American Journal of Medical Genetics 135A:81–85 (2005)

Clinicial ReportAcrofacial Dysostosis Type RodrıguezBoyan Dimitrov,1 Irina Balikova,2 Nely Jekova,3 Lilija Vakrilova,3 Jean-Pierre Fryns,1* and Emil Simeonov2

1Center for Human Genetics, University Hospital Gasthuisberg, University of Leuven, Belgium2Pediatric Clinic, University Hospital ‘‘Alexandrovska’’, Medical University of Sofia, Bulgaria3Neonatology Clinic, University Hospital of Obstetrics and Gynecology ‘‘Maichin Dom’’, Medical University of Sofia, Bulgaria

The acrofacial dysostoses (AFD) are a clinicallyand causally heterogeneous group of conditionscharacterized by mandibulofacial dysostosis anda variety of limb anomalies. Several abnormalitiesaffecting different internal organs and the centralnervous system (CNS) have been described. De-pending on the type of limb defects, two majorgroups have been delineated: (1) with predomi-nantly pre-axial anomalies, Nager type AFD, and(2) with predominantly post-axial involvement,Genee–Wiedemann form of AFD, also known asPOADS, respectively. Other forms of ‘‘true AFD’’have been described as Kelly, Reynolds, Arens(also Tel Aviv form), Rodrıguez (or Madridform), Richieri–Costa, and Patterson–Stevenson–Fontaine types. However, whether they are dis-tinct entities or represent variants of the samecondition remains unclear. Rodırguez AFD wasdescribed as a new lethal form of AFD in threeaffected sibs with severe mandibular hypoplasia,severe predominantly pre-axial limb deficien-cies, absent fibulae and ribs, and internal organanomalies, the most remarkable of which arearrhinencephaly and abnormal lung lobulation.We present a newborn girl with Rodrıguez type ofAFD, who died a few days after the birth due torespiratory failure. The phenotype and the causeof this condition are discussed.� 2005 Wiley-Liss, Inc.

KEY WORDS: acrofacial dysostosis; mandibulo-facial dysostosis; pre-axial limbdefects; post-axial limb defects;Rodrıguez syndrome

INTRODUCTION

The acrofacial dysostoses (AFDs) represent a number ofconditions characterized by the combination of mandibulofa-cial dysostosis and limb defects in varying degrees. Theyappear to represent polytopic developmental field defects dueto causal heterogeneity [Opitz et al., 1993]. In 1993, on a purelyclinical basis, Opitz et al. delineated twomajor groups of AFDs:(1)Nager syndromewithpredominantly pre-axial limbdefects;and (2) Genee–Wiedemann syndrome with much more pro-minent post-axial limb defects. These authors also recognized

other rare forms of AFDs and acrofacial field defects as a partof ‘‘related conditions’’ or chromosomal abnormalities [Opitz,1987; Opitz et al., 1993].

Rodrıguez et al. [1990] described three affected sibs withsevere, apparently lethal AFD with severe mandibular hypo-plasia, predominantly pre-axial limb deficiencies, absentfibulae and ribs, and internal organ anomalies, the most re-markable of which are arrhinencephaly and abnormal lunglobulation.However, one of these sibs hadwhatmay be regard-ed ‘‘severeNager syndrome.’’ Subsequently, a fewadditional orpreviously published cases were thought to be examples ofRodrıguez AFD [Hecht et al., 1987; Fryns and Kleczkowska,1991; Petit et al., 1992;Oostra et al., 1998;Wessels et al., 2002].The subsequent editorial correspondence [Fryns, 1992, 1999;Hecht, 1992; Rodrıguez et al., 1992a,b; Oostra et al., 1999] hasreopened the discussion about the nosology and classificationof severe AFDs.

We present a newborn girl with an acrofacial dysostosisconsistent with that described by Rodrıguez et al. [1990].

CLINICAL REPORT

A newborn girl died 6 days after birth due to severerespiratory problems. She was born at 36 weeks of gestation,after Caesarean section because of maternal pre-eclampsia,the second pregnancy in a family with a healthy 40-year-oldmother and a 36-year-old father. The first pregnancy endedin spontaneous abortion. Results of biochemical screeningfor Down syndrome in the second trimester were normal. Thefamily history was unremarkable. Birth-weight and -lengthwere 1,300 g and 45 cm, respectively. For severe respiratorydistress she required mechanical respiratory support. Onexamination she had short, down-slanting palpebral fissures,deep-set eyes, hypertelorism, prominent nasal bridge, medi-ally sparse eyebrows, low temporal hair line,microstomia, thinlips, marked micrognathia with protruding pre-maxilla, lowset abnormally modeled ears with absent external auditorymeatus (Fig. 1a,b). There was severe hypotonia with hypo-reflexia. The arms and forearms were very short, withmore severely affected forearms, and the hands appeared tobe attached directly to the upper arms (Fig. 1d). Thumbs wereabsent and there was complete cutaneus syndactyly betweenthe third and fourth fingers and bilateral clinodactyly of fifthfingers. Therewas also a duplication of the terminal phalanx ofthe second left finger, which gave it a thumb-like appearance,and bilateral duplication of the terminal phalanges of thefourth fingers (Fig. 1c,d). She had proximally placed hallucesand the fourth and fifth toes of the right foot were shorter, withpartial syndactyly (Fig. 3a,b). Autopsy did not show any ano-malies of brain, thoracic, or abdominal organs. Skull and limbradiographs demonstrated severe hypoplasia of the mandible,fused temporomandibular joint, hypoplastic scapulae, 11 ribs,hypoplastic shoulder girdle, rudimentary triangular humeri,single, hypoplastic forearm bones, absent first digital rays andcutaneous syndactyly 3–4, duplication of the distal phalanx ofthe second finger and additional ossification centers between

*Correspondence to: Jean-Pierre Fryns, Centre for HumanGenetics, University Hospital Gasthuisberg, Herestraat 49, 3000Leuven, Belgium.E-mail: Jean-Pierre.Fryns@med.kuleuven.ac.be

Received 6 October 2004; Accepted 26 January 2005

DOI 10.1002/ajmg.a.30673

� 2005 Wiley-Liss, Inc.

Fig. 1. a–d: Newborn girl with severe acrofacial dysostosis and typical facial appearance.

the second and third phalanges of the left third and fourthfingers, duplication of the terminal phalanx of the fourth fingerof the right hand, hypoplastic second and third phalanges ofthe fifth fingers of both hands, hypoplastic pelvic girdle withvertical position of the pelvic bones and hypoplastic ischii,

absence of right fibula and hypoplastic left fibula, curved righttibia, shortness of all bones of the first rays of both feet, andabsent secondphalanges of fourthandfifth toes of the right foot(Figs. 2e,f and 3c,d).

Chromosomes were apparently normal (46,XX).

Fig. 2. a–f: Postmortem photographs and radiographs of upper limbs demonstrating the hand defects with more severely affected radial rays.

Fig. 3. a–c: Postmortem photographs of legs showing proximally placed halluces, shortness, and partial syndactyly of right fourth and fifth toes (a, b).The roentgenograms demonstrate the shortness of all first ray bones of the feet and absent second phalanges of the fourth and fifth toes of the right foot (c).

Acrofacial Dysostosis 83

TABLE

I.AllCurren

tlyPublish

edCasesRep

resentingAcrofacialDysostoses

(AFD)TypeRod

rıguez*

Rod

rıguez

etal.

[1990]

Frynsand

Kleczkow

ska[1991]

Hechtet

al.

[1987]

Petitet

al.

[1992]

Bateset

al.[2002]

Wessels

etal.

[2002]

Present

case

2004

12

34

56

78

910

Gestation

(wee

ks)

?41

40

28–29

31

20

24

21

27

36

Birth

weight(kg)

2.020

2.500

2.850

0.690

1.530

?0.465

Normal

0.718

1,300

Birth

length

(cm)

??

50

?42

??

Normal

?45

OFC

(cm)

??

??

29.2

?23.5

Normal

??

Face Sev

eremicrognathia

þþ

þþ

þþ

þþ

þþ

Malarhypop

lasia

þþ

þþ

þþ

þþ

þþ

Malformed

ears

þþ

þþ

þþ

þþ

þProminen

t,broadnasa

lbridge

þþ

þþ

þþ

þþ

þþ

Dow

n-slantingpalpeb

ralfissures

þþ

þþ

þþ

þþ

þþ

Cleft

palate

þþ

High,arched

�þ

High,arched

þþ

þ�

Atretic

earcanals

þþ

Narrow

canals

Narrow

canals

þ?

þþ

þþ

X-rayfindings

Vertebralanom

alies

��

��

��

þ�

��

Shou

lder

girdle

hypop

lasia

þþ

��

��

??

þþ

Eleven

ribs

þ�

þ�

��

þ�

þþ

Hypolastic

scapulae

þþ

��

��

��

?þ

Short(absent)

humerus

þþ

��

��

þ�

þm

þSingle

(absent)

forearm

þþ

��

��

þ�

hþ

mþ

Radioulnarsynostosis

��

þþ

þ�

��

��

Pre-axialthumbdefects

þ�

þþ

þþ

þOligod

actyly

iOligod

actyly

nþ

Post-axialfinger

defects

þþ

��

�þ

þOligod

actyly

iOligod

actyly

nþ

Cutaneo

usfinger

syndactyly

??

1–2

�1–2

�c

?dþ

3–4

3–4

Pelvic

girdle

hypop

lasia

?þ

��

��

þ?

?þ

Absent/hypop

lastic

isch

ii�

þ�

��

��

?�

þLow

erlimbdefects

a�

��

��

�þ

eþ

jþ

o�

Absent/hypop

lastic

fibulae

�þ

��

��

þþ

jþ

þPre-axialtoedefects

��

?�

��

þOligod

actyly

k�

þPost-axialtoedefects

�þ

?�

��

þOligod

actyly

k�

þToe

syndactyly

??

4–5

��

�?

�4–5

4–5

Autopsy

Card

iacmalformation

sþ

þ�

þ�

�þ

��

�CNSmalformation

sb�

��

��

�þ

f�

��

Arh

inen

cephaly

þþ

��

��

��

þ�

Absentlunglobulation

�þ

��

��

þ�

þ�

Ren

alanom

aly-

��

��

�þ

þþ

�Gen

italanom

aly

��

��

��

þþ

��

Karyotype

�46,XY

46,XY

�46,XX

�46,XX

46,XX

46,XX

46,XX

Sex

MM

MM

FF

FF

FF

Earlylethality

þþ

þþ

þPT

PT

PT

PT

þCon

sanguinity

��

��

��

þ�

�Possible

mod

eof

inheritance

AR

AR

AR

Sporadic

AR

AR

ARg

Sporadic

lSporadic

Sporadic

(þ),present;(�

),absent;(?),unknow

nor

itis

not

men

tion

edin

thetext;M,male;F,female;PT,pregnancy

wasterm

inated;AR,autosomalrecessive.

*Thecase

ofOostraet

al.[1998]is

not

included

because

ofinsu

fficien

tdetailed

description

ofthephen

otype.

aOther

limbdefects

not

inthis

table.

bCNSmalformation

sdifferentfrom

arrhinen

cephaly.

c Patien

t2of

Hechthadproxim

alfusion

oftherightfourthandfifthmetacarp

als.

dProxim

alfusion

oftherightfourthandfifthmetacarp

als.

eAbsence

ofalllogbon

esof

lower

limbs.

f Thirdven

tricle

hydrocephaly

dueto

aqued

uctalsten

osis

andagen

esis

ofcorp

uscallosum.

gTheARmod

eof

inheritance

inthis

patien

twasconfirm

edbyFryns[1999].

hSev

eresh

ortnessof

ulnaeandradii.

i Distalphalanxduplication

ofboththumbs,distaltw

ophalanxduplication

ofthirddigits,andon

lythreemetacarp

als.

j Shortandbow

edtibiaeandseverelysh

ortened

fibulae.

kIn

thetextis

written

thattherewereon

lyfourmetatarsals.

l Parents

werefirstcousinsandanARinheritance

could

besu

spected.

mAsingle,dysp

lastic,andangulatedbon

ewasdetectedbetwee

nthehandsandthesh

oulders.

nTherighthandhadfourdigitsandhypop

lastic

fourthray,andthelefthandhadon

lythreefingerswithou

trecognizable

thumb.

oShortandbow

edtibiae.

DISCUSSION

Over the last 14 years, a few additional reports of patients(Table I) with a phenotype of severe, lethal AFD similar to thesiblings presented by Rodrıguez et al. [1990] were published.Fryns and Kleczkowska [1991] described a newborn boy withsevere AFD, pre-axial upper limb malformations, and con-genital heart defect resembling the third patient of Rodrıguez.In 1992, Hecht [1992] commented that a previously publishedautosomal recessive case of AFD [Hecht et al., 1987] present-ed striking similarities to the sibs reported by Rodrıguezet al. In a correspondence to the editor, Rodrıguez et al.[1992a,b] disagreed with this diagnosis because of the absenceof typical additional skeletal and internal abnormalities. Atthat time, Petit et al. [1992] confirmed the existence of thisnew form of AFD. The proposita seemed to be similar to patient2 of Rodrıguez et al. [1990]. A second affected sib was brieflyreported a few years later [Fryns, 1999], supporting the hypo-thesis of autosomal recessive inheritance, or germinal mosai-cism of a dominant gene.

In 1999, a case with ‘‘severe Nager syndrome with orofacialclefting and phocomelia’’ published by Oostra et al. [1998] wasrecognized as an example of Rodrıguez syndrome [Fryns, 1999;Oostra et al., 1999].

Bates et al. [2002] described what was thought to be ‘‘a newlethal form of AFD.’’ However, the clinical findings arecomparable to those of the patients of Rodrıguez et al. [1990],Petit et al. [1992], and Wessels et al. [2002]. Moreover in thatinstance, there was consanguinity and autosomal recessiveinheritance seemed reasonable.

Recently,Wessels et al. [2002] described a pre-natally ascer-tained female fetus with Rodrıguez AFD and stressed theimportance of internal abnormalities (arrhinencephaly andabnormal lung lobulation) in the diagnosis.

The findings in our patient completely overlap those ob-served in Rodrıguez AFD.

On the basis of the above cases some hallmark findingsemerge in this form of lethal AFD: (1) typical facial anomalieswith severe mandibulofacial dysostosis, absence of auditorycanals, and cleft palate; (2) pre-axial and post-axial handand foot defects with more prominent pre-axial involvement;(3) and additional skeletal anomalies such as 11 ribs, severedysgenesis, and/or agenesis of long bones of upper limbs,anomalies of pelvic bones (hypoplastic/absent ischii), andhypoplasia or agenesis of fibulae. A variety of abnormalitiesaffecting CNS (arrhinencephaly, callosal agenesis), lungs(hypoplastic/hypolobated lungs), heart, and urogenital systemhave been described and further support the diagnosis of AFDtype Rodrıguez. However, the differential diagnosis in the

group of lethal AFDs is not so unequivocal and in the ob-servations reported by Hecht et al. [1987], Fryns andKleczkowska [1991], and Oostra et al. [1998], the diagnosis ofRodrıguezAFDshouldbe taken inaccount at leastwith respectto appropriate genetic counseling of the families. However,until we will get deeper insight into the underlying causalmechanism in this group of lethal AFDs, the debate between‘‘splitters and lumpers’’ in this ‘‘field’’ will remain open.

REFERENCES

Bates AW, Hall CM, Morgan H, Rosser EM, Scheimberg I. 2002. Lethalacrofacial dysostosis, pre- and post-axial defects of the hands, andbilateral renal agenesis. Clin Dysmorphol 11:63–66.

Fryns JP. 1992. Reply to Dr. Rodrıguez et al. Am J Med Genet 42:852.

Fryns JP. 1999. On the nosology of severe acrofacial dysostosis with limbdeficiency. Am J Med Genet 82:282–283.

Fryns JP, Kleczkowska A. 1991. New lethal acrofacial dysostosis syndrome.Am J Med Genet 39:223–224.

Goldstein DJ, Mirkin LD. 1988. Nager acrofacial dysostosis: Evidence forapparent heterogeneity. Am J Med Genet 30:741–746.

Hecht JT. 1992.New lethal acrofacial dysostosis syndrome. AmJMedGenet42:400.

Hecht JT, Immken LL, Harris LF, Malini S, Scott CI Jr. 1987. The Nagersyndrome. Am J Med Genet 27:965–969.

Oostra RJ, Baljet B, Hennekam RC. 1998. Severe acrofacial dysostosis withorofacial clefting and tetraphocomelia diagnosed in the plaster cast of a100-year-old anatomical specimen. Am J Med Genet 78:195–197.

Oostra RJ, Baljet B, Hennekam RC. 1999. Reply to letter to the Editor ofJean-Pierre Fryns ‘‘on the nosology of severe acrofacial dysostosis withlimb deficiency’’. Am J Med Genet 82:283.

Opitz JM. 1987. Nager ‘‘syndrome’’ versus ‘‘anomaly’’ and its nosology withthe postaxial acrofacial dysostosis syndrome of Genee and Wiedemann.Am J Med Genet 27:959–963.

Opitz JM, Mollica F, Sorge G, Milana G, Cimino G, Caltabiano M. 1993.Acrofacial dysostoses: Review and report of a previously undescribedcondition: The autosomal or X-linked dominant Catania form of acro-facial dysostosis. Am J Med Genet 47:660–678.

Petit P, Moerman P, Fryns JP. 1992. Acrofacial dysostosis syndrome typeRodrıguez: A new lethal MCA syndrome. Am J Med Genet 42:343–345.

Rodrıguez JI, Palacios J, Urioste M. 1990. New acrofacial dysostosissyndrome in 3 sibs. Am J Med Genet 35:484–489.

Rodrıguez JI, Palacios J,UriosteM. 1992a.Response toDr.Hecht. AmJMedGenet 42:401.

Rodrıguez JI, Palacios J,UriosteM. 1992b.Acrofacial dysostosis syndromes.Am J Med Genet 42:851.

Wessels MW, Den Hollander NS, Cohen-Overbeek TE, Lesnik ObersteinMS, Nash RM, Wladimiroff JW, Niermeijer MF, Willems PJ. 2002.Prenatal diagnosis and confirmation of the acrofacial dysostosissyndrome type Rodrıguez. Am J Med Genet 113:97–100.

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