Table 1 Genotype and Phenotypic Variability in Some Reported Cases of Raine syndrome

1

c.1603C >T (p.Arg535Trp)

Exon 10

Homozygous missense mutation

M

Yes

neonatal death

Caucasian

Periosteal bone formation, Osteosclerosis, Thoracic Hypoplasia, brachycephaly with very large anterior and posterior fontanelles, prenatal fractures of both clavicles and some ribs

Prominent forehead, short neck, proptosis, midfacial hypoplasia, depressed nasal bridge, exophthalmos, hypoplastic nose with choanal atresia, high arched palate with mid-line groove but no cleft, hyperplastic nodular gums, low set ears, small jaw

Not Reported

Not Reported

Kingston et al., 1991 [9]

Simpson et al., 2007 [21]

2

c.915-3C>G

Intron 4/Exon 5 acceptor splice-site change

Homozygous splice site mutation

M

No

neonatal death

Arab

Periosteal bone formation, Osteosclerosis, Thoracic Hypoplasia, and marked bowing of the femurs, tibiae, ulnae, short limbs

Prominent forehead, short neck, proptosis, midfacial hypoplasia, depressed nasal bridge, wide anterior fontanelle, exophthalmos, bilateral choanal atresia, large protruding tongue

Not Reported

Not Reported

Al-Gazali et al., 2003 [24]

Simpson et al., 2007 [21]

3

c.1121T>G (p.Leu374Arg)

Exon 6

Homozygous missense mutation

F

Yes

neonatal death

Turkish

Periosteal bone formation, Osteosclerosis, Thoracic Hypoplasia, Pulmonary Hypoplasia, hypoplastic fingernails, Brachydactyly, metaphyseal flaring, narrow medula

Bi-temporally narrowed forehead, short neck, proptosis, midfacial hypoplasia, depressed nasal bridge, carp-shaped mouth with narrow lips, large low set ears, posteriorly rotated ears, smooth and prominent philtrum

Gingival hyperplasia

Diffused intracerebral Calcifications, microcephaly

Hulskamp et al., 2003 [14]

Simpson et al., 2007 [21]

4

45, XY psudic (7;7) (p22;p22)

NA

Chromosome 7 rearrangement and micro deletion. FAM20C gene is located within the deleted region

M

No

neonatal death

(died 2 h after birth)

Unknown

Lethal osteosclerotic bone dysplasia, irregular periosteal bone formation along the clavicles and ribs, skull had wide cranial sutures with evidence of premature closure, base of the skull showed an increased thickness of all bony landmarks, pulmonary Hypoplasia, Thoracic Hypoplasia

Prominent forehead, short neck, proptosis, midfacial hypoplasia, and a depressed nasal bridge

Not Reported

Not Reported

Simpson et al., 2007 [21]

5

c.1093G>A (p.Gly365Arg)

Exon 6

Homozygous

M

Yes

neonatal death

Unknown

Periosteal bone formation, Osteosclerosis, Thoracic Hypoplasia, Pulmonary Hypoplasia

Prominent forehead, short neck, proptosis, midfacial hypoplasia, depressed nasal bridge

Not Reported

Not Reported

Simpson et al., 2007 [21]

6

c.1094G>A (p.Gly365Glu)

Exon 6

Compound heterozygous mutation

F

No

neonatal death

Unknown

Periosteal bone formation, Osteosclerosis

Prominent forehead, short neck, proptosis, midfacial hypoplasia, depressed nasal bridge

Unknown

Cerebral Calcifications

Simpson et al., 2007 [21]

7

c.1322-2A>G

Intron 7 /Exon 8

Intron 7/Exon 8 acceptor splice-site mutation

8

c.914+5G>C

Exon 4 /Intron 4

Exon 4/Intron 4 donor splice site mutation

F

No

neonatal death

Unknown

Periosteal bone formation, Osteosclerosis, Thoracic Hypoplasia, Pulmonary Hypoplasia

Prominent forehead, short neck, proptosis, midfacial hypoplasia, depressed nasal bridge

Unknown

Cerebral Calcifications

Simpson et al., 2007 [21]

9

c.1404-1G>A

Intron 8 /Exon 9

Intron 8/Exon 9 acceptor splice site mutation

10

c.1309G>A (p.Asp437Asn)

Exon 7

Homozygous missense mutation

M

Yes

(Age 8 years at the time of inverstigation)

The details of death is unavailable

Unknown

Sclerosing bone dysplasia, metaphyseal sclerosis of the long bones, diffuse abnormalities of the skull, thickening and coarse trabeculation, prominent mastoid bulges, short stature

Brachycephaly, downslanted eyes, hypoplastic nose, small downturned mouth, proptosis, turribrachycephaly, plagiocephaly, downslanting palpebral fissures, proptosis, depressed nasal bridge, small nose, protruding tongue, thick alveolar margins, low-set ears

High palate, abnormal teeth

Hydrocephalus, impaired early development, with an increase in age severe developmental delay observed

Simpson et al., 2009 [11]

11

c.796G>A (p.Gly266Arg)

Exon 2

Compound Heterozygous missense mutation

M

No

(Age 11 years at the time of inverstigation). The details of death is unavailable

Unknown

Sclerosing bone dysplasia, pectus excavatum, bulbous fingertips, thick fingers, large halluces, short stature

Turribrachycephaly, hypertelorism, arched eyebrows, an inferiorly placed right eye, low-set and protuberant ears, flat nasal bridge with rounded and bulbous nasal tip and prominent alae nasi, sunken midface, wide mouth with large tongue, relative prognathism

Secondarily edentulous

Hydrocephalus, impaired early development, with an increase in age severe developmental delay observed

Simpson et al., 2009 [11]

12

c.796G>A (p.Gly266Arg)

Exon 3

13

c.1630C>T (p.Arg544Trp)

Exon 10

Homozygous missense mutation

M

Yes

died 38 days after birth

Indian subcontinent

Wide metaphysic, cortical hyperostosis, Osteosclerosis, bowed femur, narrow thorax

Cleft palate, long philtrum, open mouth appearance, midfacial hypoplasia, flat face, depressed nasal bridge, small nose, choanal atresia, entropion of eyelids, proptosis, low set ears, prominent forehead, clover leaf skull

Hypoplastic maxilla (excluding the molar region), small mandible/ micrognathia,

Microcephaly

Kochar et al., 2010 [20]

14

c.940C>T (p.Pro314Ser)

(two siblings; Case 1 and Case 2)

Exon 4

Homozygous missense mutation

F (n = 2)

yes

(Age 1 year and 4 years at the time of investigation)

The details of death is unavailable

Algerian

Case 1: Osteosclerosis

Case 2: cerebral calcifications within parieto-occipital and periventricular white matter, increased density of vertebral bodies and calcifications of several intervertebral disks, presence of chain-like calcifications

Case 1: High forehead, hypertelorism with bilateral epicanthal folds and slightly downslanting palpebral fissures, nasal root hypoplasia, anteverted nares, dysplastic and posteriorly angulated ears with prominent lobule.

Case 2: brachycephaly, bilateral epicanthal folds, midface and nasal root hypoplasia with absence of nasal crest and micrognathia.

High palate, small teeth with enamel dysplasia.

Normal psychomotor development at the time of investigation

Fradin et al., 2011 [13]

15

c.803C>T (p.Thr268Met)

Exon 3

Compound heterozygous missense mutation

M (n = 2)

No

(Age 18 years at the time of investigation). The details of death is unavailable

Norway

Osteosclerosis, short distal phalanges

Dolicocephaly, a narrow face with a narrow malar region, prominent forehead, depressed nasal bridge, low set eyes, hypotelorism, prognathism, a high arched palate with a midline ridge, small mouth, flat malar area

Tooth decay (evident by approximately 18 months of age) periapical abscesses. enlarged pulp chambers, elongated pulp horns up to the enamel-dentin junction, globular defects in the dentine, gingival hyperplasia

Slightly delayed language and fine motor skills at age 11 years.

Rafaelsen et al., 2013

[28]

16

c.915C>A (p.Y305X)

Exon 4

Age 16 years at the time of investigation). The details of death is unavailable

17

46,XY.arr[hg19] 7p22.3 (36480-523731)

chromosome 7p22.3

Homozygous

Complex rearrangement of chromosome and deletion of 487-kb at chromosomal location 7p22.3 that contains FAM20C gene

Unknown

Unknown

The details of death is unavailable

Unknown

Diffuse osteosclerosis, appositional new bone formation, the obliteration of the medullary cavities, narrow thorax, pseudo-rib fractures, small distal phalanges

Prominent forehead, eye proptosis, severe depression of the nasal bridge with short upturned nose, midface hypoplasia, micrognathia,  protruding tongue,

Unknown

Unknown

Ababneh et al., 2013 [43]

18

c.1222C>T

(p.Arg408Trp)

Exon 6

Homozygous mutation

M

Yes

(Age 61years at the time of investigation). The details of death is unavailable

Japanese

Hypophosphatemic osteomalacia, periosteal bone formation in the long bones, bone mineral density in the femoral neck, ossification of the posterior longitudinal ligament

Not reported

Worn out teeth, dental demineralization, loss of all teeth by the age of 17 years

Not reported

Takeyari et al., 2014 [29]

19

c.784+ 5G>C*

(p.Trp202Cysfs*37)

(three siblings)

After Exon 2

Homozygous donor splice site mutation

F (n = 1)

M (n = 2)

Yes

(Age 21 years; 22 years and 27 years at the time of investigation). The details of death is unavailable

Brazilian

Case 2: Short fingers

Case 1,2,3: Dysplastic ears, midface hypoplasia, exophthalmos,

Case 1,2,3: Dental caries, calculus, severe gingivitis, dental plaque, open bite malocclusion, abnormal enamel, high arched and narrow palate, micrognathia, periapical abscesses, yellow brownish discoloration of teeth

Case 1: Intracranial calcifications,

Case 2: microcephaly,

Case 3: microcephaly,

Acevedo et al., 2015 [8]

20

c.1487C>T (p.Pro496Leu)

(two siblings)

Exon 9

Homozygous missense mutation

M (n = 2)

Yes

(Age 13 years and 12 years at the time of investigation).

The details of death is unavailable

Brazilian

Case1,2: small hands with bulbous fingertips and clinodactyly of the fifth fingers, under-mineralized distal phalanges, shaft and growth plate under-mineralization, bowing of the radius bones

Case 1,2: choanal atresia, low set ears, a hypoplastic nose with depressed nasal bridge, prominent alae nasae, down-slanting palpebral fissures and exophthalmos

Case 1,2: midface hypoplasia, micrognathia, high arched and narrow palate, enlarged gingival and palatal mucosa, unerupted permanent teeth, hypoplastic AI. recurrent periapical dental abscesses

Case 1,2: delay in psychomotor development, microcephaly

Acevedo et al., 2015 [8]

21

c.1228T>A (p.Ser410Thr)

Exon 6

Homozygous missense mutation

unknown

unknown

The details of death is unavailable

Unknown

unknown

unknown

unknown

Unknown

Emory Genetics Laboratory; 2016

[47]

22

c.676T > A

(p.Trp226Arg)

Exon 2

Homozygous missense mutation

F (n = 2)

M (n = 1)

Yes

The details of death is unavailable

Moroccan

Not Reported

Not Reported

amelogenesis imperfecta

learning disability, seizures

Elalaoui et al., 2016 [30]

23

c.1135G>A (p.Gly379Arg)

Exon 6

Homozygous missense mutation

M

Yes

The details of death is unavailable

South East Asian

Osteosclerosis, widening of the metaphyses of the long bones, thick and short ribs, fracture of the mid-shaft of the left clavicle, bowing of long bones, bilateralperiventricular and parenchymal punctate calcifications

Choanal atresia, frontal bossing, proptosis, mid-face hypoplasia with a depressed nasal bridge, bulbous nasal tip, tented upper lip

Not Reported

Abnormal/dystonic movements, hypertonia, hyper reflexia

Mahmood et al., 2017 [7]

24

c.1228T>A (p.Ser410Thr)

Exon 6

Homozygous missense mutation

F

Yes

Age 6 years the time of investigation). The details of death is unavailable

Indian

Osteosclerosis, hallux valgus, sandal gap deformity, clinodactyly of toes, pes planus

Flat forehead, epicanthal folds, hypertelorism, depressed and low nasal bridge with bulbous nasal tip, flaring nares, prominent philtrum, pointed chin.

No orodental anomalies were observed.

psychomotor developmental delay

Present case