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.

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).

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.

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in PROP1.

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.

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 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

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 (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 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.

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

• Fertility is reduced in individuals with PROP1-related CPHD.
• If an individual with PROP1-related CPHD were fertile, each offspring would be an obligate heterozygote (carrier) for a disease-causing mutation in PROP1.
• Heterozygotes are asymptomatic.

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 testing 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 such as PROP1-related combined pituitary hormone deficiency that 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.

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 10-3-11. [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 10-3-11. [PubMed: 18057375]

Literature Cited

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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]
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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]
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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]

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