HUMAN MUTATION Mutation in Brief (2009) Online
MUTATION IN BRIEF
Phenotypic Spectrum of STRA6 Mutations: from
Matthew-Wood Syndrome to Non-lethal
Anophthalmia

Nicolas Chassaing1,2,3, Christelle Golzio4,5, Sylvie Odent6, Léopoldine Lequeux3, Adeline Vigouroux3,
Jelena Martinovic-Bouriel7, Francesco Danilo Tiziano8, Lucia Masini9, Francesca Piro10, Giovanna Maragliano11,
Anne-Lise Delezoide12, Tania Attié-Bitach4,5,7, Sylvie Manouvrier-Hanu13, Heather C. Etchevers1,4,
and Patrick Calvas1,2,3*
1 INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, 31300 France; 2 Université Toulouse III Paul-
Sabatier, Toulouse, 31400 France; 3 CHU Toulouse, Hôpital Purpan, Service de Génétique Médicale, Toulouse, 31300 France;
4 INSERM, U781, Hôpital Necker-Enfants Malades, Paris Cedex 15, 75743 France; 5 Université Paris Descartes, Hôpital
Necker-Enfants Malades, Paris, 75743 France; 6 CHU Rennes, Hôpital Sud, Service de Génétique Médicale, Rennes, 35203
France; 7 Département de Génétique, Hôpital Necker-Enfants Malades, Paris Cedex 15, 75743 France
8 Institute of Medical Genetics, Catholic University, Rome, Italy; 9 Institute of Obstetrics and Gynecology, Catholic University,
Rome, Italy; 10 Operative Unit of Pathology, S. Giovanni Hospital, Rome, Italy; 11 Complex Unit of Neonatology, S. Giovanni
Hospital, Rome, Italy; 12 GHU Nord, Hôpital Robert Debré, Service de Biologie du Développement, Paris Cedex 19, 75935
France; 13 CHRU Lille, Hôpital Jeanne de Flandre, Service de Génétique Clinique, Lille Cedex, 59037 France

*Correspondence to Pr Patrick Calvas, Service de Génétique Médicale, Pavillon Lefebvre, CHU Purpan, Place du Dr Baylac,
31059 Toulouse Cedex 9, France.
Tel.: +33 5 61 77 90 79; fax: +33 5 62 74 45 58.
E-mail : calvas.p@chu-toulouse.fr

Received 11 December 2008; accepted revised manuscript 08 March 2009.

Communicated by Mark H. Paalman

Matthew-Wood, Spear, PDAC or MCOPS9 syndrome are alternative names used to refer to
combinations of microphthalmia/anophthalmia, malformative cardiac defects, pulmonary
dysgenesis, and diaphragmatic hernia. Recently, mutations in STRA6, encoding a membrane
receptor for vitamin A-bearing plasma retinol binding protein, have been identified in such
patients. We performed STRA6 molecular analysis in three fetuses and one child diagnosed
with Matthew-Wood syndrome and in three siblings where two adult living brothers are
affected with combinations of clinical anophthalmia, tetralogy of Fallot, and mental
retardation. Among these patients, six novel mutations were identified, bringing the current
total of known STRA6 mutations to seventeen. We extensively reviewed clinical data
pertaining to all twenty-one reported patients with STRA6 mutations (the seven of this
report and fourteen described elsewhere) and discuss additional features that may be part of
the syndrome. The clinical spectrum associated with STRA6 deficiency is even more variable
than initially described. © 2009 Wiley-Liss, Inc.
KEY WORDS: STRA6, anophthalmia, Matthew-Wood syndrome, PDAC syndrome, MCOPS9

© 2009 WILEY-LISS, INC.
DOI: 10.1002/humu.21023

Expanding the Clinical Spectrum of STRA6 Mutations
INTRODUCTION
Variable combinations of microphthalmia/anophthalmia, pulmonary agenesis/dysplasia, diaphragmatic hernia
and malformative cardiac defects have been infrequently reported over the last three decades (Ostor et al., 1978;
Spear et al., 1987; Smith et al., 1994; Seller et al., 1996; Berkenstadt et al., 1999; Priolo et al., 2004; Lee et al.,
2006; Li and Wei, 2006; Chitayat et al., 2007; Golzio et al., 2007; Pasutto et al., 2007). Such associations have
been called Matthew-Wood or Spear syndrome, while Chitayat et al. (2007) devised the acronym PDAC
(Pulmonary hypoplasia/agenesis, Diaphragmatic hernia/eventration, Anophthalmia/microphthalmia and Cardiac
Defect), and the Mendelian Inheritance in Man database has adopted the term MCOPS9 for “syndromic
microphthalmia 9” (MIM# 601186). Recently, mutations in STRA6 (MIM# 610745), encoding a membrane
receptor for the vitamin A-bearing plasma retinol binding protein, have been found in patients with malformations
in the PDAC spectrum (Golzio et al., 2007; Pasutto et al., 2007; White et al., 2008; West et al., 2009).
We report herein novel STRA6 mutations in three fetuses and one child diagnosed with Matthew-Wood
syndrome, and in three siblings where two adult living brothers are affected with combinations of clinical
anophthalmia, tetralogy of Fallot, and mental retardation. This is the first description of adult patients bearing
STRA6 mutations. These additional cases emphasize that the clinical spectrum associated with STRA6 mutations is
extremely variable.

PATIENTS AND METHODS
Patients
Case 1
This male fetus from healthy and unrelated parents was delivered at 23 weeks of gestation after an ultrasound
scan documented bilateral diaphragmatic hernia, anophthalmia and cardiopathy. Autopsy confirmed the presence
of bilateral severe microphthalmia (Fig 1A), bilateral diaphragmatic hernia, and a complex heart malformation
(hypoplastic left heart syndrome with common atrium and dextroposition of the aorta). The lungs were hypoplastic
and dysplastic. The karyotype was 46, XY.
Case 2
This patient has previously been described (Chitayat et al., 2007; patient 7). Briefly, she was the fifth child of
consanguineous parents, born at term after a normal pregnancy, with normal growth parameters. She displayed an
association of bilateral anophthalmia (Fig 1B), heart malformation, subglottic laryngeal stenosis, bilateral unilobar
lungs, hypoplastic left kidney and right vesico-ureteral reflux, supernumerary spleen and hypoplastic uterus. Her
karyotype was 46, XX. She died at 19 months post-operatively for an unknown reason, after surgery was
performed to expand ocular orbits.
Family 3 (Cases 3-1, 3-2, 3-3)
Case 3-1:
A 40 year old patient was referred after his healthy sister came in for genetic counseling. He is the first child of
healthy and unrelated parents. He has moderate mental retardation associated with bilateral anophthalmia and
tetralogy of Fallot. Facial dysmorphy includes very short palpebral fissures and closed eyelids, a thin nasal bridge
and broad nasal tip (Fig 1C). The hands are small and broad. His height is 160 cm (-2.25 SD) and his karyotype is
46, XY.

Case 3-2:
A sister of case 3-1 died in the first days of life from a tetralogy of Fallot. She reportedly had bilateral clinical
anophthalmia but did not undergo autopsy.



Case 3-3: