What are the causes of premature greying of hair in a patient with early‑onset greying (before age 30 in men or 35 in women) and how should it be evaluated and managed?

Causes and Treatment of Premature Grey Hair

Premature grey hair (before age 30 in men or 35 in women) requires systematic evaluation for treatable causes—particularly thyroid dysfunction and nutritional deficiencies—before considering cosmetic management, as correcting underlying disorders can reverse greying in some cases.

Primary Evaluation: Rule Out Treatable Causes

Thyroid Assessment (Highest Priority)

• Thyroid dysfunction is a critical, treatable cause that directly interferes with melanocyte pigment production and should be evaluated in every patient with premature greying 1
• Order TSH, free T4, and anti-thyroglobulin antibodies as first-line testing 1
• Correcting identified thyroid abnormalities can lead to reversal of premature greying 1

Nutritional Deficiencies

• Vitamin D₃ deficiency shows the strongest association with premature greying; check serum levels and supplement if <20 ng/mL (<50 nmol/L) 1, 2
• Serum ferritin should be assessed, as iron deficiency is the most common nutritional deficiency worldwide and associates with hair pigmentation changes 2
• Check zinc levels, as zinc serves as a cofactor for multiple enzymes involved in hair follicle function 2
• Consider folate and vitamin B12 levels in the diagnostic work-up 1, 2

Hematologic Screening

• Obtain a complete blood count with hemoglobin to screen for underlying hematologic disorders 1

Red Flags: When to Consider Genetic/Syndromic Causes

High-Risk Features Requiring Genetic Evaluation

Refer for TERT/TERC mutation testing if premature greying occurs with any of the following 1, 3:

• Nail or skin changes (dystrophy, ridging, pigmentary abnormalities)
• Sensorineural hearing loss
• Signs of early aging (premature wrinkles, skin atrophy)
• Pulmonary symptoms (dyspnea, chronic cough suggesting fibrosis)
• Hepatic symptoms (jaundice, ascites suggesting cirrhosis)
• Cytopenias on complete blood count

Cancer Surveillance for Mutation Carriers

• TERT/TERC mutation carriers have substantially increased risk of head and neck cancers, anogenital cancers, and skin cancer, necessitating lifelong surveillance 1
• These patients may develop pulmonary fibrosis, liver dysfunction, bone marrow abnormalities, and myelodysplastic syndromes 3

Other Genetic Syndromes

• Fanconi anemia and dyskeratosis congenita may present with premature greying plus dysmorphic facial features, short stature, thumb hypoplasia, and pulmonary fibrosis 1
• Chediak-Higashi Syndrome and Griscelli Syndrome type 2 are rare causes characterized by oculocutaneous albinism, immunodeficiency, and recurrent pyogenic infections 3

Underlying Mechanisms

Pathophysiology

• Premature greying results from complex interplay of genetic, environmental, and cellular factors affecting melanogenesis in hair follicles 4
• Oxidative stress and reactive oxygen species (ROS) generation play central roles, with intrinsic factors (genetic variants) and extrinsic factors (UV radiation, smoking, pollution) contributing 5
• Melanogenesis depends on tyrosinase enzyme activity and is regulated by multiple factors including α-melanocyte-stimulating hormone (α-MSH), vitamins, and minerals 6

Associated Conditions

• Studies exploring links between premature greying and osteopenia, hearing loss, smoking, obesity, dyslipidemia, and cardiovascular disease have yielded mixed results 4
• Approximately 20% of patients with alopecia areata have premature greying as part of autoimmune-mediated melanocyte dysfunction 2

Treatment Approach

Correct Identified Deficiencies First

• Supplement vitamin D according to general international pediatric/adult dosing guidelines if levels are <20 ng/mL, with maintenance therapy for chronic deficiency 1, 2
• Replace iron if ferritin is low, as this is the most common correctable nutritional cause 2
• Supplement zinc and folate if deficient 3, 2
• Treat thyroid dysfunction aggressively, as this offers the best chance for reversal 1

Emerging Medical Therapies

• A topical formulation containing palmitoyl tetrapeptide 20 (a biomimetic α-MSH agonist) applied 1 mL twice daily showed >90% conversion of grey to pigmented hair after 5 months in one case report 6
• Oral biotin and calcium pantothenate supplements were used adjunctively in this case 6
• These treatments remain investigational with limited evidence 6, 5

Cosmetic Management

• Temporary hair colorants remain the most common approach but carry risks of allergic reactions, inflammation, and paradoxical hair loss 5
• Camouflage cosmetics and fake tanning products may be considered for patients who prefer not to use active treatments 7

Common Pitfalls to Avoid

• Do not dismiss premature greying as purely cosmetic without first ruling out thyroid disease and nutritional deficiencies, as these are reversible 1
• Do not overlook genetic red flags (nail changes, hearing loss, pulmonary symptoms) that warrant cancer surveillance 1, 3
• Do not order excessive genetic testing in isolated premature greying without associated systemic features 1
• Recognize that 34-50% of cases may have spontaneous partial repigmentation over time, making observation reasonable after excluding treatable causes 2

Current Treatment Limitations

• Despite continuous research, effective evidence-based treatments for idiopathic premature greying are lacking and remain an area of active investigation 4, 5
• The exact mechanism leading to premature greying is not well understood at the molecular level, limiting targeted therapeutic development 5
• Natural repigmentation is occasionally reported but remains unpredictable and uncommon 4