What is the diagnosis for a patient with Retinitis Pigmentosum (RP), ataxia, short stature, and paralysis?

Diagnosis: Ataxia-Pancytopenia Syndrome (SAMD9L-related) or NARP Syndrome

The combination of retinitis pigmentosa, ataxia, short stature, and paralysis is most suggestive of either ataxia-pancytopenia syndrome (caused by SAMD9L mutations) or NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa), both of which are rare syndromic forms of retinitis pigmentosa with overlapping neurological features. 1, 2

Primary Diagnostic Considerations

Ataxia-Pancytopenia Syndrome (SAMD9L)

• SAMD9L mutations cause an autosomal dominant syndrome characterized by ataxia and bone marrow failure, which can present with the constellation of symptoms described 1
• This syndrome is associated with MDS and AML risk, making hematologic surveillance essential 1
• The presence of short stature is a recognized feature of this condition 1

NARP Syndrome (Mitochondrial Disorder)

• NARP syndrome (Neuropathy, Ataxia, and Retinitis Pigmentosa) is a mitochondrial disorder that presents with this specific triad 2
• The "paralysis" component likely represents the neuropathy/muscle weakness characteristic of mitochondrial disease 3, 2
• Cerebellar ataxia is a prominent feature, often with cerebellar atrophy on MRI 3, 4
• Short stature can occur due to mitochondrial dysfunction affecting growth 2

Differential Diagnoses to Consider

Other Ciliopathies and Metabolic Disorders

• Bardet-Biedl syndrome: Can present with RP, ataxia, and short stature, though typically includes obesity and polydactyly 2
• Joubert syndrome: Features cerebellar ataxia and can include RP, though the "molar tooth sign" on MRI is pathognomonic 2

PHARC and PCARP Syndromes

• PHARC syndrome (ABHD12 mutations): Polyneuropathy, Hearing loss, Ataxia, Retinitis pigmentosa, and Cataract 5
• PCARP syndrome (FLVCR1 mutations): Posterior column ataxia with retinitis pigmentosa 5
• Both can present with progressive ataxia and RP, though paralysis is less prominent 5

Oliver-McFarlane Syndrome

• Features RP, cerebellar ataxia, and short stature with characteristic trichomegaly (long eyelashes) 4
• Brain MRI shows cerebellar atrophy and hyperintense signal in corticospinal tracts 4
• The presence of sparse scalp hair and very long eyelashes is a distinguishing feature 4

Ataxia-Telangiectasia

• Presents with cerebellar ataxia and can have ocular findings, though retinitis pigmentosa is not typical 1
• Associated with immunodeficiency and ocular telangiectasias rather than RP 1

Diagnostic Workup Algorithm

Initial Clinical Assessment

• Document growth parameters: Plot height on growth charts to confirm short stature (below 3rd percentile or <-2 SD) 1, 6
• Neurological examination: Assess cerebellar signs (dysmetria, dysdiadochokinesia, intention tremor, ataxic gait) and document the nature of "paralysis" (weakness, spasticity, or neuropathy) 1
• Ophthalmologic evaluation: Fundoscopy to confirm RP features (bone spicule pigmentation, retinal pigment epithelium changes, optic nerve pallor, arterial attenuation) 3

Essential Ophthalmologic Testing

• Optical coherence tomography (OCT): To assess for macular atrophy and photoreceptor layer integrity 3
• Visual field testing: Typically shows concentric reduction in RP 3
• Full-field electroretinogram (ERG): Demonstrates rod and cone dysfunction characteristic of RP 3
• Multifocal ERG: Provides detailed assessment of macular function 3

Neuroimaging

• Brain MRI without contrast: Essential to evaluate for cerebellar atrophy (seen in NARP, Oliver-McFarlane, and other syndromes) and corticospinal tract signal abnormalities 1, 3, 4
• Look specifically for the "molar tooth sign" if Joubert syndrome is suspected 2

Metabolic and Mitochondrial Workup

• Cerebrospinal fluid lactate levels: Elevated in mitochondrial disorders like NARP syndrome 3
• Serum lactate and pyruvate: May be elevated in mitochondrial disease 2
• Muscle biopsy: Can demonstrate ragged red fibers and mitochondrial abnormalities if mitochondrial disease is suspected 3
• Electromyogram (EMG): To characterize neuropathy pattern (axonal vs. demyelinating) 3, 5

Genetic Testing Strategy

• Whole-exome sequencing (WES) or targeted NGS panel for syndromic RP is the most efficient approach given the clinical heterogeneity 5, 7
• Prioritize testing for:
  • SAMD9L gene (ataxia-pancytopenia syndrome) 1
  • Mitochondrial DNA analysis for NARP syndrome (m.8993T>G or m.8993T>C mutations) 2
  • ABHD12 (PHARC syndrome) 5
  • FLVCR1 (PCARP syndrome) 5
  • PNPLA6 (Oliver-McFarlane syndrome) 5, 4

Additional Laboratory Studies

• Complete blood count with differential: To screen for bone marrow failure/pancytopenia (SAMD9L) 1
• Vitamin E levels: To exclude ataxia with vitamin E deficiency 2
• Phytanic acid levels: To exclude adult Refsum disease 2
• Very long chain fatty acids: To exclude peroxisomal disorders like Zellweger spectrum 2

Critical Clinical Pitfalls to Avoid

Delayed Diagnosis Due to Clinical Heterogeneity

• Syndromic RP often has delayed appearance of typical symptoms, significantly prolonging the diagnostic process 5
• The combination of symptoms may not present simultaneously, leading to fragmented evaluations by different specialists 3, 5

Missing Multisystem Involvement

• Failure to perform comprehensive ophthalmologic examination in patients with ataxia and short stature can delay recognition of syndromic disease 3
• The ophthalmology examination may be the key factor leading to suspicion of syndromic disease 3

Inadequate Genetic Testing

• Single-gene testing is insufficient given the genotypic multiplicity of syndromic RP 7
• More than 40 genes cause non-syndromic RP alone, and syndromic forms add substantial complexity 7
• WES or comprehensive NGS panels are essential for diagnosis 5

Overlooking Hematologic Surveillance Needs

• If SAMD9L-related ataxia-pancytopenia syndrome is diagnosed, regular monitoring for MDS/AML is mandatory given the high malignancy risk 1
• Bone marrow failure can develop progressively and requires ongoing surveillance 1

Multidisciplinary Team Requirements

A multidisciplinary team including a neurologist, geneticist, and ophthalmologist is essential for diagnosis, as no single specialist can adequately evaluate all components of these complex syndromes 3, 5. Additional specialists may include:

• Pediatric endocrinologist (for growth evaluation) 1, 6
• Hematologist/oncologist (if SAMD9L-related syndrome is diagnosed) 1
• Metabolic specialist (if mitochondrial or metabolic disorder is suspected) 2