ORPHA: 228426;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q11.22 | Autoimmune disease, multisystem, with facial dysmorphism | 613385 | Autosomal recessive | 3 | ITCH | 606409 |
A number sign (#) is used with this entry because of evidence that multisystem autoimmune disease with facial dysmorphism (ADMFD) is caused by homozygous or compound heterozygous mutation in the ITCH gene (606409) on chromosome 20q11.
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.
Brittain et al. (2019) reported a 23-year-old woman with marked short stature, severe early-onset chronic lung disease, facial dysmorphisms (dolichocephaly, proptosis, maxillary hypoplasia, small chin, low-hanging columella), and symmetric camptodactyly of fingers 3-5. In contrast to prior reported patients, she had normal intellect. She also had additional skeletal features including kyphoscoliosis, mild generalized joint hypermobility, and retained primary dentition as well as severe gastrointestinal reflux.
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).
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.
In a 23-year-old woman with ADMFD, Brittain et al. (2019) identified compound heterozygous frameshift mutations in the ITCH gene (606409.0001-606409.0002). The mutations were found by trio exome sequencing, and each parent was heterozygous for one of the mutations.
Brittain, H. K., Feary, J., Rosenthal, M., Spoudeas, H., Deciphering Developmental Disorders (DDD) Study, Wilson, L. C. Biallelic human ITCH variants causing a multisystem disease with dysmorphic features: a second report. Am. J. Med. Genet. 179A: 1346-1350, 2019. [PubMed: 31091003] [Full Text: https://doi.org/10.1002/ajmg.a.61169]
Lohr, N. J., Molleston, J. P., Strauss, K. A., Torres-Martinez, W., Sherman, E. A., Squires, R. H., Rider, N. L., Chikwava, K. R., Cummings, O. W., Morton, D. H., Puffenberger, E. G. Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease. Am. J. Hum. Genet. 86: 447-453, 2010. [PubMed: 20170897] [Full Text: https://doi.org/10.1016/j.ajhg.2010.01.028]