Discordant monozygotic twins for macrocephaly‐capillary malformation

Macrocephaly-cutis marmorata telangiectatica congenita (MIM 602501) is a rare multiple congenital abnormalities/intellectual disability and overgrowth disorder, comprising macrocephaly, cutis marmorata, midline facial capillary malformation often involving the lips and/or philtrum, syndactyly, hemihyperplasia, central nervous system (CNS) abnormalities, and developmental delay. First described in 1997 [Clayton-Smith et al., 1997; Moore et al., 1997], this syndromewas subsequently namedmacrocephalycapillary malformation (M-CM) by Toriello and Mulliken [2007]. Here, we report on the first case of discordant monozygotic twins with M-CM, and the proband has unique features. The proband is the fourth of five girls from second-degree consanguineous Turkish parents. An elder sister had camptodactyly, truncal hypotonia, and labia majora/clitoral hypertrophy. She died at 11 months with encephalopathy of unknown etiology. The proband was born at 35 weeks of gestation by caesarean for macrocephaly and fetal distress after an uneventful monochorial/ monoamniotic twin pregnancy. Birth weight was 2,470 g (90th centile onmonozygotic twin growth chart, 50th centile on singleton growth chart), birth length was 46 cm (50th centile on singleton growth chart), and occipito-frontal circumference (OFC) was 35.5 cm (>90th centile on singleton growth chart). APGAR scores were 8 at 1min and 10 at 5min. Clinical examination showed frontal bossing, nasal, and frontal capillary malformations, intermittent right eye strabismus, hypertelorism, right epicanthus, long philtrum, vaulted palate, full lips, deep palmar creases, gap between first and second toes, axial and peripheral hypotonia, generalized capillarymalformation that fadedwith age, and thick subcutaneous tissue (Fig. 1). During the neonatal period, profound episodes of hypoglycemia required treatment with intra-venous glucose perfusion until the 4th day of life. Metabolic investigations, including plasma and urine amino acids, urine organic acids, blood lactate, ammonia, and insulin, were normal both at the time of hypoglycemia episodes and when controlled at 8 months of age. A transfontanellar ultrasound in the neonatal period showed thalamic and periventricular calcifications and mild ventricular hydrocephaly. Auditory and visual evoked potentials were normal. Her OFC curves increased disproportionately with age. A CT-Scan performed at 6 months showed bilateral hydrocephaly (Evans’ index 0.32), but no posterior fossa abnormalities. A brain MRI at 7 months showed cerebellar tonsillar herniation (CTH), hydrocephaly, and indirect signs of cerebral hypertension (hydrocephaly with enlarged subarachnoid pericerebral space). Ventricular shunting at 11months (Fig. 1C) improvedboth theOFC,which remained at 51 cm until death, and psychomotor development. At 19 months, she had tonic-clonic movements of right upper limb accompanied by crying and cutaneous flushing. An EEG showed slow basal rhythm and paroxysm on the left part of her brain. There was no seizure recurrence onValproate therapy. Chest X-ray showed 11 pairs of ribs. There were no other osseous abnormalities. Thermoregulation instability appeared after the first year of life with a usual temperature between 38 and 39 C. Feeding difficulties were experienced throughout life and major milestones were delayed (unable to sit alone, no words at 17 months). She smiled easily and had good interactive contact. She died at 23 months from disseminated intravascular coagulation following a common respiratory viral infection. Autopsy was refused by the parents.