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Background <p>Alpha thalassemia/mental retardation X-linked (ATR-X) syndrome is a rare congenital disorder caused by mutations in the <i>ATRX</i> gene. It predominantly affects males and is characterized by a broad spectrum of clinical features including intellectual disability, distinctive craniofacial/skeletal anomalies, urogenital malformations, and alpha thalassemia. Dysglycemia and diabetes are not currently recognized as an endocrine-associated comorbidity of ATR-X syndrome.</p> Case Report <p>This case report presents a 14-year-old male with ATR-X syndrome who was admitted for pseudomonal tracheitis. Initial evaluation incidentally revealed marked hyperglycemia (random glucose 499&#xa0;mg/dL), prompting further workup. Fasting glucose was 320&#xa0;mg/dL, HbA1c was 10.2%, and mild ketosis was present without acidosis, consistent with diabetes mellitus. Type 1 diabetes-associated antibodies were ultimately negative, and his presentation was not consistent with other common forms of diabetes, such as type 2 diabetes. As per relatives, the patient had polyuria, polydipsia, and unintentional weight loss of 15 pounds in the prior month. Family history was significant for a 20-year-old brother also with ATR-X syndrome who was diagnosed at 16 years of age with insulin-dependent diabetes of unknown etiology. The patient started basal-bolus insulin with adjustments based on glycemic trends as per continuous glucose monitoring (CGM) with improvements in his glucose levels throughout admission. He was discharged on this regimen and a CGM.</p> Conclusions <p>While not previously described in humans, murine models have demonstrated structural and inflammatory changes, associating <i>ATRX</i> deficiency with glucose dysregulation. Pancreatic histopathological findings include interlobular edema, ductal dilation, loss of lobular organization, ductal dysplasia, perivascular/peripancreatic/islet/acinar inflammation, hyperplasia of the islet cells, and fatty infiltration. These pancreatic findings in <i>ATRX</i>-deficient mice provide a plausible mechanism for the impaired glucose tolerance, dysregulated insulin secretion, and β-cell dysfunction seen in this case. This case suggests a possible association between ATR-X syndrome and clinical diabetes not previously reported in humans. This report highlights the importance of consideration of and monitoring for diabetes mellitus in patients with ATR-X syndrome as a direct consequence of the syndrome itself.</p>

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Case Report: Diabetes Mellitus as a Novel Endocrine Manifestation of Alpha Thalassemia X-Linked Intellectual Disability (ATR-X) Syndrome

  • 期刊论文

  • 发表日期：

    2026年7月25日

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  • Carmen Nahir Plaza Mejías,
  • Griselda Álvarez,
  • Andrew Kanouse

摘要

Background

Alpha thalassemia/mental retardation X-linked (ATR-X) syndrome is a rare congenital disorder caused by mutations in the ATRX gene. It predominantly affects males and is characterized by a broad spectrum of clinical features including intellectual disability, distinctive craniofacial/skeletal anomalies, urogenital malformations, and alpha thalassemia. Dysglycemia and diabetes are not currently recognized as an endocrine-associated comorbidity of ATR-X syndrome.

Case Report

This case report presents a 14-year-old male with ATR-X syndrome who was admitted for pseudomonal tracheitis. Initial evaluation incidentally revealed marked hyperglycemia (random glucose 499 mg/dL), prompting further workup. Fasting glucose was 320 mg/dL, HbA1c was 10.2%, and mild ketosis was present without acidosis, consistent with diabetes mellitus. Type 1 diabetes-associated antibodies were ultimately negative, and his presentation was not consistent with other common forms of diabetes, such as type 2 diabetes. As per relatives, the patient had polyuria, polydipsia, and unintentional weight loss of 15 pounds in the prior month. Family history was significant for a 20-year-old brother also with ATR-X syndrome who was diagnosed at 16 years of age with insulin-dependent diabetes of unknown etiology. The patient started basal-bolus insulin with adjustments based on glycemic trends as per continuous glucose monitoring (CGM) with improvements in his glucose levels throughout admission. He was discharged on this regimen and a CGM.

Conclusions

While not previously described in humans, murine models have demonstrated structural and inflammatory changes, associating ATRX deficiency with glucose dysregulation. Pancreatic histopathological findings include interlobular edema, ductal dilation, loss of lobular organization, ductal dysplasia, perivascular/peripancreatic/islet/acinar inflammation, hyperplasia of the islet cells, and fatty infiltration. These pancreatic findings in ATRX-deficient mice provide a plausible mechanism for the impaired glucose tolerance, dysregulated insulin secretion, and β-cell dysfunction seen in this case. This case suggests a possible association between ATR-X syndrome and clinical diabetes not previously reported in humans. This report highlights the importance of consideration of and monitoring for diabetes mellitus in patients with ATR-X syndrome as a direct consequence of the syndrome itself.