Van Maldergem et al.Appendix e2

Supplementary Figure Legend

Figure e-2. Representative brain imaging studies in Debré type cutis laxa from patients 4 (A-C), 7 (D-F), 8 (G-I), 5 (M-O) and 11 (P-R), and a normal control (J-L). In all but patient 11, axial and coronal images at the level of the lateral ventricles demonstrate an abnormally thick 6-10 mm cortex in the frontal and parietal regions on both sides with the frontal pole and posterior parietal regions less severely involved (white arrows B, E, F, H, I and N). The cortical ribbon appears smooth in some images (C, E, F, H and I), and irregular in others (B and N). Midline sagittal and lower axial images show a normal cerebellum in patients 7, 8 and 5 (D, G, M and O), while no images of the vermis were available for patient 4. All images from patient 11 show abnormally prominent sulci consistent with moderate cerebral and cerebellar atrophy (P-R).

Clinical histories of Patients 3 to 11

Patient 3. This boy was born to Turkish first cousins and was referred for evaluation at 3.5 months because of enlarged anterior fontanelle and redundant skin. Examination showed a normal OFC (39.5 cm, 50th percentile) and marked cutis laxa. He walked without assistance at 21 months, but soon after developed meningeal signs and a brain MRI revealed DWM and hydrocephalus that was treated with a shunt. His OFC was 49.5 cm (50th centile). At 4 years, he was seen again (figure 1E) and a skin biopsy was performed that demonstrated paucity of the elastin network and sparse misshapen elastic fibers.

The available MRI images (figure 3GI) demonstrated an abnormally thick 78 mm and irregular cortex over at least the superior frontal lobe, while a subsequent CT scan showed markedly enlarged and rounded lateral ventricles consistent with hydrocephalus. Images through the posterior fossa demonstrated typical DWM including small and upwardly rotated cerebellar vermis, cystic dilatation of the 4th ventricle, and enlarged posterior fossa with an elevated tentorium. The brainstem appeared mildly thin and the cerebellar hemispheres mildly small.

Patient 4. This girl was born at term to unrelated Sicilian parents, and her neonatal exam demonstrated cutis laxa (figure 1G). Her birth weight was 2550 g and OFC 30 cm (–2.2 SD) at 36 weeks gestation. Her development was delayed, and she had the onset of generalized epilepsy at 9 years, which proved unresponsive to antiepileptic drugs. Her IQ was measured at 3550. At 11.5 years, her weight (25th centile) and height (50th centile) were normal, but her OFC was small (50 cm, –3 SD). On serial exams, she had pretibial pseudoecchymotic skin lesions resembling those observed in types I and II Ehlers-Danlos syndrome, abundant dry and coarse hair, and ataxia. The wrinkling of her skin became less apparent in the second decade (figure GI). By 14 years, her cognitive function deteriorated so that she could not sustain a conversation, and had severe generalized hypotonia (figure GII-GIII).

Her brain MRI (figure e2A-C) shows reduced sulcation with an irregular cortical surface and abnormally thick (~10 mm) cortex over the posterior frontal, perisylvian and parietal regions, as well as mildly enlarged lateral ventricles. The corpus callosum and cerebellum appear normal.

Patient 5. This boy was born at 31 weeks gestation to consanguineous Portuguese parents with birth weight 2150 g, length 46 cm (both 90th percentile) and OFC 29 cm (50th percentile). During his first year of life, he had recurrent infections and failure to thrive, and was diagnosed with Ehlers-Danlos syndrome due to hypermobile joints and redundant skin. His developmental milestones were delayed including walking with support at 3 years. He had generalized seizures. At 13 years, he entered the hospital for abdominal pain and vomiting that was caused by spontaneous rupture of his spleen, which required splenectomy. Evaluations demonstrated a small jaw, scoliosis, hip dysplasia, splenomegaly and thrombocytopenia in addition to cutis laxa. He underwent bilateral lens replacement for corneal dystrophy at 15 years.

His brain MRI (figure e2MO) demonstrated reduced sulcation with an irregular cortical surface and mildly thick ~10 mm cortex over the posterior frontal, perisylvian and anterior parietal regions, and mild atrophy over the remainder of the cerebral hemispheres. Other changes included mildly enlarged lateral ventricles with normal corpus callosum and brainstem. The 4th ventricle was mildly enlarged, more likely due to cerebellar atrophy.

Patient 6. This boy was born at term to first cousin Bedouin parents with birth weight 3605 g (50th percentile) and OFC 33 cm (–2 SD). His first exam demonstrated Erb’s palsy, redundant skin, pectus excavatum, bilateral cryptorchidism and right inguinal hernia. His developmental milestones were delayed with sitting at 11 months, walking at 21months and a few words at 2 years. At 2 years, his weight was 11.3 kg, length 85 cm (both 25th percentile) and OFC 43.5 cm (–4.5 SD). He had microcephaly with dysmorphic features consisting of an abnormally large (7x9 cm) anterior fontanelle, downslanting palpebral fissures, prominent supraorbital ridges, telecanthus, broad nasal bridge, prominent ears, deep philtrum, sagging cheeks, tented upper lip and micrognathia. Wrinkly skin, especially on the abdomen and hands, and prominent veins, was striking. Other abnormalities included fair hair compared to relatives, inverted nipples, pectus excavatum, bilateral transverse palmar creases, distended abdomen, bilateral cryptorchidism and right inguinal hernia. His developmental quotient was 62 at 29 months using the Bayley Scales of Infant Development, but his neurological exam was otherwise unremarkable.

His brain MRI (figure e2DF) showed mildly short frontal lobes, reduced gyri and shallow sulci typical of severe microcephaly, as well as mildly thick and irregular cortex in the frontal, perisylvian and parietal regions on both sides. The white matter had patchy streaks of high signal consistent with prominent perivascular spaces. The cerebellum appeared normal in size, but the cisterna magna was large.

Patient 7. The younger sister of patient 6 was born at 38 weeks gestation. At 22 weeks gestation, prenatal ultrasound diagnosed tetralogy of Fallot. Her birth weight was 3080 g (35th percentile) and her OFC 29.5 cm (–4.5 SD). She had cutis laxa, congenital hip dislocation, right clavicle fracture and Erb’s palsy, and had surgery for her heart defect. At 11 months, her weight was 7.3 kg (2nd centile), height 69.5 cm (10th centile), and OFC 38 cm (–6 SD). She had clinical features similar to her brother including marked microcephaly, facial dysmorphia, fair hair, large anterior fontanelle and wrinkly skin, and also had mild abducens paresis without nystagmus, normal tone and reflexes, and extensor plantar responses. Her developmental milestones were delayed. At 17 months she was able to walk and run, and communicated primarily with gestures. Her DQ was at 64 on the Bayley Scales of Infant Development. Her brain MRI (figure e2GI) showed changes similar to those of her brother.

Patient 8. This girl was born at term to unrelated French parents with birth weight 2800 g, length 47 cm and OFC 30.5 cm (–3 SD). She had marked hypotonia, overfolded skin, large anterior fontanelle, and dysmorphic facial appearance consisting of telecanthus, downslanting palpebral fissures, flat philtrum and small mouth. She developed respiratory distress due to choanal atresia, which was surgically repaired. Skin biopsy demonstrated extreme rarefaction of elastic tissue with small fibers, although the two components of elastic fibers were present. She was adopted and educated in a special school. At 17 years, her weight, height and OFC were normal (47 kg, 163 cm and 53.2 cm, the latter 10th percentile). She had moderate mental retardation with good social interactions, and a history of easy bruising and recurrent epistaxis. Her cutis laxa was much improved from early childhood, obvious only on her lower abdomen and face. Her hair was thick and abundant. IEF of serum transferrins and brain imaging were not performed.

Patient 9. This boy was born at 38 weeks gestation to unrelated Caucasian parents from southern Moravia (CzechRepublic). Their first pregnancy resulted in spontaneous abortion. The forceps extraction resulted in clavicle fracture and Erb’s palsy. His birth weight was 3000 g, length 51 cm and OFC at 50th percentile. His newborn exam showed obvious cutis laxa, facial dysmorphia with downslanting palpebral fissures, and a large anterior fontanelle. Head ultrasound detected a brain hemorrhage. Skin biopsy demonstrated marked rarefaction of elastic fibers and uneven diameter of collagen fibers in skin, typical of cutis laxa (I. Anton-Lamprecht, Heidelberg, Germany). At 6 months, he was treated for hip dysplasia and bilateral inguinal hernias. He first sat at 10 months and walked alone at 20 months, both delayed. Exam demonstrated mild mental retardation, hypotonia, high myopia (>10 diopters) and valgus deformity of feet. At 8 years, he had onset of generalized seizures that responded poorly to antiepileptic drugs. At 10 years, he still had typical facial dysmorphism including a persistently open anterior fontanelle. He attends a special school for the mentally retarded. He has a mild cognitive deficit with IQ 50-70, and remains very hypotonic. His progeroid appearance and cutis laxa are less marked than in infancy (figure 1C). A CT scan of his brain performed at 14 years shows general atrophy and frontal pachygyria.

Patient 10. The younger sister of patient 4 was born at 36 weeks gestation following premature rupture of membranes with birth weight 2850 g, length 48 cm and OFC 34 cm (25th centile). Although the delivery was normal, she had a spontaneous fracture of the left clavicle. At 3 months, she had wrinkly skin, typical facial dysmorphia, joint hyperlaxity, inguinal hernia, and hip dislocation. She made better developmental progress than her brother including language skills. She had high myopia (>10 diopters) and abundant, thick, dry hair. At 5 years, she still had typical facial dysmorphism (figure 1D). Elevated liver enzymes were found, and at 6 years she died of pneumonia. Autopsy showed diffuse atrophy of the brain, but structure of the cortex appeared normal (G. Lyon, Paris).

Patient 11. This girl (figure 1F) and one of her brothers were previously described12 (Ogur et al 1994). Another affected sister died of pneumonia at 9 years and another brother at 11 years. Her OFC was small at birth (–4.5 SD) and remained small (46 cm, –2 SD) at 6 years. Following the original report, she experienced a slow downward course with progressive motor and cognitive decline from the age of 10 years, and later progressive hearing loss. She lost the ability to walk at 17 years and soon after became bedridden (figure 1FI and FII). At 23 years, she was alert and able to follow simple commands, but spoke only with single words. Her head and eyes frequently deviated to the left. She had slurred speech, subtle right facial paralysis and mild quadriplegia demonstrated by loss of muscle size, brisk deep tendon reflexes and bilateral Babinski signs. An EEG was normal. Brain MRI shows diffuse cerebral and cerebellar atrophy with enlarged ventricles (figure e2PR), and apparently no cortical dysplasia.