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Craniofacial anomalies, cataracts, congenital heart disease, sacral neural tube defects, and growth and developmental retardation in two sisters: a new autosomal recessive MCA/MR syndrome?
  1. J Siegel-Bartlet1,*,
  2. A Levin2,
  3. A S Teebi1,
  4. S J Kennedy1
  1. 1Section of Clinical Genetics and Dysmorphology, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada
  2. 2Department of Ophthalmology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada
  1. Correspondence to:
 Professor A S Teebi, Section of Clinical Genetics and Dysmorphology, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada;

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Neural tube defects are usually multifactorial. They can also be associated with a number of underlying monogenic or chromosomal conditions. These include autosomal recessive disorders, such as Meckel-Gruber, Roberts, and Walker-Warburg syndromes, and chromosomal anomalies, such as microdeletion 22q11.1 Also, teratogenic conditions, such as valproate embryopathy, may also have an association with neural tube defects.2 We present an apparently autosomal recessive, syndromic form of sacral neural tube defects resulting in tethered cord in two female sibs.


Patient 1 was born to a G4, P3 mother and has three healthy, older maternal half sibs who have a different father. Her parents are of mixed European descent and non-consanguineous. The pregnancy history was negative for maternal illness or known teratogen exposure. Labour began spontaneously at 38 weeks. The delivery was complicated by fetal bradycardia following artificial rupture of the membranes. An emergency caesarian section was performed because of abruptio placentae. The birth weight was 1750 g (<3rd centile), head circumference was 30.5 cm (<3rd centile), and length 45.5 cm (<3rd centile). Apgar scores were 3 at one minute and 8 at five minutes. Two vessels were present in the umbilical cord. The placenta was found to have areas of calcification with a few foci of intravillous thrombosis and mild acute chorioamnionitis.

Atrial and ventricular septal defects, detected in infancy, were repaired at 10 months. A sacral dimple prompted an MRI of the spine which showed a low lying conus medullaris at the lower aspect of L2 (fig 1). The patient's tethered cord was surgically repaired at 30 months. The patient has required a fundoplication and is fed by gastrostomy tube. She has also had surgical release of her heel cords and the tendons behind her knees.

Figure 1

(A, B) Patient 1. T1 (TR540/TE10) sagittal and axial image of the cord shows the conus extending to the L2-3 disc level.

She had her first ophthalmological examination at our institution at 18 months of age. Two weeks before this examination she had a left nasolacrimal duct probing at another centre for presumed obstruction. No external lacrimal system anomalies were present. At our initial examination, she showed normal visual responses for her age, clear lenses, and a normal eye examination with the exception of moderate, bilateral, symmetrical hyperopia (+5.50 sphere OU) for which spectacles were prescribed. By 23 months of age, she had developed a small accommodative esotropia that was well controlled with her hyperopic spectacles. At 30 months, her eye examination was once again normal. However, two months later her mother noted a white abnormality in the pupils. Examination showed bilateral, dense, white cataracts with a clear zone at the Y sutures. At surgery, the cortical portion of the cataracts had a very wispy consistency and was very adherent to the surrounding capsule. Retinal examination before the presence of cataracts had always been normal. At the time of presentation with cataracts, it was difficult to view the retina although there was an impression of possible optic atrophy. Postoperatively, she has been noted to have mild retinal vessel tortuosity and bilateral temporal pallor of each optic nerve. She subsequently developed bilateral aphakic glaucoma that is controlled medically.

In view of the rapid onset of the cataract, a laboratory evaluation was undertaken. Sodium, potassium, chloride, calcium, creatinine, cholesterol, thyroid function studies, serum and urine amino acids, urine reducing substances, and serum lactate levels were all normal. MRI of the brain, chromosomes, FISH for microdeletion 22q11, very long chain fatty acids, urine organic acids and oligosaccharides, mucopolysaccharide screen, and carbohydrate deficient glycoprotein testing have been normal. Subtelomeric FISH and SKY were later performed to search for cryptic chromosomal rearrangements and the results were normal.

A spine x ray at 5 years of age showed multiple compression deformities of the spine resulting in thoracolumbar dextroscoliosis, thoracic kyphosis, and lumbar lordosis. Generalised decreased bone density and borderline delayed bone age were also noted. Her growth has continued to be delayed. At 8.6 years, her height was 97 cm (<3rd centile), weight was 16.8 kg (<3rd centile), and head circumference 46.5 cm (<3rd centile). She has a low anterior hairline with widow's peak, persistent drooling, and a short philtrum with full lips (fig 2A, B). She has a geographic tongue with white lines. Her central incisors are prominent and widely spaced (fig 2C). She has micrognathia. Her ears are small but similar to her mother's. Her chest is barrel shaped and prominent. She has bilateral inverted nipples. She has thoracic kyphosis, with some lordosis, mild scoliosis and mild gibbus. The veins in the shoulder region are prominent. Longitudinal grooves were noted on both the fingernails and the toenails. There was no limitation of movement of the upper limbs and hands. There was limitation of movement of both knees but this may be secondary to her neurological abnormalities. She has central hypotonia with peripheral hypertonia. This patient has remained preambulatory and preverbal. At the age of 8, she was recognised to be having seizures by EEG and was started on carbamazepine.

Figure 2

(A, B, C) Patient 1. Whole body and close up of face and mouth. Note the broad central incisors. (D, E) Patient 2. Whole body and close up of face. Note the remarkable similarity to patient 1.

Patient 2, the younger sib of patient 1, was noted to have normal fetal growth on ultrasound at 20.9 weeks' gestation. However, by 33 weeks' gestation the fetus was noted to be small for gestational age. The placenta was noted on ultrasound to have prominent venous lakes and possible degenerative changes. Amniotic fluid volume was mildly increased. The baby was born at 36 weeks' gestation with a birth weight of 1800 g (<3rd centile). A muscular ventricular septal defect with patent foramen ovale was diagnosed in infancy, but subsequently closed spontaneously. A tethered cord was repaired at 13 months of age.

Her first eye examination at our centre at 13 months of age showed clear lenses. She had mild hyperopia (+2.00 diopters) and astigmatism (+1.00 diopters). Retinal examination was normal with the exception of bilateral temporal peripapillary atrophy. In view of her sister's history, she was followed every six months. At 20 months of age, she was noted to have multiple, globular, anterior, cortical dot lens opacities which were worse in the right eye (fig 3). Six weeks later, the opacities had increased in size and she also had new posterior subcapsular cataracts that were worse in the left eye along with an opacified lamella within each lens. Cataract surgery was performed at which time the same subcapsular cortical material was noted. At 3 years of age, she shows good corrected visual function in both eyes with an alternating exotropia of 20-25 prism diopters and chronic bilateral blepharitis. She has also developed bilateral aphakic glaucoma which is controlled medically.

Figure 3

Patient 2. Cataract. Note multiple, globular, anterior, cortical dot lens opacities.

Her serum lactate was normal. A spine x ray at 2 years of age showed mild, generalised decreased bone density and borderline delayed bone age. Chromosomes, FISH for microdeletion 22q11, very long chain fatty acids, urine organic acids and oligosaccharides, mucopolysaccharide screen, and carbohydrate deficient glycoprotein testing have all been normal. Subtelomeric FISH and SKY were normal.

Like her sister, her growth has remained delayed. At 6 years of age, her weight was 16.4 kg (3rd centile), length was 95 cm (<3rd centile), and head circumference was 46.5 cm (<3rd centile). Her facies are similar to her older sister (fig 2D, E). She has central hypotonia with peripheral hypertonia. She has a low frontal hairline with a widow's peak. Her eyebrows are broad, but have sparse hair. Her philtrum is short and she has prominent, widely spaced central incisors. She has micrognathia. Her ears are small. She has stiff joints in her upper limbs and hands. In her lower limbs, there is limitation in the movement of her knees. Her nails are normal. Examination of her genitalia showed pubic hair. Unlike her sib, this patient was almost walking by the age of 2 years. Unfortunately, she had a near drowning bathtub accident that aggravated her neurodevelopmental injury and she never regained this ability. Like her sister, she cannot talk. Following the accident, this patient developed seizures that are controlled medically.


The hallmark manifestations in this family include a characteristic craniofacial appearance, atrial ventricular septal heart defects, sacral neural tube defects, cataracts developing in early childhood, and growth and developmental retardation (table 1).

Table 1

Manifestations of the new MCA/MR syndrome in two female sibs

The combination of eye abnormalities and neural tube defects is well documented in several disorders that include warfarin embryopathy,3 Walker-Warburg syndrome,4 oculocerebrocutaneous syndrome, Meckel-Gruber syndrome,5 and Knobloch vitreoretinopathy.6 However, only Walker-Warburg and Knobloch syndromes occasionally have cataracts as a component and in those circumstances other ocular malformations not present in our patients are invariably present. Also, the neural tube defect present in this family is specific, sacral neural tube defect with tethered cord. Kousseff7 reported sibs with sacral neural tube defects and conotruncal heart defects, but without cataracts. A similar case was subsequently reported.8 The pattern of anomalies seen in Kousseff syndrome is different from that seen in this family.

The cataracts observed in these children had a distinctive morphology. Earlier diagnosis of patient 2 allowed for definition of the phenotype, whereas we presume that complete progression had already occurred in patient 1 at the time of diagnosis. The cataracts had rapid onset in the third year of life with multifocal heterogeneous involvement of the cortex including anterior globular opacities, posterior subcapsular opacities, a lamellar component, and an unusual, subcapsular, diffuse, wispy consistency noted at surgery. To our knowledge, these cataracts do not fit any previously described phenotype that would encompass all of the findings observed. Posterior subcapsular and lamellar cataracts are non-specific and non-diagnostic. They can be seen as isolated idiopathic disorders, heritable cataracts, or secondary to a multitude of causes especially in the case of posterior subcapsular opacity that can be the result of trauma, steroids, or intraocular inflammation. The acute onset of cataracts may suggest a metabolic derangement that we were unable to identify. Most developmental cataracts have a slower progressive onset. Neither child had an acute event that could be identified as a precipitating factor.

The unusual constellation of findings suggests to us that these sisters share a single genetic aetiology with early onset indicated by the presence of malformations occurring in embryogenesis, cardiac and neural tube defects. Perhaps the continued growth and developmental retardation and the onset of cataracts in early childhood would suggest an ongoing metabolic effect as part of this syndrome. In the absence of cryptic chromosomal rearrangements, this disorder is probably inherited in an autosomal recessive manner.


We thank the family for their cooperation. We also thank Rozmin Visram for her secretarial assistance.



  • * Present address: Genetics Department, Alfigen, Pasadena, California, USA