Table 1.
Clinical Findings of Proband (Subject 1) and Other Subjects with Recessive RTTN Variants
| Previously Reported Patients | ||||||||
|---|---|---|---|---|---|---|---|---|
| Subject (S) | S1 (Proband) | S2 | S3 | S4 | S5 | S6 | S7 | S8 |
| Age* | Deceased 4 months | 12 years | 14 years | 18 years | 16 years | 12 years | 11 years | 6 years |
| Sex | Male | Male | Male | Female | Male | Male | Male | Male |
| Family History | Negative | Affected brother (S3) and sister (S4) | Affected brother (S2) and sister (S4) | 2 affected brothers (S2, S3) | Negative | 2 affected brothers (S7, S8) | 2 affected brothers (S6, S8) | 2 affected brothers (S6, S7) |
| Pregnancy/delivery | 33 weeks | 38 weeks | NR | NR | 40 weeks | Term | NR | NR |
| Head circumference (SD) | Age 6 weeks: 27.5cm | Age 12 years: −2.5 SD | Age 24 years: −2 SD | NR | Age 16 years: 0 SD | Age 12 years: 34.2cm (−8.2 SD) | Age 10 years: 34cm (−8.2 SD) | Age 6 years: 34.5cm (−8.2 SD) |
| Height (SD) | Age 12 years: −2 SD | Age 24 years: −1 SD | NR | Age 16 years −2.5 SD | Age 12 years: 111cm (−5.6 SD) | Age 10 years: 95.5cm (−7.2 SD) | Age 6 years: 91.3cm (−5 SD) | |
| Weight (SD) | Birth weight 1710g (− 0.78 SD) | Birth weight −2 SD | NR | NR | Birth weight: 0 SD | Birth weight: 1kg (−4.1 SD) Age 12years: 14.8kg (− 8.1 SD) |
Age 10 years: 10.8kg (−12.6 SD) | Age 6 years: 9kg (−10.2 SD) |
| Brain MRI Findings | Simplified gyri, ponto-cerebellar hypoplasia, intractable epilepsy | Asymmetric (R>L), irregular gyral pattern of posterior frontal-perisylvian and parietal regions, reduced-volume white matter beneath cortical malformation, mildly enlarged lateral ventricles, thin corpus callosum | Extensive asymmetric (R>L), irregular gyral pattern involving posterior frontal-perisylvian and parietal regions, mildly enlarged lateral ventricles, mildly short corpus callosum, small cerebellar vermis and hemispheres, mildly enlarged fourth ventricle | NR | Bilateral polymicrogyric cortex in temporal areas around sylvian fissure, partietal, occipital areas, reduced parietal and occipital white matter, thin splenium of corpus callosum | Severe microcephaly, few sulcations, bilateral pachygyria, shallow Sylvian fissures | NR | NR |
| Other clinical features | Bilateral microophthalmia, microstomia, microretrognathia, smooth philtrum, relatively large, cupped, low-set ears, bilateral contractures of knees and ankles, mild campto-dactyly with contractures of inter-phalangeal joints, bilateral syndactyly of fourth and fifth fingers and second to fifth toes, microphallus, cryptorchidism, appendicular hypertonia | Seizures, severe intellectual disability, small kidney volume | Seizures, moderate intellectual disability | Seizures, moderate intellectual disability | Seizures, severe intellectual disability | Single kidney, microcephaly related craniofacial dysmorphism, mild bilateral hearing loss, short stature, severe intellectual disability | Sacral lesion cephalad to gluteal crease without spinal cord abnormality, right pelvic ectopic kidney, hypospadias, undescended testis, short stature, severe intellectual disability | Sacral lesion cephalad to gluteal crease, short stature, severe intellectual delay |
| RTTN Variants | c.190G>T (p.Val64Phe)/c.32-3C>T | c.2796A>T (p.Leu932Phe)/c.2796A>T (p.Leu932Phe) | c.2796A>T (p.Leu932Phe)/c.2796A>T (p.Leu932Phe) | c.2796A>T (p.Leu932Phe)/c.2796A>T (p.Leu932Phe) | c.80G>A (p.Cys27Tyr)/c.80G>A (p.Cys27Tyr) | c.2885+8A>G/c.2885+8A>G | c.2885+8A>G/c.2885+8A>G | c.2885+8A>G/c.2885+8A>G |
| Reference | Kheradmand1 | Kheradmand1 | Kheradmand1 | Kheradmand1 | Shamseldin2 | Shamseldin2 | Shamseldin2 | |
| Previously Reported Patients | |||||||
|---|---|---|---|---|---|---|---|
| Subject (S) | S9 | S10 | S11 | S12 | S13 | S14 | S15 |
| Age* | 5.5 years | Newborn | Newborn | 35 months | 21 months | 5 years | 10 years |
| Sex | Male | Male | Male | Male | Female | Female | Female |
| Family History | Two healthy female siblings | Affected brother (S11) | Affected brother (S10) | Affected sister (S13) | Affected brother (S12) | Affected sister (S15) | Affected sister (S14) |
| Pregnancy/delivery | 34 weeks, severe IUGR | Term, severe IUGR | 37 weeks | Term | Term | NR | NR |
| Head circumference (SD) | Birth OFC: 25cm (−4.7 SD) Age 3 years: 34.5cm (−9.2 SD) Age 5.5 years: 36cm (−11.3 SD) |
Birth OFC: 24cm (−5SD) | Birth OFC 24cm (−4.5SD) | Birth OFC: 28 cm (−5.5 SD) Age 35 mos: 34.8cm (−9.3 SD) |
Birth OFC: 27 cm (−5.3 SD) Age 21 mos: 32cm (−10.5 SD) |
−4.4 SD | −5.2 SD |
| Height (SD) | Birth length: 38cm (−3.5 SD) Age 3 years: 75.2cm (−5.5 SD) Age 5.5 years: 92.1cm (−4.1 SD) |
Birth Length 31.5cm (−5 SD) | Birth length 34.5cm (−6 SD) | Birth length 47cm (−2.3 SD) Age 35 mos: 75.5cm (−4.8 SD) |
Birth length 44cm (−2.9 SD) Age 21 mos: 63.6cm (−6.4 SD) |
NR | NR |
| Weight (SD) | Birth weight: 1590g (−2 SD) Age 3 years: 9kg (−3.9 SD) Age 5.5 years: 13.6kg (−2.8 SD) |
Birth weight 1150g (−4 SD) | Birth weight 860g (−6 SD) | Birth weight 3kg (−1.47 SD) Age 35 mos: 7.5kg (−5.4 SD) |
Birth weight 2.6kg (−1.7 SD) Age 21 mos: 6kg (−5 SD) |
NR | NR |
| Brain MRI Findings | Severe microcephaly with simplified gyration | Severe microcephaly, severe cerebral and cerebellar hypoplasia, incomplete separation of cerebral hemispheres, dysgenesis of corpus callosum, large posterior cyst, multiple areas of lissencephaly and/or pachygyria and polymicrogyria, multiple subependymal gray matter heterotopias | Severe microcephaly, severe cerebral and cerebellar hypoplasia, agenesis of corpus callosum, reduced sulcation, deformed ventricles, large CSF intensity areas occupying majority of supratentorial compartments bilaterally | Lissencephaly of frontal lobes, periventricular gray matter heterotopia, reduced number of cerebral cortical convolutions, less deep sulci, thickened cortex (pachygyria), pons hypoplasia | Lissencephaly, periventricular gray matter heterotopia, quadrigeminal cistern arachnoid cyst extending into right occipital region, pons hypoplasia | Diffuse pachygyria | Mild frontal lissencephaly, posterior frontal pachygyria, parieto-occipital subcortical band heterotopia |
| Other clinical features | Delayed cognitive and speech development, secondary craniosynostosis, microcephalyrelated craniofacial dysmorphism, increased tone | Sloping forehead, high broad nasal bridge, multiple joint contractures, failure to thrive, death at 2 months from cardiopulmonary arrest | Sloping forehead, joint contractures, cryptorchidism, duodenal atresia, death at 17 days | Congenital dermatitis (diffuse eczema), receding forehead and chin, protruding nose, hypotelorism with prominent eyes, slightly upturned palpebral fissures, simple helices, severe growth failure, bilateral cryptorchidism, atrial septal defect, motor and speech delays | Congenital dermatitis (diffuse eczema), receding forehead and chin, protruding nose, hypotelorism with prominent eyes, slightly upturned palpebral fissures, simple helices, atrial septal defect, severe growth failure, motor and speech delays | Short stature, moderate intellectual disability, bilateral metatarsus primus varus | Short stature, Tetralogy of Fallot, posterior embryotoxin, moderate intellectual disability |
| RTTN Variants | c.3190A>C (p.Lys1064Gln)/c.3190A>C (p.Lys1064Gln) | c.1732G>C (p.Ala578Pro)/c.5750A>G (p.Asp1917Gly) | c.1732G>C (p.Ala578Pro)/c.5750A>G (p.Asp1917Gly) | c.2953A>G (p.Arg985Gly)/c.2953A>G (p.Arg985Gly) | c.2953A>G (p.Arg985Gly)/c.2953A>G (p.Arg985Gly) | c.4186delC (p.E1397Kfs*7)/c.2594A>G (p.H865R) | c.4186delC (p.E1397Kfs*7)/c.2594A>G (p.H865R) |
| Reference | Shamseldin2 | Shamseldin2 | Shamseldin2 | Grandone3 | Grandone3 | Rump4 | Rump4 |
IUGR: intrauterine growth restriction; BW: birthweight; SD: standard deviation; OFC: occipitofrontal circumference, CSF: Cerebrospinal fluids; NR: not reported
*
Age at time of observation
1
Kheradmand Kia S, Verbeek E, Engelen E, Schot R, Poot RA, de Coo IF, Lequin MH, Poulton CJ, Pourfarzad F, Grosveld FG, Brehm A, de Wit MC, Oegema R, Dobyns WB, Verheijen FW, Mancini GM. RTTN mutations link primary cilia function to organization of the human cerebral cortex. Am J Hum Genet. 2012;91:533–40.
2
Shamseldin H, Alazami AM, Manning M, Hashem A, Caluseiu O, Tabarki B, Esplin E, Schelley S, Innes AM, Parboosingh JS, Lamont R, Care4Rare Canada C, Majewski J, Bernier FP, Alkuraya FS. RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans. Am J Hum Genet. 2015;97:862–8.
3
Grandone A, Torella A, Santoro C, Giugliano T, Del Vecchio Blanco F, Mutarelli M, Cirillo M, Cirillo G, Piluso G, Capristo C, Festa A, Marzuillo P, Miraglia Del Giudice E, Perrone L, Nigro V. Expanding the phenotype of RTTN variations: a new family with primary microcephaly, severe growth failure, brain malformations and dermatitis. Clin Genet. 2016;90:445–50.
4
Rump P, Jazayeri O, van Dijk-Bos KK, Johansson LF, van Essen AJ, Verheij JB, Veenstra-Knol HE, Redeker EJ, Mannens MM, Swertz MA, Alizadeh BZ, van Ravenswaaij-Arts CM, Sinke RJ, Sikkema-Raddatz B. Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly. BMC Med Genomics. 2016;9:7.