Jennifer Shin, MS, Skyler Muchmore MSII, Robin D. Clark, MD

Case Summary:

A Genetics consultation was requested for a term female infant with a cloverleaf skull and multiple congenital anomalies. She was born by Cesarian section at 38 weeks 5 days gestation to a 29-year-old G2P1 mother. Father was 30 years old. Pregnancy was complicated by maternal obesity, polyhydramnios, prenatal diagnosis of fetal ventriculomegaly, and Chiari 1 malformation.

The physical exam was noteworthy for major and minor anomalies: 

Cloverleaf skull with turricephaly (Figure 1a); moderately tense anteriorly displaced fontanelle; flat midface; maxillary hypoplasia, class III malocclusion with excess tissue on the lower alveolar ridge (Figure 1b), with a prominence at the midline; intact, high arched palate, shallow and widely spaced orbits, posterior auricular pits and indentations, bilateral preauricular and lobular pits and excess nuchal skin 

Broad adducted thumbs and great toes (Figure 1c) without syndactyly and with a range of motion of all joints. 

The caudal appendage at the base of the spine has a blind central pit with a hard, bony consistency (Figure 1d) 

Thick umbilical stump with excess epithelialization extending 2-3 cm up the cord (Figure 1e) 

Anteriorly placed anus at the base of the introitus; edematous and widely separated labia; unable to visualize clitoris. 

Hyperkeratotic palms and soles (Figure 1f); deep palmar and plantar creases with many accessory creases and rugae on the face 

Brain imaging with CT and MRI showed multisuture craniosynostosis (coronal and lambdoid) with cloverleaf skull, dysmorphic bilateral cerebral hemispheres with scalloping along the posterior parieto-occipital lobes, thinning of the corpus callosum, hypoplastic posterior fossa with low-lying cerebellar tonsils, midfacial hypoplasia, and shallow orbits with associated proptosis and hypertelorism and lateral ventriculomegaly. A patent foramen ovale was visualized at 8 days by echocardiogram. She was treated with positive pressure ventilation for upper airway obstruction. During her 3-month hospitalization, she required a ventriculoperitoneal shunt, tracheostomy, and gastrostomy tube. The first step in the surgical correction of her craniosynostosis, a posterior distraction, is planned at about four months of age. 

Family history was not significant. The parents are both of Mexican ancestry, and consanguinity was denied. 

A craniosynostosis gene panel testing revealed a recurrent de novo pathogenic variant in FGFR2: c.1124A>G, p.Tyr375Cys. Chromosome microarray was negative. 

Discussion: 

Craniosynostosis is a relatively common congenital anomaly that affects about 1 in 2000 children. (1) Although most cases of craniosynostosis involve a single suture and are not associated with other anomalies, approximately 5% involve multiple sutures, which are more often syndromic with a genetic etiology (Figure 2). (2) This infant has the most severe manifestation of craniosynostosis with premature fusion of both coronal and lambdoidal sutures, causing a cloverleaf-shaped skull. The genetic cause in her case is a heterozygous de novo pathogenic variant (p.Tyr375Cys or Y375C) in the FGFR2 gene, which encodes the fibroblast growth factor receptor type 2. Activating variants in this family of genes (FGFR1, FGFR2, and FGFR3) are responsible for many craniosynostosis and chondrodysplasia syndromes. 

Like the other members of this class, FGFR2 is a transmembrane tyrosine kinase signaling factor that usually forms a dimer and activates a growth-stimulating signal when ligands bind to its extracellular domains (Figure 3). (3) The pathogenic FGFR2 variants responsible for craniosynostosis cause a gain of function in either a ligand-dependent or ligand-independent manner. Two tissue-specific isoforms of FGFR2 have different ligand binding domains (IIIb, KGFR, IIIc, and BEK) and selectively target epithelial and mesenchymal tissues. The Y375C variant adds a cysteine residue, which is thought to increase ligand-independent dimerization in both the mesenchymal and epithelial isoforms, constitutively activating the growth-stimulating pathway in both tissue types. 

The Y375C variant in FGFR2 is the most common variant responsible for Beare-Stevenson syndrome (BSS; OMIM #123790). (4) The incidence of BSS is unknown, and only about 25 cases have been reported worldwide. In this rare condition, cloverleaf skull occurs in the context of cutis gyrata on the scalp or elsewhere, skin tags, creases on the ears, skin furrows on the palms and soles, enlarged and elongated umbilical stump, anal and genital anomalies. (5) A caudal appendage or pseudotail, described more accurately as a sacrococcygeal eversion, has been reported in many affected individuals with BSS and the Y375C variant. (6-8 ) 

Pfieffer syndrome (PS; OMIM# 101600) was initially considered because of the baby’s broad great toes and thumbs, but her features are more compatible with BSS even in the absence of cutis gyrate of the scalp. (9) There is considerable phenotypic overlap between BSS and other craniosynostosis syndromes like PS, such as a cloverleaf skill, airway obstruction, hydrocephalus, and Chiari malformation. (10) Compared to other craniosynostosis syndromes, the prognosis for BSS is worse. To our knowledge, there have been no survivors beyond the age of 13. Fifty percent of individuals with the Y375C variant have not survived past two years of age. (11). 

Practical applications: 

1. Pay attention to minor anomalies. They can be the keys to a correct diagnosis. The presence of facial rugae, a long epithelialized umbilical stump, multiple ear creases, and deep furrows on the palms and soles established the diagnosis of Beare-Stevenson syndrome in this child. 
2. Seek a unifying diagnosis. Beare-Stevenson syndrome is caused by enhanced signaling of mesenchymal (bone) and epithelial (skin) isoforms of FGFR2, explaining its varied effects on different tissue types. 
3. Order genetic testing when craniosynostosis is severe (cloverleaf skull), involves multiple sutures or is associated with extraskeletal anomalies. 

References:

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4. OMIM #123790: Beare-Stevenson cutis gyrata syndrome
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9. OMIM #101600: Pfieffer syndrome
10. Wenger T, Miller D, Evans K. FGFR Craniosynostosis Syn- dromes Overview. 1998 Oct 20 [updated 2020 Apr 30]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023. PMID: 20301628.
11. McGaughran J, Sinnott S, Susman R, Buckley MF, Elakis G, Cox T, Roscioli T. A case of Beare-Stevenson syndrome with a broad spectrum of features and a review of the FGFR2 Y375C mutation phenotype. Clin Dysmorphol. 2006 Apr;15(2):89- 93. doi: 10.1097/01.mcd.0000194407.92676.9d. PMID: 16531735.

Disclosures: The authors have no relevant disclosures