6JMed Genet 1997;34:366-370

Further delineation of Nevo syndrome

L I Al-Gazali, D Bakalinova, E Varady, J Scorer, M Nork

AbstractNevo syndrome is an autosomal recessivesyndrome characterised by prenatal over-growth, joint laxity, kyphosis, wrist drop,spindle shaped fingers, and volar oedema.Four children from two families have beenreported previously. We report two fur-ther children from two unrelated Arabfamilies from two different tribes. Bothpresented at birth with hypotonia, jointlaxity, kyphosis, wrist drop, spindleshaped fingers, and volar oedema. Bothhave delayed motor development at theages of 2 years 10 months and 3 monthsrespectively. Cognitive development isnormal in one, and the other case appearsto be developing normally at 3 months ofage. One has, in addition, a wide spinalcanal on MRI of the spine indicating somedegree ofdural ectasia. This report bringsthe total number ofchildren reported withthis syndrome to six from four families;three of these families are Arab. Thisindicates that the gene for this syndromeis probably commoner in Arabs than inother populations.(JMed Genet 1997;34:366-370)

Keywords: Arabs; joint laxity; overgrowth

A

B

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v.. \ . #/Figure 1 Case 1 at 3 months (A) and 2 years 10 months(B). Note deep set eyes with epicanthic folds, large, low setears, hyperextended neck, and kyphosis. (Photographsreproduced with permission.)

Department ofPaediatrics, Faculty ofMedicine and HealthSciences, United ArabEmirates University,PO Box 17666, Al Ain,UAEL I Al-Gazali

Department ofRadiology, Faculty ofMedicine and HealthSciences, United ArabEmirates University,Al Ain, UAED Bakalinova

Department ofPaediatrics, TawamHospital, Al Ain, UAEE VaradyJ Scorer

Department ofRadiology, TawamHospital, Al Ain, UAEM Nork

Correspondence to:Dr Al-Gazali.

Received 27 June 1996Revised version accepted forpublication 26 November1996

Nevo et al' reported three cases from an inbredArab family with prenatal overgrowth, hypoto-nia, kyphosis, and wrist drop with spindleshaped fingers. They suggested that their casesrepresented autosomal recessive Sotos syn-drome. Cohen2 suggested that the combinationof abnormalities in the children described byNevo et al' were striking and could represent apreviously undescribed syndrome. Hilderinkand Brunner3 reported a child from a consan-guineous Dutch family with similar features.We report two other children from twounrelated Arab families with this syndrome.

Case reportsCASE 1This male child is the fourth child of a highlyinbred Arab family from the UAE. The parentsand all the other children are normal. Preg-nancy and delivery at term were normal. Hisbirth weight was 2780 g (<10th centile). Nolength or head circumference measurementsare available. After birth he was noted to behypotonic with lax joints and dorsal kyphosis.He had the following dysmorphic features: aprominent forehead with bitemporal narrow-ing, deep set eyes with epicanthic folds, higharched palate, and large, abnormal, low set ears(fig 1). He kept his neck in a hyperextendedposition. His shoulders were high and the chest

Figure 2 Case 1. Wrist drop with spindle shapedfingers.

was narrow. The hands and feet were large andoedematous. In addition, there was wrist drop,ulnar deviation of the hands, spindle shapedfingers, and valgus deformity of the left foot (fig2). He had umbilical hernia and a leftundescended testis.At 2 weeks of age his weight was 3.5 kg (50th

centile), length was 57 cm (>90th centile), andhead circumference 35 cm (50th centile). Hismotor developmental milestones were delayed.He sat at 10 months and was able to stand withhelp at 23 months. His cognitive developmentwas normal. Ophthalmological, neurological,and cardiac evaluation were normal. Muco-polysaccharide screening and chromosomeanalysis were normal. Skeletal survey at 3months showed extensive hyperextension of

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367Further delineation ofNevo syndrome

Figure 3 Case 1. Moderate kyphosis of the upper andlower thoracic spine.

Figure 4 X ray of the pelvis in case 1 at 1 year of age.The right epiphyseal ossification centre of the femoral headis smaller than the left. There is subluxation of the rightfemur.

the neck owing to severe cervical lordosis andkyphosis of the upper and lower thoracic spine(fig 3). There were no vertebral abnormalitiesapart from elongation of the pedicles in thecervical vertebrae. The thorax appeared nar-row with increased AP diameter. There were11 pairs of ribs. In the pelvis there weredysplastic acetabular roofs but the hips werenot grossly dislocated. There was ulnar devia-tion of the fingers of both hands and the meta-carpals and phalanges appeared long. The longbones appeared normal.Xray of the pelvis and spine at 1 year of age

showed subluxation of the right femur with ahypoplastic right femoral head (fig 4), in-creased interpeduncular distance of the distallumbar vertebrae, and an increase in the angleof kyphosis of the thoracic spine. There wasextreme hyperlordosis of the cervical spine.MRI of the spine at 2 years 4 months showed awide spinal canal and CSF space in both thehyperlordotic cervical and in the thoraco-lumbar regions (figs 5 and 6). There was noevidence ofposterior scalloping of the vertebralbodies or changes in the pedicles. The spinalcord appeared normal.At 2 years 10 months he had normal speech

development and had just started to walk. Hismuscle tone appeared normal and joint laxityimproved; in particular the wrist joint appearednormal with normal function of both hands.Neurological examination was normal. His

Figure 5 MRI scan of the cervical spine in case 1 showinghyperlordotic spine with wide spinal canal and CSF space._e_~W-_~ _ 9| X_,Figure 6 Sagittal MRI of the thoracolumbar spineshowing abnormally wide spinal canal and CSF space inthe lower dorsal and lumbar spine.

weight was 14 kg (<50th centile) and height 98cm (>90th centile using the charts of Tanner etal4 and 75th centile and 95th centile respec-tively using the chart devised for Saudi Arabianchildren5). However, it was difficult to get anaccurate measurement of his height because ofhis severe spinal deformity. Consent for x rayfor bone age was refused by the parents.

CASE 2This male child is the first child of distantlyrelated Arab parents of UAE origin. The fam-ily is not related to the first family and is from adifferent tribe, although both families comefrom the Al Ain district. The mother was 19years old and the father 22 years old. Both arenormal. Pregnancy was normal and delivery at37 weeks' gestation was by LSCS because ofbreech presentation. His birth weight was 2700g (50th centile), length 53 cm (>90th centile),and head circumference 33 cm (50th centile).After birth he was noted to be floppy with apoor cry. He had the following dysmorphicfeatures: dolicocephaly, low set ears, and a higharched palate. The joints were lax and therewas bilateral wrist drop, oedema of the dorsumof the hands and feet, spindle shaped fingers,

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Figure 7 Case 2. Wrist drop with volar oedema andspindle shapedfingers. Note mild pectus excavatum.

and valgus deformity of the right foot (fig 7).There was mild dorsal kyphosis, pectus carina-tum, and a left undescended testis. Hedeveloped respiratory stridor in the first monthof life which was thought to be the result oflaryngomalacia. Chromosome analysis was

normal. Skeletal survey in the neonatal periodshowed kyphosis of the dorsolumbar spine withoval shaped vertebral bodies and long vertebralarches (fig 8). The thorax appeared narrow

with increased anteroposterior diameter. Thelong bones and pelvis appeared normal. In thehands there was increased soft tissue and spin-dle shaped fingers (fig 9). X ray of the hips at 2months of age showed well developed femoralepiphyses. At 4 months he had delayed motordevelopment and normal social responses. Hisweight was 5.75 kg (>Oth centile), length 66.5cm (>90th centile), and head circumference40.5 cm (50th centile using the charts of Tan-ner et al' and 25th and >>90th centile respec-

tively using charts for Saudi Arabian children5).At 4 months of age his carpal bone age was

between 6 and 8 months (Greiilich-Pylemethod)6 and x ray of the feet showed the pres-

ence of talus, calcaneus, and tail of the firstcuboid bone.7

DiscussionNevo et al' reported three cases from an inbredArab family with increased prenatal growth,hypotonia, kyphosis, and wrist drop with spin-dle shaped fingers. Hilderink and Brunner3reported a Dutch child from a consanguineousfamily with similar features, confirming theidentity of this syndrome.The children in this report show many simi-

larities to the cases reported by Nevo et al' andHilderink and Brunner.3 Table 1 summarisesthe clinical and radiological features of thepatients in this report and the previouslyreported cases.

Figure 8 X ray of the spine of case 2 showing kyphosis ofthe dorsolumbar spine and oval shaped vertebral bodieswith long vertebral arches.

Figure 9 X ray of the hand of case 2 showing spindleshapedfingers and increased soft tissue.

The clinical features of Nevo syndrome aretypical and include increased prenatal growth,joint laxity, hypotonia, kyphosis, wrist dropwith spindle shaped fingers, volar oedema, val-gus deformity of the feet, and cryptorchidism.These features were present in all the reportedcases, including the two cases in this report,and constitute the main findings of this

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369Further delineation ofNevo syndrome

Table 1 Clinical and radiologicalfeatures of our patients compared to previously publishedcases

Nevo et al' Hilderink Present casesand

1 2 3 Brunner' 1 2

GeneralConsanguinity + + + + + +Race Arab Arab Arab Dutch Arab (UAE) Arab (UAE)Sex Male Female Male Male Male MaleGestation Term Term Term Term Term 37 weeksBirthweight (g) 3200 3800 3400 2950 2780 2700Length (cm) 62 58 53

ClinicalHypotonia + + + + + +Kyphosis + + + + + +Oedema of hands and

feet + + + + +Spindle shaped fingers + + + + +Wrist drop + + + + + +Prominent forehead + + - + + +Large,low setears + + + - + +High palate + + - + + +Narrow shoulders - - + + + +Narrow thorax - - - + + +Umbilical hernia + - - + +Cryptorchidism + + + + +Tracheomalacia - - - - - +Hyperbilirubinaemia + + + +Normal mental

development + - + + ? +

RadiologicalKyphosis + + + + + +Scoliosis + + - - +Abnormal vertebrae - +wedge shape - - - + ovalHip subluxation + - - - +Osteoporosis + + - + +Advanced bone age + - + + ND +Wide spinal canal ? ? ? ? + ?

ND=not done.

syndrome. Other features include a prominentforehead, a high palate, large, prominent, lowset ears, large hands and feet, narrow shouldersand thorax, and umbilical hernia.Motor development is usually delayed in this

syndrome. This is the result of the joint laxityand hypotonia, and although hypotonia im-proves with time, some degree of joint laxitypersists. Cognitive development on the otherhand appears to be within the normal range.

One case only (case 2 of Nevo et al') had men-

tal retardation which was attributed to neonatalhyperbilirubinaemia. This latter feature, whichwas reported in all the previous cases, was

absent in our cases. Hyperbilirubinaemia alsooccurs in Sotos syndrome (another overgrowthsyndrome) and is thought to result fromasphyxia and bruising resulting from prolongedand difficult deliveries of these babies owing totheir large size.8 These factors might also berelevant to the aetiology ofhyperbilirubinaemiain Nevo syndrome, although prolonged labourleading to fetal distress was mentioned in one

case only.3 Radiological features include hipdysplasia with subluxation, kyphosis and scol-iosis, and advanced bone age (table 1). Otherradiological features include osteoporosis andwedge shaped vertebrae (case 2 of Nevo et al').The vertebrae in case 2 in this report appearedoval shaped with elongated arches. No neuro-

radiological abnormalities have been reportedin this syndrome. MRI scan of the brain was

normal in one case.3 MRI scan of the spine incase 1 in this report showed a wide spinal canalin the cervical and lumbar region indicatingsome degree of dural ectasia.' This feature has

been reported in other heritable connective tis-sue disorders like Ehlers-Danlos syndromel0and Marfan syndrome.9 It was suggested thatdural ectasia in these disorders arises from thecontinuous and somewhat pulsatile pressure ofcerebrospinal fluid on a connective tissuemembrane that is weakened by a defect ofextracellular matrix.9 A similar explanationcould be offered in Nevo syndrome since manyof the features in this syndrome indicate a con-nective tissue defect.The perinatal hypotonia which is a consist-

ent feature of Nevo syndrome could explainsome of the features that characterise this syn-drome, like the facial appearance, kyphosis,and the valgus deformity of the feet. Therefore,conditions which lead to fetal akinesia se-quence should be considered in the differentialdiagnosis of Nevo syndrome. However, over-growth differentiates this syndrome from otherconditions which lead to fetal akinesia se-quence. These are usually characterised byintrauterine growth retardation rather than theovergrowth usually seen in Nevo syndrome."In addition, in fetal akinesia sequence, thelimbs are usually fixed at a given joint in flexionor extension with complete or partial limitationof movement," which is different from thecomplete wrist drop owing to joint laxityconsistently seen in Nevo syndrome.There are many similarities between Nevo

syndrome and Marfan syndromes.'2 In fact,this diagnosis was initially considered in case 1.However, the presence of wrist drop, volaroedema, and spindle shaped fingers are typicalof Nevo syndrome. Other differentiating fea-tures include the lack of lens dislocation andheart lesion in Nevo syndrome and thedifferent mode of inheritance.The combination of wrist drop, volar

oedema, and spindle shaped fingers with otherfeatures easily differentiates this syndromefrom Sotos syndrome,8 13 another disorderwhich should be considered in the differentialdiagnosis.The two families reported here are Arab

Bedouins from the UAE. Similarly, the familyreported by Nevo et all were Arabs living inIsrael (table 1). It is possible, therefore, that thegene for this syndrome is more common inArabs than in other populations. This isperhaps because of the presence of a high levelof inbreeding among Arabs, which has led tothe appearance of several rare recessive disor-ders that are extremely uncommon in otherpopulations.

The authors would like to thank Ms Maria Shelly D'Silva for hersecretarial assistance and Mr Ashok Prasad for his photographicwork.

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