Table 1.
Clinical features of four patients with de novo mutations in the last exon of the ZNF148 gene
| Patient 1 | Patient 2 | Patient 3 | Patient 4 | |
|---|---|---|---|---|
| Gender and current age | Girl, 6.7 years | Boy, died on postnatal day 6 after sudden bradycardia | Girl, 11.7 years | Girl, 7 years |
| ZNF148 mutation | c.1792A > T; p.Lys598* | c.1583dup; p.Ser529Glufs*2 | c.970dup; p.Ser324Phefs*14 | c.1581_1582insC; p.Lys528Glnfs*3 |
| Additional variants | SART3 c.1526A > G; p.Asn509Ser TCERG1 c.2359G > A; p.Asp787Asn |
None | PDCD4 c.1198C > G; p.Gln400Glu homozygous | COL3A1 c.3938A > G; p.K1313R; heterozygous, maternally inherited, MAF 0.26%; classified as VUS in ClinVar (RCV000181114.1) |
| Pregnancy | Uncomplicated, mother noted diminished fetal movements | Decelerative CTG just before birth | Uncomplicated | Renal cysts and heart defect on fetal ultrasound |
| Birth | Uneventful, 35 + 4 weeks | CS at 31 + 2 weeks, Apgar scores 2-4-7, not breathing, pale, hypotonic, and lactic acidosis postpartum | CS at 38 + 5 weeks, Apgar scores 5-6-8, hypotonic and hyporeactive, Continuous Positive Airway Pressure for respiratory insufficiency | Induced vaginal delivery at 36 + 0 weeks. Apgar scores 4-7-8. Apneic at delivery, responding to PPV. Started on PGE for known COA. |
| Birth weight | 2.68 kg (–0.30 SD) | 1.84 kg (+0.04 SD) | 3.315 kg (+0.14 SD) | 1.990 kg (–1.49 SD) |
| Birth length | 47 cm (–0.37 SD) | 39 cm (–2.62 SD) | 49 cm (–0.50 SD) | 42 cm (–2.55 SD) |
| Birth head circumference | 32 cm (–0.75 SD) | 29.2 cm (–0.37 SD) | 35 cm (+0.49 SD) | 28.5 cm (–3.2 SD) |
| Feeding problems | Severe, tube feeding need for sufficient caloric intake | Not applicable | Feeding problems during first week with 5 days of tube feeding | Feeding problems during neonatal period with tube feedings. Persistent FTT |
| Length | 110.2 (–2.29 SD) at 6.6 years | 40 cm (–2.5 SD) at 6 days | 151.7 (+0.04 SD) at 11.3 years, catch up with growth hormone substitution therapy started at 3 years because of growth retardation (–2.48 at 2.7 years), and growth hormone deficiency | 93.47 cm (–5.11 SD) at 6 years of age |
| Weight | 17 kg (–1.09 SD for length) at 6.6 years | 1.84 kg (+0.04 SD) at 6 days | 38.4 kg (–0.33 SD for length) at 11.3 years | 11.79 kg (0%ile, z-score –5.71) at 6 years of age |
| Head circumference | (–2.76 SD) at 6.5 years | 29.2 cm (–0.37 SD) at 6 days | 58.2 cm (+2.84 SD) at 11.3 years and fluctuating above and below +3 SD between 6 and 10 years | 41 cm (–8.7 SD) at 6 years |
| Developmental milestones | Walked independently at 3 years. Spoke 3 years | Not applicable | Walked independently at 4 years and started talking > 3 years | Rolled over at 3 months. Crawled at 18 months. Walked independently at 4 years. Approximately 20 words |
| Cognition | WPPS1–III (2.6–3.1 years) at 3.7 years: TIQ 57 (95% CI 52–74) disharmonic profile: VIQ 72, PIQ 55. WPPSI-III-NL 2.6–7.11 years) TIQ 59 (95% CI 54–71), VIQ 72 (68–85), PIQ 63 (57–77) Mild intellectual delay |
Not applicable | WISCIII at 8 years Total IQ 58, verbal IQ 62, perfomal IQ 69 Attends school for children with severe learning problems |
No formal developmental assessment. Attends elementary school receiving special education through the public school system. Uses communication devices for expressive language. Receptive language seems good |
| Head | Triangular-shaped face with pointed chin | Coarse face, slight frontal bossing | Slight frontal bossing, triangular-shaped face with pointed chin | Oval-shaped face with mild bitemporal constriction |
| Hair | Normal blond straight head hair, hypertrichosis of arms and back | Hypertrichosis with lanugo hair on face | Curly hair | Fine hair |
| Eyes | Epicanthus, upslanted palpebral fissures Hyperopia +6.5 D |
Slight right epicanthus, wide-set eyes, remarkable broad left eyebrow with long hairs | Wide-set, slight epicanthus, downslanting palpebral fissures | Mild telecanthus, upslanting, short and narrow palpebral fissures hyperopia, mild bilateral optic nerve hypoplasia |
| Nose | Full nasal tip, prominent columella | Long, smooth philtrum | Prominent columella | Prominent nose with low-hanging prominent columella |
| Philtrum | Deeply grooved | Smooth | Normal | Smooth |
| Mouth | Full lower lip | Normal | Wide-set points of upper vermilion | Wide mouth with thin upper vermillion border; highly arched palate, widely spaced teeth of abnormal shape |
| Ears | Prominent crus helicis of right ear | Large | Low-set and posteriorly rotated | Unusual shape with underfolded helix and prominent anthelix |
| Jaw | Pointed chin | Slight micrognathia, pointed chin | Pointed chin | Pointed chin with prognathia |
| Thorax | Normal | Wide-spaced inverted nipples | Normal | Normal |
| Limbs | Congenital trigger thumb, dysplastic nail of left hallux | Bilateral talipes equinovarus with deeply grooved foot soles | Pedes plani, slight genua valga | Bilateral talipes equinovarus |
| Genital | Normal | Undescended right testis | Normal | Normal |
| Puberty | No | No | Early breast development starting at 8 years | No |
| Epilepsy | No | + (EEG burst suppression) | No | No |
| Brain | MRI brain: thin corpus callosum, slightly delayed myelination, suggestion of bilateral parieto-occiptalpolymicrogyria, periventricular hyperintensities | MRI brain: absent corpus callosum, wide lateral ventricles, bleeding | MRI brain: absent corpus callosum, colpocephaly | CT brain: suspected partial deficiency of the rostrum of the corpus callosum; non-specific foci in the left frontal and left occipital skull of unknown etiology. No MRI |
| Heart | Normal | Open ductus arteriosus, heavy heart – no evidence of cardiomyopathy | Normal | Coarctation of aorta, mitral valve stenosis |
| Kidneys | Renal ultrasound not done yet | Multicystic dysplastic left kidney, pyelectasia/ hydronephrosis of right kidney | Normal renal ultrasound | Multicystic dysplastic right kidney. History of multiple urinary tract infections. Normal voiding cystourethrogram |
| Endocrine | Not investigated | Not investigated | Early signs of puberty, growth hormone deficiency | Normal bone age and growth hormone status |
| Other | Recurrent upper airway infections, delayed intestinal mobility problems, late first tooth eruption > 3 years | Short neck | Frequent rhinitis in the first year | Frequent otitis media status post tympanostomy and tube placement |