a Genetics Unit, Department of Paediatrics, Faculty of Medicine, University of Received 29 June 2004 Accepted 3 November 2004

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1 Original article 1 Further delineation of Al-Gazali syndrome (multiple skeletal abnormalities with anterior segment anomalies of the eye and early lethality) in a Malaysian family Meow-Keong Thong a, Lee-Gaik Chan b and Hua-Sen Ting b We present two siblings from a consanguineous Malaysian family with multiple skeletal abnormalities, anterior segment anomalies of the eye and early lethality. These features are consistent with a syndrome first described by Al-Gazali and we provide further delineation of the syndrome. Clin Dysmorphol 14:1 5 c 2005 Lippincott Williams & Wilkins. Clinical Dysmorphology 2005, 14:1 5 Keywords: skeletal abnormalities, joint contractures, fractures, anterior segment anomalies of the eye a Genetics Unit, Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia and b Department of Paediatrics, Sarawak General Hospital, Malaysia. Correspondence and requests for reprints to Dr. M.K. Thong, Genetics Unit, Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. Tel: ; fax: ; thongmk@um.edu.my Received 29 June 2004 Accepted 3 November 2004 Introduction Al-Gazali et al. (1994) first reported an apparently new syndrome in 1994, based on the findings in two siblings with anterior segment anomalies of the eye, clefting, skeletal abnormalities and early lethality born to consanguineous parents. Al-Gazali et al. (1999) reported a further complex consanguineous family with two siblings who presented with joint contractures, skeletal abnormalities, anterior segment anomalies of the eye and early lethality, supporting the identity of the new autosomal recessive syndrome. We are not aware of further reports on patients with this specific constellation of clinical features. We report two affected siblings with similar features from a consanguineous Malaysian family, supporting the existing of the Al-Gazali syndrome and providing further delineation of the syndrome. Clinical report We report a family of Bidayuh descent from the Malaysian state of Sarawak. The 40-year-old father and 38-year-old mother are second cousins. They have had three spontaneous abortions, one male stillbirth and four live births. Two of the live-born siblings were affected by similar clinical features; the eldest male child died at seven months (patient 2) and the second male (a twin) died at one month (proband patient 1). The couple have two healthy boys, one aged 4 years and the surviving twin. Both the parents appeared well. The mother was diagnosed as thyrotoxic and was on propylthyrouracil until the second trimester of the last pregnancy. She remained euthyroid until after giving birth. She also had impaired c 2005 Lippincott Williams & Wilkins glucose tolerance that required only dietary control during the last pregnancy. Patient 1 The proband was a male, the second of a twin pregnancy (dizygotic and dichorionic), delivered by Caesarean section at 35 weeks gestation. The antenatal period was uneventful. His birth weight was 2.16 kg, length 40 cm and head circumference 32 cm. He was noted to have multiple dysmorphic features which consisted of a prominent occiput, small nose, low set and malformed ears, bilateral corneal opacities and slight downward slanting of both palpebral fissures (Figure 1 and 2). The anterior fontanelle was enlarged and the sutures were widened. There were gross abnormalities of the limbs with bowing of both legs and bilateral talipes equinovarus (Figure 3) and fractures involving both upper limbs and the right femur. There was no hip dislocation. The fingers appeared long and spindled-shaped and there were fixed flexion contractures at the interphalangeal joints with adduction of both thumbs (Figure 4). There was also a thoraco-lumbar scoliosis, and hypospadias with chordee. Cardiovascular examination revealed a soft systolic murmur grade 2/6 at the right sternal edge. Abdominal examination was unremarkable. Ophthalmological review showed undeveloped conjunctivae meshed with the cornea and diagnosed as developmental malformations of the anterior segments of both eyes. Echocardiography showed tricuspid regurgitation and mild pulmonary hypertension. Cranial ultrasound showed bilateral ventriculomegaly and prominent corpus callosum. A computerized tomogram of the brain showed mild ventriculomegaly and increased lucent areas in the

2 2 Clinical Dysmorphology 2005, Vol 14 No 1 Fig. 1 Fig. 3 Anterior view of patient 1. Note small nose, low set and malformed ears, bilateral corneal opacities and slight downward slanting of both palpebral fissures. Patient 1 showing talipes equinovarus. Fig. 4 Fig. 2 Lateral view of patient 1. Note prominent occiput, small nose and low set, malformed ears. Patient 1 showing fixed flexion contractures at the interphalangeal joints with adduction of the thumbs. basal ganglia (Figure 5). Skeletal survey revealed generalized osteopenia with poor mineralization of the calvarium (Figure 6) and multiple fractures without callus formation. The fractures include bilateral transverse fractures of the humeral head, bilateral midshaft ulnar and radial fractures (Figure 7) and fracture of the right femur (Figure 8). There was bowing of proximal end of both left ulnar and radius, elongation of the ulnae and radio-ulnar synostosis. The fibulae were long, and scoliosis was confirmed in the thoraco-lumbar region. Other laboratory investigations including thyroid function tests, creatine kinase, acid-base balance, liver and renal function tests and a full blood count were normal. Screening for intrauterine infections (toxoplasmosis, rubella, cytomegalovirus, herpes simplex and syphilis) were negative. The baby developed aspiration pneumonia, was ventilatordependent and died at one month of age. Chromosomal study was not done. The first twin was completely well with a birth weight of 1.96 kg. Physical examination was normal except for mild hypospadias. There were no skeletal abnormalities, contractures or eye abnormalities noted.

3 Al-Gazali syndrome in a Malaysian family Thong et al. 3 Fig. 5 Fig. 7 Patient 1: Computerized tomogram of the brain showing mild ventriculomegaly and increased lucent areas in the basal ganglia. Patient 1 showing bilateral transverse fractures of the humeral head, bilateral midshaft ulnar and radial fractures. Fig. 6 Fig. 8 Patient 1: X-ray showing poor mineralization of the calvarium. Patient 1 showing a fracture of the right femur. Patient 2 The medical records of the first child born to the couple, who died five years earlier, were reviewed following the death of the patient 1. The male child was delivered at term with birth weight of 2.1 kg with Apgar scores of 6 and 8 at one and five minutes, respectively. Assessment at birth noted the following congenital abnormalities: arthrogryposis multiplex consisting of flexion deformities of both wrists, bilateral talipes equinovarus and flexion deformities of all the interphalangeal joints. The left knee joint was dislocated and the clavicles were absent. The fontanelles were widened and there was depressed nasal bridge with hypertelorism. He was described as having right keratitis and anterior staphyloma in the left

4 4 Clinical Dysmorphology 2005, Vol 14 No 1 Table 1 Comparison of Al-Gazali cases and present study Features Al-Gazali et al. (1994) Al-Gazali et al. (1999) Present study Clinical Prenatal growth retardation Large cornea Corneal clouding Small mouth Cleft palate High Long fingers Clinodactyly + + Oligodactyly + Syndactyly + Camptodactyly Contractures of large joints Bulging anterior chest wall Talipes equinovarus Congenital heart disease + +? + + Lethality 60 d 30 d 2 d 50 d 30 d 180 d * Hypospadias + + * Small crumpled ears + * Large fontanelles + + * Down-slanting palpebral fissures + + * Absent clavicles + * Scoliosis + Radiology Osteopenia Poor mineralization of calvarium m thickness base of skull-occiput Abnormal distal humeral metaphyses Elongation of ulna Bowing of radius Radioulnar synostosis Long slender fibula Fractures Rib abnormalities + + Abnormal vermis + + Hyperechogenic basal ganglia areas + + Hydrocephalus + + d = days; + = present; = absent; blank = not mentioned. * Clinical features representing further delineation of the condition. eye. He had a hypospadias with chordee. Chromosomal study was normal male 46,XY, and both the echocardiography and cranial ultrasound were reported as normal. A skeletal survey was done but was not available for review as the films were destroyed. He was treated for neonatal sepsis and skeletal deformities and discharged at 2 weeks of age. The patient died at 6 months of age following a chest infection. Discussion The proband and his older sibling both had intrauterine growth retardation, bilateral talipes equinovarus, contractures of the large joints, camptodactyly, multiple fractures, abnormalities of the anterior segment of the eyes and early lethality. In addition, the proband also had large cornea, a small mouth, skeletal abnormalities such as generalized poor mineralization of the calvarium with thick base of skull, osteopenia, radio-ulnar synostosis, long fibula and ulna and bowed radius as well as long fingers. There was also congenital heart disease and CT brain changes such as increased lucent area in the basal ganglia and ventriculomegaly. The chromosomal study was normal in one of our two patients and the parents were consanguineous, suggesting autosomal recessive inheritance. The patients features were very similar to a new syndrome described by Al-Gazali et al. (1994, 1999) (Table 1). Features found in the two children but not in the four previously reported cases include hypospadias, enlarged fontanelles and malformed ears. One of them had thoraco-lumbar scoliosis while the other had absent clavicles. Clinical features not found in our family were cleft palate and certain skeletal abnormalities such as syndactyly, oligodactyly and clinodactyly. There are a number of similarities with Antley Bixler syndrome which include low set nasal bridge, unusual ears, osteopenia, fractures, radioulnar synostosis, thin ribs, bowing of long bones, heart disease, anal and genital abnormalities. However in Antley Bixler syndrome craniosynostosis is common and it is not usually associated with contractures and eye changes other than prominent eyes (Antley and Bixler, 1975). Antley Bixler syndrome may be heterogeneous with some cases reported as due to FGFR2 mutations (Chun et al., 1998) and others

5 Al-Gazali syndrome in a Malaysian family Thong et al. 5 associated with defects in steroid biosynthesis (Reardon et al., 2000). It is this latter group with genital abnormalities that resembles our patients. Other conditions that may give rise to intrauterine growth retardation, contractures and multiple fractures were considered. Osteogenesis imperfecta is unlikely as this is not associated with anterior segment abnormalities of the eyes and contractures. Bruck syndrome may present with fractures and contractures but is not associated with early lethality or eye changes (Brady et al., 1997). The patients described by Illum et al. and Schrander-Stumper et al., as discussed by Al-Gazali et al. (1999), did not correlate well with the findings in our patients. Michels syndrome may present with cleft lip and palate, anterior chamber anomalies with corneal clouding, radioulnar synostosis and ptosis but not with multiple fractures and contractures and early lethality (Michels et al., 1978). The maternal exposure to propylthyrouracil as well as her mild gestational diabetes are not likely to have contributed to the pattern of abnormalities seen in her sons. As this constellation of abnormalities appeared to be distinct, we have provisionally named this condition the Al-Gazali syndrome. The features in two siblings of this Malaysian family are consistent with the syndrome and provide further delineation of the spectrum of anomalies. References Al-Gazali LI, Al-Talabani J, Mosawi A, Lytle W (1994). Anterior segment anomalies of the eye, clefting and skeletal abnormalities in two sibs of consanguineous parents: Michels syndrome or new syndrome? Clin Dysmorphol 3: Al-Gazali LI, Bakir M, Sadaghatian MR, Nath R, Haas D (1999). Anterior segment anomalies of the eye associated with multiple skeletal abnormalities and early lethality: confirmation of an autosomal recessive syndrome. Clin Dysmorphol 8: Antley RM, Bixler D (1975). Trapezoidocephaly, midfacial hypoplasia and cartilage abnormalities with multiple synostoses and skeletal fractures. Birth Defects OAS 11: Brady AF, Patton MA (1997). Osteogenesis imperfecta with arthrogryposis multiplex congenita (Bruck syndrome) evidence for possible autosomal recessive inheritance. Clin Dysmorphol 6: Chun K, Siegel-Bartelt J, Chitayat D, Phillips J, Ray PN (1998). FGFR2 mutation associated with clinical manifestations consistent with Antley Bixler syndrome. Am J Med Genet 77: Michels VV, Hittner HM, Beaudet AL (1978). A clefting syndrome with ocular anterior chamber defect and lid anomalies. J Pediatr 93: Reardon W, Smith A, Honour JW, Hindmarsh P, Das D, Rumsby G, et al. (2000). Evidence for digenic inheritance in some cases of Antley Bixler syndrome? J Med Genet 37:26 32.