American Journal of Medical Genetics 83:82–87 (1999) Microcephaly, Colobomatous Microphthalmia, Short Stature, and Severe Psychomotor Retardation in Two Male Cousins: A New MCA/MR Syndrome? André Mégarbané,1* Soha Haddad-Zebouni,2 Rima Nabbout,3 Antoine H. Khoury,4 and Elias I. Traboulsi5 1 Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon Service de Radiologie, Hôtel-Dieu de France, Beirut, Lebanon 3 Service de Pédiatrie, Hôtel-Dieu de France, Beirut, Lebanon 4 Service d’Ophtalmologie, Hôtel-Dieu de France, Beirut, Lebanon 5 Center for Genetic Eye Diseases, Cleveland Clinic Eye Institute, Cleveland, Ohio 2 We report on 2 male cousins with minor facial anomalies, microcephaly, colobomatous microphthalmia, psychomotor retardation, short stature, and skeletal malformations. The children belong to a highly inbred family. We conclude that these patients have a previously undescribed autosomal-recessive syndrome. Am. J. Med. Genet. 83:82–87, 1999. © 1999 Wiley-Liss, Inc. KEY WORDS: autosomal recessive; coloboma; consanguinity; mental retardation; microcephaly; microphthalmia; short stature INTRODUCTION Colobomatous microphthalmia is a common malformation that may be present in many syndromes. Nearly 150 conditions with microphthalmia have been delineated [Warburg, 1993]. Many of these syndromes have overlapping clinical findings, making differentiation difficult. Characteristic clinical findings, modes of inheritance, or specific chromosome abnormalities facilitate diagnosis. We describe 2 cousins with minor facial anomalies, microcephaly, colobomatous microphthalmia, psychomotor retardation, short stature, and skeletal malfor- Grant sponsor: Jérôme Lejeune Foundation. *Correspondence to: André Mégarbané, M.D., Ph.D., Unité de Génétique Médicale, Faculté de Médecine, Université SaintJoseph, 42 rue de Grenelle, 75007 Paris, France. E-mail: [email protected] Received 12 May 1998; Accepted 23 November 1998 © 1999 Wiley-Liss, Inc. mations. We postulate that these patients have a hitherto unreported autosomal-recessive malformation syndrome. CLINICAL REPORT This kindred (Fig. 1) resides in southern Lebanon and belongs to the Shiite Muslim community. Case 1 H.J. (VI-3, Fig. 1) is the last child of healthy consanguineous parents. When he was born, the father and the mother were 28 years old. Gestation was unremarkable and there was no exposure to toxins or known teratogens. The baby was delivered by cephalic presentation at 40 weeks. Birth weight was 2,500 g (3rd centile), and length was 50 cm (50th centile). Microphthalmia OD, flexion deformity of the right knee, right foot equinovarus, and tetralogy of Fallot were noted at birth. At age 3 years he developed seizures that are well-controlled with medication. We first examined him at age 5 years. He weighed 8.5 kg, and had a length of 81 cm and an occipitofrontal circumference (OFC) of 46.2 cm (all below the 3rd centile). Psychomotor delay was evident and he was unable to walk, speak, or react normally to simple orders. He had a poor appetite. The child was hypotonic. He had microcephaly, right microphthalmia, horizontal nystagmus, an oedematous eyelid on the right side, wide flat nasal bridge, anteverted nostrils, long philtrum, a high-arched palate, and retrognathia (Fig. 2a,b). Teeth were normally erupted for age but there were two conical lateral incisors. Dermatoglyphic palm patterns were unremarkable. The right lower limb was shorter than the left. Colobomatous Microphthalmia MCA/MR Syndrome 83 Fig. 1. Pedigree of present family. Solid squares indicate affected individuals with colobomatous microphthalmia. Stippled square indicates the affected boy with cataracts, and shaded circle indicates the affected girl without ocular malformations. There was an undescended right testicle. Ophthalmological evaluation documented a right microphthalmia, nystagmus, an esotropia of 10 prism diopters without limitation of motility, and posterior synechiae for 360° OD, with an elliptical pupil. The fundus was not visualized. There was a coloboma OS that involved the optic disc and was 5 disc diameters large. Computed tomography of the brain showed mild cortical atrophy, and a small right globe and orbit. Electroencephalography disclosed multiple independent epileptic foci. The radiological examination of the skeleton demonstrated thin diaphyses, thinning of the lateral third of the clavicles, thin ribs, tall vertebral bodies, brachymetacarpy, cone-shaped epiphyses of the distal phalanges of the third and fourth fingers of the left hand, and a general aspect of amyotrophy (Fig. 3a,c). Abdominal ultrasound findings and auditory brain-stem responses were normal. Echocardiography disclosed tetralogy of Fallot. He had irondeficiency anemia, but results of hemoglobin electrophoresis, blood glucose levels, urinalysis, amino-acid studies of plasma and urine, and liver and thyroid function studies were unremarkable. Chromosomes (high-resolution G- and R-banding) were normal (46,XY). Ophthalmological findings of the parents and their other children were normal. Their physical findings were normal as well, except for the sister of the propositus (VI-2, Fig. 1). She had been born at term with a weight of 2,900 g (25th centile) and a length of 50 cm (45th centile). She had bilateral congenital hip luxation, bilateral talipes equinovalgus, and an intolerance to lactose. At age 8 years her weight was 18 kg (3rd centile), height was 110 cm (<3rd centile), and OFC was 49.7 cm (5th centile). There were normally formed but carrious teeth, most probably due to prolonged bottle feeding. She had a high-arched palate, and was severely mentally retarded (Fig. 4). Radiographs showed thin diaphyses, thinning of the lateral third of the clavicles, thin ribs, brachymetacarpy of the fourth and fifth digits, brachyphalangy of the middle phalanx of the fourth digit, and cone-shaped epiphyses of the first metacarpal. An EEG showed epileptic foci and disorganized tracing. Case 2 A.J. (VI-7, Fig. 1), a boy, is the last child of healthy consanguineous parents. When he was born, the father was 36 and the mother 25 years old. Pregnancy and delivery were normal. Birth weight was 3,000 g (25th centile), length 50 cm (25th centile), and OFC 33 cm (10th centile). 84 Mégarbané et al. Fig. 2. a: Facial appearance of H.J. at age 5 years. b: Profile of H.J. Note micrognathia. At the time of examination, he was 40 days old. Weight was 3,500 g (50th centile), length 52 cm (25th centile), and OFC 34 cm (10th centile). He was hypotonic, and had a round face, 3 × 3 cm anterior fontanel, anteverted nares, normally positioned ears, long philtrum, micrognathia (Fig. 5a,b), undescended right testicle, bilateral microphthalmia more pronounced on the right side, an inferior coloboma of the iris, and choroid OU. Both pupils reacted normally to light. A magnetic resonance imaging examination of the head was performed and did not show malformations of the brain. Echocardiogram and abdominal ultrasound findings were normal. Results of complete blood count, blood glucose, urinalysis, amino-acid studies of plasma and urine, liver and thyroid function studies, and TORCH screen were all unremarkable. Chromosomes (high-resolution G- and R-banding) were normal (46,XY). At age 6 months, his length was 64 cm (3rd centile), weight 5,300 g (<3rd centile), and OFC 39.2 cm (3rd centile). All cranial sutures were closed. The radiological findings of the skeleton were unremarkable. His parents had previously given birth to 2 boys, and a girl. The eldest boy (VI-4, Fig. 1) died at age 7 years for unclear reasons. He was profoundly retarded, hypotonic, and very thin, and had congenital cataracts. The other children and both parents are normal. DISCUSSION The 2 cousins who form the subject of this report both have microcephaly, colobomatous microphthalmia, psychomotor retardation, short stature, and for one of them, various osseous malformations. Some of these findings are also seen in Lenz microphthalmia syndrome, recessive Waardenburg microphthalmia syndrome, and CHARGE syndrome. Lenz syndrome is a rare X-linked recessive condition first reported by Lenz . Our patients also have microphthalmia, coloboma, microcephaly, congenital cardiac defects, mental retardation, and short stature. The presence of congenital cataracts in patient VI-4 (Fig. 1) may be fortuitous but may also be considered as a manifestation of the same abnormal gene that causes microphthalmia. The mentally retarded girl (VI-2, Fig. 1) has most of the abnormalities of her affected brother except for the ophthalmological findings. She could be considered a carrier of an X-linked syndrome. Carrier Fig. 3. a: X-ray of H.J.’s left hand. Note thin diaphyses, cone-shaped epiphyses, brachymetacarpy, and a general aspect of amyotrophy. b: X-ray of H.J.’s thorax, showing the thinning of the lateral third of the clavicles and of the ribs. c: X-ray of pelvis, showing subluxation of the hips, thin diaphyses, and amyotrophy. 86 Mégarbané et al. Fig. 4. Sister of propositus at age 8 years. females in Lenz microphthalmia syndrome may have short stature, microcephaly, and mental retardation [Hermann and Opitz, 1969; Krishnamurthy et al., 1998]. The absence of these manifestations in the mothers of our patients could be explained by the Lyon hypothesis. Nevertheless, the lack of some major components of Lenz syndrome [Traboulsi et al., 1988] such as dental, digital, and urogenital anomalies, in addition to the severe mental retardation, distinct facial appearance, and osseous malformations of the patients reported herein, make a diagnosis of Lenz syndrome unlikely. Although the pedigree is compatible with X-linked inheritance, the high degree of consanguinity suggests autosomal-recessive inheritance instead. In 1935, Waardenburg described a syndrome of anophthalmia with malformations of hands and feet, mental retardation, and short stature [Waardenburg, 1961]. Since then, 11 families have been reported with different patterns of malformations, which helps to extend the wide range of expressivity of this rare syndrome. The patients of the present report do not have any of the digital anomalies of Waardenburg syndrome [Mégarbané et al., 1998]. Furthermore, no cardiovascular or visceral malformations have been reported in the recessive Waardenburg microphthalmia syndrome. CHARGE syndrome is characterized by coloboma of the iris or choroid, heart defects, atresia of the choanae, growth and developmental retardation, genitourinary Fig. 5. a: Face of A.J. at age 40 days. Note right microphthalmia, anteverted nares, and long philtrum. b: Profile of A.J. Note micrognathia. Colobomatous Microphthalmia MCA/MR Syndrome malformations, and ear abnormalities. A diagnosis is made in the presence of 4 of the 6 major criteria, one of which should be either choanal atresia or a coloboma. Although our patients fulfill some of these criteria, autosomal-recessive inheritance of the CHARGE syndrome has not been reported. Another rare condition that could be considered in the differential diagnosis is the X-linked recessive syndrome of microcephaly, microphthalmia, corneal opacities, spastic quadriplegia, hypospadias, cryptorchidism, agenesis of the corpus callosum, and hydrocephaly described by Siber . Seemanova and Lesny  described a boy and his sister’s son with microcephaly, microphthalmia, congenital cataract, upslanting palpebral fissures, high-arched palate, retrognathia, severe mental deficiency, growth retardation, hypogenitalism, and spasticity. Warburg et al.  reported on 2 sibs and a cousin, from an inbred Pakistani family, with microcephaly, microcornea, congenital cataracts, optic nerve atrophy, small pupils bound by posterior synechiae, prominent ears, hypertrichosis, agenesis of the corpus callosum, severe mental retardation, and hypogenitalism. None of these syndromes fit the patients reported herein. Finally, Al Frayh and Haque  described a mentally retarded boy with anophthalmia/microphthalmia, coloboma of the iris, microcephaly, hypogonadism, cardiac malformation, and short stature, but no osseous abnormalities or seizures and with different facial abnormalities, helping us to differentiate this syndrome from the one reported herein. Thus, our patients represent a new recessive syndrome with intrafamilial variability in expression of the genetic defect that might be secondary to epigenetic factors. On the other hand, it is also possible that this inbred family possesses two genetic malformation syndromes, the sister of the proband showing one, and the 87 proband both of them, while the cousin of the proband has only the syndrome of microcephaly, colobomatous microphthalmia, psychomotor retardation, and short stature. ACKNOWLEDGMENTS We are indebted to Ms. Valérie Delague and Ms. Nabiha Salem for their technical assistance. RERERENCES Al Frayh AR, Haque KN. 1987. 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