Clinical Cases in Pigmentary Disorders

This book provides a guide to the diagnosis and management of pigmentary disorders. Each chapter explores a different clinical case to give the reader an interdisciplinary understanding of treatment options. Particular attention is given to the treatment of hypopigmentation, hypomelanosis and discoloration with cases highlighting the effects of drug intake, genetic alterations and the polluted environment.

Clinical Cases in Pigmentary Disorders examines therapeutic approaches through evidence-based best practice techniques and is relevant to dermatologists, oncologists, pharmacologists and pathologists.

• Language: English
• Publisher: Springer
• Release date: Aug 24, 2020
• ISBN: 9783030508234

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© Springer Nature Switzerland AG 2020

T. Lotti et al. (eds.)Clinical Cases in Pigmentary DisordersClinical Cases in Dermatologyhttps://doi.org/10.1007/978-3-030-50823-4_1

1. 15-Year-Old Female with Palmar, Periorbital, Oral Mucosal, and Gingival Hyperpigmentation

Mahin Alamgir¹ , Britney N. Wilson², Young Lee³ and Babar Rao¹

(1)

Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

(2)

New Jersey Medical School, Newark, NJ, USA

(3)

Chungnam National University, Daejeon, South Korea

A 15-year-old Asian female presents to the emergency room due to a 4-month history of increasing fatigue, nausea, and vomiting. She vomited between 3 and 12 times a day and displayed signs of dehydration due to her inability to tolerate oral intake. She also complained of a 12 lb weight loss despite no changes in diet and a sense of lightheadedness when she stands abruptly. She was diagnosed with alopecia areata 2 years ago and was treated with monthly intralesional triamcinolone injections for 3 months.

Physical examination of the scalp revealed three well-defined patches of hair loss without scarring. Further examination revealed hyperpigmentation of the area around the eyes, dorsa of the hands, palmar creases, buccal mucosa, oral cavity, and gingiva (Figs. 1.1 and 1.2). The patient reported this hyperpigmentation has worsened over the last year.

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Fig. 1.1

Hyperpigmentation of the palms, a common finding in Addison’s disease. Image courtesy of Dr Young Lee and Dr Jeung-Hoon Lee, Professor Emeritus, Chungnam National University, Daejeon, South Korea

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Fig. 1.2

Hyperpigmentation of the oral mucosa, another characteristic finding of Addison’s disease. Image courtesy of Dr Young Lee and Dr Jeung-Hoon Lee, Professor Emeritus, Chungnam National University, Daejeon, South Korea

Her temperature is 99.7 °F, pulse is 89/min, and blood pressure is 101/67 mmHg. Her pregnancy test came back negative, sodium level was 127 mEq/L, potassium was 5.6 mEql/L, thyroid-stimulating hormone was 4.2 μU/mL, AM cortisol was 1 μg/dL.

Dermatology was consulted. What’s your diagnosis?

Differential Diagnoses

1.

Addison’s disease

2.

Cushing’s disease

3.

Peutz-Jeghers Syndrome

Diagnosis

Addison disease.

Discussion

Addison’s disease is an insidious syndrome resulting from primary adrenocortical insufficiency [1]. In the US, the most common cause of primary adrenocortical insufficiency is autoimmune adrenalitis, which may occur sporadically or as a manifestation of polyglandular autoimmune syndromes such autoimmune thyroiditis and type 2 diabetes mellitus. Infectious adrenalitis due to tuberculosis is the most common cause of primary adrenal insufficiency world-wide, though rare in the US [2]. Other causes of Addison’s disease include adrenal hemorrhage and adrenalectomy. Addison’s disease causes various symptoms including progressive generalized bronze hyperpigmentation, slowly progressive weakness, fatigue, anorexia, nausea, vomiting and diarrhea [1]. Patients can also present with loss of libido as a result of hypoandrogenism.

Patients with primary adrenal insufficiency develop hyperkalemia and hyponatremia because mineralocorticoids stimulate sodium reabsorption and potassium excretion; thus a deficiency results in increased excretion of sodium and decreased excretion of potassium. Glucocorticoid deficiency contributes to hypotension as cortisol upregulates α1 receptors in arterioles and increases their sensitivity to norepinephrine and epinephrine.

Hyperpigmentation is a result of increased levels of adrenocorticotropic hormone (ACTH), a hormone released from the anterior pituitary. ACTH, γ- and β-lipotropin, β-endorphin, and melanocyte-stimulating hormone (MSH) share a common precursor hormone, pro-opiomelanocortin (POMC) [3]. In primary adrenal insufficiency, POMC production is strongly increased in response to the drop in cortisol levels along with concomitant release of MSH causing bronze hyperpigmentation of the skin and oral mucosa [4].

Diagnosis is based on clinical presentation, laboratory studies, and endocrine evaluation. Morning serum cortisol levels: <3 μg/dL (<80 nmol/L) without exogenous glucocorticoid administration and failure of cortisol to rise >20 μg/dL after cosyntropin (exogenous ACTH) administration confirm adrenal insufficiency [2]. Treatment of Addison’s disease includes glucocorticoid and mineralocorticoid replacement.

Cushing’s disease is another endocrine disorder that could result in hyperpigmentation in a similar distribution. Cushing’s disease is characterized by excess glucocorticoids due to hypersecretion of ACTH from a pituitary adenoma. ACTH production drives the adrenal cortex to secrete excess cortisol. Hyperpigmentation results due to excessive ACTH production because melanocyte stimulating hormone is cleaved from the same precursor as ACTH. Symptoms of Cushing’s disease such as hypertension, hyperglycemia, central obesity, hypernatremia, hypokalemia, and metabolic alkalosis make this diagnosis less likely.

Peutz-Jeghers syndrome is a hamartomatous hereditary polyposis syndrome that is frequently associated with mucocutaneous hyperpigmentation of the lips (perioral lentigines), buccal mucosa, palms, and soles. Mutations in the STK11 gene (also known as LKB1) , a tumour suppressor gene, cause most cases of Peutz-Jeghers syndrome [5]. The early presentation of pigmented macules in infancy and early childhood found in PJS make this a less likely diagnosis in our patient.

Based on the patient’s presentation, prior autoimmune disorder history, laboratory results, and endocrine evaluation, a diagnosis of Addison’s disease, primary adrenocortical insufficiency, was made. She was treated with cortisol replacement via 50 mg intravenous hydrocortisone, followed by oral hydrocortisone and mineralocorticoid replacement via 62.5 μg fludrocortisone. Most symptoms of her adrenal insufficiency symptoms including the hyponatremia resolved in 6 days and within 3 weeks her hyperpigmentation had resolved.

Early recognition of Addison’s disease is vital because hypocortisolism can be a life threatening condition during periods of stress (e.g., surgery, trauma, infections). Early treatment is needed to prevent adrenal crisis, which is a severe, acute type of adrenal insufficiency that manifests with shock, fever, impaired consciousness, and severe abdominal pain [4].

Key Points

Hyperpigmentation is an important clue in the diagnosis of Addison disease.

Hyperpigmentation in Addison’s is due to the production of melanocyte-stimulating-hormone, which shares a common precursor molecule with ACTH.

Hyperpigmentation in Addison disease typically resolves with long-term glucocorticoid and mineralocorticoid therapy.

References

1.

Wolff K, Johnson R, Saavedra AP, Roh EK. Fitzpatrick’s color atlas and synopsis of clinical dermatology, 8e. New York: McGraw-Hill; 2017.

2.

Husebye E, Løvås K. Pathogenesis of primary adrenal insufficiency. Best Pract Res Clin Endocrinol Metab. 2009;23(2):147–57.Crossref

3.

Costanzo LS. Physiology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2017.

4.

Benner BJM, Alsma J, Feelders RA. Hyponatraemia and hyperpigmentation in primary adrenal insufficiency. BMJ Case Rep. 2019;12(3):e227200.Crossref

5.

https://​ghr.​nlm.​nih.​gov/​condition/​peutz-jeghers-syndrome#genes

© Springer Nature Switzerland AG 2020

T. Lotti et al. (eds.)Clinical Cases in Pigmentary DisordersClinical Cases in Dermatologyhttps://doi.org/10.1007/978-3-030-50823-4_2

2. A 5-Year-Old Boy with White Spots on His Trunk, Acne, and Pink Urine

Mahin Alamgir¹ , Britney N. Wilson² and Babar Rao¹

(1)

Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

(2)

New Jersey Medical School, Newark, NJ, USA

A 5-year-old boy is brought to the emergency room by his parents because of pink urine and acne eruption for 3 weeks. His parents note that he’s been eating less and frequently complains of stomach pains. His teachers report that he has been easily distracted in class and performs at a significantly lower level than his peers. He was born preterm at 36 weeks due to abnormal fetal heart tracings and has a history of several infantile seizures. His vital signs are within normal limits. Physical examination shows a palpable abdominal mass and bilateral costovertebral angle tenderness. Ultrasound reveal giant bilateral renal angiomyolipomas (AML) and small hepatic AMLs. There are 12 ellipsoid, hypopigmented macules on his trunk, lower legs, and buttocks that were better observed with Wood’s light (Fig. 2.1). KOH preparation results were negative. Examination of his face revealed multiple scattered red papules in a malar distribution. Multiple calcified subependymal nodules were noted in the brain on CT. Dermatology is consulted to examine the hypopigmented lesions. What is the most likely diagnosis for this clinical presentation and these lesions?

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Fig. 2.1

Ovoid, well-demarcated, hypopigmented macule representing an ash leaf spot on the back of this young boy. Picture contributed by Dr Jason H Miller, Schweiger Dermatology, and reproduced with permission

Differential Diagnoses

1.

Tuberous Sclerosis

2.

Neurofibromatosis 1

3.

Tinea versicolor

4.

Vitiligo

Diagnosis

Tuberous sclerosis

Discussion

Tuberous sclerosis (TS) is a rare, autosomal dominant, neurocutaneous disorder that is caused by mutations in the tuberous sclerosis complex genes (TSCS1 or TSCS2) Tumor-suppressor genes TSCS1 and TSCS2 code for harmartin and tuberin which are involved in cellular signaling mediated by mammalian target of rapamycin (mTOR) [1]. This mutation results in aberrant mTOR activity which leads to genetically programmed hyperplasia of ectodermal and mesodermal cells [3]. Tuberous sclerosis is characterized by a variety of lesions in the skin, heart, kidney, and CNS in the form of hamartomas. The classic triad of this disease consists of seizures, mental retardation, and angiofibromas. Facial angiofibromas, which appear clinically as red acne-like papules, are pathognomonic for TS but do not appear until the 3rd or 4th year [3]. Other cutaneous manifestations include ash leaf spots, shagreen patches, and confetti lesions. The hypopigmentation of ash-leaf spots is because of smaller melanosomes and defective transfer of melanin to keratinocytes [2]. Ash leaf spots, white macules frequently found on the trunk, are diagnostically important because they are usually present at birth [1]. The presentation of three of more white spots in an infant increases the suspicion of TS. 86% of patients with Tuberous sclerosis present with infantile spasms seizures and 49% of patients suffer from mental retardation [3].

The history of seizures, developmental delays, CNS lesions, and multiple macules make Neurofibromatosis 1 (NF1) a plausible differential diagnosis. NF1 is an autosomal-dominant disorder that manifest as congenital abnormalities, tumors, and hamartomas in the skin, nervous system, bones, and endocrine glands [3]. The absence of pathognomonic Lisch nodules (pigmented hamartomas of the iris), café-au-lait macules, and neurofibromas in our patient make this diagnosis less likely.

Another differential diagnosis for the hypopigmented lesions in our patient include tinea versicolor, superficial fungal infection localized to the stratum corneum that results in altered pigment in the epidermis [1]. Lesions in tinea versicolor appear as finely scaling patches of varying colors that include pink, white, and tan. The failure of KOH preparation to reveal short hyphae mixed with spores and the presence of extracutaneous symptoms like hematuria and seizures make this diagnosis less likely.

Vitiligo is another plausible differential diagnosis for the hypopigmented macules presented in our patient. Vitiligo is an acquired, autoimmune condition that results in the functional disappearance of melanocytes from affected skin [1]. Unlike Tuberous sclerosis, the lesions of vitiligo are completely depigmented, are sharply demarcated, and often present in a symmetric distribution. Though the negative KOH preparation in our patient leaves vitiligo as a possible diagnosis, the presence of seizures and angiofibromas in our patient makes this diagnosis less likely.

Based on our patient’s clinical presentation a diagnosis of Tuberous sclerosis was made. His parents decided against the use of electrosurgery for the removal of angiofibromas and renal angiomyolipomas. Instead the patient was prescribed topical sirolimus, an mTOR inhibitor, to treat the angiofibromas and renal angiomyolipomas.

Key Points

Tuberous sclerosis is an uncommon causes of white spots.

Classic triad includes seizures, mental retardation, and angiofibromas.

Other skin manifestations include white macular ash leaf spots, shagreen patches, and confetti lesions

The gene products affected in Tuberous sclerosis are involved in cellular signaling mediated by mTOR and therefore, topical sirolimus, an mTOR inhibitor, can be used as treatment

References

1.

Marks JG, Miller JJ. 1—Introduction. In: Marks JG, Miller JJ, editors. Lookingbill and Marks’ principles of dermatology. 6th ed. London: Elsevier; 2019.

2.

Mistry KA, Sood D, Bhoil R, et al. A classic case of tuberous sclerosis with multisystem involvement including giant bilateral renal angiomyolipomas presenting as massive hematuria. Pol J Radiol. 2015;80:435–41.Crossref

3.

Wolff K, Johnson R, Saavedra AP, Roh EK. Fitzpatrick’s color atlas and synopsis of clinical dermatology, 8e. New York: McGraw-Hill; 2017.

© Springer Nature Switzerland AG 2020

T. Lotti et al. (eds.)Clinical Cases in Pigmentary DisordersClinical Cases in Dermatologyhttps://doi.org/10.1007/978-3-030-50823-4_3

3. A 58-Year-Old Male with Bronze Hyperpigmented Skin Over the Nape of the Neck and Extremities

Britney N. Wilson¹, Mahin Alamgir²  and Babar Rao²

(1)

New Jersey Medical School, Newark, NJ, USA

(2)

Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

A 58-year-old Caucasian male presents to the physician due to generalized fatigue, arthralgias of the metacarpophalangeal joints, and abdominal discomfort for 2 months. He has hypertension, hyperlipidemia, and type 2 diabetes mellitus. His grandfather died of liver cancer at the age of 62 years. He is 5 ft 7 in. tall and weighs 205 lb. BMI is 32.11 kg/m². His temperature is 98 °F, pulse is 106/min, and blood pressure is 130/80 mmHg. Physical examination reveals bronze hyperpigmented skin over the nape of the neck and extremities (Figs. 3.1 and 3.2). The liver is palpated 5 cm below the right costal margin. Wood’s light reveal lime green fluorescence of the patient’s urine.

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Fig. 3.1

Widespread, generalized grayish-brown hyperpigmentation on the trunk. Image courtesy of Dr Shawana Sharif, Rawal Pindi Medical College, Pakistan

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Fig. 3.2

Hyperpigmented macules and patches on the flexor arm and forearm. Image courtesy of Dr Shawana Sharif, Rawal Pindi Medical College, Pakistan

Laboratory studies:

Hemoglobin: 9.1 g/dL

Iron: 248 μg/dL

Ferritin: 583 ng/dL

Transferrin saturation: 87%

Leukocyte count: 9900/mm³

Platelet count: 282,000/mm³

Serum Glucose: 218 mg/dL

Creatinine: 1.2 mg/dL

Albumin: 4.2 mg/dL

Total bilirubin: 1.1 mg/dL

Alkaline phosphatase: