PRENATAL DIAGNOSISPrenat Diagn 2007; 27: 967–969.Published online 29 June 2007 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/pd.1797

RESEARCH LETTER

Prenatal diagnosis of Fryns syndrome associated with amicrodeletion at 8p23.1

Chih-Ping Chen1,2,3,4*, Tzu-Hao Wang5, Yann-Jang Chen6,7, Tung-Yao Chang1, Yu-Peng Liu8,Chin-Yuan Tzen9, Schu-Rern Chern2 and Wayseen Wang2

1Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China2Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China3Department of Biotechnology and Bioinformatics, Asia University, Taichung, Taiwan, Republic of China4College of Chinese Medicine, China Medical University, Taichung, Taiwan, Republic of China5Department of Obstetrics and Gynecology, Lin-Kou Medical Center, Chang-Gung Memorial Hospital, Chang-Gung University,Tao-Yuan, Taiwan, Republic of China6Faculty of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan, Republic of China7Department of Pediatrics, Veteran General Hospital, Taipei, Taiwan, Republic of China8Department of Radiology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China9Department of Pathology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China

KEY WORDS: 8p23.1; Fryns syndrome; microdeletion; MRI; prenatal diagnosis

A 33-year-old, unmarried, primigravid woman wasreferred to the hospital at 24 weeks’ gestation becauseof abnormal sonographic findings. The mother and thefather were not consanguineous and healthy. Therewas no family history of congenital malformations.A cytogenetic study performed on the amniotic fluidcells revealed a karyotype of 46,XX at the 850-band stage. Level II ultrasound at 24 weeks’ gestationrevealed polyhydramnios, macrocephaly with a head

*Correspondence to: Chih-Ping Chen, Department of Obstetricsand Gynecology, Mackay Memorial Hospital, 92, Section 2,Chung-Shan North Road, Taipei, Taiwan, Republic of China.E-mail: cpc mmh@yahoo.com

circumference of 24.1 cm (>95th centile), ventricu-lomegaly, increased nuchal thickness, micrognathia, aleft congenital diaphragmatic hernia, a single umbilicalartery, large for gestational age and left renal hypoplasia.Magnetic resonance imaging (MRI) showed cerebellarhypoplasia, left pulmonary hypoplasia, left diaphrag-matic hernia and left renal hypoplasia (Figure 1(A) and(B)). A diagnosis of Fryns syndrome was made. Thepregnancy was terminated at 25 weeks’ gestation. A1064-g female baby was delivered with a body lengthof 35 cm and a head circumference of 26.5 cm. Theproband manifested characteristic dysmorphism of Frynssyndrome, including macrocephaly, brachytelephalangy,nail hypoplasia, a short webbed neck with redundant

(a)(b)

Figure 1—Prenatal magnetic resonance imaging (MRI) scans at 24 weeks’ gestation show (A) left diaphragmatic hernia with intestines in theleft hemithorax and left renal hypoplasia, and (B) cerebellar hypoplasia. RL: right lung, I: intestines, RK: right kidney, LK: left kidney

Copyright 2007 John Wiley & Sons, Ltd. Received: 7 April 2007Accepted: 16 May 2007

Published online: 29 June 2007

968 C.-P. CHEN ET AL.

posterior nuchal skin, a coarse face, a flat and broadnasal bridge, hypertelorism, macrostomia, microretrog-nathia, and low-set ears (Figure 2). An autopsy con-firmed the prenatal diagnosis. However, there was noevidence of congenital heart defects. We used Nim-bleGen’s high-density tiling oligonucleotide arrays toinvestigate the genomic imbalances at the critical regionsfor congenital diaphragmatic hernia. High-resolutioncomparative genomic hybridization (HR-CGH) arraysof fetal DNA revealed a 0.7-Mb deletion at 8p23.1(Figure 3). The deletion interval at 8p23.1 was from7 227 000 to 7 916 187 bp. The deletion was verified byBAC clone probes 499J9 (7 582 055–7 764 571 bp) and185K20 (7 680 355–7 856 126 bp). The genes encodedin this region include sperm associated antigen 11(SPAG11 ), defensin, beta 104B (DEFB104B ), beta106B (DEFB106B ), beta 105B (DEFB105B ), beta 107B(DEFB107B ), and olfactory receptor, family 7, sub-family E, member 157 pseudogene (OR7E157P ). Theparental DNAs were studied by HR-CGH arrays and nogenomic imbalances could be identified. The parentalkaryotypes were normal.

Fryns syndrome (OMIM 229 850) is a commonautosomal recessive syndrome that is associated withcongenital diaphragmatic hernia, pulmonary hypopla-sia, brachytelephalangy, craniofacial dysmorphism, oro-facial clefting and malformations of internal organs(Slavotinek, 2004). Prenatal diagnosis of Fryns syn-drome has been well documented. The present case wasassociated with fetal overgrowth, macrocephaly, poly-hydramnios, and nuchal thickening. Slavotinek (2004)reported that polyhydramnios occurred in 55.8% ofthe cases with Fryns syndrome. Fryns (1995) sug-gested the association of prenatal overgrowth with Frynssyndrome. Van Wymersch et al. (1996) reported theprenatal 3-D ultrasound reconstruction of the facialdysmorphism associated with Fryns syndrome. Cystic

Figure 2—Craniofacial dysmorphism of the proband at birth

hygroma or nuchal thickening has been noted to bean important sonographic marker for Fryns syndromein addition to congenital diaphragmatic hernia (Bulaset al., 1992; Hosli et al., 1997; Sheffield et al., 1998).The present case was also associated with prenatallydetected ventriculomegaly, cerebellar hypoplasia, andrenal dysplasia. Ventricular dilation and hydrocephalusare the most common cranial abnormalities associatedwith Fryns syndrome. However, the association withcerebellar hypoplasia, as shown in this case, is veryunusual. Slavotinek (2004) reviewed 52 cases of Frynssyndrome and found that 23% had ventricular dila-tion/hydrocephalus, 13.5% had agenesis of the corpuscallosum, 13.5% had neuronal and cerebellar hetero-topias, 9.6% had Dandy–Walker variants/hypoplasia ofthe cerebellar vermis, 3.8% had cerebellar hypoplasia,and 11.5% had renal dysplasia. Prenatal diagnosis ofcongenital diaphragmatic hernia with multiple mal-formations should include a differential diagnosis of

Figure 3—High-resolution comparative genomic hybridization (HR-CGH) analysis of fetal DNA using NimbleGen’s high-density tilingoligonucleotide arrays (Madison, WI, USA) shows a deletion at 8p23.1 encompassing a deleted region from 7 227 000 to 7 916 187 bp

Copyright 2007 John Wiley & Sons, Ltd. Prenat Diagn 2007; 27: 967–969.DOI: 10.1002/pd

FRYNS SYNDROME ASSOCIATED WITH MICRODELETION AT 8p23.1 969

Fryns syndrome, Pallister–Killian syndrome, Wiede-mann–Beckwith syndrome, Brachman–De Lange syn-drome, Simpson–Golabi–Behmel syndrome, Donnaisyndrome, Denys–Drash syndrome and Perlman syn-drome.

Various cytogenetic and molecular imbalances havebeen identified in cases with congenital diaphragmatichernia. For example, Kantarci et al. (2006) diagnoseda de novo 5-Mb microdeletion at 1q41-q42.12 in aninfant with congenital diaphragmatic hernia. Slavotineket al. (2005) detected microdeletions at 15q26.2 and8p23.1 in three patients with Fryns syndrome by meansof array comparative genomic hybridization (CGH).McPherson et al. (1993) reported similarity between Pal-lister–Killian syndrome with mosaic tetrasomy 12p andFryns syndrome. Faivre et al. (1998) and Shimokawaet al. (2005) observed an 8p23.1 deletion by conven-tional cytogenetics in patients with congenital diaphrag-matic hernia. Slavotinek et al. (2006) by performingarray CGH in 29 probands with congenital diaphrag-matic hernia have mapped four CDH-critical regions onchromosomes 15q26.2, 8p23.1, 4p16.3, and 1q41-q42.We additionally report a microdeletion at 8p23.1 andthe prenatal MRI findings in a fetus with congenitaldiaphragmatic hernia and Fryns syndrome.

ACKNOWLEDGEMENTS

This work was supported by research grants NSC-95-2314-B-195-015 form the National Science Counciland MMH-E-96004 from Mackay Memorial Hospital,Taipei, Taiwan.

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Copyright 2007 John Wiley & Sons, Ltd. Prenat Diagn 2007; 27: 967–969.DOI: 10.1002/pd