Autoimmune Disease, Multisystem, With Facial Dysmorphism

A number sign (#) is used with this entry because of evidence that multisystem autoimmune disease with facial dysmorphism (ADMFD) is caused by homozygous mutation in the ITCH gene (606409) on chromosome 20q11.

Clinical Features

Lohr et al. (2010) studied 10 Old Order Amish children from 8 related and consanguineous families with organomegaly, failure to thrive, developmental delay, dysmorphic features, and autoimmune inflammatory cell infiltration of the lungs, liver, and gut. Growth was stunted, and 6 of the 10 patients required gastrostomy tube feeding, although only 2 had overt symptoms of malabsorption, due to autoimmune enteropathy and chronic diarrhea. Distinctive craniofacial features included relative macrocephaly with frontal bossing, dolichocephaly, orbital proptosis, flattened midface with a prominent occiput, small chin, and low posteriorly rotated ears. The liver and spleen were typically more than 4 cm below the costal margin. The remainder of the physical examination was significant for global hypotonia and campto- or clinodactyly, and all children were delayed in gross motor skills and cognitive skills. Chronic lung disease was present in 9 of the 10 children, often clinically characterized as asthma and consisting of a cellular, nonspecific interstitial pneumonitis; respiratory failure was the cause of death in all 3 children who were deceased, at 6 months, 1.2 years, and 3 years of age, respectively. Four of the 10 children developed hypothyroidism, and autoantibodies were found in the 3 who were tested; 3 patients had autoimmune hepatitis; and 1 was diagnosed with type 1 diabetes mellitus.

Mapping

Lohr et al. (2010) performed genomewide autozygosity mapping in 5 Old Order Amish patients with syndromic multisystem autoimmune disease and identified a 19-Mb homozygous block in the pericentromeric region of chromosome 20, bounded by rs2038383 and rs2067084 and containing 258 known or hypothetical genes. The authors noted that the prominent autoimmune disease in 1 of the patients was similar to the autoimmune findings in mice null for the candidate gene ITCH (606409).

Molecular Genetics

In 10 Old Order Amish patients with syndromic multisystem autoimmune disease mapping to chromosome 20q11, Lohr et al. (2010) sequenced the candidate gene ITCH and identified homozygosity for a frameshift mutation (606409.0001) in all. None of the 9 heterozygous sibs or parents were symptomatic or dysmorphic.