Epiphyseal Dysplasia, Multiple, With Early-Onset Diabetes Mellitus

A number sign (#) is used with this entry because of evidence that Wolcott-Rallison syndrome is caused by homozygous mutation in the EIF2AK3 gene (604032), which encodes translation initiation factor 2-alpha kinase-3, on chromosome 2p11.

Description

Wolcott-Rallison syndrome is a rare autosomal recessive disorder characterized by permanent neonatal or early infancy insulin-dependent diabetes. Epiphyseal dysplasia, osteoporosis, and growth retardation develop at a later age. Other frequent multisystem manifestations include hepatic and renal dysfunction, mental retardation, and cardiovascular abnormalities (summary by Delepine et al., 2000).

Clinical Features

Wolcott and Rallison (1972) described 2 brothers and a sister with infancy-onset diabetes mellitus and multiple epiphyseal dysplasia. Demineralization of bone with multiple fractures, tooth discoloration, and skin abnormalities were also noted. The parents were not related. Extracellular collagen fibers of varying thickness and intracellular collagen-like fibers suggest an abnormality in collagen synthesis and/or processing (Stoss et al., 1982). Stoss et al. (1982) reported affected brother and sister. Insulin-dependent diabetes mellitus was discovered at 5 weeks of age in the girl and at 10 weeks in the boy. Limited hip abduction was noted in the girl at age 1 year and she ceased to grow after age 6. At age 12 she had pain in many joints and short-trunk dwarfism with normal facies. The liver extended 8 cm below the right costal margin and the spleen was also enlarged. The brother was found to have diabetes when he became comatose at age 10 weeks. (The 2 sibs were born 14 years apart.) He developed renal insufficiency from which he died at the age of 11. The radiologic findings in this disorder are those of a spondyloepiphyseal dysplasia. Stoss et al. (1982) proposed that diabetes and chondrodysplasia are independent manifestations of a pleiotropic gene. Mauriac syndrome is the designation given dwarfism with hepatosplenomegaly and unregulated IDDM in children or adolescents. Glycosylation of connective tissue proteins, comparable to that which results in hemoglobin A1c, produces phenotypic changes, e.g., stiff joints in the hands.

Al-Gazali et al. (1995) described this syndrome in 2 brothers born to consanguineous Omani parents. Both children presented with diabetes, which was diagnosed at the age of 2 months in 1 brother and at the age of 2 weeks in the other. The radiologic abnormalities in 1 brother (osteoporosis, mild platyspondyly, small flattened epiphyses, bilateral coxa valga with narrow iliac wings) were evident from the age of 6 months. The first child of this couple, a female infant, died at the age of 2 months after weight loss, irritability and diarrhea. None of these sibs had hepatomegaly.

Bonthron et al. (1998) described a family in which the proband, born to first-cousin parents, died at 2 years of age from the sequelae of poorly controlled diabetes. The child had gray-blue sclerae, high-arched palate, and absent teeth. There was thoracolumbar kyphosis and bowing of the femora with undertubulation and thin cortices of the long bones with osteopenia. In addition, there was severe brachycephaly and poor ossification of the skull and wormian bones.

Abdelrahman et al. (2000) described a 3-year-old Saudi boy with infantile onset of hyperglycemia, recurrent hepatitis, renal insufficiency, developmental delay, and skeletal epiphyseal dysplasia. Idiopathic recurrent self-resulting hepatitis and renal impairment appeared to be associated features in this case. Bin-Abbas et al. (2001) reported further details of the same patient. Bin-Abbas et al. (2002) described a brother and sister with similar features including infantile onset of hyperglycemia, recurrent hepatitis, renal insufficiency, developmental delay, epiphyseal dysplasia, and central hypothyroidism.

Durocher et al. (2006) described 2 apparently unrelated children with mutation-proven Wolcott-Rallison syndrome. The first infant was diagnosed with diabetes at 4 weeks of age and had multiple episodes of hepatitis; x-ray examination revealed demineralization and epiphyseal dysplasia of the long bones. At 4 years of age, the patient developed hyperglycemia without acidosis and died shortly after from multiorgan failure. The second infant was diagnosed with diabetes at 6 months of age; at 4 years of age, the patient was reexamined due to short stature and overweight, at which time spine x-rays showed diffuse demineralization of thoracic and lumbar vertebrae. At age 7, the patient was noted to have platyspondyly and diffuse demineralization of the spine as well as an atlantoaxial subluxation. The patient also had anemia that did not respond to treatment with iron. At age 8, the child continued to have short stature and obesity but had not developed any hepatic or renal problems. Durocher et al. (2006) concluded that there is no simple relationship between clinical manifestations and EIF2AK3 mutations.

Cytogenetics

Stewart et al. (1996) reported an association of the Wolcott-Rallison syndrome and mitral valve stenosis, laryngeal stenosis with hypoplastic lungs, hypoplastic pancreas with interstitial fibrosis and reduction of acinar tissue, arhinencephaly, and abnormal flattening of the midbrain in a 4-year-old girl who had del(15)(q11-q12). Stewart et al. (1996) suggested that a gene for Wolcott-Rallison syndrome may lie in the region 15q11-q12.

Mapping

On the basis of 2 consanguineous families, Delepine et al. (2000) mapped the Wolcott-Rallison syndrome locus, which they symbolized WRS, to a region of less than 3 cM on chromosome 2p12.

Molecular Genetics

In 2 consanguineous families with Wolcott-Rallison syndrome, Delepine et al. (2000) identified different mutations in the EIF2AK3 (604032.0001; 604032.0002) that segregated with the disorder in each family.

In one of the sibs with Wolcott-Rallison syndrome reported by Al-Gazali et al. (1995), Brickwood et al. (2003) identified a splice site mutation in the EIF2AK3 gene (604032.0003).

In 2 apparently unrelated children with Wolcott-Rallison syndrome, born into 2 families from the same region of Quebec and sharing the same French surname, Durocher et al. (2006) identified homozygosity for a nonsense mutation in the EIF2AK3 gene (604032.0005).

Exclusion Studies

Bonthron et al. (1998) hypothesized that the PAX4 gene, which is required for pancreatic islet beta cell development in the mouse, was a good candidate for Wolcott-Rallison syndrome; however, they found no mutations in the PAX4 gene in the child they described or in 1 of the 2 children described by Al-Gazali et al. (1995). Bonthron et al. (1998) concluded that it was unlikely that PAX4 was involved in the etiology of Wolcott-Rallison syndrome but that it remained a good candidate for other forms of neonatal diabetes mellitus.