Subhadra Ramanathan MSc, MS, Robin D. Clark MD

Clinical Summary: 

A 7-month-old female was referred to Pediatric Genetics for preaxial polydactyly and syndactyly of both hands and feet (Figure 1a–c) and a positive family history of a similarly affected father. She was normocephalic (OFC at nine mos Z-score 1.05) with bilateral epicanthal folds and telecanthus. Her pediatrician had prescribed a helmet for plagiocephaly, which had resolved by the time of the visit. The exam and visit were completed by telehealth (video). 

Imaging studies on the infant showed preaxial polydactyly of both feet. The first metatarsal of the left foot was associated with two sets of proximal and distal phalanges. The distal phalanx of the second digit was bifid with partial soft tissue fusion of the first and second digits and, possibly, third digits on the left and partial soft tissue fusion of the first, second, and third digits on the right. 

X-rays also showed preaxial polydactyly of both hands with bif first digits as well as soft tissue mass with punctate calcification arising off the fifth digit at the level of the proximal interphalangeal joint (postaxial polydactyly) on the left. There was partial soft tissue fusion of the first and second digits. 

The infant was otherwise healthy, feeding well with normal stooling and voiding. No hearing or vision concerns were identified. She was developmentally on target. 

The family history was significant for her father with similar pre-and postaxial polydactyly with broad thumbs, broad toes, and preaxial polydactyly of the right foot with syndactyly. He had prominent supraorbital ridges, downslanting palpebral fissures, and hypertelorism. While the paternal grandmother was reported to be asymptomatic, at least one of her family members had digit anomalies. Parents were of Hispanic ancestry; parental consanguinity was denied. 

The clinical features in the patient and her father—polydactyly and craniofacial dysmorphisms—were suggestive of Greig cephalopolysyndactyly syndrome (GCPS), inherited in an autosomal dominant manner due to pathogenic variants (mutations) in the GLI3 gene. Molecular genetic testing confirmed the diagnosis and detected a pathogenic variant in GLI3, a deletion of exon 4, in our patient. 

Discussion: 

Polydactyly is the most common hereditary limb malformation, characterized by supernumerary fingers or toes. The estimated prevalence is 1/630 and 1/3300 among Caucasians and between 1/100 and 1/300 in African Americans. (1) While non-syndromic polydactyly can be multifactorial or inherited in an autosomal dominant manner, over 100 syndromes have also been associated with this birth defect. 

The two most common types are postaxial polydactyly (PAP), with the extra digit at the fifth finger or toe (on the ulnar/ peroneal side), and preaxial polydactyly (PPD), having the extra digit attached on the greater toe or thumb side (radial/ medial). Isolated postaxial polydactyly is ten times more common in African Americans and is more common in males. Preaxial polydactyly is 3–4 times more common in Native Americans than in Caucasians or African Americans. It is more often unilateral and more common in females. It may be seen with other anomalies in infants of diabetic mothers. (2) Mesoaxial (central) polydactyly, when there is duplication of the second, third, or fourth digits of the hands or feet, is very rare. 

Pathogenic variants (mutations) in GLI3 are associated with both non-syndromic and syndromic polydactyly: Grieg cephalopolysyndactyly syndrome (GCPS), Pallister-Hall syndrome, as well as isolated polydactyly classified as postaxial polydactyly types A1 and B and preaxial polydactyly, type IV. All of these are inherited in an autosomal dominant manner. 

There are known genotype-phenotype correlations in GLI3 (Figure 3). GCPS is caused by truncating mutations upstream or within of the zinc finger domain (ZFD) as well as missense and nonsense variants in other parts of the gene that result in haploinsufficiency of the gene. (5) A small proportion of GCPS is associated with the deletion of the GLI3 gene as part of a contiguous gene deletion on chromosome 7p14. (6) 

The exon 4 deletion in our patient is upstream of the ZFD in exon 12. 

Pallister-Hall syndrome is caused by frameshift, nonsense, and splicing mutations in the middle third of the GLI3 gene, corresponding to exon 14 and parts of exons 13 and 15. 

GCPS is characterized by craniofacial features (Table 1), including macrocephaly, frontal bossing, prominent forehead, scaphocephaly, and hypertelorism associated with pre- and postaxial polydactyly. There may be broad or duplicated thumbs, broad or duplicated halluces, and cutaneous syndactyly of the fingers and toes. It is highly penetrant, meaning that those with mutations in the gene express clinical features in a family, but there can be inter- and intrafamilial phenotypic variability. (7) Less frequently, it can also include craniosynostosis, typically midline: metopic or sagittal. (8) 

Developmental delay, intellectual disability, or seizures appear to be uncommon manifestations (~<10%) of GCPS and may be more common in individuals with large (>300-kb) deletions that encompass GLI3. Approximately 20% of individuals with GCPS have hypoplasia or agenesis of the corpus callosum. 

Surveillance primarily involves reviewing head growth in infants and children; if faster than normal or neurologic concerns arise, a brain MRI is indicated. 

Practical Applications: 

1. Evaluate for craniosynostosis when you suspect GCPS or syndromic polydactyly when there is complex polydactyly or syndactyly. 
2. Suspect a genetic etiology when there is a positive family history of polydactyly, even when isolated. 
3. Order chromosome microarray analysis if there are other anomalies and/or growth or developmental concerns to evaluate for a contiguous gene deletion syndrome 
4. Genotype-phenotype correlations in GLI3-associated polydactyly help distinguish diagnoses with overlapping clinical features and help guide clinical management. 
5. Understand the differences in the incidence of polydactyly based on ancestry: isolated postaxial polydactyly is quite common in African Americans, while preaxial polydactyly is common in Native Americans. 
6. Isolated polydactyly can be sporadic and multifactorial. Postaxial polydactyly is seen more commonly in males. 
7. Preaxial polydactyly is less common, and mesoaxial polydactyly is the least common. 

References: 

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2. Diagnostic Imaging: Obstetrics. Third Edition, 2017; Edited by Paula J. Woodward 
3. Litingtung Y, Dahn RD, Li Y, Fallon JF, Chiang C. Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature. 2002 Aug 29;418(6901):979– 83. doi: 10.1038/nature01033. Epub 2002 Aug 18. PMID: 12198547. 
4. Lopez-Rios J, Speziale D, Robay D, Scotti M, Osterwalder M, Nusspaumer G, Galli A, Holländer GA, Kmita M, Zeller R. GLI3 constrains digit number by controlling both progenitor proliferation and BMP-dependent exit to chondrogenesis. Dev Cell. 2012 Apr 17;22(4):837–48. doi: 10.1016/j.devcel.2012.01.006. Epub 2012 Mar 29. PMID: 22465667; PMCID: PMC4486391. 
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6. Kozma K, Bembea M, Jurca CM, Ioana M, Streață I, Şoşoi SŞ, Pirvu A, Petchesi CD, Szilágyi A, Sava CN, Jurca A, Ujfalusi A, Szűcs Z, Szakszon K. Greig Cephalopolysyndactyly Contiguous Gene Syndrome: Case Report and Literature Review. Genes (Basel). 2021 Oct 23;12(11):1674. doi: 10.3390/ genes12111674. PMID: 34828280; PMCID: PMC8623992. 
7. https://www.omim.org/entry/175700 
8. Hurst JA, Jenkins D, Vasudevan PC, Kirchhoff M, Skovby F, Rieubland C, Gallati S, Rittinger O, Kroisel PM, Johnson D, Biesecker LG, Wilkie AO. Metopic and sagittal synostosis in Greig cephalopolysyndactyly syndrome: five cases with intragenic mutations or complete deletions of GLI3. Eur J Hum Genet. 2011 Jul;19(7):757–62. doi: 10.1038/ejhg.2011.13. Epub 2011 Feb 16. PMID: 21326280; PMCID: PMC3128494. 
9. Biesecker LG, Johnston JJ. Greig Cephalopolysyndactyly Syndrome. 2001 Jul 9 [Updated 2024 Feb 15]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1446/ PMID: 20301619 

Disclosure: There are no reported conflicts.