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Dopamine-Responsive Growth-Hormone Deficiency and Central Hypothyroidism in Sepiapterin Reductase Deficiency

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JIMD Reports, Volume 24

Part of the book series: JIMD Reports ((JIMD,volume 24))

Abstract

Sepiapterin reductase (SR) deficiency is a rare autosomal recessively inherited error of tetrahydrobiopterin (BH4) biosynthesis, resulting in disturbed dopaminergic and serotonergic neurotransmission. The clinical phenotype is characterized by dopa-responsive movement disorders including muscular hypotonia, dystonia, and parkinsonism. Due to the rarity of the disease, the phenotype of SR deficiency is far from being completely understood. Here, we report a 7-year-old boy, who was referred for diagnostic evaluation of combined psychomotor retardation, spastic tetraplegia, extrapyramidal symptoms, and short stature. Due to discrepancy between motor status and mental condition, analyses of biogenic amines and pterins in CSF were performed, leading to the diagnosis of SR deficiency. The diagnosis was confirmed by a novel homozygous mutation c.530G>C; p.(Arg177Pro) in exon 2 of the SPR gene. Because of persistent short stature, systematic endocrinological investigations were initiated. Insufficient growth-hormone release in a severe hypoglycemic episode after overnight fasting confirmed growth-hormone deficiency as a cause of short stature. In addition, central hypothyroidism was present. A general hypothalamic affection could be excluded. Since dopamine is known to regulate growth-hormone excretion, IGF-1, IGF-BP3, and peripheral thyroid hormone levels were monitored under l-dopa/carbidopa supplementation. Both growth-hormone-dependent factors and thyroid function normalized under treatment. This is the first report describing growth-hormone deficiency and central hypothyroidism in SR deficiency. It extends the phenotypic spectrum of the disease and identifies dopamine depletion as cause for the endocrinological disturbances.

Competing interests: None declared

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Abbreviations

3-OMD:

3-O-methyldopa

5-HIAA:

5-Hydroxyindoleacetic acid

5-HTP:

5-Hydroxytryptophan

BH2 :

Dihydrobiopterin

BH4 :

Tetrahydrobiopterin

CSF:

Cerebrospinal fluid

HVA:

Homovanillic acid

l-dopa:

Levodopa

Phe:

Phenylalanine

SR:

Sepiapterin reductase

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Authors and Affiliations

  1. Division of Neuropediatrics and Metabolic Medicine, Department of General Pediatrics, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany

    Matthias Zielonka, Nenad Blau, Georg Friedrich Hoffmann & Thomas Opladen

  2. Pediatric Department, Jahra Hospital, Qadisiya, Kuwait

    Nawal Makhseed

  3. Division of Pediatric Endocrinology, Department of General Pediatrics, University Hospital Heidelberg, Heidelberg, Germany

    Markus Bettendorf

Authors
  1. Matthias Zielonka
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  2. Nawal Makhseed
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  3. Nenad Blau
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  4. Markus Bettendorf
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  5. Georg Friedrich Hoffmann
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  6. Thomas Opladen
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Corresponding author

Correspondence to Thomas Opladen .

Editor information

Editors and Affiliations

  1. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  2. Division of Metabolism and Children’s Research Centre, University Children’s Hospital Zuri, Zurich, Switzerland

    Matthias Baumgartner

  3. Tulane University Medical School, New Orleans, Louisiana, USA

    Eva Morava

  4. Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, Minnesota, USA

    Marc Patterson

  5. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, United Kingdom

    Shamima Rahman

  6. Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: Verena Peters

Appendices

Synopsis

Systematic endocrinological investigations should be performed in patients with sepiapterin reductase deficiency as dopamine depletion might result in growth-hormone deficiency and central hypothyroidism associated with cognitive impairment and life-threatening hypoglycemic episodes. Analyses of biogenic amines in CSF should be considered in the metabolic workup of children with fasting hypoglycemia and neurologic symptoms.

References to Electronic Databases

Phenylalanine hydroxylase, EC 1.14.16.1; tyrosine hydroxylase, EC 1.14.16.2; tryptophan hydroxylase, EC 1.14.16.4; nitric-oxide synthase, EC 1.14.13.39

Competing Interest Statement

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Details of Contributions of Individual Authors

All authors contributed to clinical care and diagnostic evaluation of this patient. The manuscript was prepared and written by Matthias Zielonka and Thomas Opladen. All authors contributed to the critical revision of the manuscript for intellectual content and gave final approval for the version to be published.

Name of One Author Who Serves as Guarantor

Thomas Opladen accepts full responsibility for the work and/or conduct of the study, had access to the data, and controlled the decision to publish.

Ethical Approval

No approval from the institutional review board was necessary as this is a case report without inclusion of any identifying information.

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Zielonka, M., Makhseed, N., Blau, N., Bettendorf, M., Hoffmann, G.F., Opladen, T. (2015). Dopamine-Responsive Growth-Hormone Deficiency and Central Hypothyroidism in Sepiapterin Reductase Deficiency. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 24. JIMD Reports, vol 24. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_450

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  • DOI: https://doi.org/10.1007/8904_2015_450

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  • Print ISBN: 978-3-662-48226-1

  • Online ISBN: 978-3-662-48227-8

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