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IMAGe syndrome(IMAGE)

MedGen UID:
337364
Concept ID:
C1846009
Disease or Syndrome
Synonym: Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies
SNOMED CT: Intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomaly syndrome (702384004); IMAGe syndrome (702384004)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: 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 individuals with two pathogenic alleles, either homozygotes (two copies of the same 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
Source: 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.
 
Gene (location): CDKN1C (11p15.4)
 
Monarch Initiative: MONDO:0013873
OMIM®: 614732
Orphanet: ORPHA85173

Disease characteristics

Excerpted from the GeneReview: IMAGe Syndrome
IMAGe syndrome is an acronym for the major findings of intrauterine growth restriction (IUGR), metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary abnormalities (in males). Findings reported in individuals with a clinical and/or molecular diagnosis include: IUGR; Some type of skeletal abnormality (most commonly delayed bone age and short stature, and occasionally, metaphyseal and epiphyseal dysplasia of varying severity); Adrenal insufficiency often presenting in the first month of life as an adrenal crisis or (rarely) later in childhood with failure to thrive and recurrent vomiting; Genital abnormalities in males (cryptorchidism, micropenis, and hypospadias) but not in females. Hypotonia and developmental delay are reported in some individuals; cognitive outcome appears to be normal in the majority of individuals. [from GeneReviews]
Authors:
Samantha A Schrier Vergano  |  Matthew A Deardorff   view full author information

Additional descriptions

From NCBI curation
Disease characteristics. IMAGe syndrome is an acronym for the major findings of intrauterine growth restriction (IUGR), metaphyseal dysplasia, adrenal hypoplasia congenita (AHC), and genitourinary abnormalities (in males). All 25 individuals with a clinical and/or molecular diagnosis reported to date have had: •IUGR; •Some sort of skeletal abnormality (most commonly delayed bone age and short stature and, occasionally, metaphyseal and epiphyseal dysplasia of varying severity); •Adrenal insufficiency typically presenting in the first month of life as an adrenal crisis or rarely later in childhood with failure to thrive and recurrent vomiting; and •Genital abnormalities in males (cryptorchidism, micropenis, and hypospadias) but not in females. Although hypotonia and developmental delay are reported in some, cognitive outcome appears to be normal in the majority.
From OMIM
IMAGE is a rare multisystem disorder characterized by intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies. Patients with this condition may present shortly after birth with severe adrenal insufficiency, which can be life-threatening if not recognized early and steroid replacement therapy commenced. Other reported features in this condition include hypercalciuria and/or hypocalcemia, craniosynostosis, cleft palate, and scoliosis (summary by Balasubramanian et al., 2010). A recessive form of IMAGE with immunodeficiency (IMAGEI; 618336) is caused by mutation in the POLE gene (174762) on chromosome 12q24.  http://www.omim.org/entry/614732
From MedlinePlus Genetics
The combination of intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies is commonly known by the acronym IMAGe. This rare syndrome has signs and symptoms that affect many parts of the body.

Most affected individuals grow slowly before birth (intrauterine growth restriction) and are small in infancy. They have skeletal abnormalities that often become apparent in early childhood, although these abnormalities are usually mild and can be difficult to recognize on x-rays. The most common bone changes are metaphyseal dysplasia and epiphyseal dysplasia; these are malformations of the ends of long bones in the arms and legs. Some affected individuals also have an abnormal side-to-side curvature of the spine (scoliosis) or thinning of the bones (osteoporosis).

Adrenal hypoplasia congenita is the most severe feature of IMAGe syndrome. The adrenal glands are a pair of small glands on top of each kidney. They produce a variety of hormones that regulate many essential functions in the body. Underdevelopment (hypoplasia) of these glands prevents them from producing enough hormones, a condition known as adrenal insufficiency. The signs of adrenal insufficiency begin shortly after birth and include vomiting, difficulty with feeding, dehydration, extremely low blood glucose (hypoglycemia), and shock. If untreated, these complications can be life-threatening.

The genital abnormalities associated with IMAGe syndrome occur only in affected males. They include an unusually small penis (micropenis), undescended testes (cryptorchidism), and the opening of the urethra on the underside of the penis (hypospadias).

Several additional signs and symptoms have been reported in people with IMAGe syndrome. Some affected individuals have distinctive facial features, such as a prominent forehead, low-set ears, and a short nose with a flat nasal bridge. Less commonly, people with this condition have premature fusion of certain bones of the skull (craniosynostosis), a split in the soft flap of tissue that hangs from the back of the mouth (cleft or bifid uvula), a high-arched roof of the mouth (palate), and a small chin (micrognathia). Other possible features of IMAGe syndrome include high levels of calcium in the blood (hypercalcemia) or urine (hypercalcuria) and a shortage of growth hormone in childhood that results in short stature.  https://medlineplus.gov/genetics/condition/intrauterine-growth-restriction-metaphyseal-dysplasia-adrenal-hypoplasia-congenita-and-genital-anomalies

Clinical features

From HPO
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Hypercalciuria
MedGen UID:
43775
Concept ID:
C0020438
Finding
Abnormally high level of calcium in the urine.
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Postnatal growth retardation
MedGen UID:
395343
Concept ID:
C1859778
Finding
Slow or limited growth after birth.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Craniosynostosis syndrome
MedGen UID:
1163
Concept ID:
C0010278
Disease or Syndrome
Craniosynostosis refers to the premature closure of the cranial sutures. Primary craniosynostosis refers to the closure of one or more sutures due to abnormalities in skull development, and secondary craniosynostosis results from failure of brain growth.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Epiphyseal dysplasia
MedGen UID:
95932
Concept ID:
C0392476
Congenital Abnormality
Delayed skeletal maturation
MedGen UID:
108148
Concept ID:
C0541764
Finding
A decreased rate of skeletal maturation. Delayed skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Metaphyseal dysplasia
MedGen UID:
1677924
Concept ID:
C5194606
Disease or Syndrome
The presence of dysplastic regions in metaphyseal regions.
Hypercalcemia
MedGen UID:
5686
Concept ID:
C0020437
Disease or Syndrome
An abnormally increased calcium concentration in the blood.
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.
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.
Adrenal hypoplasia
MedGen UID:
337539
Concept ID:
C1846223
Pathologic Function
Developmental hypoplasia of the adrenal glands.
Decreased response to growth hormone stimulation test
MedGen UID:
1784655
Concept ID:
C5539399
Finding
Insufficient responses to growth hormone (GH) provocation tests. GH deficiency is defined as a serum peak GH concentration less than 10 ng/mL on provocation with a combination of at least two separate stimulation tests.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for IMAGe syndrome in Orphanet.

Professional guidelines

PubMed

Çamtosun E, Dündar İ, Akıncı A, Kayaş L, Çiftci N
J Clin Res Pediatr Endocrinol 2021 Feb 26;13(1):88-99. Epub 2020 Sep 17 doi: 10.4274/jcrpe.galenos.2020.2020.0132. PMID: 32938577Free PMC Article
Malikova J, Flück CE
Horm Res Paediatr 2014;82(3):145-57. Epub 2014 Aug 1 doi: 10.1159/000363107. PMID: 25096886
Simm PJ, McDonnell CM, Zacharin MR
J Paediatr Child Health 2004 Nov;40(11):596-9. doi: 10.1111/j.1440-1754.2004.00482.x. PMID: 15469526

Recent clinical studies

Etiology

Çamtosun E, Dündar İ, Akıncı A, Kayaş L, Çiftci N
J Clin Res Pediatr Endocrinol 2021 Feb 26;13(1):88-99. Epub 2020 Sep 17 doi: 10.4274/jcrpe.galenos.2020.2020.0132. PMID: 32938577Free PMC Article
Buonocore F, Achermann JC
Clin Endocrinol (Oxf) 2020 Jan;92(1):11-20. Epub 2019 Oct 30 doi: 10.1111/cen.14109. PMID: 31610036Free PMC Article
Hsieh S, White PC
J Clin Endocrinol Metab 2011 Jun;96(6):E925-8. Epub 2011 Apr 6 doi: 10.1210/jc.2011-0015. PMID: 21470994
Tan TY, Jameson JL, Campbell PE, Ekert PG, Zacharin M, Savarirayan R
Am J Med Genet A 2006 Aug 15;140(16):1778-84. doi: 10.1002/ajmg.a.31365. PMID: 16835919
Simm PJ, McDonnell CM, Zacharin MR
J Paediatr Child Health 2004 Nov;40(11):596-9. doi: 10.1111/j.1440-1754.2004.00482.x. PMID: 15469526

Diagnosis

Bolomiti M, Båtnes-Pedersen E, Telman G, Januszkiewicz-Lewandowska D
Cancer Genet 2021 Aug;256-257:100-105. Epub 2021 May 26 doi: 10.1016/j.cancergen.2021.05.006. PMID: 34098225
Buonocore F, Achermann JC
Clin Endocrinol (Oxf) 2020 Jan;92(1):11-20. Epub 2019 Oct 30 doi: 10.1111/cen.14109. PMID: 31610036Free PMC Article
Flück CE
Eur J Endocrinol 2017 Sep;177(3):R99-R111. Epub 2017 Apr 27 doi: 10.1530/EJE-17-0128. PMID: 28450305
Eggermann T, Binder G, Brioude F, Maher ER, Lapunzina P, Cubellis MV, Bergadá I, Prawitt D, Begemann M
Trends Mol Med 2014 Nov;20(11):614-22. Epub 2014 Sep 25 doi: 10.1016/j.molmed.2014.09.001. PMID: 25262539
Malikova J, Flück CE
Horm Res Paediatr 2014;82(3):145-57. Epub 2014 Aug 1 doi: 10.1159/000363107. PMID: 25096886

Therapy

Binder G, Ziegler J, Schweizer R, Habhab W, Haack TB, Heinrich T, Eggermann T
Clin Epigenetics 2020 Oct 19;12(1):152. doi: 10.1186/s13148-020-00945-y. PMID: 33076988Free PMC Article
Kim YM, Seo GH, Kim GH, Ko JM, Choi JH, Yoo HW
BMC Med Genet 2018 Mar 5;19(1):35. doi: 10.1186/s12881-018-0546-4. PMID: 29506479Free PMC Article
Lindemeyer RG, Rashewsky SE, Louie PJ, Schleelein L
Anesth Prog 2014 Winter;61(4):165-8. doi: 10.2344/0003-3006-61.4.165. PMID: 25517553Free PMC Article

Prognosis

Luo N, Li HJ, Lin Z, Li Y, Gao HM
Clin Lab 2024 Jul 1;70(7) doi: 10.7754/Clin.Lab.2024.240229. PMID: 38965965
Tan TY, Jameson JL, Campbell PE, Ekert PG, Zacharin M, Savarirayan R
Am J Med Genet A 2006 Aug 15;140(16):1778-84. doi: 10.1002/ajmg.a.31365. PMID: 16835919

Clinical prediction guides

Binder G, Ziegler J, Schweizer R, Habhab W, Haack TB, Heinrich T, Eggermann T
Clin Epigenetics 2020 Oct 19;12(1):152. doi: 10.1186/s13148-020-00945-y. PMID: 33076988Free PMC Article
Kerns SL, Guevara-Aguirre J, Andrew S, Geng J, Guevara C, Guevara-Aguirre M, Guo M, Oddoux C, Shen Y, Zurita A, Rosenfeld RG, Ostrer H, Hwa V, Dauber A
J Clin Endocrinol Metab 2014 Oct;99(10):E2117-22. Epub 2014 Jul 24 doi: 10.1210/jc.2014-1949. PMID: 25057881Free PMC Article

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