Expanded Phenotypic and Longitudinal Data on ITCH Ubiquitin Ligase Deficiency
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
ITCH ubiquitin ligase deficiency is an autosomal recessive disorder characterized by systemic autoimmunity, immunodeficiency, dysmorphic features, and severe proportional short stature. First described in 2010 by Lohr et al. in a cohort of 10 individuals from a consanguineous Amish community in Indiana, only four additional cases have since been reported. Due to its ultra-rare nature, the natural history of ITCH deficiency remains poorly understood. In this study, we provide updated clinical data on the original cohort as well as on newly diagnosed individuals. Additionally, we present novel phenotypic observations of ITCH deficiency in the neonatal period, expanding our understanding of its early manifestations and progression.
Methods:
The original cohort of 10 individuals was enrolled under an Institutional Review Board (IRB) protocol approved by the IRB at Indiana University School of Medicine. Subsequent participants were enrolled in the same protocol upon presentation with relevant symptoms and confirmation of ITCH deficiency through commercial genetic testing. Clinical data were collected through retrospective chart reviews.
Results:
An additional 6 individuals were enrolled in the study since the original publication, bringing the total cohort to 16. All 6 newly enrolled individuals were homozygous for ITCH p.I132Nfs*9. While 4 of these individuals were from the same Amish community, the other 2 were from a different Amish group. Of the 16 individuals, only 5 are currently alive, with the oldest surviving until 25 years of age. Causes of death included complications from autoimmune disease, chronic lung disease, and neonatal respiratory failure.
At birth and in early childhood, individuals exhibited short limbs and relative macrocephaly, but these features became more proportional with age. However, all individuals experienced severe, yet proportional, short stature throughout life, with height and weight consistently between -5 and -7 Z-scores on the CDC growth chart. Autoimmune manifestations included autoimmune hepatitis, NMDA-receptor encephalitis, arthritis, and enteropathy. Various immunosuppressive and immunomodulatory treatments were attempted, with limited success.
Three individuals were diagnosed with ITCH deficiency either prenatally or shortly after birth. All presented with dysmorphic features, including short limbs and relative macrocephaly, and exhibited significant respiratory distress and cardiac dysfunction. Two brothers passed away within days of birth, while the surviving individual developed neonatal diabetes requiring insulin therapy. Notably, the surviving individual had four siblings with similar physical features, all of whom were either stillborn or died shortly after birth.
Conclusion:
This study follows the natural history of 16 individuals with ITCH deficiency, including 10 from the original cohort described by Lohr et al. ITCH deficiency is associated with significant autoimmunity, presenting with a broad spectrum of clinical manifestations. Mortality is high, with two-thirds of affected individuals passing away before the age of 30. Among those who survive into adulthood, almost all continue to experience severe short stature, chronic lung disease, and autoimmune symptoms. The condition is also linked to severe perinatal symptoms and carries a notable risk of neonatal mortality or intrauterine fetal demise. While no cure currently exists, recent work by Patel et al. (2021) demonstrated successful symptom amelioration in an individual with ITCH deficiency, suggesting that targeted treatments may hold promise. Early detection of ITCH deficiency could be crucial for managing symptoms and improving long-term outcomes.
ITCH ubiquitin ligase deficiency is an autosomal recessive disorder characterized by systemic autoimmunity, immunodeficiency, dysmorphic features, and severe proportional short stature. First described in 2010 by Lohr et al. in a cohort of 10 individuals from a consanguineous Amish community in Indiana, only four additional cases have since been reported. Due to its ultra-rare nature, the natural history of ITCH deficiency remains poorly understood. In this study, we provide updated clinical data on the original cohort as well as on newly diagnosed individuals. Additionally, we present novel phenotypic observations of ITCH deficiency in the neonatal period, expanding our understanding of its early manifestations and progression.
Methods:
The original cohort of 10 individuals was enrolled under an Institutional Review Board (IRB) protocol approved by the IRB at Indiana University School of Medicine. Subsequent participants were enrolled in the same protocol upon presentation with relevant symptoms and confirmation of ITCH deficiency through commercial genetic testing. Clinical data were collected through retrospective chart reviews.
Results:
An additional 6 individuals were enrolled in the study since the original publication, bringing the total cohort to 16. All 6 newly enrolled individuals were homozygous for ITCH p.I132Nfs*9. While 4 of these individuals were from the same Amish community, the other 2 were from a different Amish group. Of the 16 individuals, only 5 are currently alive, with the oldest surviving until 25 years of age. Causes of death included complications from autoimmune disease, chronic lung disease, and neonatal respiratory failure.
At birth and in early childhood, individuals exhibited short limbs and relative macrocephaly, but these features became more proportional with age. However, all individuals experienced severe, yet proportional, short stature throughout life, with height and weight consistently between -5 and -7 Z-scores on the CDC growth chart. Autoimmune manifestations included autoimmune hepatitis, NMDA-receptor encephalitis, arthritis, and enteropathy. Various immunosuppressive and immunomodulatory treatments were attempted, with limited success.
Three individuals were diagnosed with ITCH deficiency either prenatally or shortly after birth. All presented with dysmorphic features, including short limbs and relative macrocephaly, and exhibited significant respiratory distress and cardiac dysfunction. Two brothers passed away within days of birth, while the surviving individual developed neonatal diabetes requiring insulin therapy. Notably, the surviving individual had four siblings with similar physical features, all of whom were either stillborn or died shortly after birth.
Conclusion:
This study follows the natural history of 16 individuals with ITCH deficiency, including 10 from the original cohort described by Lohr et al. ITCH deficiency is associated with significant autoimmunity, presenting with a broad spectrum of clinical manifestations. Mortality is high, with two-thirds of affected individuals passing away before the age of 30. Among those who survive into adulthood, almost all continue to experience severe short stature, chronic lung disease, and autoimmune symptoms. The condition is also linked to severe perinatal symptoms and carries a notable risk of neonatal mortality or intrauterine fetal demise. While no cure currently exists, recent work by Patel et al. (2021) demonstrated successful symptom amelioration in an individual with ITCH deficiency, suggesting that targeted treatments may hold promise. Early detection of ITCH deficiency could be crucial for managing symptoms and improving long-term outcomes.