In some cases, it can be difficult to differentiate sickle cell disease from other diagnoses, given that there may be significant overlap of symptoms.^[1]

• The differential diagnosis of sickle cell disease includes other conditions that may present with fatigue, infection, bone pain, such as:

• Thalassemia
• Acute leukemia
• Autoimmune hemolytic anemia^[1]
• HbSC disease
• HbS-beta-thalassemia
• Septic arthritis^[2]
• Polycythemia vera
• Systemic lupus erythematosus
• Other hemoglobinopathies

Sickle cell disease must be differentiated from other causes of diabetes insipidus.

Type of DI	Subclass	Disease	Defining signs and symptoms	Lab/Imaging findings
Central	Acquired	Histiocytosis	Bone lysis and fracture Purulent otitis media Diabetes insipidus and delayed puberty Maxillary, mandibular, and gingival disease Rash and maculoerythematous skin lesions Scaly, erythematous scalp patches Lung involvement GI bleeding Lymph node enlargement[3]	CD1a and CD45 + Interleukin-17 (ILITA)
		Craniopharyngioma	Headache Endocrine dysfunction Diabetes insipidus Hypothyroidism Adrenal failure Diabetes insipidus (e.g., excessive fluid intake and urination) Growth failure and delayed puberty	Suprasellar calcified cyst on MRI
		Sarcoidosis	Systemic complaints Fever Anorexia Arthralgias Pulmonary complaints Dyspnea on exertion Cough Chest pain, Hemoptysis (rare) Diabetes mellitus	Hypercalcemia Hypercalciuria (noncaseating granulomas) Elevated alkaline phosphatase Serum amyloid A (SAA) ACE levels may be elevated
	Congenital	Hydrocephalus	Cognitive deterioration Headaches Neck pain Blurred vision Unsteady gait Incontinence such as polyuria	Dilated ventricles on CT and MRI
		Wolfram Syndrome (DIDMOAD)	Diabetes Insipidus Diabetes Mellitus Optic Atrophy Deafness	Negative islet cell antibodies Optic atrophy on electroretinogram Deafness on audiogram Atrophy of brain stem on MRI
Nephrogenic	Acquired	Drug-induced (demeclocycline, lithium)	Polyuria Polydipsia Nocturia	Urine osmolality <100 mmol/ Arginine vasopressin level >4.6 pmol/ Little or no response to administration of exogenous arginine vasopressin
		Hypercalcemia	Polyuria Polydipsia Gastrointestinal disturbances Pathological fractures Confusion Palpitations and cardiac arrhythmias	Ca levels greater than 11 meq/L
		Hypokalemia	Polyuria Hyporeflexia Palpitations and cardiac arrhythmias	K levels less than 3meq/L on CBC
		Multiple myeloma	Pathologic bone fractures Bleeding Hypercalcemia leading to polyuria Infection Hyperviscosity Anemia	IgG or IgA spike on serum protein electrophoresis Monoclonal M spike Disordered plasma cell proliferation on bone marrow biopsy
		Sickle cell disease	Chronic pain Anemia Aplastic crisis Splenic sequestration Infection Isosthenuria presenting with polyuria	Hemoglobin level is 5-9 g/dL Hematocrit is decreased to 17-29% Peripheral blood smears demonstrate target cells, elongated cells, and characteristic sickle erythrocytes MRI can demonstrate avascular necrosis of the femoral and humeral heads
Primary polydipsia		Psychogenic	Polyuria Polydipsia Nocturia	Dry mucus membrane History of psychiatric disorders
Gestational diabetes insipidus			Polyuria Polydipsia Nocturia Pregnancy	Dry mucus membranes Pregnancy
Diabetes mellitus			Polyuria Polydipsia Nocturia Weight gain	Elevated blood sugar levels >126 Elevated HbA1c > 6.5