What are the clinical features, genetic cause, diagnostic work‑up, and management recommendations for a pediatric patient presenting in early infancy with silvery‑gray hair, skin hypopigmentation, severe neurologic involvement (developmental delay, seizures, hypotonia, ataxia, peripheral neuropathy) and no immune dysregulation suggestive of Griscelli syndrome type 1?

Griscelli Syndrome Type 1: Clinical Features, Diagnosis, and Management

Griscelli syndrome type 1 (GS1) is a fatal neurodegenerative disorder caused by MYO5A mutations, characterized by silvery-gray hair, skin hypopigmentation, and severe progressive neurological deterioration including developmental delay, seizures, hypotonia, and ataxia, with no immune dysregulation or effective treatment available. 1

Clinical Features

Pigmentary Abnormalities

• Silvery-gray hair and skin hypopigmentation are present from birth, with large melanin clumps visible in hair shafts and retention of melanosomes in melanocytes 1
• These pigmentary changes are pathognomonic when combined with the neurological profile described below 1

Neurological Manifestations (Distinguishing Feature of GS1)

• Primary neurological impairment dominates the clinical picture, distinguishing GS1 from GS2 (which has secondary neurological damage from hemophagocytic lymphohistiocytosis) 1
• Severe developmental delay and psychomotor regression occur after a short period of normal development 1, 2
• Refractory seizures are common and often resistant to multiple antiepileptic medications including clobazam, cannabinol, zonisamide, ketogenic diet, lacosamide, and levetiracetam 3
• Hypotonia with loss of deep tendon reflexes develops early 1
• Ataxia and oculomotor abnormalities including nystagmus, diplopia, and retinal problems 1, 4
• Peripheral neuropathy may be present 1
• Dysphagia complicates feeding 1

Absence of Immune Dysregulation

• Little to no recurrent infections occur in GS1, a critical distinguishing feature from GS2 1
• No hemophagocytic lymphohistiocytosis (HLH) "accelerated phase" develops in GS1, unlike GS2 where HLH is nearly universal and often fatal 1
• Hepatosplenomegaly is typically absent in GS1 1

Genetic Cause

• Mutations in the MYO5A gene encoding Myosin Va cause GS1 1, 5
• Myosin Va is a molecular motor protein essential for melanosome transport in melanocytes and vesicle trafficking in neurons 5
• Specific MYO5A F-exon deletions can produce an identical phenotype restricted to hypopigmentation and neurological features 5
• The condition follows autosomal recessive inheritance 1, 5
• Seizure severity may be compounded by additional chromosomal abnormalities (e.g., 18p11.32p11.31 deletion reported in one case with particularly refractory seizures) 3

Diagnostic Work-Up

Initial Clinical Assessment

• Examine hair shafts under light microscopy for large, irregularly distributed melanin clumps—this finding is diagnostic when combined with clinical features 1, 6
• Skin biopsy reveals melanosome accumulation in melanocytes 7
• Detailed neurological examination documenting developmental milestones, tone, reflexes, seizure activity, and ophthalmological findings 1, 4

Laboratory Evaluation

• Peripheral blood smear should NOT show giant azurophilic granules (which are pathognomonic for Chédiak-Higashi syndrome, not GS1) 1, 6
• Immune function screening (immunoglobulin levels, lymphocyte subsets, NK cell function) should be normal or near-normal, distinguishing GS1 from GS2 1
• Screen for HLH criteria (fever, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia)—these should be absent in GS1 1, 2

Genetic Confirmation

• Molecular genetic testing with MYO5A gene sequencing is essential for definitive diagnosis and to distinguish GS1 from GS2 (RAB27A mutations) and GS3 (MLPH mutations) 1, 2, 5
• Genetic testing is critical because prognosis, treatment options, and genetic counseling differ markedly among GS subtypes 4
• When genetic testing is unavailable, the presence of severe neurological symptoms without immune dysregulation or HLH strongly suggests GS1 over GS2 2

Neuroimaging

• Brain MRI may show cerebral atrophy and other structural abnormalities, though specific patterns are not well-characterized 3

Management Recommendations

Neurological Management

• Aggressive antiepileptic therapy for seizure control, though seizures are often refractory to multiple medications 3
• Combination therapy may include lacosamide, levetiracetam, clobazam, and ketogenic diet, though complete seizure control is rarely achieved 3
• Supportive care for hypotonia and developmental delay including physical therapy, occupational therapy, and speech therapy 4
• Management of dysphagia with feeding modifications or gastrostomy tube placement as needed 1

Prognosis and Counseling

• No curative treatment exists for GS1, unlike GS2 where hematopoietic stem cell transplantation can be life-saving 4
• Neurological manifestations are progressive and irreversible 1, 4
• Long-term survival is possible with one reported patient alive at age 21 years with severe mental and motor retardation but no other complications 4
• Death typically occurs in early childhood from neurological complications, though survival into adulthood has been documented 1, 4

Genetic Counseling

• Provide autosomal recessive inheritance counseling with 25% recurrence risk for future pregnancies 1, 5
• Prenatal diagnosis is available through molecular genetic testing when familial mutations are known 4

Critical Diagnostic Pitfalls

• Failing to distinguish GS1 from GS2 leads to inappropriate treatment decisions—GS2 requires urgent hematopoietic stem cell transplantation for HLH, while GS1 does not benefit from this intervention 1, 4
• Misdiagnosing as Chédiak-Higashi syndrome—CHS has giant lysosomal granules on blood smear and a bleeding diathesis, features absent in GS1 1, 6
• Not recognizing that neurological symptoms in GS1 are primary (due to MYO5A mutation affecting neuronal vesicle trafficking) versus secondary in GS2 (due to HLH infiltration) 1, 2, 7
• Assuming all hypopigmentation syndromes with neurological features require immunological evaluation—GS1 has minimal immune dysfunction 1, 6