Patient 1 is the first child of healthy non consanguineous parents, born after a previous early miscarriage. During pregnancy, intra uterine growth retardation (IUGR) was diagnosed at 26 weeks’ gestation (WG). Later on, ventricular septal defect was identified on the third trimester ultrasound, together with single umbilical artery. Chromosome analysis and 22q11.2 FISH performed on amniotic fluid were normal. He was born at 35 WG by caesarean section performed for maternal preeclampsia, with a birth weight of 1.900 kg (10–25th centile), a length of 43 cm (10–25th centile), and a head circumference of 30 cm (10–25th centile). At birth, several malformations were identified including an imperforate anus, a bilateral iris coloboma, bilateral single palmar creases, bilateral II–III toe syndactyly, hypoplastic 5th toes with absent 5th toe nails, and a micropenis with a coronal hypospadias and a left cryptorchidism. The cardiac malformation was confirmed. He was first referred to the genetic clinic at 4 months, having severe hypotonia and post natal growth retardation with a weight of -4SD, a height of -3DS and a HC of -3SD. Striking dysmorphic features were identified comprising of dysplastic asymmetric ears, large and high forehead, hypoplastic nasal bridge, small nose with anteverted nares, up-slanting palpebral fissures, bilateral epicanthus and a high palate (). His skin appeared very dry. Later on, he underwent surgery for left inguinal hernia where nystagmus was noted.
Facial characteristics of the 4 patients. A: Patient 1. B: Patient 2. C: Patient 3. D: Patient 4. Note high and large forehead on patients 1, 2 and 4.
Developmental delay occurred secondarily. Head control was acquired at 19 months. At 2 years, he was sitting by himself and his growth parameters were in the normal range with height -1SD, weight -1SD and HC -1SD. Unfortunately, he died at home by the age of 25 months due to unknown cause. Parents declined post-mortem examination. Several investigations were performed that includes, high resolution chromosome banding which was normal, along with renal scan, skeletal x-rays, electromyogram and nerve conduction velocities. Visual evoked potentials and 7-dehydrocholesterol were also normal except brain MRI that revealed cerebral atrophy and enlarged ventricles.
Patient 2 is the third child of healthy non consanguineous parents. He was born after a normal pregnancy, at 38 WG with normal growth parameters (weight 3.170 kg, height 53 cm and HC 33 cm). Hypospadias was noted at birth in association with hypotonia and short proximal implanted thumbs. Dysmorphic features comprising of high and large forehead with small mouth were observed (). Developmental delay occurred later on, and walking independantly was achieved at 29 months. When referred to the genetic clinic at 3 years, growth parameters were normal. However, joint laxity was noted, but thumbs and facial features were still abnormal. High resolution chromosome banding was normal, along with renal and heart ultrasounds. However, skeletal x-rays revealed bilateral short first metacarpals, eye examination identified bilateral papilloedema and thick corpus callosum was noted on brain MRI.
Patient 3 is the second child born to healthy non consanguineous parents. During pregnancy, Fallot tetralogy was suspected and chromosomes including 22q11.2 by FISH analysis were observed to be normal on aminotic fluid. He was born at 39 WG, with normal growth parameters (weight 3.450 kg, height 49.5 cm and HC 35 cm). At birth, the cardiac anomaly was confirmed and he underwent several surgical interventions. Developmental delay was secondarily noted with head control achieved at 9 months, sitting at 15 months and walking at 3 years. Speech was also delayed (first words at 3 years). When referred to the genetic clinic at the age of 3 years, dysmorphic features were noted with asymmetric dysplastic ears, thin upper lip and widely-spaced teeth (). His skin was dry. Eye examination revealed strabismus and hypermetropia. A bilateral sensorineural deafness was identified. High resolution chromosome banding was normal. Brain MRI revealed hypoplastic olfactory bulbs. Semi-circular canals were normal. CHD7 molecular analysis was normal that ruled out CHARGE syndrome.
Patient 4 is the first child of healthy non consanguineous parents. During pregnancy, intra uterine growth retardation was noted. She was born at 37 WG with a weight of 1.850 kg, height of 45.5 cm and HC of 31 cm. At birth, dysmorphic facial features were noted with large and high forehead, flat midface, thin lips, small mouth and posteriorly rotated ears. Developmental delay was noted, with sitting at 11 months, walking at 2½ years and first words at 3 years. When reviewed in the genetic clinic at the age of 7 years, growth parameters were normal. Dysmorphic features were still present () with adducted thumbs and genu valgum. Eye examination revealed hypermetropia. High resolution chromosome banding was normal together with metabolic investigations, brain MRI and molecular analyses that ruled out Prader-Willi syndrome and Steinert disease.