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Pituitary hormone deficiency, combined, 1(CPHD1)

MedGen UID:
414421
Concept ID:
C2751608
Disease or Syndrome
Synonyms: CPHD1; Pituitary hormone deficiency, combined or isolated, 1; POU1F1-Related Combined Pituitary Hormone Deficiency
 
Gene (location): POU1F1 (3p11.2)
 
Monarch Initiative: MONDO:0024464
OMIM®: 613038

Definition

Combined pituitary hormone deficiency (CPHD) in man denotes impaired production of growth hormone (GH; 139250) and one or more of the other 5 anterior pituitary hormones. Mutations of the POU1F1 gene in the human and Pit1 in the mouse are responsible for pleiotropic deficiencies of GH, prolactin (PRL; 176760), and thyroid-stimulating hormone (TSH; see 188540), while the production of adrenocorticotrophic hormone (ACTH; see 176830), luteinizing hormone (LH; 152780), and follicle-stimulating hormone (FSH; 136530) are preserved (Wu et al., 1998). Some patients exhibit only GH deficiency, although approximately 50% of isolated GH deficiency progresses to CPHD (Gergics et al., 2021). In infancy severe growth deficiency from birth as well as distinctive facial features with prominent forehead, marked midfacial hypoplasia with depressed nasal bridge, deep-set eyes, and a short nose with anteverted nostrils and hypoplastic pituitary gland by MRI examination can be seen (Aarskog et al., 1997). Some cases present with severe mental retardation along with short stature (Radovick et al., 1992). Reviews Voss and Rosenfeld (1992) reviewed the development and differentiation of the 5 pituitary cell types: galactotropes, gonadotropes, corticotropes, thyrotropes, and somatotropes. As indicated by the mutations in PIT1 described later, combined pituitary hormone deficiency can have either autosomal dominant or autosomal recessive inheritance, depending on the part of the PIT1 molecule affected by the mutation. Some mutations have a dominant-negative effect. Genetic Heterogeneity of Combined Pituitary Hormone Deficiency CPHD2 (262600), associated with hypogonadism, is caused by mutation in the PROP1 gene (601538). CPHD3 (221750), which is associated with rigid cervical spine and variable sensorineural deafness, is caused by mutation in the LHX3 gene (600577). CPHD4 (262700) is caused by mutation in the LHX4 gene (602146). CPHD5 (see septooptic dysplasia, 182230) is caused by mutation in the HESX1 gene (601802). CPHD6 (613986) is caused by mutation in the OTX2 gene (600037). CPHD7 (618160) is caused by mutation in the RNPC3 gene (618016). CPHD8 (620303) is caused by mutation in the ROBO1 gene (602430). [from OMIM]

Clinical features

From HPO
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Severe postnatal growth retardation
MedGen UID:
347510
Concept ID:
C1857641
Finding
Severely slow or limited growth after birth, being four standard deviations or more below age- and sex-related norms.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
Yellow pigmentation of the skin due to bilirubin, which in turn is the result of increased bilirubin concentration in the bloodstream.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Prolonged neonatal jaundice
MedGen UID:
347108
Concept ID:
C1859236
Finding
Neonatal jaundice refers to a yellowing of the skin and other tissues of a newborn infant as a result of increased concentrations of bilirubin in the blood. Neonatal jaundice affects over half of all newborns to some extent in the first week of life. Prolonged neonatal jaundice is said to be present if the jaundice persists for longer than 14 days in term infants and 21 days in preterm infants.
Hypopituitarism
MedGen UID:
9386
Concept ID:
C0020635
Disease or Syndrome
A condition of diminution or cessation of secretion of one or more hormones from the anterior pituitary gland. This may result from surgical or radiation ablation, non-secretory pituitary neoplasms, metastatic tumors, infarction, pituitary apoplexy, infiltrative or granulomatous processes, and other conditions.
Isolated prolactin deficiency
MedGen UID:
75758
Concept ID:
C0271586
Finding
A reduced level of prolactin in the blood circulation. Prolactin is a protein hormone that is secreted by lactotrophs in the anterior pituitary and that stimulates mammary gland development and milk production.
Anterior pituitary hypoplasia
MedGen UID:
347950
Concept ID:
C1859775
Congenital Abnormality
Underdevelopment of the anterior pituitary gland.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Delayed cranial suture closure
MedGen UID:
75805
Concept ID:
C0277828
Finding
Infants normally have two fontanels at birth, the diamond-shaped anterior fontanelle at the junction of the coronal and sagittal sutures, and the posterior fontanelle at the intersection of the occipital and parietal bones. The posterior fontanelle usually closes by the 8th week of life, and the anterior fontanel closes by the 18th month of life on average. This term applies if there is delay of closure of the fontanelles beyond the normal age.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Finding
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Hoarse voice
MedGen UID:
5602
Concept ID:
C0019825
Sign or Symptom
Hoarseness refers to a change in the pitch or quality of the voice, with the voice sounding weak, very breathy, scratchy, or husky.
Macroglossia
MedGen UID:
44236
Concept ID:
C0024421
Disease or Syndrome
Increased length and width of the tongue.
Concave nasal ridge
MedGen UID:
78105
Concept ID:
C0264169
Finding
Nasal ridge curving posteriorly to an imaginary line that connects the nasal root and tip.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Midface retrusion
MedGen UID:
339938
Concept ID:
C1853242
Anatomical Abnormality
Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.
Short nose
MedGen UID:
343052
Concept ID:
C1854114
Finding
Distance from nasion to subnasale more than two standard deviations below the mean, or alternatively, an apparently decreased length from the nasal root to the nasal tip.
Pretibial myxedema
MedGen UID:
450990
Concept ID:
C0033103
Disease or Syndrome
A diffuse, non-pitting edema and thickening of the skin usually on the anterior aspect of the lower legs spreading to the dorsum of the feet.
Hypothyroidism
MedGen UID:
6991
Concept ID:
C0020676
Disease or Syndrome
Deficiency of thyroid hormone.
Reduced circulating growth hormone concentration
MedGen UID:
82880
Concept ID:
C0271561
Disease or Syndrome
Concentration of growth hormone in the blood circulation below normal limits.
Decreased thyroid-stimulating hormone level
MedGen UID:
717708
Concept ID:
C1295607
Finding
Reduced amount of the thyroid-stimulating hormone (TSH), which is produced by the anterior pituitary gland and stimulates the function of the thyroid gland.
Impaired growth-hormone response to insulin stimulation test
MedGen UID:
1374054
Concept ID:
C4476958
Finding
Failure of growth hormone levels to respond adequately (by increasing) to the insulin tolerance test (ITT).
Decreased circulating free T3
MedGen UID:
1687899
Concept ID:
C5139195
Finding
A reduced concentration of free 3,3',5-triiodo-L-thyronine in the blood circulation.
Decreased circulating free T4 concentration
MedGen UID:
1743550
Concept ID:
C5421592
Finding
A reduced concentration of free thyroxine (fT4) in the blood circulation.
Reduced TSH response to thyrotrophin-releasing hormone stimulation test
MedGen UID:
1759429
Concept ID:
C5421596
Finding
A lower than normal TSH response to thyrotrophin-releasing hormone stimulation test.
Deeply set eye
MedGen UID:
473112
Concept ID:
C0423224
Finding
An eye that is more deeply recessed into the plane of the face than is typical.

Recent clinical studies

Etiology

Wu W, Fan X, Yu Y, Wang Z, Wang Y
Gynecol Endocrinol 2018 Jan;34(1):36-39. Epub 2017 Jun 24 doi: 10.1080/09513590.2017.1336216. PMID: 28649890

Diagnosis

Verma V, Singh RK
J Clin Res Pediatr Endocrinol 2020 Nov 25;12(4):444-449. Epub 2020 Apr 6 doi: 10.4274/jcrpe.galenos.2020.2019.0194. PMID: 32248673Free PMC Article
Hu Y, Wang Q, Wang Z, Wang F, Guo X, Li G
Int J Mol Med 2015 Feb;35(2):358-66. Epub 2014 Nov 28 doi: 10.3892/ijmm.2014.2016. PMID: 25434367Free PMC Article

Therapy

Verma V, Singh RK
J Clin Res Pediatr Endocrinol 2020 Nov 25;12(4):444-449. Epub 2020 Apr 6 doi: 10.4274/jcrpe.galenos.2020.2019.0194. PMID: 32248673Free PMC Article
Hu Y, Wang Q, Wang Z, Wang F, Guo X, Li G
Int J Mol Med 2015 Feb;35(2):358-66. Epub 2014 Nov 28 doi: 10.3892/ijmm.2014.2016. PMID: 25434367Free PMC Article

Prognosis

Verma V, Singh RK
J Clin Res Pediatr Endocrinol 2020 Nov 25;12(4):444-449. Epub 2020 Apr 6 doi: 10.4274/jcrpe.galenos.2020.2019.0194. PMID: 32248673Free PMC Article
Boda H, Miyata M, Inagaki H, Shinkai Y, Kato T, Yoshikawa T, Kurahashi H
Eur J Med Genet 2019 Nov;62(11):103570. Epub 2018 Nov 8 doi: 10.1016/j.ejmg.2018.11.004. PMID: 30414530

Clinical prediction guides

Verma V, Singh RK
J Clin Res Pediatr Endocrinol 2020 Nov 25;12(4):444-449. Epub 2020 Apr 6 doi: 10.4274/jcrpe.galenos.2020.2019.0194. PMID: 32248673Free PMC Article
Boda H, Miyata M, Inagaki H, Shinkai Y, Kato T, Yoshikawa T, Kurahashi H
Eur J Med Genet 2019 Nov;62(11):103570. Epub 2018 Nov 8 doi: 10.1016/j.ejmg.2018.11.004. PMID: 30414530

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