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Pituitary hormone deficiency, combined 1(CPHD1)

MedGen UID:
414421
Concept ID:
C2751608
Disease or Syndrome
Synonyms: CPHD1; POU1F1-Related Combined Pituitary Hormone Deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): POU1F1 (3p11.2)
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). 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). 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). [from GTR]

Additional descriptions

From OMIM
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). 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). 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).  http://www.omim.org/entry/613038
From GHR
Combined pituitary hormone deficiency is a condition that causes a shortage (deficiency) of several hormones produced by the pituitary gland, which is located at the base of the brain. A lack of these hormones may affect the development of many parts of the body. The first signs of this condition include a failure to grow at the expected rate and short stature that usually becomes apparent in early childhood.People with combined pituitary hormone deficiency may have hypothyroidism, which is underactivity of the butterfly-shaped thyroid gland in the lower neck. Hypothyroidism can cause many symptoms, including weight gain and fatigue. Other features of combined pituitary hormone deficiency include delayed or absent puberty and lack the ability to have biological children (infertility). The condition can also be associated with a deficiency of the hormone cortisol. Cortisol deficiency can impair the body's immune system, causing individuals to be more susceptible to infection.Rarely, people with combined pituitary hormone deficiency have intellectual disability; a short, stiff neck; or underdeveloped optic nerves, which carry visual information from the eyes to the brain.  https://ghr.nlm.nih.gov/condition/combined-pituitary-hormone-deficiency

Clinical features

Hypothyroidism
MedGen UID:
6991
Concept ID:
C0020676
Disease or Syndrome
A syndrome that results from abnormally low secretion of THYROID HORMONES from the THYROID GLAND, leading to a decrease in BASAL METABOLIC RATE. In its most severe form, there is accumulation of MUCOPOLYSACCHARIDES in the SKIN and EDEMA, known as MYXEDEMA.
Deeply set eye
MedGen UID:
8638
Concept ID:
C0014306
Disease or Syndrome
Abnormal recession of the eyeball within the eye socket.
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 \
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.
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.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Macroglossia
MedGen UID:
44236
Concept ID:
C0024421
Disease or Syndrome
A finding indicating enlargement of the tongue.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
A skeletal deformity characterized by an unusually prominent forehead. Causes include acromegaly, Hurler syndrome, Silver-Russell syndrome, and thalassemia major.
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
Anatomical Abnormality
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Deeply set eye
MedGen UID:
8638
Concept ID:
C0014306
Disease or Syndrome
Abnormal recession of the eyeball within the eye socket.
Macroglossia
MedGen UID:
44236
Concept ID:
C0024421
Disease or Syndrome
A finding indicating enlargement of the tongue.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
A skeletal deformity characterized by an unusually prominent forehead. Causes include acromegaly, Hurler syndrome, Silver-Russell syndrome, and thalassemia major.
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.
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.
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).
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.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Anatomical Abnormality
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Prominent forehead
MedGen UID:
401234
Concept ID:
C1867446
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Midface retrusion
MedGen UID:
767172
Concept ID:
C3554258
Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.
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.
Hypothyroidism
MedGen UID:
6991
Concept ID:
C0020676
Disease or Syndrome
A syndrome that results from abnormally low secretion of THYROID HORMONES from the THYROID GLAND, leading to a decrease in BASAL METABOLIC RATE. In its most severe form, there is accumulation of MUCOPOLYSACCHARIDES in the SKIN and EDEMA, known as MYXEDEMA.

Recent clinical studies

Etiology

Rohayem J, Drechsel H, Tittel B, Hahn G, Pfaeffle R, Huebner A
Horm Res Paediatr 2016;86(2):106-116. Epub 2016 Aug 3 doi: 10.1159/000448098. PMID: 27487097
Castinetti F, Reynaud R, Saveanu A, Jullien N, Quentien MH, Rochette C, Barlier A, Enjalbert A, Brue T
Eur J Endocrinol 2016 Jun;174(6):R239-47. Epub 2016 Jan 5 doi: 10.1530/EJE-15-1095. PMID: 26733480
Otto AP, França MM, Correa FA, Costalonga EF, Leite CC, Mendonca BB, Arnhold IJ, Carvalho LR, Jorge AA
Pituitary 2015 Aug;18(4):561-7. doi: 10.1007/s11102-014-0610-9. PMID: 25315032
Castinetti F, Reynaud R, Quentien MH, Jullien N, Marquant E, Rochette C, Herman JP, Saveanu A, Barlier A, Enjalbert A, Brue T
J Endocrinol Invest 2015 Jan;38(1):1-12. Epub 2014 Sep 9 doi: 10.1007/s40618-014-0141-2. PMID: 25200994
Aykut A, Ozen S, Sımsek DG, Onay H, Cogulu O, Darcan S, Ozkinay F
J Pediatr Endocrinol Metab 2014 Jan;27(1-2):171-4. doi: 10.1515/jpem-2013-0208. PMID: 24025721

Diagnosis

Ziemnicka K, Budny B, Drobnik K, Baszko-Błaszyk D, Stajgis M, Katulska K, Waśko R, Wrotkowska E, Słomski R, Ruchała M
J Appl Genet 2016 Aug;57(3):373-81. Epub 2015 Nov 25 doi: 10.1007/s13353-015-0328-z. PMID: 26608600Free 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
Otto AP, França MM, Correa FA, Costalonga EF, Leite CC, Mendonca BB, Arnhold IJ, Carvalho LR, Jorge AA
Pituitary 2015 Aug;18(4):561-7. doi: 10.1007/s11102-014-0610-9. PMID: 25315032
Castinetti F, Reynaud R, Quentien MH, Jullien N, Marquant E, Rochette C, Herman JP, Saveanu A, Barlier A, Enjalbert A, Brue T
J Endocrinol Invest 2015 Jan;38(1):1-12. Epub 2014 Sep 9 doi: 10.1007/s40618-014-0141-2. PMID: 25200994
Bonfig W, Krude H, Schmidt H
Eur J Pediatr 2011 Aug;170(8):1017-21. Epub 2011 Jan 20 doi: 10.1007/s00431-011-1393-x. PMID: 21249393

Therapy

Rohayem J, Drechsel H, Tittel B, Hahn G, Pfaeffle R, Huebner A
Horm Res Paediatr 2016;86(2):106-116. Epub 2016 Aug 3 doi: 10.1159/000448098. PMID: 27487097
Mao J, Xu H, Wang X, Huang B, Liu Z, Zhen J, Nie M, Min L, Wu X
Hum Reprod 2015 Sep;30(9):2031-7. Epub 2015 Jul 3 doi: 10.1093/humrep/dev158. PMID: 26141714
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
Turton JP, Strom M, Langham S, Dattani MT, Le Tissier P
Clin Endocrinol (Oxf) 2012 Mar;76(3):387-93. doi: 10.1111/j.1365-2265.2011.04236.x. PMID: 22010633
Zhang H, Wang Y, Han L, Gu X, Shi D
Horm Res Paediatr 2010;74(2):98-105. Epub 2010 Apr 15 doi: 10.1159/000313375. PMID: 20395664

Prognosis

Rohayem J, Drechsel H, Tittel B, Hahn G, Pfaeffle R, Huebner A
Horm Res Paediatr 2016;86(2):106-116. Epub 2016 Aug 3 doi: 10.1159/000448098. PMID: 27487097
Ziemnicka K, Budny B, Drobnik K, Baszko-Błaszyk D, Stajgis M, Katulska K, Waśko R, Wrotkowska E, Słomski R, Ruchała M
J Appl Genet 2016 Aug;57(3):373-81. Epub 2015 Nov 25 doi: 10.1007/s13353-015-0328-z. PMID: 26608600Free PMC Article
Mao J, Xu H, Wang X, Huang B, Liu Z, Zhen J, Nie M, Min L, Wu X
Hum Reprod 2015 Sep;30(9):2031-7. Epub 2015 Jul 3 doi: 10.1093/humrep/dev158. PMID: 26141714
Otto AP, França MM, Correa FA, Costalonga EF, Leite CC, Mendonca BB, Arnhold IJ, Carvalho LR, Jorge AA
Pituitary 2015 Aug;18(4):561-7. doi: 10.1007/s11102-014-0610-9. PMID: 25315032
Bechtold-Dalla Pozza S, Hiedl S, Roeb J, Lohse P, Malik RE, Park S, Durán-Prado M, Rhodes SJ
Horm Res Paediatr 2012;77(1):41-51. Epub 2012 Jan 26 doi: 10.1159/000335929. PMID: 22286346Free PMC Article

Clinical prediction guides

Ziemnicka K, Budny B, Drobnik K, Baszko-Błaszyk D, Stajgis M, Katulska K, Waśko R, Wrotkowska E, Słomski R, Ruchała M
J Appl Genet 2016 Aug;57(3):373-81. Epub 2015 Nov 25 doi: 10.1007/s13353-015-0328-z. PMID: 26608600Free PMC Article
Bechtold-Dalla Pozza S, Hiedl S, Roeb J, Lohse P, Malik RE, Park S, Durán-Prado M, Rhodes SJ
Horm Res Paediatr 2012;77(1):41-51. Epub 2012 Jan 26 doi: 10.1159/000335929. PMID: 22286346Free PMC Article
Carlomagno Y, Salerno M, Vivenza D, Capalbo D, Godi M, Mellone S, Tiradani L, Corneli G, Momigliano-Richiardi P, Bona G, Giordano M
J Endocrinol Invest 2009 Sep;32(8):653-8. Epub 2009 May 12 doi: 10.1007/BF03345736. PMID: 19498317
Kelberman D, Turton JP, Woods KS, Mehta A, Al-Khawari M, Greening J, Swift PG, Otonkoski T, Rhodes SJ, Dattani MT
Clin Endocrinol (Oxf) 2009 Jan;70(1):96-103. Epub 2008 Jun 25 doi: 10.1111/j.1365-2265.2008.03326.x. PMID: 19128366
Reynaud R, Gueydan M, Saveanu A, Vallette-Kasic S, Enjalbert A, Brue T, Barlier A
J Clin Endocrinol Metab 2006 Sep;91(9):3329-36. Epub 2006 May 30 doi: 10.1210/jc.2005-2173. PMID: 16735499

Recent systematic reviews

Chemaitilly W, Armstrong GT, Gajjar A, Hudson MM
J Clin Oncol 2016 Dec 20;34(36):4315-4319. Epub 2016 Oct 31 doi: 10.1200/JCO.2016.70.1847. PMID: 27998231
De Rienzo F, Mellone S, Bellone S, Babu D, Fusco I, Prodam F, Petri A, Muniswamy R, De Luca F, Salerno M, Momigliano-Richardi P, Bona G, Giordano M; Italian Study Group on Genetics of CPHD.
Clin Endocrinol (Oxf) 2015 Dec;83(6):849-60. Epub 2015 Aug 6 doi: 10.1111/cen.12849. PMID: 26147833
Jadhav U, Harris RM, Jameson JL
Mol Cell Endocrinol 2011 Oct 22;346(1-2):65-73. Epub 2011 Jun 13 doi: 10.1016/j.mce.2011.04.017. PMID: 21672607Free PMC Article
Darzy KH, Pezzoli SS, Thorner MO, Shalet SM
J Clin Endocrinol Metab 2007 May;92(5):1666-72. Epub 2007 Feb 6 doi: 10.1210/jc.2006-2599. PMID: 17284618
Petak SM, Nankin HR, Spark RF, Swerdloff RS, Rodriguez-Rigau LJ; American Association of Clinical Endocrinologists.
Endocr Pract 2002 Nov-Dec;8(6):440-56. PMID: 15260010

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