Greig Cephalopolysyndactyly Syndrome

Greig cephalopolysyndactyly (GCPS) syndrome is

named after David Middleton Greig for his 1926

description of a patient with unusual head shape,

hypertelorism, and limb anomalies. It is a rare, pleio-

tropic, multiple congenital anomaly syndrome charac-

terized by the primary clinical triad of polysyndactyly,

macrocephaly, and hypertelorism.

Synonyms and Related Disorders

Cephalopolysyndactyly; Polysyndactyly with peculiar

skull shape

Genetics/Basic Defects

1. Inheritance: Autosomal dominant with high pene-

trance in majority of cases.

2. Caused by mutations in the transcription factor

GLI3 on chromosome 7p13 resulting in functional

haploinsufficiency of GLI3. The mutations include:

a. Point mutations

b. Frameshift mutations

c. Translocation mutations

d. Deletion mutations

e. Insertion mutations

3. Allelic to the Pallister-Hall syndrome (PHS) and

one form of the acrocallosal syndrome:

a. Severe GCPS phenotype is likely caused by dele-

tion of contiguous genes and substantially

overlaps with the mild end of the acrocallosal

syndrome (an autosomal recessive disorder

characterized by pre- or postaxial polydactyly,

syndactyly, agenesis corpus callosum, ocular

hypertelorism, macrocephaly, moderate to

severe mental retardation, intracerebral cysts,

seizures, and umbilical and inguinal hernias).

b. GLI3 mutations can also cause PHS, post-

axial polydactyly type A, and other GLI3

morphopathies. GCPS and PHS are likely allelic

with distinct modes of pathogenesis.

4. Phenotypes caused by mutations in GLI3 are

diverse, discrete, variable, and pleiotropic. The

mutations in GLI3 that cause PHS and GCPS

correlate with the phenotypes on two levels:

a. Many types of inactivating mutations cause

GCPS.

b. Whereas PHS is caused almost exclusively

by truncation mutations in the middle third of

the gene.

5. Mutations in genes other thanGLI: possible in some

patients with a GCPS phenotype.

Clinical Features

1. The primary clinical triad.

a. Macrocephaly

b. Hypertelorism

c. Polysyndactyly

2. Variable clinical manifestations

3. Developmental history:

a. Feeding problems/failure to thrive

b. Developmental delay, seizures, and psychomo-

tor retardation: more likely in a child with

rare CNS malformations or uncommon hydro-

cephalus and more common in individuals

with large (>300 kb) deletions that encompass

GLI3

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_111,# Springer Science+Business Media, LLC 2012

987

4. Craniofacial features: highly variable

a. Significant hypertelorism (increased interpupillary

distance) with or without telecanthus (increased

inner canthal distance) in some patients

b. Macrocephaly, not typically associated with

CNS anomalies, such as hydrocephalus and

seizures

5. Digital anomalies:

a. Polydactyly:

i. Classically described as preaxial.

ii. May occur in any limb.

iii. Postaxial may be more common than

preaxial.

iv. Most common finding: postaxial polydac-

tyly of the hands and preaxial polydactyly

of the feet.

v. Severity varies widely among individuals

and among limbs in the same individual.

This can vary from an apparently normal

extremity, through subtle broadening of the

thumb or hallux, tiny postaxial nubbins, to

partially bifid digits, hypoplastic supernu-

merary digits, fully formed supernumerary

digits, and higher order polydactyly.

b. Cutaneous syndactyly: highly variable.

i. Absent in many patients

ii. Mild partial cutaneous syndactyly of a few

digits in some patients

iii. The spectrumcontinues through to complete

cutaneous syndactyly of all digits, not unlike

that seen in patients with Apert syndrome.

6. Less common anomalies:

a. Craniosynostosis: very few patients.

b. Mental retardation: not common.

c. Agenesis of the corpus callosum.

d. Umbilical and diaphragmatic hernias.

e. Risk of cognitive impairment appears to be

associated with the GCPS-contiguous gene

syndrome.

7. Diagnostic criteria (Johnston et al. 2005):

a. Presumptive diagnosis: a proband with:

i. Preaxial polydactyly

ii. Syndactyly of toes 1–3 or fingers 3–4

iii. Ocular hypertelorism

iv. Macrocephaly

b. Firm diagnosis:

i. Presence of an affected first-degree relative

whom the diagnosis has been independently

established

ii. A proband who has features of GCPS and

a mutation in GLI3

c. Cautions in applying above diagnostic criteria:

i. Clinical criteria: useful but not sufficiently

specific to warrant a “firm” diagnosis on

clinical grounds alone

ii. A small but significant fraction of individ-

uals with features of GCPS do not have

mutations in GLI3.iii. Features of GCPS are seen in many other

syndromes.

8. Diagnostic criteria (combined clinical-molecular

definition for the syndrome) (Biesecker 2008)

a. A presumptive diagnosis with the classic triad:

i. Preaxial polydactyly with cutaneous syn-

dactyly of at least one limb

ii. Hypertelorism

iii. Macrocephaly

b. Definitive diagnosis:

i. A phenotype consistent with GCPS but

which may not manifest all three attributes

listed above

ii. Presence of a GLI3 mutation

9. Additional definitive diagnostic criteria: persons

with a GCPS-consistent phenotype who are related

to a definitively diagnosed family member in

a pattern consistent with autosomal dominant

inheritance

10. Prognosis:

a. A mild form: excellent general health and

normal longevity reported in several large

families

b. Slight increase in the incidence of developmen-

tal delay or cognitive impairment

c. Worse prognosis in patients with large dele-

tions that include GLI311. Differential diagnosis:

a. Preaxial polydactyly type IV

b. GCPS contiguous gene syndrome

c. Acrocallosal syndrome (ACLS):

i. Inherited in an autosomal recessivemanner.

ii. Pre- or postaxial polydactyly.

iii. Syndactyly.

iv. Agenesis of the corpus callosum (rare in

GCPS).

v. Ocular hypertelorism.

vi. Macrocephaly.

vii. Moderate to severe mental retardation.

viii. Intracerebral cysts.

988 Greig Cephalopolysyndactyly Syndrome

ix. Seizures.

x. Umbilical and inguinal hernias.

xi. The milder end of the ACLS phenotype

can overlap with the severe end of the

GCPS phenotype caused by interstitial

deletions of 7p13 that delete GLI3 and

additional neighboring genes.

xii. Frequency of consanguinity, sibling

recurrences with unaffected parents, and

preliminary mapping data suggest that

ACLS can be a disorder distinct from

severe GCPS.

d. Gorlin syndrome

e. Carpenter syndrome

f. Teebi syndrome

Diagnostic Investigations

1. Radiographic studies of digital anomalies

2. CNS imaging studies:

a. For individuals showing signs of increased intra-

cranial pressure, developmental delay, loss of

milestones, or seizures

b. To evaluate hydrocephalus or other CNS

abnormalities

3. Chromosome analysis: performed either as a first

test, or in all patients who have GCPS but no muta-

tion was found by sequencing:

a. Detection of visible pure chromosomal deletions

involving 7p13 or a deletion combined with

a translocation

b. Detection of familial translocation: a risk for

offspring with unbalanced translocations in

addition to their risk of having a child with GCPS

4. Molecular genetic testing:

a. Indications:

i. Confirmatory diagnostic testing

ii. Prenatal diagnosis

b. FISH analysis: Using hybridization of the

labeled BAC clone to metaphase spreads detects

deletions in the estimated 5–10% of individuals

with large deletions.

c. Comparative genomic hybridization (CGH):

i. An array of GLI3 is available on a limited

clinical basis.

ii. CGH array would be expected to detect

a deletion that encompasses more than one

target on the array.

d. Other methodologies:

i. Loss-of-heterozygosity (LOH) analysis to

detect large deletions

ii. Sequencing of theGLI3 coding exons or scan-

ning with denaturing high-performance liquid

chromatography (DHPLC), single-strand con-

formation polymorphism (SSCP), or other

conformation detection methods: an appropri-

ate first screen for patients with typical GCPS

iii. Quantitative PCR

Genetic Counseling

1. Recurrence risk:

a. Patient’s sib:

i. De novo cases: recurrence risk low

ii. Fifty percent of siblings affected if one of the

parents is affected

iii. No instances of germlinemosaicism reported,

but it remains a possibility

iv. Proband with an unbalanced structural chro-

mosome constitution:

a) Neither parents with a structural chromo-

some rearrangement: risk to sibs negligible

b) A parent with a balanced structural

chromosome rearrangement: risk to sibs

increases and depends upon the specific

chromosome rearrangement

b. Patient’s offspring

i. Fifty percent risk of inheriting the mutation

and having an affected offspring: Since

intrafamilial variability is generally low,

affected offspring are expected to have clin-

ical findings similar to those of the parent.

ii. Offspring of an individual with a balanced

or unbalanced chromosomal rearrangement:

at risk of having a similar or related

rearrangement.

2. Prenatal diagnosis:

a. Ultrasound studies in pregnancies at 50% risk

may detect the following findings:

i. Polydactyly

ii. Ma

iii. CNS malformations such as hydrocephalus

b. Chromosome analysis of fetal cells in at-risk

families with a parent having a cytogenetically

visible 7p13 deletion or a balanced chromosomal

rearrangement.

Greig Cephalopolysyndactyly Syndrome 989

c. Molecular genetic testing: Antenatal molecular

diagnosis is technically straightforward to

perform.

d. Preimplantation genetic diagnosis (PGD): may

be available for families in which the disease-

causing mutation or chromosome abnormality

has been identified in an affected family.

3. Management:

a. Symptomatic treatment with plastic or ortho-

pedic surgery indicated for significant limb

malformations

b. Surgical repair:

i. Preaxial polydactyly of the thumbs: a higher

priority for surgical correction than postax-

ial polydactyly of the hand or polydactyly of

the foot because of the importance of the

thumbs for prehensile grasp

ii. Severe syndactyly of the fingers

iii. Surgical correction of the feet for orthopedic

complications, cosmetic benefits, and easier

fitting of shoes

References

Balk, K., & Biesecker, L. G. (2008). The clinical atlas of Greig

cephalopolysyndactyly syndrome. American Journal ofMedical Genetics. Part A, 146, 548–557.

Baraitser, M., Winter, R. M., & Brett, E. M. (1983). Greig

cephalopolysyndactyly: Report of 13 affected individuals in

three families. Clinical Genetics, 24, 257–265.Biesecker, L. G. (2002). Polydactyly: How many disorders and

how many genes? American Journal of Medical Genetics,112, 279–283.

Biesecker, L. G. (2006). What you can learn from one gene:

GLI3. Journal of Medical Genetics, 43, 465–469.Biesecker, L. G. (2008). The Greig cephalopolysyndactyly

(Review). Orphanet Journal of Rare Diseases, 3, 10–15.Biesecker, L. G. (2009). Greig cephalopolysyndactyly syn-

drome. Gene Reviews. Updated April 30, 2009. Available

at: http://www.ncbi.nlm.nih.gov/books/NBK1446/.

Debeer, P., Peeters, H., Driess, S., et al. (2003). Variable pheno-

type in Greig cephalopolysyndactyly syndrome: Clinical and

radiological findings in 4 independent families and 3

sporadic cases with identified GLI3 mutations. AmericanJournal of Medical Genetics, 120A, 49–58.

Driess, S., Freese, K., Bornholdt, D., et al. (2003). Gene symbol:

GLI3. Disease: Greig cephalopolysyndactyly syndrome.

Human Genetics, 112, 103.Duncan, P. A., Klein, R. M., Wilmot, P. L., et al. (1979). Greig

cephalopolysyndactyly syndrome. American Journal ofDiseases of Children, 133, 818–821.

Greig, D. M. (1926). Oxycephaly. Edinburgh Medical Journal,33, 189–218.

Johnston, J. J., Olivos-Glander, I., Killoran, C., et al. (2005).

Molecular and clinical analyses of Greig cephalopoly-

syndactyly and Pallister-Hall syndromes: Robust phenotype

prediction from the type and position of GLI3 mutations.

American Journal of Human Genetics, 76, 609–622.Johnston, J. J., Olivos-Glander, I., Turner, J., et al. (2003).

Clinical and molecular delineation of the Greig cephalopo-

lysyndactyly contiguous gene deletion syndrome and its dis-

tinction from acrocallosal syndrome. American Journal ofMedical Genetics, 123A, 236–242.

Johnston, J., Walker, R., Davis, S., et al. (2007). Zoom-in com-

parative genomic hybridisation arrays for the characterisa-

tion of variable breakpoint contiguous gene syndromes.

Journal of Medical Genetics, 44, e59.Kalff-Suske, M. (2000). Gene symbol: GLI3. Disease: Greig

cephalopolysyndactyly syndrome.Human Genetics, 107, 203.Kalff-Suske, M., Wild, A., Topp, J., et al. (1999). Point muta-

tions throughout the GLI3 gene cause Greig cephalopoly-

syndactyly syndrome. Human Molecular Genetics, 8,1769–1777.

Kroisel, P. M., Petek, E., & Wagner, K. (2001). Phenotype of

five patients with Greig syndrome andmicrodeletion of 7p13.

American Journal of Medical Genetics, 102, 243–249.Mendoza-Londono, R., Kashork, C. D., Shaffer, L. G., et al.

(2005). Acute lymphoblastic leukemia in a patient with

Greig cephalopolysyndactyly and interstitial deletion of

chromosome 7 del(7)(p11.2 p14) involving the GLI3 and

ZNFN1A1 genes.Genes, Chromosomes&Cancer, 42, 82–86.Pettigrew, A. L., Greenberg, F., Caskey, C. T., et al. (1991).

Greig syndrome associated with an interstitial deletion of 7p:

Confirmation of the localization of Greig syndrome to 7p13.

Human Genetics, 87, 452–456.Radhakrishna, U., Bornholdt, D., Scott, H. S., et al. (1999). The

phenotypic spectrum of GLI3 morphopathies includes auto-

somal dominant preaxial polydactyly type-IV and postaxial

polydactyly type-A/B; no phenotype prediction from the

position of GLI3 mutations. American Journal of HumanGenetics, 65, 645–655.

Wild, A., Kalff-Suske, M., Vortkamp, A., et al. (1997). Point

mutations in human GLI3 cause Greig syndrome. HumanMolecular Genetics, 6, 1979–1984.

Williams, P. G., Hersh, J. H., Yen, F. F., et al. (1997). Greig

cephalopolysyndactyly syndrome: Altered phenotype of a

microdeletion syndrome due to the presence of a cytogenetic

abnormality. Clinical Genetics, 52, 436–441.

990 Greig Cephalopolysyndactyly Syndrome

a b

Fig. 1 (a, b) A 34-year-old patient with typical facial features

characterized by macrocephaly and hypertelorism. He also has

mental retardation and seizure disorder. The hands show

postaxial polydactyly and complete cutaneous syndactyly of

digits 2–5 with fusion of nails. The feet show a partially dupli-

cated hallux with cutaneous syndactyly of several digits

a b

Fig. 2 (a, b) Radiographs of the same patient. The hands show six phalanges with partial fusion of the third and fourth metacarpals

and partial fusion of the fourth and fifth proximal phalanges. The feet shows a partially duplicated hallux

Greig Cephalopolysyndactyly Syndrome 991

a

c

b

Fig. 3 (a–c) Another patient with macrocephaly, ocular hypertelorism, and a partially duplicated great hallux

992 Greig Cephalopolysyndactyly Syndrome