Wolcott Rallison syndrome

Other Names: Wolcott Rallison syndrome; MED-IDDM syndrome; IDDM-MED syndrome

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.

Cause

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.

Inheritance

Autosomal recessive inheritance, a 25% chance

Inheritance is autosomal recessive and genetic counseling is possible.

Signs and symptoms

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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of the metaphysis(Abnormality of the wide portion of a long bone)
• Cone-shaped epiphyses of the phalanges of the hand(Cone-shaped end part of finger bones)
• Death in infancy(Infantile death)
• Dehydration
• Epicanthus(Eye folds)
• Epiphyseal dysplasia(Abnormal development of the ends of long bones in arms and legs)
• Glycosuria(Glucose in urine)
• High forehead
• Hyperglycemia(High blood sugar)
• Hypermetropia(Farsightedness)
• Hyperuricemia(High blood uric acid level)
• Microdontia(Decreased width of tooth)
• Multiple epiphyseal dysplasia
• Osteopenia
• Osteoporosis
• Renal tubular dysfunction(Abnormal function of filtrating structures in kidney)
• Short stature(Decreased body height)
• Steatorrhea(Fat in feces)
• Thin vermilion border(Decreased volume of lip)
• Transient neonatal diabetes mellitus
• Triangular face(Face with broad temples and narrow chin)
• Weight loss
• 30%-79% of people have these symptoms
• Abnormal heart morphology(Abnormality of the heart)
• Acute hepatic failure(Acute liver failure)
• Brachydactyly(Short fingers or toes)
• Chronic hepatic failure(Chronic liver failure)
• Coxa valga
• Delayed skeletal maturation(Delayed bone maturation)
• Elevated hepatic transaminase(High liver enzymes)
• Enlarged thorax(Wide rib cage)
• Gait disturbance(Abnormal gait)
• Genu valgum(Knock knees)
• Hepatomegaly(Enlarged liver)
• Hip dislocation (Dislocated hips)
• Intellectual disability(Mental deficiency)
• Intracerebral periventricular calcifications
• Ketoacidosis
• Motor delay
• Muscular hypotonia(Low or weak muscle tone)
• Narrow iliac wings
• Neutropenia(Low blood neutrophil count)
• Platyspondyly(Flattened vertebrae)
• Short thorax(Shorter than typical length between neck and abdomen)

5%-29% of people have these symptoms

• Abnormality of neuronal migration
• Exocrine pancreatic insufficiency(Inability to properly digest food due to lack of pancreatic digestive enzymes)
• Hyperlordosis(Prominent swayback)
• Hypoglycemia(Low blood sugar)
• Hypothyroidism(Underactive thyroid)
• Intrauterine growth retardation(Prenatal growth deficiency)
• Jaundice(Yellow skin)
• Kyphosis(Hunched back)
• Microcephaly(Abnormally small skull)
• Nephropathy
• Pancreatic hypoplasia(Underdeveloped pancreas)
• Recurrent fractures(Increased fracture rate)
• Reduced pancreatic beta cells
• Renal insufficiency(Renal failure)
• Seizure

1%-4% of people have these symptoms

• Coma

Diagnosis

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 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 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.

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 multiple-organ failure with predominant liver and renal dysfunction.

NIH genetic and rare disease info

• NIH info on Wolcott Rallison syndrome

Wolcott Rallison syndrome is a rare disease.

Wolcott Rallison syndrome Resources
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