Novel FGFR2 deletion in a patient with Beare–Stevenson‐like syndrome

Abstract

Beare-Stevenson syndrome (BSS; OMIM 123790) is a rare craniosynostosis syndrome characterized by cutis gyrata, acanthosis nigricans, skin tags, anogenital anomalies and a prominent umbilicus. Two activating point mutations in FGFR2, p.Y375C and p.S372C, account for 50-60% of patients with BSS, and locus and/or allelic heterogeneity have been proposed. We present a novel deletion of 21 amino acids in the FGFR2 gene, c.1506del63, in a patient with BSS. BSS results from a gain of FGFR2 function, and this deletion may act by altering the splicing of isoform IIIc, resulting in illegitimate expression and thus a gain of function of FGFR2b.The propositus (Fig. 1) was delivered by cesarean for a dizygotic twin pregnancy at term to a 40-year-old, G3P2-4 mother and a 48-year-old father. Birth parameters were weight 3,860 g (75-90th centile for a singleton male), length 51 cm (50-75th centile for a singleton male) and head circumference 36.5 cm (75-90th centile for a singleton male). Striking craniofacial features were present, including ocular proptosis with hypoplasia of the supraorbital ridges, hypertelorism with a divergent strabismus, deep creases below his eyes, a high nasal bridge, midface hypoplasia and complete atresia of the external ear canals with a left preauricular pit and bilateral ear creases. There were multiple neonatal teeth, gingival hyperplasia and a high-arched, narrow palate with a bifid uvula. Cutaneous features included cutis gyrata and acanthosis nigricans of the posterior scalp, small skin tags at the corners of the mouth, excess neck skin and a prominent umbilicus with redundant skin. A sacral tag, hypospadias and a prominent scrotal raph e were present. Examination of the hands and feet showed redundant palmar and plantar skin, slightly broad thumbs and halluces and mild skin syndactyly of the second and third toes with overlapping fourth toes. Investigations for a flat occiput and a prominent forehead at 4 months of age showed fusion of the posterior aspect of the sagittal and the proximal lambdoid sutures and cranial vault remodeling was performed at 7 months. Bilateral choanal stenosis and a mild to moderate mixed hearing loss requiring hearing aids were present. Ophthalmological examination detected mild optic nerve hypoplasia and high myopia with astigmatism requiring corrective lenses. Obstructive sleep apnea was treated with a tracheostomy and a ventriculoperitoneal shunt was placed because of an ArnoldChiari malformation with hydrocephalus. His length was 107 cm at age 6 years (3rd centile), but his other growth parameters were normal. He has had initial mild motor delays, but the propositus' neurodevelopmental progress was normal.A clinical diagnosis of BSS was made shortly after birth. At that time, targeted re-sequencing for the two previously known FGFR2 mutations, p.Y375 C and p.S372 C , was performed on DNA extracted from peripheral blood lymphocytes from the propositus, and was negative.The diagnosis of a rhabdomyosarcoma in his twin when both were 5 years of age prompted further ...

Beare–Stevenson syndrome: Two new patients, including a novel finding of tracheal cartilaginous sleeve

“…Ser372Cys has been previously reported in three patients and was found in one of the present patients (Patient 1) [Stevenson et al, ; Hall et al, ; Fonseca et al, ]. There has been an additional case of Beare–Stevenson‐like syndrome, in a patient with loss of amino acids 287–308 also in FGFR2 [Slavotinek et al, ]. That child had a unique phenotype, with partial fusion of sagittal and lamboid sutures, cutis gyrata, and normal intelligence.…”

Report of a Father With Congenital Bilateral Absence of the Vas Deferens Fathering a Child With Beare–Stevenson Syndrome

“…Very recently, Zhang et al developed a non-invasive prenatal sequencing test based on the unique molecular indexing method to diagnose dominant monogenic disorders. This test ( Stevenson et al, 1978) U S N A 2 8 3 ( Hall et al, 1992) U S 4 3 3 3 4 ( Hall et al, 1992) U S 1 30 28 5 ( Hall et al, 1992) U S 1 NA 21 6 ( Hall et al, 1992) U S 1 32 22 7 ( Andrews et al, 1993) Brazil NA 23 8 ( Bratanic et al, 1994) Slovenia 43 39 9 ( Ito et al, 1996) Japan NA 25 10 (Przylepa et al, 1996) U S 1 NA NA 11 (Krepelová et al, 1998) Czech 24 24 12 (Wang et al, 2002) Taiwan 34 31 13 (Akai et al, 2002) Japan NA NA 14 (Izakovic et al, 2003) U S N A 3 4 15 (Vargas et al, 2003) Chile 36 28 16 (Vargas et al, 2003) Brazil 30 32 17 (Upmeyer et al, 2005) U S N A N A 18 (Erol and Eser, 2006) Turkey NA NA 19 (McGaughran et al, 2006) Australia 62 28 20 (Eun et al, 2007) Korea 50 32 21 (Fonseca et al, 2008) Brazil 30 23 22 (Slavotinek et al, 2009) U S 4 8 4 0 23 (Tao et al, 2010) successfully identified cases of FGFR2-related craniosynostosis, including Apert (FGFR2: c.758C > G), Pfeiffer (FGFR2: c.870G > T), and Crouzon (FGFR2: c.1032G > A) syndromes, and it accurately distinguished those cases from other FGFR3-related skeletal disorders (e.g. thanatophoric dysplasia and achondroplasia) (Zhang et al, 2019).…”

“…Mutations in genes encoding fibroblast growth factor receptors (FGFR) were shown to cause several craniosynostosis syndromes: Crouzon (FGFR2) and Pfeiffer (FGFR1 and FGFR2), Apert (FGFR2), Muenke (FGFR3), and Jackson-Weiss (FGFR2). So far, the genetic causes of BSS are known to be FGFR2 p.Ser372Tyr and p.Tyr375Cys mutations (Ron et al, 2016), except for a unique BSS case associated with a 63 bp deletion in FGFR2 exon 8 (Slavotinek et al, 2009). These are autosomal dominant syndromes caused by de novo mutations in germ cells in an unaffected parent.…”

Atypical Skin Manifestations in <b><i>FGFR2</i></b>-Related Craniosynostosis Syndromes Broaden the Phenotypic Spectrum

“…Cutis gyrata, acanthosis nigricans, skin furrows, skin tags, and deep palmar and plantar creases are usual [Przylepa et al, 1996;Akai et al, 2002;Vargas et al, 2003;McGaughran et al, 2006;Slavotinek et al, 2009;Robin et al, 2011]. The mechanisms by which cutis gyrata and acanthosis nigricans are caused by the FGFR 2 mutations remain unclear.…”