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\begin{document}

\title{The Blue Man: Pediatric Diseases with Implications for Adulthood}



\author[1]{Karuna Dewan}%
\author[2]{Charles MacDonald}%
\author[3]{Courtney Shires}%
\affil[1]{Affiliation not available}%
\affil[2]{University of Tennseess Health Science Center}%
\affil[3]{West Cancer Center}%


\vspace{-1em}



  
  \date{May 06, 2024}


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\begin{abstract}
Blue discoloration of the skin and cartilage, or ochronosis, is a rare
physical examination finding. Here are two cases of childhood onset
ochronosis, one exogenous and one endogenous in etiology.%
\end{abstract}%



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\textbf{Introduction}

Ochronosis is a rare condition caused by the accumulation of
homogentisic acid in the connective tissues throughout the body. This
accumulation results in the discoloration of tissues to a blue-yellow
hue. This can be seen in the sclera of the eyes\textsuperscript{1},
nails\textsuperscript{2}, bones\textsuperscript{3},
skin\textsuperscript{2-5}, thyroid gland\textsuperscript{6}, substantia
niagra\textsuperscript{6}, coronary arteries\textsuperscript{6} and
cardiac valves\textsuperscript{6}. This discoloration makes for
interesting physical examination findings. The associated differential
diagnosis is quite narrow. Causes of ochronosis are either exogenous or
endogenous. Those that are exogenous include chemical exposure or
ingestion, whereas endogenous causes include inborn errors of
metabolism.

\textbf{Case Reports}

Patient 1: A 29 year-old female with Meniere's disease presented with
dizziness, hearing loss, nausea and vomiting. On physical examination
her pinnae appeared dark blue (Figure 1A). She ultimately underwent
endolymphatic sac decompression to treat Meniere's disease.
Intraoperatively her temporal bone was noted to appear blue-black
(Figure 1B). Upon further investigation the patient revealed that she
had taken Minocycline for severe acne for 8 years.

Patient 2: A 44 year-old mentally disabled male presented for
precipitous hearing loss. The patient's tympanic membranes (Figure 2A),
sclera (Figure 2B), pinnae (Figure 2C), nail beds (Figure 2D), and
gingiva (Figure 2E) were dark blue. Initially, thought to be
hemotympanum, Computerized Tomography (CT) demonstrated clear middle ear
spaces. Audiometric examination demonstrated left high-frequency
sensorineural hearing loss and right moderate to profound mixed hearing
loss. The patient's urine darkened when oxidized (Figure 2F).

\textbf{Discussion}

Multiple causes of pigmented bone and cartilage exist, including
ochronisis, metabolic bone diseases, metal deposits, sequestrum, and
metastatic disease. Ochronosis as described here, can be exogenous or
endogenous.

Exogenous ochronosis results from prolonged exposure to certain
chemicals. Patient 1 took Minocycline for severe acne for 8 years.
Minocycline, a yellow-colored, semi-synthetic tetracycline antibiotic
turns black when oxidized, causing disfiguring discoloration of the
skin, lips, nails, oral mucous, ear cartilage, conjunctiva, teeth,
bones, thyroid gland, and pigmentation of heart valves in a
dose-dependent manner. The incidence ranges between 3 and
15\%\textsuperscript{7}. Used for the treatment of a wide range of gram
positive and negative infections, onchronisis is most often seen in
patients receiving a dose of 100-200mg/day for as little as one year.
Minocycline-induced hyperpigmentation can be severely disfiguring and is
more likely to occur in certain populations of patients (eg: those with
phemphigus, pemphigoid, atopic dermatitis, or cystic acne). Pigmentation
is a commonly recognized adverse reaction associated with most of the
drugs in the tetracycline family, affecting the skin, nails, teeth, oral
mucosa, bone in the oral cavity, ocular structures, cartilage, thyroid,
and other visceral structures. Minocycline-induced hyperpigmentation
should be considered in the differential diagnosis of ochronosis. Other
medications that may cause changes in skin pigmentation include
anti-malarias, amiodarone, bleomycin and
chlorpromazine\textsuperscript{8}. Suwannarat et al. in 2004 published a
case series of 5 patients who presented with findings consistent with
ochronosis, including pigmentary changes of the ear and mild
degenerative changes of the spine and large joints. These patients were
clinically diagnosed as having alkaptonuria, but the diagnosis was
withdrawn based on normal urine HGA levels. All 5 patients were women
who had taken minocycline for dermatologic or rheumatologic disorders
for extended periods\textsuperscript{7}.

Endogenous ochronosis results from alkaptonuria (AKU), an autosomal
recessive mutation in the HGD gene resulting in a disorder of tyrosine
metabolism due to deficiency of homogentisate 1,2 dioxygenase (HGD)
activity. This causes an accumulation of homogentisic acid (HGA),
ochronosis, and destruction of connective tissue resulting in joint
disease. AKU, the working diagnosis for patient 2, is progressive, with
dark urine, onchronsis of eyes and ears, and severe ochronotic
arthropathy. It is diagnosed near birth with lifelong implications.
Ocular pigmentation is especially prominent and appears in 70\% of ACU
patients. Referred to as the Osler sign, ochronotic pigment deposition
becomes evident in the third decade of life. There is no literature to
suggest that scleral pigment deposition is associated with any effects
on visual function. If urine of an alkaptonuric patient is alkalinized
or allowed to stand, the homogentisic acid metabolizes to a melanin-like
substance, and the urine appears brown to black\textsuperscript{9}.
Aciduria causing darkly stained diapers in infancy is one method of
diagnosis. Ochronotic pigment appears in cartilage, intervertebral
disks, skin, and sclera\textsuperscript{10}. Currently, no available
treatment has been conclusively shown to prevent complications of
alkaptonuria. Restriction of dietary protein in pediatric patients has
been advocated, with the aim of reducing HGA excretion. Treatment is
currently based on symptomatology.

The differential diagnosis for blue discoloration of the skin and
cartilage is broad, these two patients presented with blue ears and
sclera of two different pediatric onset etiologies. While they have
different etiologies for their ochronosis both patients demonstrate the
adulthood implications of conditions with childhood onset.

\textbf{Acknowledgements}

None

\textbf{References}

1. Fraunfelder FT, Randall JA. Minocycline-induced scleral
pigmentation.\emph{Ophthalmology.} 1997;104(6):936-938.

2. Angeloni VL, Salasche SJ, Ortiz R. Nail, skin, and scleral
pigmentation induced by minocycline. \emph{Cutis.} 1987;40(3):229-233.

3. Rumbak MJ, Pitcock JA, Palmieri GM, Robertson JT. Black bones
following long-term minocycline treatment. \emph{Arch Pathol Lab
Med.}1991;115(9):939-941.

4. Butler JM, Marks R, Sutherland R. Cutaneous and cardiac valvular
pigmentation with minocycline. \emph{Clin Exp
Dermatol.}1985;10(5):432-437.

5. Argenyi ZB, Finelli L, Bergfeld WF, et al. Minocycline-related
cutaneous hyperpigmentation as demonstrated by light microscopy,
electron microscopy and X-ray energy spectroscopy. \emph{J Cutan
Pathol.} 1987;14(3):176-180.

6. Landas SK, Schelper RL, Tio FO, Turner JW, Moore KC, Bennett-Gray J.
Black thyroid syndrome: exaggeration of a normal process? \emph{Am J
Clin Pathol.} 1986;85(4):411-418.

7. Suwannarat P, Phornphutkul C, Bernardini I, Turner M, Gahl WA.
Minocycline-induced hyperpigmentation masquerading as alkaptonuria in
individuals with joint pain. \emph{Arthritis and
rheumatism.}2004;50(11):3698-3701.

8. Mehrany K, Kist JM, Ahmed DD, Gibson LE. Minocycline-induced
cutaneous pigmentation. \emph{Int J Dermatol.} 2003;42(7):551-552.

9. Yamaguchi S, Koda N, Ohashi T. Diagnosis of alkaptonuria by NMR
urinalysis: rapid qualitative and quantitative analysis of homogentisic
acid. \emph{The Tohoku journal of experimental
medicine.}1986;150(2):227-228.

10. Aquaron R. Alkaptonuria: a very rare metabolic disorder.\emph{Indian
journal of biochemistry \& biophysics.} 2013;50(5):339-344.

Figure Legends:

Figure 1

A: Blue pinna, B: Blue discoloration of mastoid bone

Figure 2

A: Blue tympanic membrane, B: Blue discoloration of the sclera, C: Blue
Pinna, D: Blue discoloration of nail beds, E: Blue discoloration of
teeth, F: Urine before (left) and after (right) oxidation, much darker
in color.

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