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Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies

MedGen UID:
337364
Concept ID:
C1846009
Disease or Syndrome
Synonyms: IMAGE Syndrome
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)
SNOMED CT: Intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomaly syndrome (702384004); IMAGe syndrome (702384004)
 
Gene (location): CDKN1C (11p15.4)
OMIM®: 614732
Orphanet: ORPHA85173

Definition

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; cognitive outcome appears to be normal in the majority. [from GTR]

Additional descriptions

From GeneReviews
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; cognitive outcome appears to be normal in the majority.  https://www.ncbi.nlm.nih.gov/books/NBK190103
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 syndrome 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).  http://www.omim.org/entry/614732
From GHR
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 sugar (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://ghr.nlm.nih.gov/condition/intrauterine-growth-restriction-metaphyseal-dysplasia-adrenal-hypoplasia-congenita-and-genital-anomalies

Clinical features

Small adrenal glands
MedGen UID:
83342
Concept ID:
C0342491
Finding
Developmental hypoplasia of the adrenal glands.
Growth hormone deficiency
MedGen UID:
811475
Concept ID:
C3714796
Disease or Syndrome
Insufficient production of growth hormone, which is produced by the anterior pituitary gland. Growth hormone is a major participant in control of growth and metabolism.
Cryptorchidism, unilateral or bilateral
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
Disease or Syndrome
Abnormally high level of calcium in the urine.
Micropenis
MedGen UID:
78603
Concept ID:
C0266435
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.
Hypospadias
MedGen UID:
305577
Concept ID:
C1691215
Congenital Abnormality
Displacement of the urethral opening on the ventral (inferior) surface of the penis.
Pyle metaphyseal dysplasia
MedGen UID:
82704
Concept ID:
C0265294
Disease or Syndrome
Pyle disease is characterized by long bones with wide and expanded trabecular metaphyses, thin cortical bone, and bone fragility. Fractures are common in Pyle disease, and fracture lines usually go through the abnormally wide metaphyses, revealing their fragility (summary by Kiper et al., 2016).
Intrauterine growth retardation
MedGen UID:
473406
Concept ID:
C1386048
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.
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
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.
Growth hormone deficiency
MedGen UID:
811475
Concept ID:
C3714796
Disease or Syndrome
Insufficient production of growth hormone, which is produced by the anterior pituitary gland. Growth hormone is a major participant in control of growth and metabolism.
Cryptorchidism, unilateral or bilateral
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
Disease or Syndrome
Abnormally high level of calcium in the urine.
Micropenis
MedGen UID:
78603
Concept ID:
C0266435
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.
Hypospadias
MedGen UID:
305577
Concept ID:
C1691215
Congenital Abnormality
Displacement of the urethral opening on the ventral (inferior) surface of the penis.
Hypercalcemia
MedGen UID:
5686
Concept ID:
C0020437
Disease or Syndrome
Abnormally high concentration of calcium in the peripheral blood.
Hypercalciuria
MedGen UID:
43775
Concept ID:
C0020438
Disease or Syndrome
Abnormally high level of calcium in the urine.
Pyle metaphyseal dysplasia
MedGen UID:
82704
Concept ID:
C0265294
Disease or Syndrome
Pyle disease is characterized by long bones with wide and expanded trabecular metaphyses, thin cortical bone, and bone fragility. Fractures are common in Pyle disease, and fracture lines usually go through the abnormally wide metaphyses, revealing their fragility (summary by Kiper et al., 2016).
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
Macrocephaly refers to an abnormally enlarged head inclusive of the scalp, cranial bones, and intracranial contents. Macrocephaly may be due to megalencephaly (true enlargement of the brain parenchyma), and the 2 terms are often used interchangeably in the genetic literature (reviews by Olney, 2007 and Williams et al., 2008). Autosomal recessive macrocephaly/megalencephaly syndrome is characterized by an enlarged cranium apparent at birth or in early childhood. Affected individuals have intellectual disability and may have dysmorphic facial features resulting from the macrocephaly (summary by Alfaiz et al., 2014).
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.
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.
Prominent forehead
MedGen UID:
401234
Concept ID:
C1867446
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Macrocephaly refers to an abnormally enlarged head inclusive of the scalp, cranial bones, and intracranial contents. Macrocephaly may be due to megalencephaly (true enlargement of the brain parenchyma), and the 2 terms are often used interchangeably in the genetic literature (reviews by Olney, 2007 and Williams et al., 2008). Autosomal recessive macrocephaly/megalencephaly syndrome is characterized by an enlarged cranium apparent at birth or in early childhood. Affected individuals have intellectual disability and may have dysmorphic facial features resulting from the macrocephaly (summary by Alfaiz et al., 2014).
Growth hormone deficiency
MedGen UID:
811475
Concept ID:
C3714796
Disease or Syndrome
Insufficient production of growth hormone, which is produced by the anterior pituitary gland. Growth hormone is a major participant in control of growth and metabolism.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVIntrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies
Follow this link to review classifications for Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies in Orphanet.

Recent clinical studies

Diagnosis

Özsu E, Yeşiltepe Mutlu RG, Işık O, Çizmecioğlu FM, Hatun Ş
J Clin Res Pediatr Endocrinol 2014 Dec;6(4):266-8. doi: 10.4274/Jcrpe.1355. PMID: 25541901Free 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
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
Kato F, Hamajima T, Hasegawa T, Amano N, Horikawa R, Nishimura G, Nakashima S, Fuke T, Sano S, Fukami M, Ogata T
Clin Endocrinol (Oxf) 2014 May;80(5):706-13. Epub 2013 Dec 28 doi: 10.1111/cen.12379. PMID: 24313804

Therapy

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

Clinical prediction guides

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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