Rare Endocrinology News

Disease Profile

Epiphyseal dysplasia multiple with early-onset diabetes mellitus

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Infancy

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ICD-10

E13

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Wolcott Rallison syndrome; MED-IDDM syndrome; IDDM-MED syndrome

Categories

Congenital and Genetic Diseases; Endocrine Diseases; Musculoskeletal Diseases

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 1667

Definition
Wolcott-Rallison syndrome (WRS) is a very rare genetic disease, characterized by permanent neonatal diabetes mellitus (PNDM) with multiple epiphyseal dysplasia and other clinical manifestations, including recurrent episodes of acute liver failure.

Epidemiology
Fewer than 60 cases have been reported to date. Most patients are from consanguineous families. Prevalence may therefore vary significantly between countries.WRS may be underdiagnosed because of early death before diagnosis.

Clinical description
Diabetes occurs early, generally before six months of age, is permanent and insulin-dependent from the onset. Skeletal dysplasia generally manifests within the 1st or 2nd year of life, and is associated with short stature (dwarfism with short trunk). Deficient mineralization or dysplastic changes, affecting the long bones, pelvis and vertebrae, but usually not the skull, may be seen on radiography as early as diabetes onset. Hepatic dysfunction is a 3rd characteristic feature and the most life-threatening complication, and manifests by elevated hepatic enzymes, liver enlargement and recurrent acute liver failure. Other manifestations vary between patients in type and severity and include renal dysfunction, exocrine pancreas insufficiency, intellectual deficit, hypothyroidism, neutropenia and recurrent infections. Clinical course is variable, including within the same sibship.

Etiology
WRS is caused by mutations in the EIF2AK3 gene encoding eukaryotic translation initiation factor 2-alpha kinase 3 (PKR-like endoplasmic reticulum kinase; PERK), which plays a key role in translation control during unfolded protein response.

Diagnostic methods
Diagnosis should be suspected in any infant with permanent neonatal diabetes and skeletal dysplasia and/or episodes of acute liver failure, and family history of consanguinity and/or neonatal diabetes. Diabetes is not autoimmune as shown by absence of antibodies specific for type 1 diabetes. Radiographs show early signs of multiple epiphyseal dysplasia and deficient mineralization. Molecular genetic testing confirms the diagnosis.

Differential diagnosis
Differential diagnosis is based on clinical presentation and, ultimately, genetic testing. That of NDM (see this term) includes transient NDM, and other PNDMs that may be isolated or syndromic. Differential diagnosis of skeletal dysplasia includes other spondylo-epiphyseal dysplasias such as mucopolysaccharidoses (see these terms) where diabetes may occur independently at an older age.

Antenatal diagnosis
Antenatal diagnosis should be offered to parents of a WRS patient with confirmed EIF2AK3 mutation.

Genetic counseling
Inheritance is autosomal recessive and genetic counseling is possible.

Management and treatment
Close therapeutic monitoring of diabetes should be considered and treatment with an insulin pump is recommended, especially in the first months of life, due to the risk of acute episodes of hypoglycemia. At any age, hypoglycemia should be prevented because the disease can decompensate, even if this requires maintaining the level of glucose above the objectives generally recommended in diabetic children. General anesthesia increases the risk of acute aggravation, because of particular sensitivity of patients to anesthetics, and should be avoided wherever possible. Any drug or vaccine not strictly necessary should be limited, due to the risk of triggering secondary liver and/or kidney failure.

Prognosis
Prognosis is poor and most patients die at a young age from multipleorgan failure with predominant liver and renal dysfunction.

Visit the Orphanet disease page for more resources.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Epiphyseal dysplasia multiple with early-onset diabetes mellitus. Click on the link to view a sample search on this topic.

Rare Endocrinology News

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormality of the metaphysis
Abnormality of the wide portion of a long bone
0000944
Cone-shaped epiphyses of the phalanges of the hand
Cone-shaped end part of finger bones
0010230
Death in infancy
Infantile death
Lethal in infancy

[ more ]

0001522
Dehydration
0001944
Epicanthus
Eye folds
Prominent eye folds

[ more ]

0000286
Epiphyseal dysplasia
Abnormal development of the ends of long bones in arms and legs
0002656
Glycosuria
Glucose in urine
0003076
High forehead
0000348
Hyperglycemia
High blood sugar
0003074
Hypermetropia
Farsightedness
Long-sightedness

[ more ]

0000540
Hyperuricemia
High blood uric acid level
0002149
Microdontia
Decreased width of tooth
0000691
Multiple epiphyseal dysplasia
0002654
Osteopenia
0000938
Osteoporosis
0000939
Renal tubular dysfunction
Abnormal function of filtrating structures in kidney
0000124
Short stature
Decreased body height
Small stature

[ more ]

0004322
Steatorrhea
Fat in feces
0002570
Thin vermilion border
Decreased volume of lip
Thin lips

[ more ]

0000233
Transient neonatal diabetes mellitus
0008255
Triangular face
Face with broad temples and narrow chin
Triangular facial shape

[ more ]

0000325
Weight loss
0001824
30%-79% of people have these symptoms
Abnormal heart morphology
Abnormality of the heart
Abnormally shaped heart
Heart defect

[ more ]

0001627
Acute hepatic failure
Acute liver failure
0006554
Brachydactyly
Short fingers or toes
0001156
Chronic hepatic failure
Chronic liver failure
0100626
Coxa valga
0002673
Delayed skeletal maturation
Delayed bone maturation
Delayed skeletal development

[ more ]

0002750
Elevated hepatic transaminase
High liver enzymes
0002910
Enlarged thorax
Wide rib cage
0100625
Gait disturbance
Abnormal gait
Abnormal walk
Impaired gait

[ more ]

0001288
Genu valgum
Knock knees
0002857
Hepatomegaly
Enlarged liver
0002240
Hip dislocation
Dislocated hips
Dislocation of hip

[ more ]

0002827
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Intracerebral periventricular calcifications
0007229
Ketoacidosis
0001993
Motor delay
0001270
Muscular hypotonia
Low or weak muscle tone
0001252
Narrow iliac wings
0002868
Neutropenia
Low blood neutrophil count
Low neutrophil count

[ more ]

0001875
Platyspondyly
Flattened vertebrae
0000926
Short thorax
Shorter than typical length between neck and abdomen
0010306
5%-29% of people have these symptoms
Abnormality of neuronal migration
0002269
Exocrine pancreatic insufficiency
Inability to properly digest food due to lack of pancreatic digestive enzymes
0001738
Hyperlordosis
Prominent swayback
0003307
Hypoglycemia
Low blood sugar
0001943
Hypothyroidism
Underactive thyroid
0000821
Intrauterine growth retardation
Prenatal growth deficiency
Prenatal growth retardation

[ more ]

0001511
Jaundice
Yellow skin
Yellowing of the skin

[ more ]

0000952
Kyphosis
Hunched back
Round back

[ more ]

0002808
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference

[ more ]

0000252
Nephropathy
0000112
Pancreatic hypoplasia
Underdeveloped pancreas
0002594
Recurrent fractures
Increased fracture rate
Increased fractures
Multiple fractures
Multiple spontaneous fractures
Varying degree of multiple fractures

[ more ]

0002757
Reduced pancreatic beta cells
0006274
Renal insufficiency
Renal failure
Renal failure in adulthood

[ more ]

0000083
Seizure
0001250
1%-4% of people have these symptoms
Coma
0001259