INTRODUCTION

Greig cephalopolysyndactyly syndrome [(GCPS), MIM #175700] is a disorder caused by mutations in the zinc finger gene family 3 (GLI3 gene), which is crucial for limb, brain, and craniofacial development. It follows an autosomal dominant inheritance pattern. The prevalence of this syndrome is approximately 1-9/1,000,000 (1). The GLI3 gene is located on the short arm of chromosome 7 (Chr.7-p14 band). The prominent clinical findings are macrocephaly, prominent forehead, hypertelorism, preaxial and/or postaxial polydactyly, and cutaneous syndactyly. In cases with multiple congenital anomalies, it is often assessed as a sequential gene syndrome (2,3).

The GLI3 gene encodes a pivotal transcription factor essential for embryonic development. It also controls downstream targets of the sonic hedgehog pathway, which regulates cell proliferation and differentiation (4). Approximately 80% of GCPS cases linked to GLI3 gene haploinsufficiency result from single nucleotide changes, whereas approximately 20% stem from copy number alterations (5).

The vast majority of the reported cases are postnatal with variable expression. Here, the presented case is a rare case of prenatal GCPS due to a de novo unbalanced chromosomal rearrangement belonging to the interstitial deletion of chromosome 7, covering the GLI3 gene region.

CASE REPORT

At 32 years of age, a primigravida at 21-week of gestation underwent amniocentesis because of abnormal ultrasonographic (USG) findings. USG revealed polydactyly in the feet, polyhydramnios, and aortic valve stenosis, whereas the vesica biliaris could not be visualized. The parents are non-consanguineous.

Interphase fluorescent in situ hybridization (I-FISH) analysis for common euploidies (Chr.13, 18, 21, and gonosomes) of uncultured amniocytes showed a normal hybridization pattern. Cytogenetic analysis from long-term tissue cultures revealed an interstitial deletion on the short arm of Chr.7, and metaphase FISH analysis confirmed the presence of telomeric regions [(46,XX,del(7)(7pterà7p15.1::7p12à7qter)] (Figure 1a, b).

Array comparative genomic hybridization (array-CGH) (Human Genome G3 SurePrint 8x60K ISCA Array; Agilent Technologies, Santa Clara, California) verified the deletion [17.4 megabase (Mb) deletion], including the GLI3 gene located on the 7p12.3-14.3 (hg19:7:30307418-47765428) (Figure 1c). Cytogenetic analysis was also carried out on the parents, and their karyotypes were normal. The detected unbalanced chromosomal rearrangement was considered a de novo.

After unbiased genetic counseling was given in terms of GCPS, the family decided to continue the pregnancy. Because of fetal cardiac arrest, the mother had a stillbirth at 25 weeks of gestation. Prominent forehead, biparietal narrowing, hypertelorism, flat and wide nasal bridge, broad thumbs in the hands and feet, and preaxial polydactyly in the foot were observed in the clinical examination of the exitus fetus, all consistent with GCPS (Figure 2). Written consent was obtained from the family.

DISCUSSION

GCPS is primarily caused by single nucleotide or copy number changes in the GLI3 gene. Rarely, chromosomal alteration within the deletion of related genes can cause GCPS syndrome, as in the present case. Considering other allelic disorders of the GLI3 gene, such as Pallister Hall syndrome (midaxial/postaxial polydactyly, asymptomatic bifid epiglottis, imperforate anus, and hypothalamic hamartoma), evaluation of the individual’s genetic and phenotypic characteristics pattern is essential (6). Fortunately, genetic and phenotypic correlations are well documented and can be used to diagnose each condition more accurately (5,7,8). Similar to the present case, large deletions of the GLI3 gene are more commonly associated with GCPS than with Pallister Hall syndrome.

Array-CGH analysis of this case revealed a 17.4-Mb deletion, resulting in the loss of genes such as POU6F2, GCK, TBX20, CDK13, CAMK2B, and GARS, besides the GLI3 gene. POU6F2 gene deletion may increase the risk of Wilms tumor, whereas the deletion of the GCK gene may lead to MODY (9,10). The family was informed that intellectual influence was unpredictable because of the involvement of other genes. The deletion interval of the fetus was interpreted on the DECIPHER database, and most of the dysmorphic signs were common, except for the absence of vesica biliaris.

During pregnancy, polydactyly can be diagnosed earlier, whereas macrocephaly and hypertelorism can mainly be detected in the third trimester. Fetal USG plus genetic testing make prenatal diagnosis feasible, allowing early diagnosis and appropriate management of the newborn (8). It allows the potential medical and surgical interventions that the newborn may need to follow birth. Beyond that, diagnosis is also essential for the family’s subsequent pregnancies. If chromosomal alteration is familial, counseling should be given regarding preimplantation genetic diagnosis and invasive prenatal testing. Even if the parental karyotype analysis is normal and considered de novo, the risk of recurrence exists, albeit low, because of possible changes that cannot be detected by conventional cytogenetic analysis, such as gonadal mosaicism and familial micro-inversions.

In sum, this case holds significance as it was prenatally diagnosed on the basis of suspicious fetal ultrasound findings and subsequently confirmed through genetic testing. GCPS syndrome can be challenging to diagnose prenatally (11). As in this case, families should be briefed on the condition, its potential causes, and prenatal diagnosis and management options.

Ethics

Informed Consent: The parent of the case signed the written informed consent form.

Authorship Contributions

Surgical and Medical Practices: T.N., P.T.C., Concept: T.H., G.K., M.Y.K., Design: T.H., G.K., M.Y.K., Data Collection or Processing: T.H., M.Y.K., Analysis or Interpretation: T.H., G.K,  M.Y.K., Literature Search: T.H., Writing: T.H., M.Y.K.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.