Congenital Cataract- Stepwise approach to determining etiology

Preform History and Physical Examination to Determine if one of the following present

• Multiple Congenital Anomalies
• Isolated Ocular Abnormalities
• One organ system abnormality
• No other abnormalities

Do Chromosome Analysis to screen for the following:

• Trisomy 18
• Trisomy 21
• Turner Syndrome
• Edward Syndrome
• Partial Trisomy 10q
• Translocations: 3:4, 2:14, 2:16

If Chromosome Analysis Normal consider:

• Hallerman-Strieff syndrome: dental anomalies
• Schprintzen syndrome: cardiac anomalies
• Cerebral-oculo-facial syndrome: microcephaly
• Cockayne syndrome: microcephaly
• Fetal rubella syndrome: microcephaly
• Marinesco-Sjögren syndrome: microcephaly
• Mowat-Wilson syndrome
• Rubenstein-Taybi syndrome: microcephaly
• Smith-Lemli-Opitz syndrome: microcephaly
• Walker-Warburg syndrome: hydrocephalus
• Zellweger syndrome: long-chain fatty acids
• Lowe Syndrome***

• Aniridia
• PHPV
• Uveitis
• Retinoblastoma

Do skeletal survey to determine:

• Short limbed dwarfism
  • Camarati-Englemann syndrome
  • Chondrodysplasia punctata
  • Hypochondrodysplasia
  • Kniest syndrome
• Bony changes
  • Fetal warfarin exposure
  • Mannosidosis
  • Marshall-Stickler syndrome
  • Schwartz-Jampel syndrome
• Limb anomalities
  • Fetal Varicella infection
  • Klippel-Trenaunay-Weber syndrome
  • Proteus syndrome
  • Roberts syndrome

Myotonic dystrophy: Muscle wasting

• Refsum disease
• Alport syndrome

May not be noted until teeth erupt

• Canine radicomegaly
• Nance-Horan syndrome (X-linked)
• Oculo-dental digital syndrome

• Focal dermal hypoplasia
• Gorlin syndrome
• Incontinentia Pigmenti
• Rothmund-Thompson syndrome
• Fabry disease

• Clouston syndrome (hidrotic ectodermal dysplasia) OMIM #129500
  • normal sweat and sebaceous gland function
  • total alopecia
  • severe dystrophy of the nails
  • hyperpigmentation of the skin especially over the joints
  • normal teeth
  • strabismus
  • mental deficiency
  • clubbing of the fingers
  • palmar hyperkeratosis
  • extensive kindred of French extraction that migrated to Canada, Scotland, and northern United States
• Nail-Patella syndrome OMIM #161200
  • dysplasia of the nails
  • absent or hypoplastic patellae (60-90%)
  • abnormality of the elbows interfering with pronation and supination (60-90%)
  • nephropathy
  • hearing loss
  • keratoconus
  • glaucoma, microcornea, microphakia
• Pachyonychia congenita syndrome OMIM #167200
  • onychogryposis
  • hyperkeratosis of the palms, soles, knees and elbows
  • tiny cutaneous horns in many areas
  • eukoplakia of the oral mucous membranes
  • Hyperhidrosis of the hands and feet

Peter’s Plus B3GALTL Yes Yes Short limbs, ID, heart defects Pierpont ME, Brueckner M, Chung WK, et al. Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555769/. Circulation. 2018;138(21):e653-e711. doi:10.1161/CIR.0000000000000606. Nance-Horan NHS Sometimes Yes Dental anomalies, facial features Pierpont ME, Brueckner M, Chung WK, et al. Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555769/. Circulation. 2018;138(21):e653-e711. doi:10.1161/CIR.0000000000000606., Rechsteiner D, Issler L, Koller S, et al. Genetic Analysis in a Swiss Cohort of Bilateral Congenital Cataract. https://jamanetwork.com/journals/jamaophthalmology/fullarticle/10.1001/jamaophthalmol.2021.0385?utm_source=openevidence&utm_medium=referral. JAMA Ophthalmology. 2021;139(7):691-700. doi:10.1001/jamaophthalmol.2021.0385. OFCD BCOR Yes (palate) Yes Cardiac, limb anomalies Rechsteiner D, Issler L, Koller S, et al. Genetic Analysis in a Swiss Cohort of Bilateral Congenital Cataract. https://jamanetwork.com/journals/jamaophthalmology/fullarticle/10.1001/jamaophthalmol.2021.0385?utm_source=openevidence&utm_medium=referral. JAMA Ophthalmology. 2021;139(7):691-700. doi:10.1001/jamaophthalmol.2021.0385. Stickler COL2A1, COL11A1 Yes (palate) Yes Myopia, hearing loss, arthritis Hall JG, Herrod H. The Stickler Syndrome Presenting as a Dominantly Inherited Cleft Palate and Blindness. https://pubmed.ncbi.nlm.nih.gov/1219119. Journal of Medical Genetics. 1975;12(4):397-400. doi:10.1136/jmg.12.4.397. Roberts ESCO2 Yes Yes Limb reduction, growth deficiency Pierpont ME, Brueckner M, Chung WK, et al. Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555769/. Circulation. 2018;138(21):e653-e711. doi:10.1161/CIR.0000000000000606. Trisomy 13 Chromosomal Yes Yes Multiple anomalies Stoll C, Alembik Y, Roth MP. Co-Occurring Anomalies in Congenital Oral Clefts. https://pubmed.ncbi.nlm.nih.gov/35179301. American Journal of Medical Genetics. Part A. 2022;188(6):1700-1715. doi:10.1002/ajmg.a.62689.

Do a screen for the following:

• CBC: elevated white count
• Blood Glucose or HbA1C: hyperglycemia
• RBC Galactokinase serum level: galactosemia
• TORCH titer
  • IgG (maternal may last 6 months) and consider IgM if signs of inflammation
  • Toxoplasma- IgG +/- IgM
  • Syphilis- total antibodies with reflex confirmation
  • Rubella- IgG +/- IgM
  • Cytomegalovirus IgG +/- IgM
  • Herpes- HSV 1&2 specific IgG +/- IgM

If screen above is normal: Early onset Cataract genetic testing program by Travere Therapeutics (18 months to 35 years old with infection causes ruled out): LINK

Consider Genetics referral if syndrome above suspected