eMedicine Specialties > Dermatology > Pediatric Diseases

Hartnup Disease: Differential Diagnoses & Workup

Author: Lidija Kandolf Sekulovic, MD, PhD, Associate Professor, Head of the First Division, Department of Dermatology and Venereology, Military Medical Academy, Serbia
Coauthor(s): Djordjije Karadaglic, MD, DSc, Professor, School of Medicine, University of Podgorica, Podgorica, Montenegro; Ljubomir Stojanov, MD, PhD, Professor, University of Belgrade School of Medicine, Serbia
Contributor Information and Disclosures

Updated: Feb 6, 2009

Differential Diagnoses

Ataxia-Telangiectasia
Hydroa Vacciniforme
Pityriasis Alba
Xeroderma Pigmentosum

Other Problems to Be Considered

Rash

Infantile atopic eczema
Seborrheic eczema
Nutritional pellagra (Misdiagnosis can be prevented by performing urine chromatography.)
Congenital poikilodermas with photosensitivity (eg, Cockayne syndrome)
Malar rash of lupus erythematosus
Carcinoid syndrome (may lead to disturbance of tryptophan metabolism and pellagralike rash)
Indicanuria in inborn errors of amino acid metabolism (eg, phenylketonuria, blue diaper syndrome)

Central nervous system

Ataxia-telangiectasia (can cause diagnostic difficulties, especially in patients with mild skin involvement)
Systemic lupus erythematosus (can be confused if photosensitivity with neuropsychiatric symptoms is present)
Other ataxias with biochemical and genetic defects

Workup

Laboratory Studies

  • Urine chromatography3,16,17,20,22
    • Increased levels of neutral amino acids (eg, glutamine, valine, phenylalanine, leucine, asparagine, citrulline, isoleucine, threonine, alanine, serine, histidine, tyrosine, tryptophan) and indican are found in the urine.
    • Urinary indoxyl derivatives (ie, 5-hydroxyindoleacetic acid) may be demonstrated following an oral tryptophan load.
    • Urine excretion of proline, hydroxyproline, and arginine remains normal, which differentiates Hartnup disease from other causes of gross aminoaciduria.
    • Perform urine chromatography to exclude nutritional pellagra.
  • Plasma concentrations of amino acids are usually normal.3,16,17,20,22

Procedures

  • Jejunal biopsy may be required in selected patients (transport defect may be identified in vitro).
  • Skin biopsy may be required in selected patients.17,19,20,21

Histologic Findings

Changes in the skin are similar to those seen in pellagra. Findings are not diagnostic and include hyperkeratosis, parakeratosis, epidermal atrophy, hyperpigmentation of the basal layer, and a mild superficial dermal lymphocytic infiltrate. Bullae may be either intraepidermal or subepidermal. Hyperplasia of the sebaceous glands with follicular dilatation and plugging may occur.19,20,21

More on Hartnup Disease

Overview: Hartnup Disease
Differential Diagnoses & Workup: Hartnup Disease
Treatment & Medication: Hartnup Disease
Follow-up: Hartnup Disease
Multimedia: Hartnup Disease
References
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References

  1. Baron DN, Dent CE, Harris H, Hart EW, Jepson JB. Hereditary pellagra-like skin rash with temporary cerebellar ataxia, constant renal amino-aciduria, and other bizarre biochemical features. Lancet. Sep 1 1956;271(6940):421-8. [Medline].

  2. Bröer S, Cavanaugh JA, Rasko JE. Neutral amino acid transport in epithelial cells and its malfunction in Hartnup disorder. Biochem Soc Trans. Feb 2005;33:233-6. [Medline].

  3. Galadari E, Hadi S, Sabarinathan K. Hartnup disease. Int J Dermatol. Dec 1993;32(12):904. [Medline].

  4. Bröer A, Cavanaugh JA, Rasko JE, Bröer S. The molecular basis of neutral aminoacidurias. Pflugers Arch. Jan 2006;451(4):511-7. [Medline].

  5. Seow HF, Broer S, Broer A, et al. Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. Nat Genet. Sep 2004;36(9):1003-7. [Medline].

  6. Kleta R, Romeo E, Ristic Z, et al. Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder. Nat Genet. Sep 2004;36(9):999-1002. [Medline].

  7. Broer S, Cavanaugh JA, Rasko JE. Neutral amino acid transport in epithelial cells and its malfunction in Hartnup disorder. Biochem Soc Trans. Feb 2005;33:233-6. [Medline].

  8. Nozaki J, Dakeishi M, Ohura T, et al. Homozygosity mapping to chromosome 5p15 of a gene responsible for Hartnup disorder. Biochem Biophys Res Commun. Jun 8 2001;284(2):255-60. [Medline].

  9. Bröer A, Klingel K, Kowalczuk S, Rasko JE, Cavanaugh J, Broer S. Molecular cloning of mouse amino acid transport system B0, a neutral amino acid transporter related to Hartnup disorder. J Biol Chem. Jun 4 2004;279(23):24467-76. [Medline].

  10. Symula DJ, Shedlovsky A, Dove WF. Genetic mapping of hph2, a mutation affecting amino acid transport in the mouse. Mamm Genome. Feb 1997;8(2):98-101. [Medline].

  11. Seow HF, Broer S, Broer A, et al. Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. Nat Genet. Sep 2004;36(9):1003-7. [Medline].

  12. Azmanov DN, Kowalczuk S, Rodgers H, et al. Further evidence for allelic heterogeneity in Hartnup disorder. Hum Mutat. Oct 2008;29(10):1217-21. [Medline].

  13. Azmanov DN, Rodgers H, Auray-Blais C, et al. Persistence of the common Hartnup disease D173N allele in populations of European origin. Ann Hum Genet. Nov 2007;71:755-61. [Medline].

  14. Broer S. Apical transporters for neutral amino acids: physiology and pathophysiology. Physiology (Bethesda). Apr 2008;23:95-103. [Medline].

  15. Broer S. Apical transporters for neutral amino acids: physiology and pathophysiology. Physiology (Bethesda). Apr 2008;23:95-103. [Medline].

  16. Milovanovic DD. A clinicobiochemical study of tryptophan and other plasma and urinary amino acids in the family with Hartnup disease. Adv Exp Med Biol. 2003;527:325-35. [Medline].

  17. Schmidtke K, Endres W, Roscher A, et al. Hartnup syndrome, progressive encephalopathy and allo-albuminaemia. A clinico-pathological case study. Eur J Pediatr. Dec 1992;151(12):899-903. [Medline].

  18. Wilcken B, Yu JS, Brown DA. Natural history of Hartnup disease. Arch Dis Child. Jan 1977;52(1):38-40. [Medline].

  19. Oakley A, Wallace J. Hartnup disease presenting in an adult. Clin Exp Dermatol. Sep 1994;19(5):407-8. [Medline].

  20. Levy H. Hartnup Disorder. In: Scriver CR, Beaudet A L, Sly WS, Valle D. The metabolic and molecularbases of inherited disease. New York: McGraw-Hill; 2001:4957–4969.

  21. Stojanov LJ, Karadaglic DJ. Skin changes in children with inborn errors of amino acids metabolism. In: Karadaglic DJ, ed. Dermatology. Belgrade: Vojnoizdavacki zavod-Verzal Press; 2000:1505-12.

  22. Scriver CR, Mahon B, Levy HL, et al. The Hartnup phenotype: Mendelian transport disorder, multifactorial disease. Am J Hum Genet. May 1987;40(5):401-12. [Medline].

  23. Seyhan ME, Selimoglu MA, Ertekin V, Fidanoglu O, Altinkaynak S. Acrodermatitis enteropathica-like eruptions in a child with Hartnup disease. Pediatr Dermatol. May-Jun 2006;23(3):262-5. [Medline].

  24. Camargo SM, Bockenhauer D, Kleta R. Aminoacidurias: Clinical and molecular aspects. Kidney Int. Apr 2008;73(8):918-25. [Medline].

  25. Henderson HE, Goodman R, Schram J, Diamond E, Daneel A. Biochemical screening for inherited metabolic disorders in the mentally retarded. S Afr Med J. Nov 7 1981;60(19):731-3. [Medline].

  26. Milovanovic D, Djukic A, Stepanovic R, Pekovic D, Vranjesevic D. [Hartnup disease (report of 2 cases in one family)]. Srp Arh Celok Lek. Mar-Apr 2000;128(3-4):97-103. [Medline].

  27. Jonas AJ, Butler IJ. Circumvention of defective neutral amino acid transport in Hartnup disease using tryptophan ethyl ester. J Clin Invest. Jul 1989;84(1):200-4. [Medline].

  28. Mahon BE, Levy HL. Maternal Hartnup disorder. Am J Med Genet. Jul 1986;24(3):513-8. [Medline].

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Further Reading

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Keywords

Hartnup disease, Hartnup disorder, Hartnup aminoaciduria, Hartnup syndrome, MIM #234500, Mendelian Inheritance in Man #234500

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Contributor Information and Disclosures

Author

Lidija Kandolf Sekulovic, MD, PhD, Associate Professor, Head of the First Division, Department of Dermatology and Venereology, Military Medical Academy, Serbia
Lidija Kandolf Sekulovic, MD, PhD is a member of the following medical societies: European Academy of Dermatology and Venereology and Serbian Association of DermatoVenereologists
Disclosure: Nothing to disclose.

Coauthor(s)

Djordjije Karadaglic, MD, DSc, Professor, School of Medicine, University of Podgorica, Podgorica, Montenegro
Djordjije Karadaglic, MD, DSc is a member of the following medical societies: American Academy of Dermatology, European Academy of Dermatology and Venereology, and Serbian Association of DermatoVenereologists
Disclosure: Nothing to disclose.

Ljubomir Stojanov, MD, PhD, Professor, University of Belgrade School of Medicine, Serbia
Disclosure: Nothing to disclose.

Medical Editor

Mark A Crowe, MD, Assistant Clinical Instructor, Department of Medicine, Division of Dermatology, University of Washington School of Medicine
Mark A Crowe, MD is a member of the following medical societies: American Academy of Dermatology and North American Clinical Dermatologic Society
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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