Browse

You are looking at 1 - 3 of 3 items

Baris Akinci Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA
Division of Endocrinology and Metabolism, Dokuz Eylul University, Izmir, Turkey

Search for other papers by Baris Akinci in
Google Scholar
PubMed
Close
,
Rasimcan Meral Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

Search for other papers by Rasimcan Meral in
Google Scholar
PubMed
Close
,
Diana Rus Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

Search for other papers by Diana Rus in
Google Scholar
PubMed
Close
,
Rita Hench Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

Search for other papers by Rita Hench in
Google Scholar
PubMed
Close
,
Adam H Neidert Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

Search for other papers by Adam H Neidert in
Google Scholar
PubMed
Close
,
Frank DiPaola Division of Pediatric Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA

Search for other papers by Frank DiPaola in
Google Scholar
PubMed
Close
,
Maria Westerhoff Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

Search for other papers by Maria Westerhoff in
Google Scholar
PubMed
Close
,
Simeon I Taylor Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA

Search for other papers by Simeon I Taylor in
Google Scholar
PubMed
Close
, and
Elif A Oral Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

Search for other papers by Elif A Oral in
Google Scholar
PubMed
Close

Summary

A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients.

Learning points:

  • A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years.

  • Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed.

  • The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin.

  • Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite.

  • Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.

Open access
Syed Ali Imran Division of Endocrinology and Metabolism, Dalhousie University, Halifax, Nova Scotia, Canada

Search for other papers by Syed Ali Imran in
Google Scholar
PubMed
Close
,
Khaled A Aldahmani Division of Endocrinology, Tawam Hospial, Al-Ain, UAE

Search for other papers by Khaled A Aldahmani in
Google Scholar
PubMed
Close
,
Lynette Penney Department of Pediatrics, Tawam Hospial, Al-Ain, UAE

Search for other papers by Lynette Penney in
Google Scholar
PubMed
Close
,
Sidney E Croul Department of Pathology, Tawam Hospial, Al-Ain, UAE

Search for other papers by Sidney E Croul in
Google Scholar
PubMed
Close
,
David B Clarke Department of Neurosurgery, Dalhousie University, Halifax, Nova Scotia, Canada

Search for other papers by David B Clarke in
Google Scholar
PubMed
Close
,
David M Collier Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, UK

Search for other papers by David M Collier in
Google Scholar
PubMed
Close
,
Donato Iacovazzo Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, UK

Search for other papers by Donato Iacovazzo in
Google Scholar
PubMed
Close
, and
Márta Korbonits Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, UK

Search for other papers by Márta Korbonits in
Google Scholar
PubMed
Close

Summary

Early-onset acromegaly causing gigantism is often associated with aryl-hydrocarbon-interacting receptor protein (AIP) mutation, especially if there is a positive family history. A15y male presented with tiredness and visual problems. He was 201 cm tall with a span of 217 cm. He had typical facial features of acromegaly, elevated IGF-1, secondary hypogonadism and a large macroadenoma. His paternal aunt had a history of acromegaly presenting at the age of 35 years. Following transsphenoidal surgery, his IGF-1 normalized and clinical symptoms improved. He was found to have a novel AIP mutation destroying the stop codon c.991T>C; p.*331R. Unexpectedly, his father and paternal aunt were negative for this mutation while his mother and older sister were unaffected carriers, suggesting that his aunt represents a phenocopy.

Learning points:

  • Typical presentation for a patient with AIP mutation with excess growth and eunuchoid proportions.

  • Unusual, previously not described AIP variant with loss of the stop codon.

  • Phenocopy may occur in families with a disease-causing germline mutation.

Open access
Renata Lange Endocrine Section, Hospital Federal da Lagoa, Rio de Janeiro, Brazil

Search for other papers by Renata Lange in
Google Scholar
PubMed
Close
,
Caoê Von Linsingen Endocrine Section, Hospital Federal da Lagoa, Rio de Janeiro, Brazil

Search for other papers by Caoê Von Linsingen in
Google Scholar
PubMed
Close
,
Fernanda Mata Endocrine Section, Hospital Federal da Lagoa, Rio de Janeiro, Brazil

Search for other papers by Fernanda Mata in
Google Scholar
PubMed
Close
,
Aline Barbosa Moraes Department of Internal Medicine and Endocrine Section, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal de Rio de Janeiro, Rua Prof. Rodolpho Paulo Rocco, 255, 9th Floor, Ilha do Fundão, Rio de Janeiro, 21941-913, Brazil

Search for other papers by Aline Barbosa Moraes in
Google Scholar
PubMed
Close
,
Mariana Arruda Department of Internal Medicine and Endocrine Section, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal de Rio de Janeiro, Rua Prof. Rodolpho Paulo Rocco, 255, 9th Floor, Ilha do Fundão, Rio de Janeiro, 21941-913, Brazil

Search for other papers by Mariana Arruda in
Google Scholar
PubMed
Close
, and
Leonardo Vieira Neto Endocrine Section, Hospital Federal da Lagoa, Rio de Janeiro, Brazil
Department of Internal Medicine and Endocrine Section, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal de Rio de Janeiro, Rua Prof. Rodolpho Paulo Rocco, 255, 9th Floor, Ilha do Fundão, Rio de Janeiro, 21941-913, Brazil

Search for other papers by Leonardo Vieira Neto in
Google Scholar
PubMed
Close

Summary

Ring chromosomes (RCs) are uncommon cytogenetic findings, and RC11 has only been described in 19 cases in the literature. Endocrine abnormalities associated with RC11 were reported for two of these cases. The clinical features of RC11 can result from an alteration in the structure of the genetic material, ring instability, mosaicism, and various extents of genetic material loss. We herein describe a case of RC11 with clinical features of 11q-syndrome and endocrine abnormalities that have not yet been reported. A 20-year-old female patient had facial dysmorphism, short stature, psychomotor developmental delays, a ventricular septal defect, and thrombocytopenia. Karyotyping demonstrated RC11 (46,XX,r(11)(p15q25)). This patient presented with clinical features that may be related to Jacobsen syndrome, which is caused by partial deletion of the long arm of chromosome 11. Regarding endocrine abnormalities, our patient presented with precocious puberty followed by severe hirsutism, androgenic alopecia, clitoromegaly, and amenorrhea, which were associated with overweight, type 2 diabetes mellitus (T2DM), and hyperinsulinemia; therefore, this case meets the diagnostic criteria for polycystic ovary syndrome. Endocrine abnormalities are rare in patients with RC11, and the association of RC11 with precocious puberty, severe clinical hyperandrogenism, insulin resistance, and T2DM has not been reported previously. We speculate that gene(s) located on chromosome 11 might be involved in the pathogenesis of these conditions. Despite the rarity of RCs, studies to correlate the genes located on the chromosomes with the phenotypes observed could lead to major advances in the understanding and treatment of more prevalent diseases.

Learning points

  • We hypothesize that the endocrine features of precocious puberty, severe clinical hyperandrogenism, insulin resistance, and T2DM might be associated with 11q-syndrome.

  • A karyotype study should be performed in patients with short stature and facial dysmorphism.

  • Early diagnosis and adequate management of these endocrine abnormalities are essential to improve the quality of life of the patient and to prevent other chronic diseases, such as diabetes and its complications.

Open access