Acromegaly differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Ahmed Elsaiey, MBBCH [2]

## Overview

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Acromegaly must be differentiated from other diseases that cause acral features like skin thickening and linear bone growth. These diseases such as Marfan syndrome, precocious puberty, prolactinoma, and pachydermoperiostosis.

## Differentiating acromegaly from other Diseases

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* Acromegaly must be differentiated from other diseases that cause acral features like skin thickening and linear bone growth. These diseases such as Marfan syndrome, precocious puberty, prolactinoma, and pachydermoperiostosis.[1][2][3][4]

Differential Diagnosis | Similar Features | Differentiating Features
Prolactinoma |

* On physical examination, prolactinoma demonstrates visual field defects and diplopia as acromegaly.
* On symptoms, prolactinoma patients complain of a headache as the acromegaly.

* On physical examination, prolactinoma demonstrates hydrocephalus that distinguishes it from acromegaly.
* On symptoms, patients with prolactinoma may show cerebrospinal fluid rhinorrhea.
* On laboratory tests, prolactinoma has a high level of prolactin that distinguishes it from acromegaly.

Marfan syndrome |

* On physical examination, Marfan syndrome has demonstrated cardiac manifestations as the acromegaly.
* On physical examination, Marfan syndrome demonstrates excess linear bone growth like acromegaly.

* On physical examination, Marfan syndrome patients have small jaws that distinguish it from acromegaly.
* Patients with Marfan syndrome have arachnodactyly with positive thumb and wrist signs.

Precocious puberty |

* On physical examination, excess linear bone growth is noticed like the acromegaly.

* On laboratory diagnosis, precocious puberty has demonstrated high levels of FSH, LH, and testosterone that distinguish it from acromegaly.

Pachydermoperiostosis (Primary hypertrophic osteoarthropathy)  |

* On physical examination, pachydermoperiostosis demonstrates thickening of skin and scalp, clubbing and arthritis like acromegaly.

* On laboratory findings, pachydermoperiostosis has low level of the serum IGF1 which distinguishes it from acromegaly.

### Less common differentials

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Acromegaly should also be differentiated from other causes of hyperprolactinemia that may present as galactorrhea, amenorrhea, (in females) and infertility (in both males and females) including:

* Physiological:
* Normal pregnancy[5]
* Pathological:
* Pituitary tumors (other than prolactinoma):[6]
* Somatotroph adenoma: Acromegaly
* Corticotroph adenoma: Cushing's syndrome
* Suprasellar tumors (tumors present in the region of the pituitary stalk)
* Hypothyroidism[7]
* Chronic renal failure[8]
* Liver disease[9]
* Cirrhosis (with or without encephalopathy)
* Viral hepatitis (with encephalopathy)
* Seizure disorder[10][11]
* Medication-induced:
* Antipsychotic medications:[12]
* Haloperidol
* Risperidone
* Antiemetic medications:
* Metoclopramide[13]
* Domperidone[14]
* Antihypertensive medications:
* Methyldopa[15]
* Verapamil[16]

Disease  | Clinical Findings  | Laboratory findings  | Management

|
|
|

Somatotroph adenoma:

Acromegaly

| Clinical features of acromegaly are due to high level of human growth hormone (hGH):

* Soft tissue swelling of the hands and feet

* Brow and lower jaw protrusion
* Enlarged hands
* Enlarged feet
* Arthritis and carpal tunnel syndrome
* Increase in teeth spacing
* Macroglossia (enlarged tongue)
* Heart failure
* Kidney failure
* Compression of the optic chiasm leading to loss of vision in the outer visual fields (typically bitemporal hemianopia)
* Headache
* Diabetes mellitus
* Hypertension
* Cardiomegaly

* Elevated insulin-like growth factor-1 (IGF-1) levels
* Elevated growth hormone levels

* Medical management:
* Octreotide
* Bromocriptine

* Surgical management:
* Endonasal transsphenoidal surgery
* Radiation therapy

Corticotroph adenoma: Cushing's syndrome | Clinical features of Cushing's syndrome are due to increased levels of cortisol:

* Rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity)
* Proximal muscle weakness
* A round face often referred to as a "moon face"
* Excess sweating
* Headache
* The excess cortisol may also affect other endocrine systems and cause, for example:
* Insomnia
* Reduced libido
* Impotence
* Amenorrhea
* Infertility
* Patients frequently suffer various psychological disturbances, ranging from euphoria to psychosis. Depression and anxiety are also common.

* Dexamethasone suppression test
* 24 hour urinary measurement of cortisol

* Medical management:
* Pasireotide
* Cabergoline
* Ketoconazole
* Metyrapone
* Mitotane
* Mifepristone
* Surgical management:
* Transsphenoidal pituitary resection

Hypothyroidism | Clinical features of hypothyroidism are due to deficiency of thyroxine:

* Fatigue

* Cold intolerance
* Decreased sweating
* Hypothermia
* Coarse skin
* Weight gain
* Hoarseness
* Goiter

* Fullness in the throat and neck

* Depression

* Emotional lability
* Attention deficit

* Elevated TSH
* Low T4
* Low T3
* Elevated anti-thyroid antibodies(anti-TPO)

| Levothyroxine
Chronic renal failure | There are no pathognomonic symptoms associated with chronic renal failure. Common non-specific symptoms of chronic renal failure include:

* Malaise
* Nausea
* Unintentional weight loss
* Pruritus
* Lower extremity edema
* Sleep disorders

| Urinalysis:

* Albuminuria

* Hematuria
* Pyuria
* Red cell or white cell casts and crystals

Fluid and electrolyte disturbances:

* Hyponatremia
* Hyperkalemia
* Hyperphosphatemia
* Hyperchloremia
* Metabolic acidosis
* Hypocalcemia

Endocrine and metabolic disturbances:

* Hyperuricemia
* Hypertriglyceridemia
* Decreased HDL levels
* Vitamin D deficiency
* Increased Parathyroid hormone levels

Hematologic abnormalities:

* Normocytic normochromic anemia
* Lymphocytopenia
* Leukopenia
* Thrombocytopenia

* Medical management:
* Blood pressure management
* Control of blood glucose
* Protein restriction
* Management of anemia
* Management of electrolyte disturbance
* Dialysis
* Surgical management
* Kidney transplant

Liver disease: Cirrhosis | The clinical features of liver cirrhosis are very nonspecific. These include:

* Right upper quadrant abdominal pain
* Fever
* Fatigue and weakness
* Loss of appetite
* Diarrhea
* Nausea and vomiting
* Weight loss
* Abdominal pain and bloating when fluid accumulates in the abdomen
* Itching
* Menstrual irregularities

* Elevated aminotransferases (AST & ALT)
* Elevated alkaline phosphatase (ALP)

* Elevated gamma-glutamyl transpeptidase

* Elevated bilirubin

* Low albumin

* Elevated prothrombin time

* Elevated globulin

* Hyponatremia

* Anemia

* Leukopenia and neutropenia

* Thrombocytopenia

* Medical management:
* Treatment is usually directed towards the treatment of complications like ascites, esophageal varices, hepatic encephalopathy, hepatorenal syndrome, and spontaneous bacterial peritonitis.
* Some chronic constitutional symptoms that should be treated include:
* Pruritis: Cholestyramine is the drug of choice
* Hypogonadism: Topical testosterone preparations
* Osteoporosis: Calcium and vitamin D
* Pain management: NSAIDS, celecoxib, opioids
* Nutrition: Adequate caloric and protein intake, and multivitamin supplementation
* Surgical management: Liver transplantation

Seizure disorder | The clinical features of seizure disorder may include:

* Change in alertness, orientation and time perception

* Mood changes, such as unexplainable fear, panic, joy, or laughter
* Changes in sensation of the skin, usually spreading over the arm, leg, or trunk
* Vision changes, including seeing flashing lights
* Rarely, hallucinations (seeing things that aren't there)
* Falling, loss of muscle control, occurs very suddenly
* Muscle twitching that may spread up or down an arm or leg
* Muscle tension or tightening that causes twisting of the body, head, arms, or legs
* Shaking of the entire body
* Tasting a bitter or metallic flavor

| Electroencephalogram |

* Medical management:
* Antiepileptic medications

Medication-induced | Clinical features of hyperprolactinemia after a specific period of regular medication ingestion  | Discontinuation of the medication for 3 days and remeasurement of prolactin levels[17] | Change to alternate medication

## Differentiating Acromegaly from Other Diseases

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Disease | Gene | Chromosome | Differentiating Features | Components of MEN | Diagnosis

|
|
|
|
|

Parathyroid | Pitutary | Pancreas
von Hippel-Lindau syndrome | Von Hippel–Lindau tumor suppressor  | 3p25.3  |

* Angiomatosis,
* Hemangioblastomas,
* Pheochromocytoma,
* Renal cell carcinoma,
* Pancreatic cysts (pancreatic serous cystadenoma)
* Endolymphatic sac tumor,
* Bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women)

| \-  | \-  | \+  |

* Clinical diagnosis
* In hereditary VHL, disease techniques such as Southern blotting and gene sequencing can be used to analyse DNA and identify mutations.

Carney complex |  PRKAR1A  | 17q23-q24  |

* Myxomas of the heart
* Hyperpigmentation of the skin (lentiginosis)
* Endocrine (ACTH-independent Cushing's syndrome due to primary pigmented nodular adrenocortical disease)

| \-  | \-  | \-  |

* Clinical diagnosis

Neurofibromatosis type 1 | RAS  | 17  |

* Scoliosis
* Learning disabilities
* Vision disorders
* Cutaneous lesions
* Epilepsy.

| \-  | \-  | \-  | Prenatal

* Chorionic villus sampling or amniocentesis can be used to detect NF-1 in the fetus.

Postnatal Cardinal Clinical Features" are required for positive diagnosis.

* Six or more café-au-lait spots over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals.
* Two or more neurofibromas of any type or 1 plexiform neurofibroma
* Freckling in the axillary (Crowe sign) or inguinal regions
* Optic glioma
* Two or more Lisch nodules (pigmented iris hamartomas)
* A distinctive osseous lesion such as sphenoid dysplasia, or thinning of the long bone cortex with or without pseudarthrosis.

Li-Fraumeni syndrome | TP53  | 17  | Early onset of diverse amount of cancers such as

* Sarcoma
* Cancers of
* Breast
* Brain
* Adrenal glands

| \-  | \-  | \-  |

Criteria

* Sarcoma at a young age (below 45)
* A first-degree relative diagnosed with any cancer at a young age (below 45)
* A first or second degree relative with any cancer diagnosed before age 60.

Gardner's syndrome | APC  |  5q21  |

* Multiple polyps in the colon
* Osteomas of the skull
* Thyroid cancer,
* Epidermoid cysts,
* Fibromas
* Desmoid tumors

| \-  | \-  | \-  |

* Clinical diagnosis
* Colonoscopy

Multiple endocrine neoplasia type 2 | RET | \-  |

* Medullary thyroid carcinoma (MTC)
* Pheochromocytoma
* Primary hyperparathyroidism

| \+  | \-  | \-  |

* Hypercalcemia
* Hypophosphatemia,
* Elevated parathyroid hormone,
* Elevated norepinephrine

Criteria Two or more specific endocrine tumors

* Medullary thyroid carcinoma
* Pheochromocytoma
* Parathyroid hyperplasia

Cowden syndrome | PTEN  | \-  |  Hamartomas  | \-  | \-  | \-  |

* PTEN mutation probability risk calculator

Acromegaly/gigantism | \-  | \-  |

* Enlargement of the hands, feet, nose, lips and ears, and a general thickening of the skin
* Hypertrichosis
* Hyperpigmentation
* Hyperhidrosis
* Carpal tunnel syndrome.

| \-  | \+  | \-  |

* An elevated concentration of serum growth hormone (GH) and insulin-like growth factor 1(IGF-1) levels is diagnostic of acromegaly.

Pituitary adenoma | \-  | \-  |

* Visual field defects classically bitemporal hemianopsia
* Increased intracranial pressure
* Migraine
* Lateral rectus palsy

| \-  | \+  | \-  |

* Elevated serum level of prolactin
* Elevated or decreased serum level of adrenocorticotropic hormone (ACTH)
* Elevated or decreased serum level of growth hormone (GH)
* Elevated or decreased serum level of thyroid-stimulating hormone (TSH)
* Elevated or decreased serum level of follicle-stimulating hormone (FSH)
* Elevated or decreased serum level of luteinizing hormone (LH)

Hyperparathyroidism | \-  | \-  | \-

* Kidney stones
* Hypercalcemia,
* Constipation
* Peptic ulcers
* Depression

| \+  | \-  | \-  |

* An elevated concentration of serum calcium with elevated parathyroid hormone level is diagnostic of primary hyperparathyroidism.
* Most consistent laboratory findings associated with the diagnosis of secondary hyperparathyroidism include elevated serum parathyroid hormone level and low to normal serum calcium.
* An elevated concentration of serum calcium with elevated parathyroid hormone level in post renal transplant patients is diagnostic of tertiary hyperparathyoidism.

Pheochromocytoma/paraganglioma |

VHL RET NF1 SDHB SDHD

| \-  | Characterized by

* Episodic hypertension
* Palpitations
* Anxiety
* Diaphoresis
* Weight loss

| \-  | \-  | \-  |

* Increased catecholamines and metanephrines in plasma (blood) or through a 24-hour urine collection.

Adrenocortical carcinoma |

* p53
* Retinoblastoma h19
* Insulin-like growth factor II (IGF-II)
* p57kip2

| 17p, 13q |

* Cushing syndrome (cortisol hypersecretion)
* Conn syndrome (aldosterone hypersecretion)
* virilization (testosterone hypersecretion)

| \-  | \-  | \-  |

* Increased serum glucose
* Increased urine cortisol
* Serum androstenedione and dehydroepiandrosterone
* Low serum potassium
* Low plasma renin activity
* High serum aldosterone.
* Excess serum estrogen.

Adapted from Toledo SP, Lourenço DM, Toledo RA. A differential diagnosis of inherited endocrine tumors and their tumor counterparts, journal=Clinics (Sao Paulo), volume= 68, issue= 7, 07/24/2013[18]

## References

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1. ↑ Abdullah NRA, Jason WLC, Nasruddin AB (2017). "Pachydermoperiostosis: a rare mimicker of acromegaly". Endocrinol Diabetes Metab Case Rep. 2017. doi:10.1530/EDM-17-0029. PMC 5445428. PMID 28567291.CS1 maint: Multiple names: authors list (link)
2. ↑ Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB; et al. (2010). "The revised Ghent nosology for the Marfan syndrome". J Med Genet. 47 (7): 476–85. doi:10.1136/jmg.2009.072785. PMID 20591885.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
3. ↑ Liu JK, Couldwell WT (2004). "Contemporary management of prolactinomas". Neurosurg Focus. 16 (4): E2. PMID 15191331.
4. ↑ Papadimitriou A, Beri D, Tsialla A, Fretzayas A, Psychou F, Nicolaidou P (2006). "Early growth acceleration in girls with idiopathic precocious puberty". J Pediatr. 149 (1): 43–6. doi:10.1016/j.jpeds.2006.02.005. PMID 16860125.CS1 maint: Multiple names: authors list (link)
5. ↑ Rigg LA, Lein A, Yen SS (1977). "Pattern of increase in circulating prolactin levels during human gestation". Am J Obstet Gynecol. 129 (4): 454–6. PMID 910825.CS1 maint: Multiple names: authors list (link)
6. ↑ Levy A (2004). "Pituitary disease: presentation, diagnosis, and management". J Neurol Neurosurg Psychiatry. 75 Suppl 3: iii47–52. doi:10.1136/jnnp.2004.045740. PMC 1765669. PMID 15316045.
7. ↑ Snyder PJ, Jacobs LS, Utiger RD, Daughaday WH (1973). "Thyroid hormone inhibition of the prolactin response to thyrotropin-releasing hormone". J Clin Invest. 52 (9): 2324–9. doi:10.1172/JCI107421. PMC 333037. PMID 4199418.CS1 maint: Multiple names: authors list (link)
8. ↑ Sievertsen GD, Lim VS, Nakawatase C, Frohman LA (1980). "Metabolic clearance and secretion rates of human prolactin in normal subjects and in patients with chronic renal failure". J Clin Endocrinol Metab. 50 (5): 846–52. doi:10.1210/jcem-50-5-846. PMID 7372775.CS1 maint: Multiple names: authors list (link)
9. ↑ Jha SK, Kannan S (2016). "Serum prolactin in patients with liver disease in comparison with healthy adults: A preliminary cross-sectional study". Int J Appl Basic Med Res. 6 (1): 8–10. doi:10.4103/2229-516X.173984. PMC 4765284. PMID 26958514.
10. ↑ Ben-Menachem, Elinor (2006). "Is Prolactin a Clinically Useful Measure of Epilepsy?". Epilepsy Currents. 6 (3): 78–79. doi:10.1111/j.1535-7511.2006.00104.x. ISSN 1535-7597.
11. ↑ Trimble MR (1978). "Serum prolactin in epilepsy and hysteria". Br Med J. 2 (6153): 1682. PMC 1608938. PMID 737437.
12. ↑ David SR, Taylor CC, Kinon BJ, Breier A (2000). "The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia". Clin Ther. 22 (9): 1085–96. doi:10.1016/S0149-2918(00)80086-7. PMID 11048906.CS1 maint: Multiple names: authors list (link)
13. ↑ McCallum RW, Sowers JR, Hershman JM, Sturdevant RA (1976). "Metoclopramide stimulates prolactin secretion in man". J Clin Endocrinol Metab. 42 (6): 1148–52. doi:10.1210/jcem-42-6-1148. PMID 777023.CS1 maint: Multiple names: authors list (link)
14. ↑ Sowers JR, Sharp B, McCallum RW (1982). "Effect of domperidone, an extracerebral inhibitor of dopamine receptors, on thyrotropin, prolactin, renin, aldosterone, and 18-hydroxycorticosterone secretion in man". J Clin Endocrinol Metab. 54 (4): 869–71. doi:10.1210/jcem-54-4-869. PMID 7037817.CS1 maint: Multiple names: authors list (link)
15. ↑ Steiner J, Cassar J, Mashiter K, Dawes I, Fraser TR, Breckenridge A (1976). "Effects of methyldopa on prolactin and growth hormone". Br Med J. 1 (6019): 1186–8. PMC 1639736. PMID 1268617.CS1 maint: Multiple names: authors list (link)
16. ↑ Fearrington EL, Rand CH, Rose JD (1983). "Hyperprolactinemia-galactorrhea induced by verapamil". Am J Cardiol. 51 (8): 1466–7. PMID 6682619.CS1 maint: Multiple names: authors list (link)
17. ↑ Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA; et al. (2011). "Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline". J Clin Endocrinol Metab. 96 (2): 273–88. doi:10.1210/jc.2010-1692. PMID 21296991.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
18. ↑ Toledo SP, Lourenço DM, Toledo RA (2013). "A differential diagnosis of inherited endocrine tumors and their tumor counterparts". Clinics (Sao Paulo). 68 (7): 1039–56. doi:10.6061/clinics/2013(07)24. PMC 3715026. PMID 23917672.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)

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