What is the likely diagnosis for a patient with unilateral cryptorchidism, brachydactyly, sensorineural hearing loss, craniofacial abnormalities, and mood disorder?

Likely Diagnosis: CHARGE Syndrome

The constellation of unilateral cryptorchidism, brachydactyly, sensorineural hearing loss, craniofacial abnormalities, and mood disorder is most consistent with CHARGE syndrome, though the brachydactyly feature is atypical and warrants consideration of alternative or overlapping diagnoses.

Clinical Reasoning

CHARGE Syndrome as Primary Diagnosis

CHARGE syndrome presents with multiple congenital malformations summarized by the acronym: Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital anomalies, and Ear anomalies/deafness 1. The patient's features align with several cardinal manifestations:

• Genital anomalies: Cryptorchidism is a recognized feature of CHARGE syndrome 1
• Ear anomalies/sensorineural hearing loss: This is one of the most specific features, with CHARGE recognized as a common cause of dual sensory impairment 1
• Craniofacial abnormalities: Multiple cranial nerve dysfunctions and facial features are characteristic 1
• Developmental/behavioral issues: Mental retardation and distinct behavioral profiles with specific cognitive problems are common in CHARGE 1

The 3C-triad (Coloboma, Choanal atresia, and abnormal semicircular Canals) represents the most specific malformations for diagnosis 1. Approximately 60% of patients have mutations in the CHD7 gene 1.

Atypical Feature: Brachydactyly

Brachydactyly is not a typical feature of CHARGE syndrome. This finding raises consideration of:

Temtamy Preaxial Brachydactyly Syndrome (TPBS): This autosomal recessive disorder presents with hyperphalangism of digits, facial dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor and mental development, and growth retardation 2. However, TPBS does not typically include cryptorchidism as a primary feature.

Alternative Considerations (Less Likely)

• Cri-du-chat syndrome: Can present with cryptorchidism, hearing loss, and developmental delays 3, but the characteristic high-pitched cat-like cry and chromosome 5p deletion would be distinctive
• Marshall syndrome: Features sensorineural hearing loss and craniofacial anomalies 4, but lacks genital anomalies
• Goldenhar syndrome: Presents with ear malformations and hearing loss 5, but facial asymmetry and hemifacial microsomia are hallmark features not described here

Diagnostic Approach

Essential Initial Evaluations

• Ophthalmologic examination: Assess for coloboma, a cardinal CHARGE feature 6
• Cardiac evaluation: Echocardiography to identify congenital heart defects present in many CHARGE patients 1
• Nasal/airway assessment: Evaluate for choanal atresia 1
• Comprehensive audiologic testing: Document type and severity of hearing loss 6
• MRI of head: Assess for semicircular canal abnormalities and neurological involvement 7
• Renal ultrasound: Screen for associated genitourinary anomalies 6

Genetic Testing Strategy

• CHD7 gene sequencing: First-line genetic test for CHARGE syndrome, positive in approximately 60% of cases 1
• Chromosomal microarray: If CHD7 negative, to evaluate for other genetic syndromes 6
• Consider CHSY1 gene testing: If brachydactyly is prominent and CHARGE features are incomplete, evaluate for TPBS 2

Cranial Nerve Assessment

Evaluate for multiple cranial nerve dysfunctions affecting:

• Olfaction (CN I)
• Swallowing (CN IX, X)
• Facial palsy (CN VII)
• Hearing (CN VIII) 1

Management Priorities

Immediate Concerns

• Airway patency: Rule out choanal atresia requiring urgent intervention 1
• Cardiac status: Life-threatening cardiovascular malformations may be present, especially critical in the first year 1
• Hearing intervention: Early amplification or cochlear implantation planning given dual sensory impairment risk 1

Multidisciplinary Coordination

Coordinated follow-up should include:

• Otolaryngology for airway and hearing management 1
• Cardiology for structural heart disease 1
• Ophthalmology for visual impairment 6, 7
• Genetics for counseling and testing 6
• Developmental pediatrics for cognitive and behavioral support 1
• Endocrinology for cryptorchidism management 1

Behavioral and Developmental Support

Mental retardation is common, though a substantial group has only limited intellectual impairment 1. The distinct behavioral profile and specific cognitive problems require specialized educational and therapeutic interventions 1.

Critical Pitfalls to Avoid

• Missing dual sensory impairment: CHARGE is one of the most common causes of combined vision and hearing loss; rehabilitation programs for deaf-blind individuals may be beneficial 1
• Overlooking cardiac defects: These can be life-threatening and require early detection 1
• Delayed hearing intervention: Early amplification is critical for language development in the context of sensorineural hearing loss 6
• Assuming isolated findings: The combination of features should prompt comprehensive syndromic evaluation rather than treating each anomaly in isolation 6