Pontocerebeallar Hypoplasias (PCH) are a group of congenital conditions, characterized by progressive hypoplasia of the brain, especially the ventral pons region. Affected children prenatally show neurological abnormalities. After birth, they present with severe developmental delay, mental retardation, and progressive neurodegeneration. Typical symptoms include hypotonia, poor feeding, and growth retardation, among others. PCH3 is an extremely rare form of PCH, characterized by cerebellar atrophy, rather than hypoplasia, accompanied by progressive microcephaly. This condition has been described to date in only three siblings within one consanguineous family.
Rajab et al. (2003) reported the clinical features of three affected children born to consanguineous Omani parents with a novel form of pontocerebellar hypoplasia with microcephaly, and conducted genetic studies to identify the genetic locus of this disorder. The first case was a 12-year old boy, born with occipito-frontal circumference (OFC), length, and weight in the 10th percentile. During infancy, he was floppy, not interested in his surroundings, had motor developmental delay as he had no head control, did not roll over or sit, and had a history of recurrent respiratory tract infection. By the age of eight months, his anterior fontanelles were closed and fundoscopic examination revealed pale optic discs. He developed generalized tonic clonic seizures after an episode of febrile convulsions at one year of age, and was on sodium valoproate. Clinically, he had microcephaly (OFC was 45 cm, increased by 5 cm only since he was 18 months), was below the third percentile in weight and height, irritable, could not crawl, sit or walk, and had dysmorphic features of marked brachycephaly, prominent eyes, low set ears with uplift of the earlobe, and spindle shaped fingers. His sexual development was Tanner stage 1, with poorly developed scrotum and 1.5 ml testicular volume. Neurologically, his muscle bulk and power were normal, but he had exaggerated deep tendon reflexes and truncal hypotonia, without any joint contractures. Other system reviews were normal. MRI brain revealed atrophic brainstem, small vermis, small cerebellum with prominent fissures, and diminished white matter volume with prominent lateral ventricles, as well as thin fully formed corpus callosum and normal sized spinal cord (visualized part only). The second sibling was born with OFC of 32 cm, length of 46 cm (fifth percentile) and weight of 3.2 kg (25th percentile), after a normal pregnancy, and was noticed to be floppy since birth. During infancy, her fontanelle was closed by six months, at which time her head circumference was 39 cm), and after an episode of prolonged febrile convulsions at the age of eight months, she developed chronic epilepsy, and she also suffered from frequent respiratory illnesses and bouts of diarrhea. At the age of six years, she was malnourished with weight and height below the third percentile, with open-mouthed appearance and craniofacial features similar to her brother with microcephaly and gum hypertrophy. She had contractures of knees and elbows and left club foot as well as thoracic scoliosis. Neurologically, she had optic atrophy, intermittent horizontal nystagmus, truncal hypotonia, and spastic limbs with exaggerated deep tendon reflexes. Thin osteopenic long bones and delayed bone age were detected on skeletal survey study and EEG revealed sharp discharges from the temporal regions bilaterally. At the age of six years, she succumbed to respiratory illness. The third sibling was born with good apgar scores by Cesarian section because of cord prolapse with measurements of 34 cm as OFC, 50 cm (fifth percentile) as length and weight of 3.2 kg (25th percentile). She had similar progression of illness as her siblings with delayed motor development during infancy and history of febrile convulsions and hospitalization for recurrent respiratory infections and constipation. At one year of age, she had similar facial features as her siblings with microcephaly (40 cm), and neurologically, she followed light (difficult to see the optic disc), failed a hearing test, had central hypotonia with spastic episodes with no clonus or fisting, normal muscle bulk but increased deep tendon reflexes with down going plantar response, and normal sensation. CT scan of the brain revealed wide sulci and Sylvian fissures, enlarged lateral ventricles, thin corpus callosum, and cerebellum atrophy as evidenced by enlarged cisterna magna. In all these patients, no edema of the limbs was found. A genome-wide linkage screening was performed on the DNA extracted from these three affected children, two unaffected siblings and the parents. The two-point and multipoint lod scores were calculated assuming autosomal recessive inheritance with penetrance of 0.99, a disease allele frequency of 0.001, and by using experimentally determined microsatellite marker allele frequencies from 28 unrelated Omani subjects. On the initial genome-wide linkage screen, the only marker with homozygosity in the patients, and heterozygosity in the parents and the unaffected sibling was D7S669 with a maximum multipoint lod score of 2.63 obtained at this region on chromosome 7. Upon fine mapping of this region, six more markers were found to be homozygous in the patients and heterozygous in the parents and the two siblings, and the candidate region (21.5 Mb) was identified in the interval between D7S502 and D7S630 with the two point lod score of 2.43 at D7S2204 and the maximum multipoint lod score of 3.23 near markers D7S669 and D7S2204. Since the parents were consanguineous and both sexes were affected, Rajab et al. (2003) concluded that inheritance was possibly autosomal recessive, and with the above findings, they were the first to identify a genetic locus of pontocerebellar hypoplasia on chromosome 7. Since this disorder was different from pontocerebellar hypoplasia type 2 as there was no dyskinesia and the MRI findings were suggestive of atrophy rather than hypoplasia, Rajab et al. (2003) had named this variant as cerebellar atrophy with progressive microcephaly (CLAM) and the gene as CLAM gene, and mentioned that further studying and identification of this gene would highlight the pathogenesis of pontocerebellar hypoplasia as well as the normal development of the brain.