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Endocrine manifestations related to inherited metabolic diseases in adults

By Marie-Christine Vantyghem, Dries Dobbelaere, Karine Mention, Jean-Louis Wemeau, Jean-Marie Saudubray and Claire Douillard


Most inborn errors of metabolism (IEM) are recessive, genetically transmitted diseases and are classified into 3 main groups according to their mechanisms: cellular intoxication, energy deficiency, and defects of complex molecules. They can be associated with endocrine manifestations, which may be complications from a previously diagnosed IEM of childhood onset. More rarely, endocrinopathies can signal an IEM in adulthood, which should be suspected when an endocrine disorder is associated with multisystemic involvement (neurological, muscular, hepatic features, etc.). IEM can affect all glands, but diabetes mellitus, thyroid dysfunction and hypogonadism are the most frequent disorders. A single IEM can present with multiple endocrine dysfunctions, especially those involving energy deficiency (respiratory chain defects), and metal (hemochromatosis) and storage disorders (cystinosis). Non-autoimmune diabetes mellitus, thyroid dysfunction and/or goiter and sometimes hypoparathyroidism should steer the diagnosis towards a respiratory chain defect. Hypogonadotropic hypogonadism is frequent in haemochromatosis (often associated with diabetes), whereas primary hypogonadism is reported in Alström disease and cystinosis (both associated with diabetes, the latter also with thyroid dysfunction) and galactosemia. Hypogonadism is also frequent in X-linked adrenoleukodystrophy (with adrenal failure), congenital disorders of glycosylation, and Fabry and glycogen storage diseases (along with thyroid dysfunction in the first 3 and diabetes in the last). This is a new and growing field and is not yet very well recognized in adulthood despite its consequences on growth, bone metabolism and fertility. For this reason, physicians managing adult patients should be aware of these diagnoses

Topics: Review
Publisher: BioMed Central
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  1. (2004). A patient with mitochondrial encephalomyopathy presenting gynecomastia with elevation of serum estriol level. Rinsho Shinkeigaku
  2. (2007). A: Characterization of the IGF system in 15 patients with Alström syndrome. Clin Endocrinol (Oxf)
  3. (2000). A: Multiple endocrine abnormalities in a child with Blackfan-Diamond anemia and hemochromatosis Significant improvement of growth velocity and predicted adult height following growth hormone treatment despite liver damage. J Pediatr Endocrinol Metab
  4. (2009). A: Mutations in the ABCC8 gene can cause autoantibody-negative insulin-dependent diabetes. Diabetes Metab
  5. (1998). A: Rapid decline of fertility in a case of adrenoleukodystrophy. Hum Reprod
  6. (2011). A: Thyroid function in Fabry disease before and after enzyme replacement therapy. Minerva Endocrinol
  7. (1994). al: Pancreatic ß-cell secretory defect associated with mitochondrial point mutation of the tRNA (LEU (UUR)) gene: a study in seven families with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Diabetologia
  8. (1987). Andria G: Evidence of polyglandular involvement in Niemann-Pick disease type B. Eur J Pediatr
  9. (2007). Andria G: Increased prevalence of thyroid autoimmunity and hypothyroidism in patients with glycogen storage disease type I.
  10. (2011). Aubourg P: Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene. Orphanet J Rare Dis
  11. (2008). AW: MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression.
  12. (2008). Bentivoglio AR: Aceruloplasminemia: a novel mutation in a family with marked phenotypic variability. Mov Disord
  13. (2003). Camp G: Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease. Hum Mutat
  14. CE: Role of the Mitochondria
  15. (2005). CH: Hypogonadism in hereditary hemochromatosis.
  16. (2008). CH: Secondary hypothyroidism in hereditary hemochromatosis: recovery after iron depletion. Thyroid
  17. (2011). Chronic pancreatitis in branched-chain organic acidurias-a case of methylmalonic aciduria and an overview of the literature.
  18. (2008). Clear cells detection in nodular thyroid disease is not always indicative of neoplasia: description of the first case of thyroid involvement in multisystem triglyceride storage disease. Thyroid
  19. (2010). Cochat P: Bone metabolism in oxalosis: a single-center study using new imaging techniques and biomarkers. Pediatr Nephrol
  20. (2010). Cochat P: Genotype-phenotype correlation in primary hyperoxaluria type 1: the pGly170Arg AGXT mutation is associated with a better outcome. Kidney Int
  21. (2007). Cognitive dysfunction and hypogonadotrophic hypogonadism in a Brazilian patient with mitochondrial neurogastrointestinal encephalomyopathy and a novel ECGF1 mutation.
  22. (2006). Colao A: Endocrine dysfunction in patients with Fabry disease.
  23. (2006). Congenital disorder of glycosylation type Ia presenting as early-onset cerebellar ataxia in an adult. Mov Disord
  24. (2011). Congenital disorders of glycosylation (CDG): it’s (nearly) all in it!
  25. (2011). Cosford ND: Potent, selective, and orally available benzoisothiazolone phosphomannose isomerase inhibitors as probes for congenital disorder of glycosylation Ia.
  26. (2011). Criteria for early identification of aceruloplasminemia. Intern Med
  27. (2007). D: Congenital disorder of glycosylation type 1a: three siblings with a mild neurological phenotype.
  28. (2000). Delange F: The potential repercussions of maternal, fetal, and neonatal hypothyroxinemia on the progeny. Thyroid
  29. (1980). diabetes mellitus, hypothyroidism, hypoparathyroidism: incidence and prevalence related to iron overload and chelation therapy in patients with thalassaemia major followed from
  30. (2004). DiMauro S: Late-onset cerebellar ataxia with hypogonadism and muscle coenzyme Q10 deficiency. Neurology
  31. (2010). DL: Rare autosomal dominant POLG1 mutation in a family with metabolic strokes, posterior column spinal degeneration, and multi-endocrine disease.
  32. (2000). Drukker A: Hypothyroidism in primary hyperoxaluria type 1. J Pediatr
  33. (2011). EA: Presentation and course of diabetes in children and adolescents with Alstrom syndrome. Pediatr Diabetes
  34. (2003). Early diagnosis of inherited metabolic disorders towards improving outcome: the controversial issue of galactosaemia.
  35. (2008). Eckfeldt JH: Hemochromatosis and Iron Overload Screening Study Research Investigators Thyroid-stimulating hormone and free thyroxine levels in persons with HFE C282Y homozygosity, a common hemochromatosis genotype: the HEIRS study. Thyroid
  36. (1998). Ehrich JH: Slowly deteriorating insulin secretion and C-peptide production characterizes diabetes mellitus in infantile cystinosis.
  37. (1992). Endocrine abnormalities in mitochondrial myopathy with external ophthalmoplegia. Clin Invest
  38. (1992). Endocrine dysfunction in Kearns-Sayre syndrome. Clin Endocrinol (Oxf)
  39. (1995). Endocrinology of the carbohydrate-deficient glycoprotein syndrome type 1 from birth through adolescence. Pediatr Res
  40. (2006). Ensari A: Rare case of Alstrom syndrome without obesity and with short stature, diagnosed in adulthood. Nephrology (Carlton)
  41. (2010). Estrogen-related receptor gamma is a key regulator of muscle mitochondrial activity and oxidative capacity.
  42. (1989). et al: Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.
  43. (2011). Fakhfakh F: The mitochondrial ND1 m.3337G > A mutation associated to multiple mitochondrial DNA deletions in a patient with Wolfram syndrome and cardiomyopathy. Biochem Biophys Res Commun
  44. (1996). Fatourechi V: MELAS- and Kearns-Sayre-type co-mutation with myopathy and autoimmune polyendocrinopathy. Ann Neurol
  45. (2008). Fertility and impact of pregnancies on the mother and child in classic galactosemia. Obstet Gynecol Surv
  46. (2008). GEDIAM (Mitochondrial Diabetes French Study Group): Retinal and renal complications in patients with a mutation of mitochondrial DNA at position 3,243 (maternally inherited diabetes and deafness) A case-control study. Diabetologia
  47. (2009). gene are associated with a variable clinical phenotype. Clin Endocrinol (Oxf)
  48. (2009). Glycogen storage disease type III presenting with secondary diabetes and managed with insulin: a case report. Cases J
  49. (1995). Gonadal function and glycoprotein hormones in the carbohydrate-deficient glycoprotein (CDG) syndrome. Acta Paediatr
  50. (2000). Grosso S: Endocrine disorders in two sisters affected by MELAS syndrome.
  51. (1993). Growth and pubertal development in nephropathic cystinosis.
  52. (2011). Grüters A: Monocarboxylate transporter 8 deficiency: altered thyroid morphology and persistent high T3/T4 ratio after thyroidectomy.
  53. (2011). GT: The adult galactosemic phenotype.
  54. (2009). Guillausseau PJ: Mitochondrial Diabetes French Study Group: The clinical variability of maternally inherited diabetes and deafness is associated with the degree of heteroplasmy in blood leukocytes.
  55. (1984). Hales CN: Intracellular ATP directly blocks K+ channels in pancreatic B-cells. Nature
  56. (2011). Hennet T: Fibrotic response in fibroblasts from congenital disorders of glycosylation.
  57. (2003). HH: New disorders in carbohydrate metabolism: congenital disorders of glycosylation and their impact on the endocrine system. Rev Endocr Metab Disord
  58. (2011). Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations. Diabetologia
  59. (2009). Hypoketotic hypoglycemia with myolysis and hypoparathyroidism: an unusual association in medium chain acyl-CoA desydrogenase deficiency (MCADD). J Pediatr Endocrinol Metab
  60. (1996). Hypoparathyroidism and insulin-dependent diabetes mellitus in a patient with Kearns-Sayre syndrome harbouring a mitochondrial DNA deletion. Clin Endocrinol (Oxf)
  61. (1995). Hypopituitarism in primary haemochromatosis, recovery after iron depletion. Postgrad Med J
  62. (2010). JA: Gonadal function in male and female patients with classic galactosemia. Hum Reprod Update
  63. (2010). Jouanolle AM: Molecular diagnosis of genetic iron-overload disorders. Expert Rev Mol Diagn
  64. (1995). JV: The prevalence of polycystic ovaries in the hepatic glycogen storage diseases: its association with hyperinsulinism. Clin Endocrinol (Oxf)
  65. (2009). Khaldi F: Diabetic ketoacidosis revealing thimine responsive megaloblastic anemia. Ann Endocrinol (Paris)
  66. (2005). Kidokoro R: Three patients with middle-age-onset hemochromatosis caused by novel mutations in the hemojuvelin gene.
  67. King MC: Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome.
  68. (2010). King MC: Mutations in the DBPdeficiency protein HSD17B54 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault syndrome.
  69. (1997). Kosaka K: In situ characterization of islets in diabetes with a mitochondrial DNA mutation at nucleotide position 3243. Diabetes
  70. (2008). Ladsous M: Beneficial effects of propylthiouracil plus Lthyroxine treatment in a patient with a mutation in MCT8. J Clin Endocrinol Metab
  71. (2004). Late-onset primary hyperoxaluria triggered by hypothyroidism and presenting as rapidly progressive renal failure–description of a new mutation. Clin Nephrol
  72. (2010). Levtchenko E: Growth retardation in children with cystinosis. Minerva Pediatr
  73. (2006). Menheere PP: The endocrine system in treated patients with classical galactosemia. Mol Genet Metab
  74. (2009). Mitochondria and diabetes mellitus: unstangling a conflictive relationship? J Inher Metab Dis
  75. (2006). Montalto G: Sex hormones and risk of liver tumor.
  76. (1998). Moraes CT: Mitochondrial encephalomyopathy and hypoparathyroidism associated with a duplication and a deletion of mitochondrial deoxyribonucleic acid.
  77. (2011). Morava E: Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway.
  78. (2011). Morava E: Nijmegen paediatric CDG rating scale: a novel tool to assess disease progression. J Inherit Metab Dis
  79. (1993). Moshang T Jr: Growth hormone deficiency in two siblings with Alström syndrome.
  80. (1997). Mousson B: Identification of a large-scale mitochondrial deoxyribonucleic acid deletion in endocrinopathies and deafness: report of two unrelated cases with diabetes mellitus and adrenal insufficiency, respectively.
  81. (2000). Murase T: Diabetes mellitus secondary to glycogen storage disease type III. Diabet Med
  82. (2010). Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans.
  83. (2007). Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy. Ann Intern Med
  84. (2010). Nishino I: State of the art in muscle lipid diseases. Acta Myol
  85. (2010). Okumura A: Central diabetes insipidus and hypothalamic hypothyroidism associated with aceruloplasminemia. Intern Med
  86. (2010). Papaxanthos-Roche A: Azoospermia as a new feature of Fabry disease. Rev Med Interne
  87. (2006). Pathophysiology of impaired ovarian failure in galactosemia. Hum Reprod Update
  88. (2011). Pérez B: Expression analysis revealing destabilizing mutations in phosphomannomutase 2 deficiency (PMM2-CDG): Expression analysis of PMM2-CDG mutations.
  89. (2011). Petrovsky N: Alström syndrome: insights into the pathogenesis of metabolic disorders. Nat Rev Endocrinol
  90. (2011). Petryk A: Early diagnosis of cerebral X-linked adrenoleukodystrophy in boys with Addison’s disease improves survival and neurological outcomes.
  91. (1997). PG: Signs of testicular insufficiency in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy: a retrospective study.
  92. (1997). Pihko H: Hypoparathyroidism in a patient with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency caused by the G1528C mutation.
  93. (2005). PM: New Alström syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med
  94. (2011). Pregnancy in women heterozygous for MCT8 mutations: risk of maternal hypothyroxinemia and fetal care.
  95. (2008). Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1. Arch Neurol
  96. (2011). Refetoff S: Inherited defects of thyroid hormone metabolism. Ann Endocrinol (Paris)
  97. (2009). Refetoff S: Selenium supplementation fails to correct the selenoprotein synthesis defect in subjects with SBP2 gene mutations. Thyroid
  98. (2009). Ristić S: The impact of hemochromatosis mutations and transferrin genotype on gonadotropin serum levels in infertile men. Fertil Steril
  99. (2010). Roach PJ: Impaired glucose tolerance and predisposition to the fasted state in liver glycogen synthase knock-out mice.
  100. (2011). Rubio-Gozalbo ME: FSH isoform pattern in classic galactosemia.
  101. (2007). Rubio-Gozalbo ME: Growth in treated classical galactosemia patients.
  102. (2007). S: Clinical features in adults with congenital disorders of glycosylation type Ia (CDG-Ia).
  103. (1998). S: Primary adrenal insufficiency in a child with a mitochondrial DNA deletion. J Inherit Metab Dis
  104. (2011). S: X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism. Mol Genet Metab
  105. (2011). Sarafoglou K: Pubertal development in ALG6 deficiency (congenital disorder of glycosylation type Ic). Mol Genet Metab
  106. (2010). Sarwal MM: Insights into novel cellular injury mechanisms by gene expression profiling in nephropathic cystinosis.
  107. (2005). Secondary diabetes mellitus: late complication of glycogen storage disease type 1b. J Pediatr Endocrinol Metab
  108. (2009). Sedel F: Inborn errors of metabolism in adults. Ann Endocrinol (Paris)
  109. (2009). Sinigaglia L: Association between iron overload and osteoporosis in patients with hereditary hemochromatosis. Osteoporos Int
  110. (2005). SunderPlassmann G: High prevalence of subclinical hypothyroidism in patients with Anderson-Fabry disease.
  111. (2008). T: Hyperkalemia in familial mitochondrial cytopathy. Clin Nephrol
  112. (1998). Tanaka T: A case of Wilson’s disease associated with hypoparathyroidism and amenorrhea. Nippon Shokakibyo Gakkai Zasshi
  113. (2011). Tarassov I: Correction of the consequences of mitochondrial
  114. (2011). Taro Matsuoka for MELAS Study Group in Japan: MELAS: A nationwide prospective cohort study of 96 patients in Japan. Biochim Biophys Acta
  115. (1996). The influence of Coenzyme Q10 on total serum calcium concentration in two patients with Kearns-Sayre Syndrome and hypoparathyroidism. Neuromuscul Disord
  116. (2009). The m.3243A > G mutation in mitochondrial DNA leads to decreased insulin sensitivity in skeletal muscle and to progressive β-cell dysfunction. Diabetes
  117. (1993). The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes presenting without stroke. Arch Neurol
  118. (2006). Thiamine transporter mutation: an example of monogenic diabetes mellitus.
  119. (2009). Thiamine-responsive megaloblastic anemia syndrome: long-term follow-up.
  120. (2010). Thyroid function and human reproductive health. Endocr Rev
  121. (2011). Tillmann V: Sex differences in the development of diabetes in mice with deleted wolframin (WFS1) gene. Exp Clin Endocrinol Diabetes
  122. (2010). Uysalol E, Yildirmak ZY: Chronic intermittent form of isovaleric acidemia mimicking diabetic ketoacidosis. J Pediatr Endocrinol Metab
  123. (2011). Vettor R: The progression from obesity to type 2 diabetes in Alström syndrome. Pediatr Diabetes
  124. (2011). Waterham HR: Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder. Hum Mutat
  125. (2006). Wemeau JL: Phenotype and HFE genotype in a population with abnormal iron markers recruited from an Endocrinology Department.
  126. (1998). Wong LJ: Mitochondrial DNA deletion with Kearns Sayre syndrome in a child with Addison disease.
  127. (2010). Wong LJ: Sequence homology at the breakpoint and clinical phenotype of mitochondrial DNA deletion syndromes. PLoS One
  128. (2001). YH: A novel mutation in the mitochondrial 16S rRNA gene in a patient with MELAS syndrome, diabetes mellitus, hyperthyroidism and cardiomyopathy.
  129. (2010). Zahediasl S: The effect of maternal hypothyroidism on the carbohydrate metabolism and insulin secretion of isolated islets in adult male offspring of rats. Horm Metab Res

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