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Seminars in Fetal & Neonatal Medicine (2005) 10, 243e257

www.elsevierhealth.com/journals/siny

Craniofacial syndromes
Mohnish Suri*
Clinical Genetics Service, City Hospital, Nottingham NG5 1PB, UK

KEYWORDS
Craniofacial syndromes; Neonate; Fetus; Diagnosis; Genetics

Summary The neonate with cranio-facial dysmorphism presents a difcult diagnostic problem as only a limited number of cranio-facial syndromes can be diagnosed with condence in the neonatal period. This review outlines a systematic approach to this problem and discusses the genetic aspects and clinical features of the common cranio-facial syndromes that can be diagnosed in the neonatal period. 2005 Elsevier Ltd. All rights reserved.

The newborn with unusual cranio-facial features represents a fairly common and difcult diagnostic problem. Only a limited number of syndromes can be diagnosed with any degree of condence in the neonatal period. These are mostly syndromes in which the diagnostic cranio-facial ndings are present in the neonatal period or syndromes for which a conrmatory test (genetic, biochemical or radiological) is available. In most situations, a period of follow-up is essential to get some idea about the growth and development of the child, and also for other clinical ndings to emerge. It is also important to remember that the characteristic cranio-facial features of some syndromes are age dependent and may not be evident at birth. This review describes a systematic approach to the neonate with cranio-facial dysmorphism followed by brief descriptions of some of the more commonly encountered cranio-facial syndromes in the neonatal period.
* Tel.: C44 115 962 7728; fax: C44 115 962 8042. E-mail address: mohnishsuri@hotmail.com

Diagnostic approach
This involves taking a detailed history and carrying out a full clinical examination. This may result in a diagnosis being made based on pattern recognition. More often, however, a short-list of possible diagnoses is made based on a few key features, and appropriate investigations are then performed to try to obtain a nal diagnosis.

History
The history can be extremely important in making a diagnosis in a dysmorphic neonate. It is important to enquire about each of the following areas.  Family history. The previous birth of a similarly affected child suggests that the condition is likely to be genetic in origin. It is, however, important to consider the possibility of the mother taking a teratogenic drug (e.g. an

1744-165X/$ - see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2004.12.002

244 anticonvulsant such as sodium valproate) in successive pregnancies or that the mother is alcoholic, which could result in more than one child being born with fetal alcohol syndrome. Parental consanguinity. This suggests that the baby may have an autosomal recessive disorder. Mode of conception. Recent studies suggest that imprinting disorders such as Beckwithe Wiedemann syndrome (BWS) may be seen more frequently in children conceived by assisted reproductive techniques such as in vitro fertilisation or intracytoplasmic sperm injection.1 Maternal drug/alcohol intake. It is essential to enquire about the maternal intake of teratogenic drugs such as sodium valproate, carbimazole, vitamin A analogues (retinoic acid, tretinoin), uconazole, warfarin and methotrexate, as well as alcohol. Fetal exposure to these agents can result in cranio-facial abnormalities in the baby. Maternal illness. Viral infections in the antenatal period are unlikely to result in the birth of a baby with cranio-facial dysmorphism, but maternal diabetes mellitus can be associated with the birth of a baby with the syndrome of femoral hypoplasiaeunusual facies.2 Antenatal scan ndings. Shortening of the long bones on serial antenatal scans suggests that the baby may have a skeletal dysplasia. The identication of congenital malformations antenatally may help with syndrome identication in a dysmorphic neonate. Invasive procedures. It is important to check whether the mother had a chorionic villus biopsy or amniocentesis for fetal chromosome analysis in the antenatal period. This is likely to be the case if congenital abnormalities were identied on antenatal scans. A normal antenatal karyotype in a dysmorphic neonate should always be conrmed postnatally on a blood sample obtained from the baby, as the resolution of chromosome analysis in cultured chorionic villi and amniocytes is not as good as in a postnatal blood sample.

M. Suri Growth parameters It is important to record not only the birth weight, but also the birth length and head circumference. Increased growth parameters are more useful diagnostic handles than intrauterine growth retardation. Segmental limb shortening (rhizomelic, mesomelic, acromelic or a combination of these), and arm span and upper segment to lower segment ratio measurements are helpful in making a diagnosis of a skeletal dysplasia, particularly if this was suspected on antenatal scans. Head The most common cranial abnormalities seen in the neonatal period include an unusually head shape and size, scalp defects, abnormalities of the fontanelles and sutural ridging. Macrocephaly in the neonatal period is a good diagnostic handle if hydrocephalus has been ruled out. Many craniosynostosis syndromes present in the neonatal period with an unusual head shape such as scaphocephaly with sagittal synostosis, brachycephaly due to premature closure of the coronal sutures or plagiocephaly from closure of only one coronal or lamboid suture. Sutural ridging is a reliable clinical sign of sutural fusion, although it is seen in only a few cases, particularly with sagittal synostosis. A cloverleaf skull shape can be seen in patients with Apert syndrome, Pfeiffer syndrome or thanatophoric dysplasia. Scalp defects can be seen in Patau and WolfeHirschhorn syndromes. Face Some syndromes that can be identied by their cranio-facial dysmorphism at birth in term babies may be difcult to diagnose in premature neonates as the facial features may not be apparent at that time. One example is BWS. The characteristic facial features of this condition (facial nevus ammeus, macroglossia and earlobe creases) may not be apparent in very premature neonates but may become apparent between 30 and 36 weeks after conception.3 Findings that may be missed unless specically looked for include microphthalmia, iris colobomas, cataracts, thick alveolar margins, accessory oral frenulae, natal teeth and cleft palate. Accessory oral frenulae can be seen in the oral-facial-digital syndromes and in Ellis-van Creveld syndrome; natal teeth can also be seen in the latter condition. Coarse facial features in the neonatal period are a good diagnostic handle. The combination of micrognathia, a U-shaped cleft of the soft palate and glossoptosis, resulting in respiratory obstruction, is known as the Pierre Robin sequence, and many syndromes can present in this manner in the neonatal period.4

Neonatal examination
This involves a head-to-toe examination conducted in a systematic manner. Important diagnostic clues can be obtained not only from the cranio-facial features, but also from other parts of the examination, as outlined below.

Craniofacial syndrome Hands and feet Single transverse palmar crease is a minor variant that can be seen unilaterally in 4% of the normal population and bilaterally in about 1%.5 Deep palmar and plantar creases are a good clue to the diagnosis of mosaic trisomy 8. Other features to look for include polydactyly, syndactyly, oligodactyly, ectrodactyly, camptodactyly, arachnodactyly, absent or hypoplastic nails, and terminal transverse defects of the ngers and toes. Ulnar ray defects can be seen in patients with de Lange syndrome, whereas radial ray defects can be seen in Roberts syndrome and Fanconi anaemia. Neck Findings that should specically be looked for include short webbed neck, torticollis, branchial pits or sinuses and thyromegaly. Chest This should include an examination of chest shape and size (a narrow chest can be seen in skeletal dysplasias), anterior axillary folds, nipples and heart. Many cranio-facial syndromes can present with congenital heart disease in the neonatal period, and this is not helpful for syndrome identication. Exceptions to this rule include atrioventricular septal defect in Down syndrome, cono-truncal abnormalities in 22q11 deletion syndrome and Ebstein anomaly in monosomy 1p36. Abdomen Anterior abdominal wall defects, particularly exomphalos, can be seen in BWS. Hepatosplenomegaly in a neonate with coarse facial features suggests an underlying metabolic disorder such as I-cell disease or GM1 gangliosidosis, or BWS. Abdominal distension can be the result of renal enlargement or ascites. Skin There are very few cranio-facial syndromes that present with diagnostic skin abnormalities in the neonatal period. Linear, erythematous areas of skin hypoplasia over the face, neck and upper trunk may be seen with microphthalmia and sclerocornea in the MIDAS syndrome.6 Cutis marmorata telangiectatica congenita (CMTC) can be seen in association with macrocephaly and a philtral haemangioma in the syndrome of macrocephalyeCMTC.7 External genitalia Ambiguous genitalia or sex reversal in dysmorphic neonates with a normal male karyotype should

245 raise the possibility of campomelic dysplasia or SmitheLemlieOpitz syndrome. Spine A prominent caudal appendage may be seen in PallistereKillian syndrome, and abnormalities of the cervical spine can be seen in Goldenhar syndrome. Tone and reexes Severe hypotonia without any signicant muscle weakness (central hypotonia) is seen in Down syndrome, PradereWilli syndrome and Zellweger syndrome. Hypertonia is seen less frequently in neonates and may be a feature of Edwards syndrome and MillereDieker syndrome.

Parental examination
Both parents should be examined, if possible, for the cranio-facial features and other ndings (such as abnormalities of the ngers and toes) identied in their baby. Some of these ndings may represent familial variants (e.g. synophrys, prominent nose, up-slanting palpebral ssures, low-set or anteverted ears), but it is also possible that one of the parents may have the same condition as their baby but not be aware of this because they have a milder phenotype. Examples include the 22q11 deletion syndrome, Stickler syndrome and ectrodactylyeectodermal-dysplasiaeclefting (EEC) syndrome.

Diagnostic groups
After taking a detailed history and carrying out a thorough physical examination, the clinician may be able to make a diagnosis by pattern or gestalt recognition or by using a few key clinical ndings to put the neonate into broad diagnostic groups. The main diagnostic groups are listed below. This is a very practical approach because it allows the clinician to restrict the diagnoses that need to be considered to a manageable number. Some conditions may appear in more than one diagnostic group, which makes it less likely that the diagnosis will be missed.  Gestalt diagnoses e Cornelia de Lange syndrome e Cri-du-chat syndrome e CHARGE association e Down syndrome e Patau syndrome

246 e WolfeHirschhorn syndrome e Oculo-auriculo-vertebral spectrum (OAVS) Coarse facial features e BWS e Fryns syndrome e GM1 gangliosidosis e I-cell disease e PallistereKillian syndrome e SimpsoneGolabieBehmel syndrome Pierre Robin sequence e 22q11 Deletion syndrome e Stickler syndrome e Campomelic dysplasia e Cerebro-costo-mandibular syndrome e Diastrophic dysplasia e Femoral hypoplasiaeunusual facies syndrome e Fetal alcohol syndrome e Treacher Collins syndrome Neonatal overgrowth e BWS e MacrocephalyeCMTC (MeCMTC) e Perlman syndrome e SimpsoneGolabieBehmel syndrome e Sotos syndrome Oro-facial clefting e Patau syndrome (midline cleft lip and palate) e EEC syndrome (cleft lip and palate) e Stickler syndrome (cleft palate) e 22q11 Microdeletion syndrome (cleft palate) e Oro-facial-digital syndromes (midline cleft lip and palate) e Van der Woude syndrome (cleft lip and palate) Craniosynostosis syndromes e Apert syndrome e Crouzon syndrome e Pfeiffer syndrome e AntleyeBixler syndrome e BeareeStevenson syndrome Limb abnormalities e Apert syndrome e Cornelia de Lange syndrome e Edwards syndrome e EEC syndrome e Mosaic trisomy 8 e Neonatal Marfan syndrome Abnormal neurology e MillereDieker syndrome e Patau syndrome e Zellweger syndrome Genital anomalies e Campomelic dysplasia e Opitz G syndrome e SmitheLemlieOpitz syndrome e CHARGE association  Skeletal dysplasias e Achondroplasia e Campomelic dysplasia e Diastrophic dysplasia e Ellis-van Creveld syndrome e Stickler syndrome

M. Suri

Investigations
The following investigations may be helpful in providing a diagnosis for a dysmorphic neonate. Chromosome analysis All dysmorphic neonates should be karyotyped. Clinical ndings suggesting that the neonate has an underlying chromosomal abnormality include symmetrical intrauterine growth retardation, hypotonia, multiple minor anomalies, major congenital malformations and a history of recurrent miscarriage in the parents. Chromosome analysis is routinely performed on peripheral blood lymphocytes. However, mosaic chromosomal abnormalities such as mosaic trisomy 8 and PallistereKillian syndrome may be difcult to detect in peripheral blood lymphocytes as the abnormal cell line is often lost from the blood. A skin biopsy may be helpful for conrming these diagnoses as skin is a slow-growing tissue and the abnormal cell line tends to persist in cultured skin broblasts or keratinocytes. Fluorescent in situ hybridisation Fluorescent in situ hybridisation (FISH) is a molecular cytogenetic technique used to detect chromosomal microdeletions that may be missed on routine chromosome analysis. FISH analysis can be used to conrm the diagnosis of WolfeHirschhorn syndrome, MillereDieker syndrome and 22q11 deletion syndrome. In situations in which a skin biopsy cannot be obtained for the diagnosis of PallistereKillian syndrome or mosaic trisomy 8, buccal smears can be obtained from the neonate and analysed by an appropriate FISH probe to conrm these diagnoses.8 Interphase FISH on uncultured blood samples can be used for the rapid detection of the common chromosomal aneuploidies in neonates.9 This should, however, always be followed by routine cytogenetic analysis of cultured peripheral blood lymphocytes to conrm the results obtained. Molecular genetic tests These are helpful only in a few situations. One example is BWS; molecular genetic tests will identify between 60% and 70% of neonates with this syndrome. Diagnostic molecular genetic tests are

Craniofacial syndrome also available for Apert syndrome and Crouzon syndrome, but these are essentially clinical diagnoses. A diagnostic molecular test is available for achondroplasia but this diagnosis can be conrmed by the characteristic clinical and radiological ndings that are apparent in the neonatal period. Metabolic tests These are indicated mainly in neonates with coarse facial features, who are likely to have an underlying metabolic disorder, and in neonates with severe hypotonia. Helpful metabolic tests include urine organic acids, glycosaminoglycans, oligosaccharides, sialic acid and a white cell and plasma lysosomal enzyme screen. Elevated levels of plasma very long-chain fatty acids and reduced levels of plasmalogens in the red cells can be used to conrm the diagnosis of Zellweger syndrome, and elevated plasma levels of 7-dehydrocholesterol is a conrmatory test for SmitheLemlieOpitz syndrome. Other useful metabolic tests include plasma glucose levels in neonates with BWS and plasma calcium levels in patients in whom the diagnosis of 22q11 deletion syndrome is suspected. Radiology A skeletal survey should be requested in neonates with evidence of limb shortening on antenatal scans and limb shortening or disproportionate short stature at birth. The skeletal survey can be used to conrm the diagnosis of achondroplasia, campomelic dysplasia and Stickler syndrome in the neonatal period. Ellis-van Creveld syndrome can also be diagnosed in the neonatal period based on the characteristic clinical and radiological ndings. A skeletal survey may also be indicated in some neonates with Pierre Robin sequence as several skeletal dysplasias can present in this manner. Periosteal cloaking of the long bones can be seen in neonates with I-cell disease, even if they are born prematurely. A chest X-ray may show an absent thymic shadow in neonates with the 22q11 deletion syndrome, and an X-ray of the knee may show patellar or epiphyseal stippling in neonates with Zellweger syndrome. X-rays of the cervical spine are indicated in neonates with suspected Goldenhar syndrome as cervical vertebral abnormalities are an important feature of this condition, and skull X-rays can be used to conrm the presence of craniosynostosis in patients with Apert or Crouzon syndrome. Neuroimaging Cranial ultrasound or magnetic resonance imaging (MRI) can be helpful in some situations. An MRI brain scan will show classical (type I) lissencephaly in the neonate with MillereDieker syndrome,

247 neuronal heterotopia in patients with Zellweger syndrome, hydrocephalus in neonates with MeCMTC and agenesis of the corpus callosum in neonates with mosaic trisomy 8. Echocardiogram This is indicated in all neonates with a cardiac murmur, a chromosomal abnormality, CHARGE association, Ellis-van Creveld syndrome, Cornelia de Lange syndrome and neonatal Marfan syndrome. Renal ultrasound scan This is helpful in patients with suspected Zellweger syndrome as they can have renal cysts at birth. Hydronephrosis can be seen in neonates with mosaic trisomy 8, horseshoe kidney in patients Edwards syndrome and nephromegaly in neonates with BWS. Renal abnormalities are frequently seen in patients with 22q11 deletion syndrome. Eye examination Cataracts are a feature of Zellweger syndrome, and cataracts, high myopia and vitreous abnormalities with retinal detachment can be seen in the neonatal period in patients with Stickler syndrome. Hearing test All neonates with CHARGE association and Stickler syndrome should have their hearing tested in the neonatal period. Tests of immune function These are rarely indicated in the neonatal period, with the possible exception of 22q11 deletion syndrome, in which T cell function should be tested prior to any live vaccinations being given to the baby.

Follow-up
If no diagnosis can be made in the neonatal period, arrangements must be made to follow the baby up as a diagnosis could emerge over time. It is far better to tell the parents that no diagnosis can be made at this stage rather then trying to t the child into a diagnosis. Diagnostic labels tend to stick and can be very difcult to remove at a later stage if the diagnosis is wrong, particularly if no alternative diagnosis can be made.

Common cranio-facial syndromes


This section describes the antenatal and neonatal ndings, the genetic aspects and the diagnosis of the most frequently seen cranio-facial syndromes of

248 the neonatal period. The reader is referred to one of the classical text books of dysmorphology10,11 and the WintereBaraitser dysmorphology database12 for a detailed description of the other cranio-facial syndromes mentioned in the previous section.

M. Suri cases have free trisomy 13, and 20% have an unbalanced rearrangement, mostly Robertsonian translocations between the long arm of one chromosome 13 and one chromosome 14.14 Mosaicism has been described and is associated with a milder phenotype and a longer survival. Between 90% and 100% of fetuses with this condition can be detected by antenatal scanning in the second trimester. Sonographic features of trisomy 13 include holoprosencephaly, midline facial anomalies such as cyclopia, hypotelorism and clefts, polydactyly, exomphalos, a single umbilical artery, congenital heart disease, intracardiac echogenic foci and polycystic kidneys.15 Newborns with trisomy 13 have characteristic cranio-facial features that include scalp defects (Fig. 1b), microcephaly with sloping forehead, hypotelorism, microphthalmia with iris colobomas, dysplastic ears, premaxillary agenesis or non-midline cleft lip, micrognathia and cleft palate. Postaxial polydactyly of the ngers (Fig. 1c) and toes is a helpful diagnostic clue. Major congenital malformations that are apparent in the neonatal period include holoprosencephaly, ocular abnormalities such as microphthalmia, iris colobomas and retinal dysplasia, cleft lip and palate, congenital heart disease, renal abnormalities such as cystic dysplasia, and genital abnormalities. The latter include hypospadias and cryptorchidism in males and clitoromegaly in females. Holoprosencephaly can be seen in 70% of patients with Patau syndrome, and this diagnosis should be suspected in any neonate with one of the characteristic facial phenotypes that are associated with holoprosencephaly (premaxillary agenesis, ethmocephaly, cebocephaly, cyclopia).19 The diagnosis can be conrmed by chromosome analysis on a blood sample. The median survival time is 2.5e7 days, with 90% of patients dying in infancy.18,20

Down syndrome (trisomy 21)


This is the most frequently encountered chromosomal abnormality at birth. The pregnancy prevalence of Down syndrome has risen due to increasing maternal age, but the widespread availability of antenatal screening tests for Down syndrome with the termination of affected pregnancies has reduced its birth prevalence from 1 in 700 to approximately 1 in 1000.13 About 95% of patients have free trisomy 21, 3e4% have an unbalanced translocation (usually a Robertsonian translocation between the long arm of one chromosome 14 and one chromosome 21), and 1e2% have mosaic trisomy 21.14 Antenatal scans can identify 65e75% of fetuses with Down syndrome.15 Sonographic markers of Down syndrome include thickened nuchal fold, cystic hygroma, hydrops, ventriculomegaly, echogenic intracardiac focus, congenital heart disease (particularly atrioventricular septal defect), duodenal atresia, mild renal pyelectasia and talipes.15 The main features in the neonatal period include at facial prole, up-slanting palpebral ssures, small nose, small dysplastic ears, excess nuchal skin folds, single palmar creases, fth nger clinodactyly, dysplasia of the pelvis, hypotonia with a poor Moro reex and hyperextensible joints.16 The diagnosis is, however, usually made by the overall facial gestalt. Other minor anomalies include Brusheld spots, epicanthic folds and a sandal gap (a wide gap between the big toe and the second toe). Congenital heart disease can be seen in 44% of patients, almost half of whom have an atrioventricular septal defect, and all neonates with Down syndrome should have an echocardiogram.17 Gastrointestinal abnormalities that can present in the neonatal period include duodenal atresia, annular pancreas and Hirschsprung disease. The diagnosis can be conrmed by routine chromosome analysis on a blood sample. Where mosaic Down syndrome is suspected, the cytogenetics laboratory should be informed so that a greater number of lymphocyte metaphases (at least 30) can be analysed.

Edward syndrome (trisomy 18)


Recent studies, following the advent of prenatal diagnosis, show that the birth incidence of trisomy 18 is between 1 in 6000 and 1 in 8000.18,21 Almost all cases show free trisomy 18, with a minority showing mosaic trisomy 18.14 Antenatal ndings include growth retardation, increased nuchal thickness with cystic hygroma, choroid plexus cysts and posterior fossa abnormalities such as DandyeWalker malformation, micrognathia, clenched hands with overlapping ngers, radial ray defects, congenital heart disease, exomphalos, neural tube defects and rocker-bottom feet.15 The main clinical features in the newborn include symmetrical intrauterine growth retardation,

Patau syndrome (Trisomy 13)


Recent studies suggest that the birth incidence of Patau syndrome is about 1 in 10 000.18 About 80% of

Craniofacial syndrome

249

Figure 1 Diagnostic features of chromosomal abnormalities. (a) Overlapping ngers with hypoplastic nails in Edwards syndrome. (b) Scalp defect in Patau syndrome. (c) Post-axial polydactyly in Patau syndrome. (d) Deep plantar furrows in mosaic trisomy 8.

cranio-facial dysmorphism, overlapping ngers with hypoplastic nails (Fig. 1a), short sternum and rocker-bottom feet. The facial features are subtle and include prominent occiput, bifrontal narrowing, low-set dysplastic ears, small mouth and micrognathia. Major congenital malformations that can

present in the neonatal period include congenital heart disease, particularly ventricular septal defect, renal abnormalities such as horseshoe kidneys, and undescended testes in males. The best clues to the diagnosis are the overlapping ngers with hypoplastic nails, and the diagnosis can be

250 conrmed by chromosome analysis on a blood sample. Median survival varies from 3 to 14.5 days, 90% of patients dying in infancy.18,20,21 The most common mode of death appears to be central apnoea.21 Mosaic trisomy 18 is associated with longer survival.

M. Suri of the hips, talipes and severe hypotonia. The facial features in the neonatal period include a round face, down-slanting palpebral ssures, hypertelorism, dysplastic, low-set and posteriorly rotated ears, and down-turned angles of the mouth. The name of the syndrome is derived from the characteristic high-pitched, cat-like cry of affected babies, but this is not seen in all cases and may also be seen in babies with other chromosomal abnormalities. The characteristic facial features and high-pitched cry should alert the neonatologist to this diagnosis, which is conrmed by routine chromosome analysis and FISH analysis with a probe from the critical region.

WolfeHirschhorn syndrome
This condition is also called 4p syndrome because it is the result of a terminal deletion of the distal short arm of chromosome 4. Almost all patients have a deletion involving a 165 kb region at 4p16.3.22 Deletions smaller than 3.5 Mb are associated with a milder phenotype without any congenital malformations.23 About 13% of patients have an unbalanced translocation.24 It has a minimum birth incidence of about 1 in 96 000.25 The condition can only be diagnosed by routine chromosome analysis in 58% of cases, but FISH analysis with a probe from the critical region at 4p16.3 will detect the deletion in over 95% of cases.24 The clinical features in the neonatal period include intrauterine growth retardation, craniofacial dysmorphism, cleft lip and palate, congenital heart disease (usually atrial septal defect or ventricular septal defect), sacral dimple, hypospadias and cryptorchidism in males, talipes and hypotonia. The characteristic cranio-facial features that may alert the neonatologist to the diagnosis are facial asymmetry, a Greek-warrior helmet appearance of the forehead with prominent forehead and glabella associated with hypertelorism, highly arched eyebrows, low-set ears with pre-auricular pit, short philtrum, downturned angles of the mouth and micrognathia. Ocular malformations such as microphthalmia and iris colobomas can also be seen. About 17e18% of patients die in infancy, with 50% of all deaths occurring in the neonatal period.25 Survivors usually have severe developmental delay and learning difculties.

Mosaic trisomy 8
This has a birth frequency of about 1 in 30 000.30 Patients with this condition have two cell lines, one with a normal karyotype and the other with trisomy 8. The degree of mosaicism varies from one tissue to another, but the phenotype does not appear to depend on the degree of mosaicism.14 The main ndings in the neonatal period include normal birth weight, non-specic cranio-facial features (low-set dysplastic ears, micrognathia), agenesis of the corpus callosum, camptodactyly of the ngers, deep palmar creases, congenital heart disease, spondylocostal abnormalities (buttery vertebrae and rib anomalies), hydronephrosis, cryptorchidism in males and characteristic deep plantar furrows (Fig. 1d). The latter nding is a good clue to the diagnosis. Camptodactyly of the ngers may also be seen, although this can appear later. Fewer than 10% of patients die during the rst 2 years of life.14 It may be possible to conrm this diagnosis in the neonate by looking for the trisomic cell line in a blood sample. The cytogenetics laboratory should, however, be informed so that they can examine at least 30 metaphases. If the diagnosis is strongly suspected clinically but the blood karyotype is normal, a skin biopsy should be performed to look for the trisomic cell line in cultured skin broblasts.

Cri-du-chat syndrome
This condition is also called 5p syndrome. It has a birth incidence of 1 in 15 000 to 1 in 50 000.26,27 Most patients have a terminal deletion of the short arm of chromosome 5, although interstitial deletions and unbalanced translocations involving 5p can also be seen.28 The critical region that is deleted in all patients is 5p15.2.29 The neonatal phenotype of cri-du-chat syndrome includes intrauterine growth retardation, microcephaly, feeding difculties, cranio-facial dysmorphism, congenital heart disease, congenital dislocation

22q11 deletion syndrome


This is the most common chromosomal microdeletion syndrome, with a minimum birth prevalence of 1 in 4000.31 It has a wide phenotypic spectrum, but the most common presentations in the neonatal period include DiGeorge syndrome and Pierre Robin sequence. Clinical features of DiGeorge syndrome include rather mild

Craniofacial syndrome cranio-facial dysmorphism, such as hypertelorism, low-set ears, micrognathia and cleft palate, congenital heart disease, particularly cono-truncal abnormalities such as interrupted aortic arch, Fallots tetralogy and truncus arteriosus, and hypocalcaemia. Abnormal T cell function is an important feature of DiGeorge syndrome, and the thymic shadow may be absent on a chest X-ray. Another phenotype of the 22q11 deletion is the velocardiofacial or Shprintzen syndrome, which can present in the neonatal period as Pierre Robin sequence.4 Renal anomalies can be seen in the antenatal period, and neonates with the 22q11 deletion can present with Potter sequence.32,33 Over 85% of patients have a 3 Mb deletion and about 8% a 1.5 Mb deletion, and these can all be detected by FISH analysis with the N25 probe.34

251 inner ear, and cranial nerve dysfunction (anosmia, facial nerve palsy, deafness and vestibular problems, or swallowing problems). Minor criteria include genital hypoplasia, developmental delay, cardiovascular abnormalities, short stature, cleft lip or palate, tracheo-oesophageal defects and characteristic facial features. The precise cause of CHARGE syndrome is unknown. There is some overlap with DiGeorge syndrome, and the 22q11 deletion has been identied in a few patients.38 There is also overlap with Goldenhar syndrome, VATER association and retinoic acid embryopathy.

Oculo-auriculo-vertebral spectrum (OAVS)


This condition may have a birth prevalence of 1 in 5600.39 This is a clinical diagnosis based entirely on the facial features. Patients with unilateral facial involvement are classied as having hemifacial microsomia, and patients with bilateral facial involvement are classied as rst and second branchial arch syndrome. The term Goldenhar syndrome is used to refer to patients with OAVS who have bilateral facial involvement, epibulbar dermoid and vertebral abnormalities. The facial features of OAVS include facial asymmetry, eyelid colobomas, epibulbar dermoid, variable ear malformations ranging from absent ear to microtia or a small but normally formed ear, pre-auricular sinuses, skin tags that may be present along a line from the tragus to the angle of the mouth, malar hypoplasia, macrosomia or pseudomacrosomia due to a cleft or pseudocleft of the angle of the mouth, and mandibular hypoplasia. Additional features that can be seen in some patients include abnormalities of the cervical spine, such as fused vertebrae or hemivertebrae, malformations of the central nervous system, multiple cranial nerve palsies, radial ray abnormalities, congenital heart disease and renal abnormalities. The cause of this condition is unknown. Monozygotic twins may be discordant for OAVS.40 Chromosome analysis should be performed in all cases.

CHARGE syndrome
This is a multiple congenital abnormality syndrome that has an estimated birth frequency of 1 in 10 000e15 000.35 CHARGE is an acronym of the major clinical features of this condition, which includes coloboma of the iris, retina or optic disc, congenital heart disease, choanal atresia, growth and mental retardation, genital abnormalities in males (small penis or cryptorchidism), ear abnormalities, facial palsy and congenital deafness. Other congenital abnormalities that can be seen in CHARGE syndrome include cleft palate, malformations of the central nervous system, tracheooesophageal stula and renal malformations.36 The condition should be suspected in any neonate with choanal atresia or iris colobomas. The craniofacial features in the neonatal period include asymmetrical facies, unilateral facial palsy, iris colobomas, malformed ears, small mouth and cleft palate. The classic CHARGE ears are asymmetrical, low-set and small, are simple or cup-shaped, may stick out at right angles from the side of the head and have a hypoplastic antihelix, a triangular concha or small or absent lobes. Ossicular malformations, aplasia of the semicircular canals and Mondini dysplasia of the cochlea may be seen on computed tomography or MRI scans of the temporal bones. Hearing should be tested in the neonatal period in all patients with CHARGE syndrome. The criteria for the diagnosis of CHARGE syndrome were recently expanded.37 According to these criteria, the diagnosis of CHARGE syndrome should be considered in any neonate with 4 major criteria or 3 major and 3 minor criteria. The major criteria include coloboma, choanal atresia, characteristic abnormalities of the external, middle or

BeckwitheWiedemann syndrome (BWS)


This condition has an estimated birth frequency of 1 in 12 000.41 Antenatal ndings include exomphalos, hepatomegaly, nephromegaly, polyhydramnios and accelerated fetal growth.42 However, polyhydramnios and accelerated fetal growth may only be evident between 25 and 36 weeks gestation.42 The major clinical features of BWS include

252 prenatal and/or postnatal overgrowth (birth weight and subsequent growth above the 90th centile), macroglossia and anterior abdominal wall defects (exomphalos or umbilical hernia). Minor features include characteristic ear signs (ear lobe creases or rounded depressions over the posterior helical rim), facial naevus ammeus (V-shaped capillary haemangioma over the forehead in the midline), hemihyperplasia (which may be present at birth), nephromegaly and neonatal hypoglycaemia. The diagnosis is made when 3 major features or 2 major and 3 minor features are present.43 Neonates with BWS may have coarse facial features, and the characteristic facial features may be absent in premature neonates.3 Monozygotic twins discordant for BWS have been reported.44 The genetics of BWS are complex. The condition is thought to result from dysregulation of several imprinted genes associated with cell cycle and growth control on chromosome region 11p15.45 About 2% of patients have a chromosomal abnormality involving 11p15, such as a paternally inherited duplication or a maternally inherited balanced or unbalanced translocation, insertion or inversion of this region. Approximately 10e20% of patients have mosaic paternal uniparental disomy (UPD) of 11p15. These patients have a paternal inheritance of both 11p15 regions in some of the cells of their body and a biparental inheritance of this region in the other cells. Recent studies suggest that almost 50% of patients with BWS have a loss of maternal methylation at the KvDMR1 locus at 11p15, and 5e10% of sporadic cases have mutations in the CDKN1C (p57KIP2) gene at 11p15.45 The precise molecular mechanism responsible for BWS in the remaining patients has not been elucidated. The diagnosis can be conrmed in about 60e70% of patients by the combination of chromosome analysis, microsatellite marker analysis to look for paternal UPD at 11p15 and methylation studies at the KvDMR1 locus. Blood samples are needed from the baby and both parents to test for paternal UPD for 11p15. A diagnostic service for CDKN1C (p57KIP2) mutation analysis is not available.

M. Suri 80% of cases are the result of new mutations. Antenatal scans seldom show signicant limb shortening before 26e28 weeks gestation, but the condition can often be diagnosed at birth. Clinical ndings in the neonatal period include reduced birth length with rhizomelic limb shortening, macrocephaly with frontal prominence, at nasal bridge, midface hypoplasia and trident anomaly of the hands (splaying of the second, third and fourth ngers). The radiological features are diagnostic and include enlarged calvarium, shortening of the long bones, shortening of the metacarpals and phalanges, progressive narrowing of the interpedicular distances or failure of the interpedicular distances to widen from L1 to L5 vertebrae, square-shaped iliac bones, horizontal acetabulae with a medial spike, narrowing of the greater sciatic notch, radiolucent areas at the proximal ends of the femora, sloping metaphyses of the distal femora and proximal tibia due to incomplete ossication (Fig. 2aee). Cranial ultrasound scans may show ventriculomegaly in some patients. Molecular genetic testing is available but is not usually needed for conrmation of the diagnosis.

Campomelic dysplasia
This is an autosomal dominant skeletal dysplasia that has a birth prevalence of 1 in 6250e 100 000.49,50 It is caused by mutations in the SOX9 gene at 17q24.3eq25.1, and most cases represent new mutations.51 A few cases have a chromosomal abnormality involving 17q23eq25, either a balanced translocation or an inversion, and in these patients the translocation breakpoint appears to interfere with the expression of the SOX9 gene by a position effect.52 Antenatal scans may show cystic hygroma, polyhydramnios and shortening of the long bones with bowing of the femora and tibia from 16e18 weeks gestation, with narrowing of the thorax, and talipes.53 There is respiratory distress in the neonatal period due to severe tracheomalacia, narrow thorax or Pierre Robin sequence. Striking limb shortening with bowing of the lower limbs and pretibial skin dimples is evident at birth. Craniofacial features include macrocephaly, large anterior fontanelle, at nasal bridge, low-set ears, cleft palate, micrognathia and short neck. Sex reversal or ambiguous genitalia are often seen in karyotypic males and are an important diagnostic clue. Other abnormalities include congenital heart disease and renal abnormalities such as hydronephrosis.

Achondroplasia
This is the most common non-lethal skeletal dysplasia, with a birth incidence of 1 in 16 000.46 Achondroplasia is an autosomal dominant disorder that is caused by mutations in the FGFR3 gene at 4p16.3.47 Almost all patients have the same mutation, a glycine to arginine substitution at position 380 (Gly380Arg) in the FGFR3 polypeptide.48 Over

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Figure 2 Skeletal survey showing radiological features of achondroplasia. (a) Macrocephaly. (b) Short metacarpals and phalanges. (c) Narrowing of interpedicular distances of the lumbar vertebrae from L1 to L5. (d) Square iliac bone with at acetabulum, narrow sacrosciatic notch and short femur with proximal metaphyseal lucency and sloping distal metaphysis. (e) Short tibia with sloping proximal metaphysis.

The radiological ndings are diagnostic and include hypoplastic scapulae, narrow, bell-shaped chest with failure of mineralisation of the pedicles of the thoracic vertebrae, narrow vertical iliac wings, dislocation of the hips, shortening of the long bones with bowing of the femora and tibiae, and delayed ossication of the distal femoral epiphysis (Fig. 3). Almost 80% of babies die in the neonatal period, most in the rst 24 h.53 Long-term survival has been reported in a small number of cases. Chromosome analysis should be performed in all cases, as patients

with a chromosome abnormality appear to have a milder phenotype. Molecular genetic testing is not available at this time.

Stickler syndrome
This is an autosomal dominant skeletal dysplasia that can be diagnosed in the neonatal period. Most cases are caused by mutations in the COL2A1 gene at 12q13, but mutations in the COL11A1 gene at 1p21 and COL11A2 gene at 6p21 can be seen in

254

M. Suri at 11q12eq13.58 Antenatal ndings include intrauterine growth retardation as an isolated nding or with other anomalies such as nuchal oedema, polydactyly and renal, cardiac, cerebral or genital anomalies.59 Neonatal ndings include intrauterine growth retardation, microcephaly, feeding difculties, hypotonia, cranio-facial dysmorphism, cleft palate, post-axial polydactyly of the hands and feet, congenital heart disease, renal abnormalities, sex reversal or ambiguous genitalia in karyotypic males, and syndactyly of the second and third toes. The cranio-facial features may draw attention to the diagnosis and include bifrontal narrowing, ptosis, small anteverted nose, low-set ears and micrognathia. The diagnosis can be conrmed by nding elevated plasma or tissue levels of 7dehydrocholesterol and low levels of cholesterol. Genetic testing has limited availability and is not needed for diagnosis.

Figure 3 Babygram showing the radiological features of campomelic dysplasia. Note hypoplastic scapulae, narrow chest, failure of ossication of the pedicles of the thoracic vertebrae, tall iliac bone and bowing of the femora and tibiae.

Cornelia de Lange syndrome


This is an autosomal dominant condition that has a birth prevalence of 1 in 10 000.60 It is caused by mutations in the NIPBL gene on 5p13.1.61 Most cases represent new mutations. The condition presents in the neonatal period with symmetrical intrauterine growth retardation, characteristic cranio-facial features, limb abnormalities, facial and body hirsutism, congenital heart disease and genitourinary abnormalities. Some children with this condition are born with a diaphragmatic hernia. The cranio-facial features include microbrachycephaly, excessive hair over the face, pencilled eyebrows with synophrys (eyebrows that meet in the midline), small anteverted nose, hairy dysplastic and low-set ears, long philtrum, thin upper lip, down-turned angles of the mouth and micrognathia. The limb abnormalities are very variable and range from ectrodactyly (Fig. 4a) to ulnar ray defects and small hands with single palmar creases, short clinodactylous fth ngers and proximally implanted thumbs. The diagnosis is clinical and based on the classical facial and limb abnormalities.

some cases.54 Stickler syndrome can present in the neonatal period with Pierre Robin sequence. It is the most frequent cause Pierre Robin sequence and accounts for about 13% of patients with this condition.55 Other cranio-facial features in the neonatal period include prominent eyes, midfacial hypoplasia and small nose. Rhizomelic limb shortening, ocular abnormalities, such as high myopia, cataracts and retinal detachment, and sensorineural hearing loss can also be seen in the neonatal period. The diagnosis can be made by the characteristic radiological ndings, which include shortening of the long bones, particularly the femora, with metaphyseal aring and coronal clefts of the thoracolumbar vertebrae.56 All neonates with Pierre Robin sequence or suspected Stickler syndrome should have regular eye examinations and hearing tests. The diagnosis is based on the clinical and radiological ndings. Molecular genetic testing is only available on a research basis.

Apert syndrome SmitheLemlieOpitz syndrome


This is a rare autosomal recessive disorder with a birth prevalence of 1 in 20 000 to 1 in 40 000.57 It is caused by a deciency of one of the enzymes in the cholesterol synthesis pathway, 3b-hydroxysterolD7-reductase, which is encoded by the gene DHCR7 This autosomal dominant craniosynostosis syndrome has a birth prevalence of 1 in 65 000.62 It is caused by mutations in the FGFR2 gene at 10q26, two missense mutations (Ser252Trp and Pro253Arg) accounting for almost all cases.63 Most cases represent new mutations. Clinical features in the

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Figure 4 Diagnostic features of Cornelia de Lange and Apert syndromes. (a) Ectrodactyly and cutis marmorata in a neonate with Cornelia de Lange syndrome. (b) Mitten-hand abnormality in Apert syndrome. (c) Mitten-feet abnormality in Apert syndrome.

neonatal period include an abnormal head shape (turri-brachycephaly) due to fusion of the coronal sutures and basal calvarial sutures, hypertelorism with proptosis, beaked nose, low-set ears, prominent lateral palatine ridges and high arched or cleft palate. The diagnosis is based on the characteristic mitten deformity of the hands and feet, with syndactyly of the second, third and fourth ngers or toes or all ve digits with fusion of the nails and with multiple bony synostoses (Fig. 4b and c). The diagnosis is easy to make clinically and can be conrmed by molecular genetic analysis.

Conclusion
Only a limited number of cranio-facial syndromes can be diagnosed in the neonatal period. A systematic approach is helpful, but in many cases the diagnosis is likely to be obtained at follow-up when information is available about growth and development, and, in some cases, with the gradual evolution of the facial phenotype. A major gene for CHARGE syndrome has recently been identied (Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, et al.

256 Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 2004;36:955-957). The gene, called CHD7, encodes chromodomain helicase DNA-binding protein-7 and is located on the long arm of chromosome 8 (8q12). Deletions of CHD7 or mutations in this gene may account for most cases of CHARGE syndrome.

M. Suri

References
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Practice points
 Only a limited number of cranio-facial syndromes can be condently diagnosed in the neonatal period  A systematic approach is essential for diagnosis  Always examine the parents of a neonate with cranio-facial dysmorphism  Chromosome analysis is an integral part of the diagnostic work-up of a dysmorphic neonate  In many neonates with cranio-facial dysmorphism, a diagnosis may only be obtained on follow-up

Research directions
Much progress has been made in the identication of genes for rare cranio-facial syndromes. This has resulted in the ability to diagnose an increasing number of cranio-facial syndromes in the neonatal period by molecular genetic analysis. However, at the present time genetic testing for many of these conditions is only available from a small number of research laboratories. Transfer of genetic testing to diagnostic laboratories may make genetic testing more widely available but the costs of analysis are likely to be signicant and may prevent accessibility to conrmatory genetic testing in many situations. Newer, more rapid and, hopefully, cheaper techniques of mutation analysis may make accessibility to genetic testing more widely available. Another major focus of ongoing research into the rare craniofacial syndromes is likely to be the determination of the natural history of many of these conditions, particularly the adult phenotype, as many parents would like to know the longterm prognosis for their children.

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