Raine Syndrome

A number sign (#) is used with this entry because of evidence that Raine syndrome is caused by homozygous or compound heterozygous mutation in the FAM20C gene (611061) on chromosome 7p22.

Description

Raine syndrome is a neonatal osteosclerotic bone dysplasia of early and aggressive onset that usually results in death within the first few weeks of life, although there have been some reports of survival into childhood. Radiographic studies show a generalized increase in the density of all bones and a marked increase in the ossification of the skull. The increased ossification of the basal structures of the skull and facial bones underlies the characteristic facial features, which include narrow prominent forehead, proptosis, depressed nasal bridge, and midface hypoplasia. Periosteal bone formation is also characteristic of this disorder and differentiates it from osteopetrosis and other known lethal and nonlethal osteosclerotic bone dysplasias. The periosteal bone formation typically extends along the diaphysis of long bones adjacent to areas of cellular soft tissue (summary by Simpson et al., 2009).

Clinical Features

Kan and Kozlowski (1992) described the postmortem findings in an infant with generalized osteosclerosis and craniofacial dysplasia representing a lethal syndrome identical to that previously reported in single cases by Raine et al. (1989) and Kingston et al. (1991). The female fetus described by Raine et al. (1989) had the combination of microcephaly, exophthalmos, hypoplastic nose and midface, gum hyperplasia, cleft palate, apparently low-set ears, and osteosclerosis. The facies in the 2 earlier cases and that reported by Kan and Kozlowski (1992) was 'fishlike.' The choanal passages were atretic in the patient of Kingston et al. (1991) and severely stenotic in the patient of Kan and Kozlowski (1992). The patients of Raine et al. (1989) and of Kan and Kozlowski (1992) had hypoplastic lungs. Multiple fracture-like rib lesions were seen on x-ray in the cases of Kingston et al. (1991) and Kan and Kozlowski (1992) but were not confirmed on histologic examination. The case of Kingston et al. (1991) had consanguineous parents.

FitzPatrick et al. (1998) described a lethal multiple malformation syndrome they called desmosterolosis (602398) because of a generalized accumulation of desmosterol. Their patient had many features of Raine syndrome, including macrocephaly, hypoplastic nasal bridge, thick alveolar ridges, and gingival nodules. However, FitzPatrick et al. (1998) also studied postmortem tissues from the case of Raine syndrome reported by Kan and Kozlowski (1992) and found no accumulation of desmosterol.

Al Mane et al. (1996) demonstrated that intracranial calcification is a component of Raine syndrome. The patient reported by Al Mane et al. (1996) was the second of 3 affected sibs reported by Rejjal (1998). The parents were first cousins and had 2 other children who were normal. The first affected child, a female, lived only a few days and was described as having microcephaly, bulging eyes, choanal atresia, and generalized osteosclerosis. Ultrasound and CT studies of the brain showed prominent calcifications, and a brief report of the case was published by Patel et al. (1992) as an example of osteopetrosis. The second affected child, a boy, was reported by Al Mane et al. (1996). Respiratory distress due to choanal atresia was not relieved by conventional surgical treatment, and tracheostomy was performed. The child died at 8 weeks of age. Radiographic studies showed diffuse osteosclerosis and widespread periosteal thickening of mandible, clavicles, scapulae, ribs, and long bones. Widespread focal cerebral calcifications were demonstrated in the periventricular white matter and basal ganglia with some meningeal calcifications as well, and these were thought to correspond to the histologic calcifications reported in the brain by Kan and Kozlowski (1992). The third affected child from the fifth pregnancy was recognized to have the same syndrome by prenatal ultrasound examination. At birth the findings were virtually identical to those in the other sibs. Autosomal recessive inheritance seems very likely as the cause of this distinctive syndrome.

Shalev et al. (1999) described a newborn girl with a lethal sclerosing bone dysplasia leading to prenatal skeletal alterations and microcephaly, proptosis, hypoplastic nose and midface, small jaw, cleft palate, hypertrophied gums, intracranial calcifications, and generalized osteosclerosis. The patient closely resembled 6 previously reported infants that had been categorized as having Raine syndrome. Autosomal recessive inheritance was postulated based on parental consanguinity in several of the previous cases and in their patient.

Acosta et al. (2000) reported a preterm male infant, the first child of a consanguineous union, whose physical examination revealed craniofacial disproportion with microcephaly, wide fontanels, exophthalmos, low nasal root and hypoplastic nose, long philtrum, small mouth, high arched and narrow palate, micrognathia, dysplastic, low-set, and rounded ears, short neck, and arthrogryposis. Postmortem findings included hypoplastic lungs. Radiologic examination showed mild and localized increase of bone density in the cranial vault and skull base and facial bones and undermodeling in the long bones. Acosta et al. (2000) considered the findings characteristic of Raine dysplasia but with mild bone involvement, with only a localized bone sclerosis and absence of prenatal fractures. The consanguinity of the parents reinforced the hypothesis of autosomal recessive inheritance in this disorder.

Hulskamp et al. (2003) reported a consanguineous Turkish couple with 3 affected children in 7 pregnancies, including a fetus of 24 weeks' gestation with full clinical and autopsy findings consistent with Raine syndrome. In addition to the generalized osteosclerosis and appositional new bone formation seen in Raine syndrome, these patients had previously unreported meso- and severe telebrachyphalangy and urogenital anomalies.

Al-Gazali et al. (2003) reported an infant from an Arab family who presented at birth with severe craniofacial anomalies including a wide anterior fontanel, exophthalmos, severe depression of the nasal bridge with a hypoplastic midface, bilateral choanal atresia, and a large protruding tongue. All the limbs were short and the thorax was small. Radiologically, there was increased bone density in some bones, periosteal new bone formation, and marked bowing of the femurs, tibias, and ulnas. Al-Gazali et al. (2003) suggested that osteosclerosis in Raine syndrome is not necessarily severe and generalized, and that bowing of the long bones is another variable radiologic feature of the syndrome.

Chitayat et al. (2007) described prenatal ultrasound, autopsy, and neuropathologic findings in a stillborn infant with Raine syndrome, the offspring of nonconsanguineous parents. A 19-week ultrasound showed no striking abnormalities, and only a retrospective review showed hypertelorism and flat profile. Thus, most of the abnormalities, including intracerebral calcifications, seem to present late in pregnancy.

Survival Beyond Infancy

Simpson et al. (2009) reported 2 unrelated boys with Raine syndrome who survived infancy and were aged 8 and 11 years. At birth, both had features typical of Raine syndrome, with craniofacial dysmorphism including brachycephaly, downslanted eyes, hypoplastic nose, and small downturned mouth. Proptosis was present at birth in one of the boys, but in the other it only became apparent at 9 months of age; the latter child also had a scaphocephalic, saddle-shaped head with a widely split metopic suture and very large anterior fontanel. Skeletal surveys revealed sclerotic bone disease in both patients. Both had hydrocephalus requiring placement of a ventriculoperitoneal shunt, following which their early development, which had been impaired, was significantly improved. The 8-year-old boy underwent examination at 6 years of age, at which time tracheostomy due to poor central respiratory control and obstructive sleep apnea was considered. Craniofacial examination revealed turribrachycephaly, plagiocephaly, downslanting palpebral fissures, proptosis, depressed nasal bridge, small nose, protruding tongue, thick alveolar margins, high palate, abnormal teeth, and low-set ears. Radiography at 7 years of age revealed prominent metaphyseal sclerosis of the long bones and diffuse abnormalities of the skull, with thickening and coarse trabeculation and prominent mastoid bulges. At 11 years of age, the other boy had turribrachycephaly, hypertelorism, arched eyebrows, an inferiorly placed right eye, and low-set and protuberant ears with hearing aids in place for mixed hearing loss. Other features included a flat nasal bridge with rounded and bulbous nasal tip and prominent alae nasi, sunken midface, wide mouth with large tongue, and relative prognathism, and he was secondarily edentulous. He also had pectus excavatum, bulbous fingertips, thick fingers, and large halluces. He had visual impairment and dysphagia, and also displayed self-stimulating behavior. Both boys had short stature, with heights at or below the 5th centile; the 8-year-old's head circumference was in the 10th to 25th centile, whereas that of the 11-year-old was less than the 5th centile (50th centile for a 10-month-old infant). Both had severe developmental delay.

Fradin et al. (2011) reported 2 sisters, born of first-cousin parents of Algerian origin, who had an attenuated phenotype of Raine syndrome with normal psychomotor development at ages 4 years and 1 year, respectively. The older sister attended regular school and had normal speech and pictural drawing skills. Her height, weight, and occipitofrontal circumference (OFC) were within normal ranges, and she had no sensorial anomalies or history of respiratory distress. She displayed attenuation of the dysmorphic features, with a high palate and small teeth with enamel dysplasia. The younger sister had short stature but weight and OFC were in the medium range, and she displayed moderate craniofacial dysmorphism. Both sisters had stenosis of the pyriform aperture without choanal atresia that was surgically repaired, and both had intracranial as well as renal calcifications. X-rays showed static or decreasing osteosclerosis compared to earlier radiographs.

Inheritance

Raine syndrome is inherited as an autosomal recessive disorder, as indicated by its occurrence in offspring of consanguineous unions and its occurrence in sibs (Mahafza et al., 2001; Hulskamp et al., 2003).

Pathogenesis

Tagliabracci et al. (2012) determined that FAM20C phosphorylates the caseins and several secreted proteins implicated in biomineralization, including the small integrin-binding ligand N-linked glycoproteins (SIBLINGs). The authors generated FAM20C missense mutants associated with lethal and nonlethal forms of Raine syndrome. The FLAG-tagged mutants were overexpressed with V5-tagged OPN (166490), a SIBLING, in U2OS cells. FAM20C secretion and OPN phosphorylation were monitored by means of protein immunoblotting. The FAM20C mutants phosphorylated OPN less efficiently than the wildtype. Most mutations prevented FAM20C secretion, despite the fact that many localized within the secretory pathway. The nonlethal P328S and D451N mutants phosphorylated OPN, albeit not as efficiently as the wildtype protein. Thus, Tagliabracci et al. (2012) concluded that mutations in FAM20C resulting in Raine syndrome appear to affect FAM20C kinase activity and secretion. Abnormal phosphorylation of the SIBLINGs accounts for the biomineralization phenotype of Raine syndrome.

Molecular Genetics

Simpson et al. (2007) identified an unusual chromosome 7 rearrangement and microdeletion in a patient with Raine syndrome and subsequently identified homozygous or compound heterozygous mutations in the FAM20C gene (611061.0001-611061.0008), located within the deleted region, in 6 patients with the disorder. Three of these patients had been described by Kingston et al. (1991), Hulskamp et al. (2003), and Al-Gazali et al. (2003).

In 2 unrelated boys with Raine syndrome who survived infancy and were 8 and 11 years of age, Simpson et al. (2009) identified homozygosity and compound heterozygosity, respectively, for missense mutations in the FAM20C gene (611061.0009-611061.0011). Simpson et al. (2009) noted that these mutations were not shared with any of the previously reported mutation-positive patients who died in infancy, suggesting that these mutations might confer a milder phenotype.

In 2 sisters, born of first-cousin parents of Algerian origin, who had an attenuated phenotype of Raine syndrome with normal psychomotor development at ages 4 years and 1 year, respectively, Fradin et al. (2011) identified homozygosity for a missense mutation in the FAM20C gene (611061.0012). The authors stated that this family expanded the phenotype of Raine syndrome to include milder nonlethal manifestations.