Bilateral periventricular nodular heterotopia with mental retardation and syndactyly in boys: A new X-linked mental retardation syndrome

Bilateral periventricular nodular heterotopia (BPNH) is a recently described malformation of neuronal migration¹ or possibly proliferation in which nodular masses of gray matter line the lateral ventricles and protrude into the lumen.^2-6 It is sometimes associated with mild cerebellar hypoplasia. Most affected individuals are females of normal intelligence who have epilepsy. A gene associated with BPNH was recently mapped to chromosome Xq28 in several families in which only females were affected.⁷

We report three unrelated boys with a new multiple congenital anomaly-mental retardation syndrome that consists of BPNH, cerebellar hypoplasia, severe mental retardation, epilepsy, and partial syndactyly of the hands or feet. Some of the affected boys also had other abnormalities such as regions of cortical dysplasia, cataracts or hypospadius, and one had a small duplication of chromosome Xq28. We hypothesize that this syndrome involves the same Zq28 locus as isolated BPNH.

Clinical reports. Patient BPNH-02 (database#LP94-054). This 15-year-old boy was born at term following an uncomplicated pregnancy and delivery. Family history was negative for other individuals with seizures, mental retardation, or congenital anomalies. Cranial MRI performed on his mother was normal, although both she and a normal sister are carriers of the same subtle chromosome abnormality described later. As an infant, he was described as irritable. His developmental milestones were delayed and included sitting at 18 months, standing at 4 years, and walking alone at 8 years. He is severely mentally retarded and unable to speak, but can use a few signs. Seizures began at 3 years of age and were characterized by staring and jerking of the arms. He has continued to have frequent atonic seizures despite treatment with anticonvulsant medications.

On examination, his weight was 52 kg (50th percentile), his height was 153 cm (10th percentile), and his occipitofrontal circumference (OFC) was 53.75 cm (less than second percentile). He had a flat occiput, round face, small lamellar cataracts, thick helices, and a high, arched palate(figure 1A). He also had short, tapered fingers; bilateral clinodactyly; bilateral syndactyly of the hands; and small feet(figure 1D). The syndactyly involved about 25% of finger length between fingers 2 and 5. Neurologic examination revealed marked generalized hypertonia, truncal ataxia, and a broad-based gait.

Cranial MRI (figure 2, A and D) revealed multiple small nodules of gray matter lining the walls of both lateral ventricles, most prominent in the frontal portion of the ventricles. It also showed dysplasia of the corpus callosum, mild diffuse atrophy, ventriculomegaly, and hypoplasia of the cerebellum. Chromosome analysis showed a small, additional dark band in distal chromosome Xq28 that results from a 2.25 to 3.25-Mb inverted duplication.⁸

Patient BPNH-03 (DB# LP94-003). This 6.5-year-old boy was born at 33 weeks gestation following a pregnancy complicated by preterm labor. Birth weight was 2.9 kg. Examination at birth was significant for cleft palate, hypospadius, equinovarus deformity of both feet, and generalized hypotonia. Cranial CT was interpreted to show large ventricles but no other abnormalities. His development was very slow. He began to roll at 10 months, hold his head up and creep at 3 years, sit at 5.5 years, and get up on his hands and knees at 6 years of age. He is severely mentally retarded and uses only two words. Seizures began at 18 months of age and are now well controlled on valproate. Family history was negative for children with similar problems; he has no siblings. Cranial MRI has not been performed on his mother.

On examination, OFC was 51.5 cm (approximately 40th percentile). He had a prominent glabella; almond-shaped eyes; large, protuberant ears with poorly formed helices; a flat philtrum; a thin upper lip; and a small jaw(figure 1B). He also had mild clubbing of the fingers, bilateral clinodactyly of the fifth fingers, long and narrow feet, and marked syndactyly of the toes (50 to 90% of the length of the toes) between all digits except 4 and 5 (figure 1E). On neurologic examination he vocalized but did not speak, and did not understand simple statements or commands. The fundus was normal. His eyes were dysconjugate with full extraocular movements and nystagmus with the fast component to the right. Motor examination revealed generalized hypotonia, decreased bulk, and normal deep tendon reflexes with three beats of ankle clonus. Plantar responses were flexor. He moved by scooting on his buttocks or crawling.

Cranial MRI (figure 2, B and E) revealed typical BPNH with a thick and contiguous layer of nodules with the signal characteristics of gray matter lining the lateral ventricular walls, cortical dysplasia most similar to polymicrogyria in the central regions, hypoplastic corpus callosum, cavum septi pellucidi, mild ventriculomegaly, delayed myelination pattern for age, and moderate cerebellar hypoplasia. Renal ultrasound was normal. Chromosome analysis at the 800-band stage and fluorescent in situ hybridization (FISH) studies with several markers from the Xq28 region were normal.⁸

Patient BPNH-12 (DB# LP96-033). This boy was born after a normal pregnancy to unrelated parents. His mother had normal head MRI results, and he has a normal older brother. His birth weight was 3.3 kg. His developmental milestones were delayed. He is severely mentally retarded but is able to walk with assistance. He had a single seizure at 3 years and diffuse paroxysmal abnormalities on EEG but has not been treated with anticonvulsants.

At 5 years his weight was 16 kg, height was 100 cm, and OFC was 49 cm(between the second and 50th percentiles). Dysmorphologic examination showed mild hirsutism, a flat occiput, a slightly wide nasal bridge with bilateral epicanthal folds, mild hypoplasia of the nasal alae, a short philtrum, large ears, and a short neck (figure 1C). He also had mild cutaneous syndactyly of toes 2 to 4, with crowding of the toes(figure 1F), coxa valgae, and clubfeet.

Cranial MRI (figure 2, C and F) showed multiple small but confluent heterotopic nodules lining both lateral ventricles. Other abnormalities consisted of mildly enlarged sylvian fissures, mild frontal lobe hypoplasia (especially of the middle and superior frontal gyri) and mildly reduced thickness of white matter in this region. No areas of typical cortical dysplasia were evident, although the gyral pattern appeared atypical over the temporal poles. An audiogram, ECG, urinalysis, and renal ultrasound were normal. Chromosome analysis at the 800-band stage and FISH studies with several markers from the Xq28 region were normal.⁸

Discussion. These three boys have striking similarities in appearance, brain abnormalities, and clinical course that far outweigh the few differences between them. We believe that the shared abnormalities are sufficient to delineate a new multiple congenital anomaly-mental retardation syndrome that consists of (1) BPNH and associated anomalies such as dysplasia of the corpus callosum and ventriculomegaly, (2) focal or regional cortical dysplasia, (3) cerebellar hypoplasia, (4) severe mental retardation, (5) epilepsy that may be intractable, (6) clinodactyly, (7) partial syndactyly of the hands or feet, and (8) probable X-linked inheritance. The hand and foot anomalies were subtle in one of the three boys, but were always present on careful examination. One boy also had short fingers and another had unusually narrow and flat feet. These and other more variable manifestations are summarized in table 1. We refer to this disorder as BPNH/MR syndrome to distinguish it from the more common classic BPNH syndrome observed predominantly in females and from several other BPNH syndromes.

Malformation syndromes with BPNH. Bilateral periventricular nodular heterotopia has generally been observed as an isolated brain malformation or associated with subcortical nodular heterotopia.⁵ But a detailed review of the literature and our own experience indicate that it may be observed in several different malformation syndromes in which it is the primary brain malformation(table 2), including two that have been observed predominately in females with normal intelligence, and five that (so far) have been observed only in males with either developmental delay and mental retardation, or early death. Bilateral periventricular nodular heterotopia may also be observed with other brain malformations such as encephaloceles, megalencephaly and hemimegalencephaly, polymicrogyria, various chromosomal aneuploidy syndromes, and other syndromes such as the peroxisomal biogenesis disorders, including Zellweger syndrome.^9,10

BPNH in females (predominantly) with normal intelligence.Classic BPNH. The phenotype of classic BPNH consists of epilepsy that may be difficult to control and normal or near-normal intelligence. MRI studies usually show thick and contiguous nodular heterotopia involving the lateral aspects of the frontal horn, trigone, and occipital horn of both lateral ventricles, although some patients including several from multiplex families have had more limited heterotopia (Dobyns, unpublished data). Some patients also have mild cerebellar hypoplasia.⁴

Previous reports have described 32 sporadic patients and 18 other affected persons from six multiplex families.⁴ Among the sporadic patients and probands of multiplex families, a striking skew of the sex ratio toward females was observed, with 31 affected females and only seven affected males. All had epilepsy and normal intelligence except for five females with borderline intelligence and three with no history of seizures.

All affected individuals in the six multiplex families were female,^5,16-19 with the possible exception of a boy who died from overwhelming spontaneous bleeding during the neonatal period.^7,19 In the largest family reported, six females and no males (except for the boy who died of bleeding) from four generations were affected, the rate of pregnancy loss was more than 50% compared with a normal rate of about 20%, and the ratio of daughters to sons was increased.¹⁹ These abnormalities all suggest that the miscarriages were male.

BPNH and Ehlers-Danlos syndrome. Two unrelated women were reported with neurologic and imaging abnormalities identical to classic BPNH, combined with a moderate connective tissue dysplasia typical of Ehlers-Danlos syndrome. The latter consisted of smooth, velvety, and hyperextensible skin with papyraceous scars, hyperextensible joints, and aneurysms of the sinuses of Valsalva in the aorta.^11,20 Electron microscopy of the skin showed rarefaction of collagen fibrils, which were also irregular in size and frayed in appearance.

BPNH in males with mental retardation and other abnormalities. During the past few years we have become aware of five seemingly distinct malformation syndromes characterized by BPNH and mental retardation (or early death) in males. At least three of these syndromes have an X-linked pattern of inheritance and all five may be X-linked, because only males have been affected. The first of these is BPNH/MR syndrome, which we report in this paper. The other four differ based on the presence of additional major malformations. Some or all of these may represent overlapping microdeletion or microduplication syndromes.

BPNH and short-gut syndrome. Two brothers were reported with BPNH and chronic idiopathic intestinal pseudo-obstruction due to a complex gastrointestinal malformation consisting of a short and malrotated small intestine, hypertrophy of the pylorus, and various defects of enteric neuronal cells.¹³ Both died in infancy due to recurrent bowel obstruction and septicemia. Although very rare, this syndrome has been observed in boys from other families as well.²¹

BPNH and congenital nephrosis. Two brothers were reported with BPNH and congenital nephrosis.¹² The liveborn boy also had hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS), a prolonged seizure intially attributed to "serous meningoencephalitis," and many subsequent, prolonged seizures. Ultrasonic examinations during a subsequent pregnancy showed enlargement of the upper cervical vertebrae, oligohydramnios, and echogenic kidneys, which prompted a therapeutic abortion at 22 weeks gestation. Autopsy in both affected boys showed BPNH and congenital nephrosis associated with mild proliferative changes in the glomeruli, collections of foam cells between tubular structures (in the older boy), and small cysts at the corticomedullary junction (in the fetus). Examination of multiple sections from the spinal cord of the fetus showed that the central canal was split into two or three separate tubes.

BPNH and frontonasal dysplasia. We recently evaluated two unrelated boys with BPNH and striking frontonasal dysplasia (Guerrini, unpublished data). Other than facial abnormality, the phenotype was similar to BPNH/MR syndrome. However, chromosome analysis was normal in both boys.

Vles ACC syndrome. This syndrome consists of partial or total agenesis of the corpus callosum (ACC), irregular lining of both lateral ventricles as visualized by CT (which strongly suggests BPNH), moderate to severe mental retardation, bilateral pyramidal tract signs, and no history of epilepsy.^14,15 This syndrome has been observed in two sets of brothers and in another man and his nephew (his sister's son), consistent with X-linked inheritance. None of the affected males had other signs of X-linked HSAS or mental retardation, adducted thumbs, spasticity, and aphasia (MASA) syndrome (both syndromes caused by mutations of the L1CAM gene).

X-linked basis of BPNH syndromes. Syndromes associated with a skew of the sex ratio toward females and an increased rate of miscarriage are hypothesized to be X-linked with early lethality in hemizygous males.²² The same mechanism implies that any liveborn affected males should have a more severe phenotype than affected females. The best known examples of this inheritance pattern are Aicardi syndrome, orofaciodigital syndrome type 1, and focal dermal hypoplasia or Goltz syndrome.

X-linked inheritance of classic BPNH was first suggested by the skewed sex ratio (reviewed⁴). It has recently been confirmed by linkage studies in several multiplex families that mapped the BPNH gene to chromosome Xq28 with a maximum lod score of 4.77 with no recombinants (theta= 0) for polymorphic markers in distal Xq28 including DXS1108 and F8c.⁷ No liveborn males with BPNH or other neurodevelopmental problems were observed in any of these families, although one liveborn male died from overwhelming spontaneous bleeding.^7,19 This interesting observation, combined with the linkage data, suggests that affected individuals in this family may carry a small structural rearrangement of Xq28 that involves both the BPNH and F8c genes, which may be located very close to each other.

The probable basis for BPNH/MR syndrome is best understood by comparison with classic BPNH. The syndrome observed in these three boys closely resembles classic BPNH because of similar heterotopia, similar or more severe cerebellar hypoplasia, and epilepsy. It differs because of severe mental retardation, syndactyly, and other minor anomalies, and a reversed sex ratio in which all three known patients are male. One of the three boys has a 2.25- to 3.25-Mb inverted duplication involving part of the same Xq28 region where the classic BPNH gene was mapped. In this boy, the mechanism of the malformation could be either disruption of the BPNH gene by one of the two duplication break points or increased gene dosage.⁸ Additional studies have not yet clarified which of these two possibilities is more likely. Nonetheless, abnormalities of the same genomic region have now been identified using different methods in females with classic BPNH and males with BPNH/MR syndrome. We therefore hypothesize that the same gene is involved in both syndromes, such that BPNH/MR syndrome represents more severe expression in males of mutations of the classic BPNH gene. Thus, liveborn affected males born to women with classic BPNH would be expected to have BPNH/MR syndrome. As a corollary, we hypothesize that classic BPNH in males with normal intelligence represents somatic rather than germline mutation of the BPNH gene.

In further support of this hypothesis, all the other BPNH syndromes associated with mental retardation are or may be X-linked, as they have been observed only in males. At least one of these syndromes is certainly X-linked based on recent linkage data. A family was recently reported with a rare form of X-linked chronic idiopathic intestinal pseudo-obstruction (CIIPX) associated with the same gut anomalies observed in the BPNH/short-gut syndrome,²³ Linkage studies mapped the CIIPX gene to distal Xq28, with a critical region clearly overlapping the critical region for the BPNH gene. Both the BPNH and CIIPX genes segregated with marker DXS1108 with no recombinants. We hypothesize that either (1) the BPNH and CIIPX phenotypes may be caused by mutations of the same gene or (2) the BPNH and CIIPX genes are located close to each other in distal Xq28 and may sometimes be inactivated by small structural rearrangements of this region. It is possible that the BPNH congenital nephrosis, BPNH/frontonasal dysplasia, and Vles ACC syndromes are also caused by small structural rearrangements in distal Xq28, but no proof is currently available.

Based on our observations we recommend that all boys with BPNH and mental retardation be evaluated for this small group of syndromes by high-resolution chromosome analysis of Xq28, supplemented when possible by fluorescence in situ hybridization with appropriate probes. A careful history for gastrointestinal and renal problems should also be obtained, supplemented when indicated by renal ultrasound and radiologic studies of the small intestine.