DiagnosisClinical DiagnosisThe 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/ORProportionate 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
ORModerate short stature with height 2-3 SD below the mean for age and growth deceleration with height velocity less than 25th percentile for age
ORSevere growth deceleration with height velocity less than fifth percentile for ageThyroid-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 maturationLuteinizing 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 cryptorchidismAdolescent males with onset of puberty after age 14 years or cessation of secondary sexual developmentAdolescent females with lack of breast development or menses by age 14 yearsProlactin (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.TestingTesting 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 PrLExogenous GnRH (gonadotropin-releasing hormone) which should increase serum concentrations of LH and FSHGrowth 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) deficiencySuggestive 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) deficiencySuggestive 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 olderConfirmatory 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) deficiencySuggestive finding. Very low or undetectable baseline prolactinConfirmatory finding. Absent response to TRH stimulationAdrenocorticotropic hormone (ACTH) deficiencySuggestive findingsLow serum concentration of sodium and glucose and elevated serum concentration of potassium in an acutely ill individualSerum 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 axisConfirmatory 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 TestingGene. 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 testingTable 1. Summary of Molecular Genetic Testing Used in PROP1-Related Combined Pituitary Hormone DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityPROP1Sequence analysisSequence variants 2, 3>98%ClinicalDeletion / duplication analysis 4Deletion of one or more exons or the whole geneFootnote 51. 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. 2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. 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).4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.5. 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.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandGrowth 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 CPHDView in own windowReferenceSimplex / Familial CasesN PatientsN FamiliesN Mutations/
N TestedOriginDateki et al [2010]Unknown71NA0JapaneseDiaczok et al [2008]Unknown19NA0UnknownDe Graaff et al [2010] Mostly simplex 78760DutchMcLennan et al [2003]Simplex 3300AustralianKim et al [2003]Simplex1200KoreanRainbow et al [2005]Mostly simplex 27260UKFernandez-Rodriguez et al [2011]Mixed simplex and familial23NA2/23SpanishTurton et al [2005]Mixed simplex and familial153NA15VariousOsorio et al [2002]Mostly simplex 76745/43BrazilianNyström et al [2011]Mixed 25232/17UnknownReynaud et al [2006]Mixed 19516520/109VariousLebl et al [2005]Mostly simplex 74NA 118/74CzechZimmermann et al [2007]Mixed simplex and familial17NA5/17UnknownVieira et al [2007]Mixed 40369/26BrazilianVallette-Kasic et al [2001]Mostly simplex 23209/23 2VariousLemos et al [2006]Mixed 46Footnote 319PortugueseHalász et al [2006]Unknown35NA15/35HungarianDeladoëy et al [1999]Familial 733635/73 2UnknownFofanova et al [1998]Mixed 14Footnote 48/14RussianPROP1 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 pairs2. Same mutation found in more than one individual from a given family3. 17 familial cases from seven families; 29 simplex cases4. Seven familial cases from four families; seven simplex casesCarrier 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.Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations in PROP1.}

Natural HistoryPROP1 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 findingsAn 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 CorrelationsNo correlation has been observed between the different PROP1 mutations and the phenotype of the affected individual.

Differential DiagnosisWhile 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]. Dattani et al [1998] found a homozygous missense HESX1 mutation (p.Arg160Cys) in a brother and sister with septo-optic dysplasia, agenesis of the corpus callosum, and CPHD (OMIM 182230).Individuals homozygous for the recessive mutation p.Arg160Cys had septo-optic dysplasia (SOD/Morsier syndrome) with agenesis of the corpus callosum and CPHD [Brickman et al 2001]. Individuals with a monoallelic mutation had milder phenotypes suggesting that they result from haploinsufficiency of the HESX1 protein [Tajima et al 2003]. 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.Glu173X, p.Ala210Val, LHX3 -/-, and p.Trp224X 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.Lys50X) 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 DeficiencyCPHD needs to be differentiated from isolated growth hormone deficiency (IGHD).GH1-related IGHDIGHD 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 HypogonadismIn 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 HypopituitarismRecently, 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsThe 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 (click for 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 (click for 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 FSHMale 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.SurveillanceGrowth 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 RiskIf 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 InvestigationSearch 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPROP15q35​.3Homeobox protein prophet of Pit-1PROP1 homepage - Mendelian genesPROP1Data 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) View in own window 262600PITUITARY HORMONE DEFICIENCY, COMBINED, 2; CPHD2 601538PROPHET OF PIT1, PAIRED-LIKE HOMEODOMAIN TRANSCRIPTION FACTOR; PROP1Normal allelic variants. PROP1 comprises three exons of 418, 233, and 339 bp and spans 3.54 kb. Transcripts are 1464 nucleotides long. Pathologic 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.Leu102Cysfs*8 (c.300_301 delGA) and a nonsense mutation p.Gln83X (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.Trp194X) 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 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference Sequencesc.2T>C(null allele)c.109+1G>T
(IVS1+1G>T)NM_006261​.4
NP_006252​.3 c.112_124delp.Ser38Profs*123c.150delAp.Arg53Aspfs*112c.157delAp.Arg53Aspfs*112c.211C>Tp.Arg71Cysc.212G>A p.Arg71Hisc.217C>Tp.Arg73Cysc.218G>Ap.Arg73Hisc.247C>Tp.Gln83X c.300_301delGA
(GA296deletion)p.Leu102Cysfs*8c.301_302delAGp.Leu102Cysfs*8c.310delCp.Arg104Glyfs*61c.343-11C>G--c.373C>Tp.Arg125Trpc.467_468insT
(467insT)p.Tyr157Leufs*36c.582G>Ap.Trp194XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal 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.