MG, Shaw NJ, Cole T, Barrett TG, Kirk JM. Mutation analysis of POUF-1, PROP-1 and HESX-1 show low frequency of mutations in children with sporadic forms of combined pituitary hormone deficiency and septo-optic dysplasia. Clin Endocrinol (Oxf). 2005;62:163–8. [PubMed: 15670191]
  48. Rajab A, Kelberman D, de Castro SC, Biebermann H, Shaikh H, Pearce K, Hall CM, Shaikh G, Gerrelli D, Grueters A, Krude H, Dattani MT. Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss. Hum Mol Genet. 2008;17:2150–9. [PubMed: 18407919]
  49. Ranke MB. Growth hormone therapy in children: when to stop? Horm Res. 1995;43:122–5. [PubMed: 7750910]
  50. Reynaud R, Barlier A, Vallette-Kasic S, Saveanu A, Guillet MP, Simonin G, Enjalbert A, Valensi P, Brue T. An uncommon phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain. J Clin Endocrinol Metab. 2005;90:4880–7. [PubMed: 15941866]
  51. Reynaud R, Chadli-Chaieb M, Vallette-Kasic S, Barlier A, Sarles J, Pellegrini-Bouiller I, Enjalbert A, Chaieb L, Brue T. A familial form of congenital hypopituitarism due to a PROP1 mutation in a large kindred: phenotypic and in vitro functional studies. J Clin Endocrinol Metab. 2004a;89:5779–86. [PubMed: 15531542]
  52. Reynaud R, Gueydan M, Saveanu A. et al. Genetic screening of combined pituitary hormone deficiency: experience in 195 patients. J Clin Endocrinol Metab. 2006;91:3329–3336. [PubMed: 16735499]
  53. Reynaud R, Saveanu A, Barlier A, Enjalbert A, Brue T. Pituitary hormone deficiencies due to transcription factor gene alterations. Growth Horm IGF Res. 2004b;14:442–8. [PubMed: 15519252]
  54. Riepe FG, Partsch CJ, Blankenstein O, Monig H, Pfaffle RW, Sippell WG. Longitudinal imaging reveals pituitary enlargement preceding hypoplasia in two brothers with combined pituitary hormone deficiency attributable to PROP1 mutation. J Clin Endocrinol Metab. 2001;86:4353–7. [PubMed: 11549674]
  55. Rimoin DL, Phillips JA III. Genetic disorders of the pituitary gland. In: Rimoin DL, Connor JM, Pyeritz RE, eds. Principles and Practice of Medical Genetics. 3 ed. New York, NY: Churchill Livingstone; 1997:1331-64.
  56. Roessler E, Du YZ, Mullor JL, Casas E, Allen WP, Gillessen-Kaesbach G, Roeder ER, Ming JE, Ruiz I, Altaba A, Muenke M. Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proc Natl Acad Sci U S A. 2003;100:13424–9. [PMC free article: PMC263830] [PubMed: 14581620]
  57. Rosén T, Johannsson G, Johansson JO, Bengtsson BA. Consequences of growth hormone deficiency in adults and the benefits and risks of recombinant human growth hormone treatment. A review paper. Horm Res. 1995;43:93–9. [PubMed: 7721271]
  58. Rosenfeld RG. Disorders of growth hormone and insulin-like growth factor secretion and action. In: Sperling MA, ed. Pediatric Endocrinology. 1 ed. Philadelphia, PA: WB Saunders. 1996:117-70.
  59. Solomon NM, Ross SA, Morgan T, Belsky JL, Hol FA, Karnes PS, Hopwood NJ, Myers SE, Tan AS, Warne GL, Forrest SM, Thomas PQ. Array comparative genomic hybridisation analysis of boys with X linked hypopituitarism identifies a 3.9 Mb duplicated critical region at Xq27 containing SOX3. J Med Genet. 2004;41:669–78. [PMC free article: PMC1735898] [PubMed: 15342697]
  60. Tajima T, Hattori T, Nakajima T, Okuhara K, Tsubaki J, Fujieda K. A novel missense mutation (P366T) of the LHX4 gene causes severe combined pituitary hormone deficiency with pituitary hypoplasia, ectopic posterior lobe and a poorly developed sella turcica. Endocr J. 2007;54:637–41. [PubMed: 17527005]
  61. Tajima T, Hattorri T, Nakajima T, Okuhara K, Sato K, Abe S, Nakae J, Fujieda K. Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. J Clin Endocrinol Metab. 2003;88:45–50. [PubMed: 12519827]
  62. Tatsumi KI, Kikuchi K, Tsumura K, Amino N. A novel PROP1 gene mutation (157delA) in Japanese siblings with combined anterior pituitary hormone deficiency. Clin Endocrinol (Oxf). 2004;61:635–40. [PubMed: 15521968]
  63. Turton JP, Mehta A, Raza J, Woods KS, Tiulpakov A, Cassar J, Chong K, Thomas PQ, Eunice M, Ammini AC, Bouloux PM, Starzyk J, Hindmarsh PC, Dattani MT. Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD). Clin Endocrinol (Oxf). 2005;63:10–8. [PubMed: 15963055]
  64. Vallette-Kasic S, Barlier A, Teinturier C, Diaz A, Manavela M, Berthezène F, Bouchard P, Chaussain JL, Brauner R, Pellegrini-Bouiller I, Jaquet P, Enjalbert A, Brue T. PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency. J Clin Endocrinol Metab. 2001;86:4529–35. [PubMed: 11549703]
  65. Vieira TC, Boldarine VT, Abucham J. Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency. Arq Bras Endocrinol Metabol. 2007;51:1097–103. [PubMed: 18157385]
  66. Vivenza D, Godi M, Faienza MF, Mellone S, Moia S, Rapa A, Petri A, Bellone S, Riccomagno S, Cavallo L, Giordano M, Bona G. A novel HESX1 splice mutation causes isolated GH deficiency by interfering with mRNA processing. Eur J Endocrinol. 2011;164:705–13. [PubMed: 21325470]
  67. Voutetakis A, Argyropoulou M, Sertedaki A, Livadas S, Xekouki P, Maniati-Christidi M, Bossis I, Thalassinos N, Patronas N, Dacou-Voutetakis C. Pituitary magnetic resonance imaging in 15 patients with Prop1 gene mutations: pituitary enlargement may originate from the intermediate lobe. J Clin Endocrinol Metab. 2004a;89:2200–6. [PubMed: 15126542]
  68. Voutetakis A, Maniati-Christidi M, Kanaka-Gantenbein C, Dracopoulou M, Argyropoulou M, Livadas S, Dacou-Voutetakis C, Sertedaki A. Prolonged jaundice and hypothyroidism as the presenting symptoms in a neonate with a novel Prop1 gene mutation (Q83X). Eur J Endocrinol. 2004b;150:257–64. [PubMed: 15012608]
  69. Voutetakis A, Sertedaki A, Livadas S, Maniati-Christidi M, Mademtzis I, Bossis I, Dacou-Voutetakis C, Messinis IE. Ovulation induction and successful pregnancy outcome in two patients with Prop1 gene mutations. Fertil Steril. 2004c;82:454–7. [PubMed: 15302300]
  70. Woods KS, Cundall M, Turton J, Rizotti K, Mehta A, Palmer R, Wong J, Chong WK, Al-Zyoud M, El-Ali M, Otonkoski T, Martinez-Barbera JP, Thomas PQ, Robinson IC, Lovell-Badge R, Woodward KJ, Dattani MT. Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet. 2005;76:833–49. [PMC free article: PMC1199372] [PubMed: 15800844]
  71. Wu W, Cogan JD, Pfäffle RW, Dasen JS, Frisch H, O'Connell SM, Flynn SE, Brown MR, Mullis PE, Parks JS, Phillips JA, Rosenfeld MG. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet. 1998;18:147–9. [PubMed: 9462743]
  72. Zhang H, Wang Y, Han L, Gu X, Shi D. A large deletion of PROP1 gene in patients with combined pituitary hormone deficiency from two unrelated Chinese pedigrees. Horm Res Paediatr. 2010;74:98–105. [PubMed: 20395664]
  73. Zimmermann A, Schenk JP, Grigorescu Sido P, Pfaffle R, Lazea C, Zimmermann T, Heinrich U, Weber MM, Bettendorf M. MRI findings and genotype analysis in patients with childhood onset growth hormone deficiency--correlation with severity of hypopituitarism. J Pediatr Endocrinol Metab. 2007;20:587–96. [PubMed: 17642419]

Suggested Reading

  1. Tajima T, Yorifuji T, Ishizu K, Fujieda K. A novel mutation (V101A) of the LHX4 gene in a Japanese patient with combined pituitary hormone deficiency. Exp Clin Endocrinol Diabetes. 2010;118:405–9. [PubMed: 19856252]

Chapter Notes

Author History

Laura CG de Graaff, MD, PhD (2011-present)
Lawrence C Layman, MD; Medical College of Georgia (1999-2011)
John A Phillips III, MD; Vanderbilt University Medical Center (1999-2011)
Cindy Vnencak-Jones, PhD; Vanderbilt University Medical Center (1999-2011)

Revision History

  • 6 October 2011 (me) Comprehensive update posted live
  • 21 November 2005 (me) Comprehensive update posted to live Web site
  • 16 June 2003 (ca) Comprehensive update posted to live Web site
  • 7 December 2000 (me) Review posted to live Web site
  • 18 October 1999 (jp) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1347PMID: 20301521
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...