OOA (Old Order Amish)

Inheritance: autosomal recessive
Genes: ITCH

E3 ubiquitin ligase deficiency

Hepatosplenomegaly
Developmental delay
Lung disease
Diarrhea
Dolichocephaly
Orbital proptosis
Flat mid-face
Small chin
Low posteriorly rotated ears
Hypotonia
Low body mass
Macrocephaly
Hypothyroidism

ITCH Autoimmune Disease

Clinical Characteristics

General description (for patients):

This is a generalized disorder with failure to thrive, growth retardation and chronic inflammation of multiple organs including the liver, spleen, lungs, thyroid, and the intestines. In addition, individuals from birth tend to have muscle floppiness, are slow to learn to walk and talk, and have an enlarged skull with prominent eyes, small chin, prominent forehead, and low-set ears. The inflammation of the intestines leads to diarrhea, while involvement of lungs leads to chronic disease sometimes diagnosed as asthma. Individuals may live to adulthood but some succumb to respiratory failure early in childhood.   

Medical description:

This autoimmune disease is an early onset, chronic and widespread malady that involves multiple organs including the liver, GI tract, spleen, lungs and thyroid. Its onset in infancy manifests as failure to thrive, poor feeding, and generalized developmental delays resulting in the retardation of cognitive and gross motor skills, hypotonia and stunted growth. There are also dysmorphic features such as relative macrocephaly, small chin, frontal bossing, flat mid-face with relative orbital proptosis, and low-set, posteriorly rotated ears. The enteropathy can lead to chronic diarrhea and failure to gain weight with oral feeding although gastrostomy tubes are seldom required. The chronic lung inflammation is often diagnosed as asthma and may lead to respiratory failure especially in young infants. Other individuals may live to adulthood.

Genetics: 

This autosomal recessive disorder has been identified in ten individuals from 8 related Old Order Amish families. All were offspring of consanguineous marriages whose ancestry traced to two common ancestral couples of the Indiana community. Autozygosity mapping in five patients identified homozygosity for a single base pair insertion in exon 6 (c.394_395insA) with heterozygosity in unaffected parents and 12 siblings. The mutation leads to truncation of the ITCH gene [located on chromosome 20 (20q11)] that codes for an E3 ubiquitin ligase.

Treatment:  

No comprehensive treatment is known. Immunosuppressive and corticosteroid treatments may ameliorate some of the symptoms. Acute infections require appropriate treatment and gastrostomy feeding may be helpful in some patients.  
PROGNOSIS: The disease is highly variable in severity with some succumbing to respiratory failure as infants while one has lived into the second decade and another into the third decade.

Ancillary treatments and support:

supportive, pulmonary therapy, supplemental feeding

Specialists and specialty centers:

gastroenterologists, pulmonologists, pediatricians, endocrinologists, nutritionists

References:

Lohr, N.J., Molleston, J.P., Strauss, K.A., Torres-Martinez, W., Sherman, E.A., Squires, R.H., Rider, N.L., Chikawava, K.R., Cummings, O.W., Morton, D.H., and Puffenberger, E.G. Human ITCH E3 ubiquitin ligasedeficiency causes syndromic multisystem autoimmune disease. Am. J. Hum. Genet. 86: 447-453, 2010. PubMed ID: 20170897