MEDICAL PAPER

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The Macrocephaly with cutis marmorata, haemangioma and syndactyly - a distinct overgrowth syndrome
By Dr J.Clayton-Smith - Consultant Clinical Geneticist - St Marys Hospital Manchester UK

Clinical Dysmorphology

We describe nine children with a similar pattern of features including macrocephaly and cutis marmorata telangiectatica congenital. All were large at birth and had a distinctive capillary haemangioma involving the philtrum and upper lip. The seven who survived all developed hydrocephalus and had developmental delay. Six developed body asymmetry and three had internal arteriovenous malformations. Syndactyly of the second and third toes and/or the third and fourth fingers or toes was commonly seen. All of the cases were sporadic. This condition is easily reconizable and should be considered in the differential diagnosis of patients presenting with overgrowth and macrocephaly.

Introduction
The association between macrocephaly, limb asymmetry and angiomatosis was documented in 1975 by Stephan et al.They described a heterogeneous group of ten patients with vascular abnormalities including Klippel-Trenauney-Weber syndrome, Struge-Weber syndrome, and cutis marmorata telangiectatica congenital. All of the patients had unexplained macrocephaly, but intellectual function was normal in seven out of the 10. One of the three mentally retarded patients was large at birth and had a midline haemangioma extending from the forehead to the chin, along with striking and persistent generalized cutis marmorata. She developed ventriculomegaly requiring the insertion of a ventriculo-peritoneal shunt at 5 months of age. She went on to develop hemihypertrophy. At 22 months of age she contracted pneumonia and died, a similar patient was reported by Meyer in 1979. This child, a male, had a large birth weight, macrocephaly, an extensive naevus flammeus of the face and body and right sided hemihypertrophy. He developed ventriculomegaly, which required shunt insertion during the first few months of life and had severe development delay. Cristaldi et al. (1975) reported two patients with hemimegalencephaly and cutaneous haemangiomata in assocation with 2/3 syndactly and severe developmental delay. One patient had a deletion of the long arm of chromosome 16.
We have observed a group of nine patients with some similarities to these reported cases, but have noted other features suggestive of a distinctive syndrome. The same clinical features were observed in a group of patients described by Toriello et al. in 1996.

Case 1

This child W.S. is the first child of unrelated Anglo-Saxon parents. The paternal grandfather had a unilateral postaxial polydactly involving one hand and one foot. W.S. was born at 37 weeks gestation by emergency Caesarean section. His birth weight was 4.3 kg, length 52cm and occipitofrontal circumference (OFC) 39cm. He was hypotonic and slow to feed and had persistant hypoglycaemia requiring an intravenous dextrose infusion for 8 days. On examination in the newborn period he had striking generalized cutis marmorata and capillary haemangiomata involving his philtrum, upper lip, forehead and left side of his cheek and chin. The lesion over his philtrum was a much deeper colour and had well-defined margins. He had postaxial polydactyly of both feet and syndactyly of the second and third toes. Ultrasound examinations of his head and abdomen were normal in particular there was no evidence of ventriculomegaly or organomegaly. On review at 10 weeks of age he had a rapidly enlarging head circumference and was found to have hydrocephalus. A ventriculo-peritoneal shunt was inserted. At 21/2 years of age his OFC was 56cm (>97th centile), weight 16.5kg (>97th centile) and length 88cm (50th-75th centile).
The cutis marmorata and capillary haemangiomata had resolved apart from persistence of the central haemangioma involving the philtrum and upper lip. There were some streaky areas of pigmented and depigmented skin over his back and limbs, running longitudinally down the limbs in the distribution of Blaschko's lines. He had a depressed nasal bridge and a high forehead with dilated superficial veins and bilateral cowlicks in his anterior hairline. His face was asymmetric and there was, obvious right-sided hemihypertrophy, hand and foot lengths on the right being 1cm greater than on the left. His shoulder gridle appeared narrow due to underdeveloped musculature. He had tapering fingers and joint hyperextensibility at the hands, wrists and elbows. His skin was loose and soft. He had a small penis and undescended testes. Developmentally he was delayed, functioning at a 6 month level. He was a sociable child with a placid temperament. He had a normal audiologiocal examination but had poor vision in his left eye and limited vision in his right eye although examination of his fundi was normal. Investigations to date include muscle biopsy, EMG, ERG, metabolic screen including white cell enzymes, mucopolysaccharide and oligosaccharide screen. All were normal, as were chromosome analyses on blood from W.S. and his parents. A skeletal survey showed only slight thinning of the long bones and bone age was 1 year at a chronological age of 21/2 years. A renal ultrasound scan showed features suggestive of an angiomyolipoma in one kidney. Review of a CT scan of the kidneys suggested that this was a static vascular lesion.

Case 2

A.M. was the second child of healthy Irish parents. Fetal movements were reduced during the pregnancy. This child, a male, was born at 39 weeks gestation by vaginal delivery. Birth weight was 4.34kg. He was a poor feeder requiring nasogastric feeds for the first week of life. He was hypotonic at birth, and was noted to have a number of dysmorphic features including plagiocephaly, syndactyly of the second and third toes, hypoplastic toenails and bilateral talipes equinovarus. He also had generalised cutis marmorata and a capillary haemangioma over the midline of his face, involving particularly his upper and lower lip. On examination at 5 months of age he remained hypotonic with marked head lag. He had some muscle weakness but had normal reflexes. His eyesight and hearing appeared to be normal. His weight was 9.24 kg (>97th centile), length 67.5cm (75th centile) and OFC 48.5cm (>97th centile). He was a sociable child, smiling from the age of 4 weeks. Chromosome analysis of cultured lymphocytes and DNA analysis of the myotonic dystrophy gene were normal. Muscule biopsy showed a Type 1 fibre predominance with normal dystrophin and no ragged red fibres. On review at 12 months of age he showed similar facial features to case 1 with a high forehead, a depressed nasal bridge and fading capillary haemangioma over the philtrum. Facial asymmetry was noted at this time. His motor milestones have been delayed, he sat at 8 months, crawled at 1 year and began to weight bear at 16 months.

Case 3

This child was the fourth infant born to healthy non-consanguineous parents. He was born at term by vaginal delivery and weighed 5.7 kg. His OFC at birth was 44cm. He had a naevus over the upper lip, which faded with time. He was markedly hypotonic at birth. He developed hydrocephalus during the first few months of life and a V.P. shunt was inserted. An MRI scan at this time showed a delay in myelination, dilated and disfigured lateral ventricles and an area of cortical dysplasia in the region of the right Sylvian fissure. At the age of 4 years, his head circumference was 61cm (>97th centile), length 95cm (3rd centile) and weight 18kg (75th centile). He had marked hypertelorism, ICD 3.5cm and OCD 10cm. He had a depressed nasal bridge with epicanthic folds, a protuberant lower lip and full cheeks. His hands and feet were small and puffy, with an increase in subcutaneous tissue over the dorsum. His nails were spoon shaped and there was bilateral syndactyly of the second and third toes. He has been investigated extensively for metabolic and mitochondrial disorders. Biochemical studies on muscle mitochondria showed impaired rates of pyruvate oxidation but there was no specific deficiency of any of the mitochondrial enzymes. Further investigation suggested a deficiency of a voltage-dependent anion channel (VDAC), a component of the outer mitochondrial membrane. Cytogenetic analysis of 100 cultured fibroblasts, 200 uncultured buccal cells and cultured lymphocytes was normal.

Case 4

This infant, a female, was the second child born to non-consanguineous parents and had a birth weight of 4.2kg and OFC of 41.3cm at 38 weeks gestation. She had generalised cutis marmorata with a capillary haemangioma of the upper lip extending to the alae of the nose. Similar haemangiomata were also present over the ears and on the lower back. She had complete syndactyly of the second and third toes on the left and partial syndactyly of the third and fourth fingers on the left hand. CT scan revealed ventriculomegaly and a localised arterio-venous malformation in the right parieto-occipital region. She had a complex cardiac malformation, which contributed to her death at the age of 1 month. At autopsy there was a haemangioma at the upper pole of the liver. Chromosome analysis of both blood and fibroblasts were normal.

Case 5

K.L.F., a male was the first child born to healthy unrelated parents. His birth weight was 4.15kg at term. At birth he was noted to have cutaneous syndactyly of the second and third toes on both feet and the third and fourth fingers of the left hand. He was hypotonic and had hyperextensible joints. He had a depressed nasal root, low-set ears and generalised cutis marmorata with a more discrete haemangioma over his forehead and upper lip. Cranial CT scan was normal at 4 days of age but over the first 4 months his head size increased, he developed hydrocephalus and a VP shunt was inserted. Subsequent cranial MRI scan at the age of 18 months showed increased signal intensity in the periventricular region. Metabolic investigations including very long chain fatty acids and lactate were normal apart from a mildly raised phytanic acid level, which was 8 mg1-1 (normal 5 mg1-1). Subsequent examination of VLCFA profile in fibroblasts and of plasmalogen biosynthesis was normal. Chromosome analysis of cultured lymphocytes and of skin fibroblasts taken from both sides of the body was normal. Motor milestones were very delayed. He crawled at the age of 20 months. At the age of 2 years he was able to say some simple words. His head circumference continued to increase above the normal rate in spite of his shunt. At 2 years his OFC was 56.2cm (>97th centile), weight 13.4kg (90th centile) and length 81.5cm (3rd centile).

Case 6

This child, a girl was the fourth child of healthy non-consanguineous parents. During the third trimester of pregnancy increased fetal growth, hydramnios and fetal hydrops were noted. She was delivered at 36-37 weeks gestation and weighed 5.58kg. length at birth was 57cm
(> 97th centile) and OFC was 40.7cm (>97th centile). She had large anterior and posterior fontanelles, generalised cutis marmorata and a capillary haemangioma involving the forehead and philtrum. The facial skin was thick and there was a dysplastic left ear with a preauricular tag. There was complete cutaneous syndactyly of the second and third toes and partial syndactyly of the third and fourth toes and third and fourth fingers. CT scan of the brain showed enlarged ventricles with hemimegalencephaly and sagittal sinus thrombosis. She had severe respiratory problems and died on the second day of life. Chromosome analysis of cultured lymphocytes and fibroblasts, metabolic screen and virology screen including parvovirus were all normal. Post mortem examination showed absence of the innominate vein and an aberrant left subclavian. There was evidence of bilateral angiomatosis at the apices of both lungs.

Case 7

P.W., a male was conceived by AID. He was born prematurely at 30 weeks gestation and weighed 1.4kg (50th centile). Initial examination showed syndactyly of the second and third toes and post-axial polydactyly of both feet. During the first month of life he presented with cardiac failure due to a supraventricular tachycardia. In the following months his head circumference increased and an ultrasound scan showed enlarged ventricles. He was noted to have extensive cutis marmorata and a haemangioma of the upper lip. He developed body asymmetry and at 2 years of age the right side of his face and the right buttock was larger than the left and his left hand was larger than the right. There was enlargement of the soft tissues of both forearms and hands. Development has been delayed. He walked at 21/2 years and attends a school for children with learning difficulties.

Case 8

S.L. was the third child of unrelated parents. His birth weight was 3.3kg at 36 weeks gestation (90th centile) and he was noted to have post-axial polydactyly of both hands and on his right foot and syndactyly of toes 2/3 on both feet. He had generalised cutis marmorata and a capillary haemangioma over the central portion of his philtrum and both lips. OFC at birth was 36.5cm (90th - 97th centile) and a cranial ultrasound at the age of 2 weeks showed mild ventricular dilation. From 3 months of age his head circumference increased significantly and a cranial CT scan at 5 months showed asymmetrical ventricular dilation, the right being markedly larger than the left. A ventriculoperitoneal shunt was inserted at 6 months of age.

Case 9

R.D., a male, was the second child of a healthy unrelated couple. His elder sibling had an isolated cleft palate. During the pregnancy an ultrasound scan showed bilateral pleural effusions. These were drained and the pregnancy progressed to a delivery by caesarean section at 38 weeks gestation. His birth weight was 3.2kg and OFC was 37.1cm (>97th centile). He was noted to have cutaneous vascular markings soon after birth, with a more discrete haemangioma over the face. He was hypotonic initially and needed tube feeding. His head circumference increased over the first few months and he required insertion of a VP shunt for hydrocephalus. CT scans suggested partial stenosis of the aqueduct of Sylvius. His development has been delayed. He was not able to sit alone before the age of 1 year and walked independently at the age of 21/2 years. He has a large head (>97th centile) with frontal bossing, facial asymmetry and a depressed nasal bridge and downslanting palpebral fissures. The skin changes have faded over time but he has developed some linear hyperpigmented streaks on his skin, which run longitudinally down the limbs in the lines of Blaschko. He has poorly developed musculature around the shoulder girdle with an increase in subcutaneous tissue over his limbs, hands and feet. All investigations to date including chromosome analysis have been normal except for X-rays of the spine, which show a possible expansion in the cervical region.

Discussion

These nine children had a similar pattern of clinical features, which are summarised in Table 1. Except for case 7, who was born prematurely, all were large at birth with cutis marmorata and similar facial haemangiomata involving the philtrum and upper lip. The haemangiomata and the cutis marmorata have faded with time in those patients who have survived. All the survivors have had persisting macrocephaly and ventricular dilatation. Six of the cases are showing significant development delay, with development in a further case being difficult to assess at the present time because of his young age. Syndactyly between toes two and three was present in all case except for case 9. Three cases also had 3 / 4 syndactyly of the fingers or toes and three cases had post-axial polydactyly. The clinical course of these three patients with polydactyly has been very similar to that of the other patients, and we consider that polydactyly is therefore part of the extended phenotype of this condition. Other features included a congental heart defect in one patient and internal vascular malformations in three. Two cases had a clear history of intra-uterine oedema with the presence of pleural effusions. Two patients went on to develop hemihypetrophy and four others had symmetry of the head and face, including the cerebral ventricles. The natural history of the condition in the survivors has been similar. Generalised cutis marmorata, capillary haemangiomata, hypotonic and macrosomia are present at birth. The head circumference increases markedly in size during the first few months and ventricular dilatation develops. Intracranial pressure is not always increased, and in those infants who have been shunted the OFC often continues to increase at a faster rate than normal even after shunting. As the head size increases the high, square forehead with frontal bossing becomes noticeable. MRI scans on two of our patients have revealed a high signal intensity within the white matter, possibly indicative of a delay in myelination. Developmental delay, especially of motor milestones is apparent from early on. The cutis marmorata and capillary haemangioma fade with time and in some patients, careful inspection of the skin may then reveal linear pigmented streaks following the lines of blaschko. Body asymmetry may become apparent and all patients have had a similar body habitus with narrow shoulder girdle due to poor musculature. Elsewhere, there is increased thickness and elasticity of the subcutaneous tissues and generalised joint laxity. There has been no evidence of organomegaly on ultrasound scan and none of the individuals have developed malignant tumours to date.

Cristaldi et al. (1995) have suggested that vascular lesions, hemihypertrophy and hemimegalencephaly may not be chance associations but are pathogenetically related. Our cases would appear to confirm this relationship although we would suggest that the CNS abnormality can be bilateral ventricular dilatation rather than hemimegalencephaly per se.
In a review of hemihypertrophy in 1965, ringrose et al. described three patients with hemihypertrophy, severe mental retardation and sydactyly who may well have had this condition. Viljoen et al. also commented upon two patients with hemihypertrophy, severe mental retardation and arrested hydrocephalus (Viljoen et al.,1984) and gorlin reported a patient in 1962 with hemihypertrophy and mental retardation who also had 2/3 syndactyly. More recently, Reardon et al. reported an infant with hemihypertrophy, hemimegalencephaly and polydactyly who also had cutis marmorata and 2/3 syndactyly (Reardon et al., 1996). It is likely that this child had the same condition.

All of our reported cases have been extensively investigated. Case 3 has recently been found to have a rare voltage-dependent anion channel (VDAC) deficiency. VDAC is a protein involved in ion transport across the mitochondrial membrane and is a constituent of the plasma membrane of mammalian brain cells. It is not yet known whether this rare abnormality is present in the other patients and whether it is related to the clinical manifestations we have described. No consistent abnormality has been found in all of the patients. The joint laxity and hyperelastic skin observed in these cases is suggestive of an underlying connective tissue abnormality. One possible is that this collection of clinical features is a manifestation of somatic mosaicism. This hypothesis is supported by the observations of the patchy vascular markings on the skin, body asymmetry (cases 1,2,6,7,8 and 8) and the pigmented skin lesions, which we have observed with time in cases 1, and 9 and which follow the lines of Blaschko. These markings are very similar to those observed in Hypomelanosis of Ito (Donnai et al.1988) and other phenotypes. No evidence of chromosomal mosaicism has been found in our cases on thorough examination of the blood. Skin from cases 3,4,5 and 6 were also normal, but mosaicism for a single gene could be implicated. The condition might also be due to a new dominant mutation or possibly due to a chromosomal microdeletion. A deletion of 16q was found in one of the patients reported by Christaldi et la. (1995), but on close scrutiny the skin abnormalities seen in this case were not identical to those seen in our patients.

Although the findings of macrocephaly in association with cutis marmorata is not entirely new, previous reports have not drawn attention to the developemental problems seen in our group, and the additional features of the distinctive philtral capillary haemangioma and syndactyly of the digits. When these are taken into consideration the overall pattern of features is easily recognizable and should be considered in large babies with macrocephaly and haemangiomata. All of these cases were sporadic and both sexes appear to be equally affected and this information is useful for counselling the families of affected patients. As with other syndromes involving overgrowth and hemihypertrophy, there may be an increased risk of childhood tumours, and although none of our patients have developed tumours so far, it may be wise to screen for these by regular abdominal palpation or ultrasound scanning.