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I Med Genet 1993; 30: 65-69
Limb/pelvis-hypoplasia/aplasia syndrome(Al-Awadi/Raas-Rothschild syndrome): report oftwo Italian sibs and further confirmation ofautosomal recessive inheritance
Gianni Camera, Giuseppe Ferraiolo, Domenico Leo, Alberto Spaziale,Silvano Pozzolo
AbstractA third family with two Italian neonatesaffected with limb/pelvis-hypoplasia/apla-sia syndrome is reported. The disordershows autosomal recessive inheritance.(J Med Genet 1993;30:65-9)
Limb/pelvis-hypoplasia/aplasia syndrome wasdefined by Raas-Rothschild et all who reportedthree sibs with severe upper and lower limbmalformations and a severely malformed pel-vis. Previously, Al-Awadi et aP had describedtwo Arab sibs with profound limb deficiency,thoracic dystrophy, unusual facies, and normalintelligence. This report describes two newcases of limb/pelvis-hypoplasia/aplasia syn-drome in Italian sibs.
Centro di GeneticaUmana, OspedaliGalliera, Mura DelleCappuccine 14, 16128Genoa, Italy.G Camera
Ospedale Villa Malta,84087 Sarno (Salerno).Italy.G FerraioloD LeoA Spaziale
ASM, 20129 Milano,Italy.S Pozzolo
Correspondence toDr Camera.
Received 15 April 1992.Revised version accepted18 June 1992.
Case reportsCASE 1
Case 1, a male, was the second child born tounrelated healthy parents at 40 weeks' gesta-tion by caesarian section. Birth weight was3700 g (50th to 70th centile), length 41 cm( < 3rd centile), head circumference 34 cm(10th to 25th centile), and chest circumference36 cm (90th to 97th centile). His sister washealthy. There was no history of teratogenicexposure or drug ingestion during the preg-nancy. The karyotype was normal 46,XY.Physical examination (fig 1) showed asymme-trical facies with epicanthic folds, large nosewith naevus flammeus on the tip, large fish-like mouth, pointed chin, high and narrow
palate, low set, dysplastic; and large ears; ashort neck; a barrel shaped chest and pectuscarinatum with increased distance betweenhypoplastic nipples; upwardly displaced ex-
ternal genitalia, glandular hypospadias, andhypoplastic scrotum with bilateral crypt-orchidism; flexion contracture of the elbowjoint and severe shortening and bowing of theforearms; very mobile wrist joints; four abnor-mally shaped digits on each hand with no
fingernails; an upward and forward displaced,small pelvis, a pilonidal sinus, a deep dimpleon the right thigh, and no gluteal cleft; andstick-like lower limbs with appendages resem-
bling hypoplastic feet.Radiographic examination (figs 2 and 3)
showed a poorly ossified calvarium and pseud-arthrosis of the right clavicle; traumatic
fractured left humerus, shortened and bowedradii, absent ulnae, and hypoplasia/aplasia ofthe metcarpals and phalanges; underdevelopediliac bones and absent pubic bones; aplasticfemora, hypoplastic tibiae, absent fibulae, andhypoplasia/aplasia of the tarsals, metatarsals,and phalanges. Ultrasonographic examinationshowed no abnormalities of internal organs.The infant died aged 16 days of respiratorydistress. No necropsy was performed.
CASE 2Case 2, a female, was the sister of case 1.Inexplicably, no fetal ultrasonography wasperformed before 30 weeks of gestation. Atthis time it showed a fetus with normalhumeri, shortened and bowed radii, absentulnae, and dysplastic, short lower limbs. Theinfant was delivered at 39 weeks by caesariansection. Birth weight was 3300 g (50th centile),birth length 41 cm (<3rd centile), head cir-cumference 32-5 cm (3rd centile), and chestcircumference 35 cm (90th centile). Sheshowed a similar phenotype to case 1 (fig 4).Ultrasonographic examination indicated noabnormalities of the internal organs. X rayexamination (figs 5 and 6) showed a poorlyossified skull, pseudarthosis of the right clav-icle, bowed radii, absence of the ulnae, hypo-plastic pelvic bones, hypoplastic femora, slen-der tibiae, absent fibulae, and hypoplasia/aplasia of the metacarpals, tarsals, metatarsals,and phalanges. The spine was considered to benormal.The clinical and radiological findings in our
patients, compared with those cases describedby Al-Awadi et aP and by Raas-Rothschild etall are reported in tables 1 and 2.
DiscussionCongenital hypoplasia of the femur is the mainsign in four uncommon disorders: limb/pelvis-hypoplasia/aplasia syndrome, proximalfemoral focal deficiency (PFFD),' femur-fibula-ulna (FFU) complex,4 and femoralhypoplasia-unusual facies syndrome.5 PFFDis a congenital absence of the proximal one-third to two-thirds of the femur and is oftenassociated with ipsilateral absence of thefibula. FFU complex is characterised by ab-sence of the proximal part of the femur withfibular defects and ulnar abnormalities. In thefemoral hypoplasia-unusual facies syndrome,
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Camera, Ferraiolo, Leo, Spaziale, Pozzolo
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Figure 2 Case 1. Pseudarthrosis of the right clavicle,hypoplastic iliac bones, absent pubic bones, absentfemora, and thin tibiae.
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Figure 1 Case 1. (A,B) patient's appearance, (C) carp shaped mouth, pointed chin,(D) dysplastic large ear, severe malformations of upper limb, malformed digits,(E,F) malformed lower limbs with appendages resembling poorly defined feet.
the femur ranges from being hypoplastic toaplastic and the facies show upward slantingpalpebral fissures, short nose, long philtrum,and micrognathia.The patients described here show upper and
Figure 3 Case 1. Left hand with four malformedfingers.
lower limb malformations and malformed pel-vis, resembling those reported in the patientswith limb/pelvis-hypoplasia/aplasia syndrome.Our patients had features not describedbefore, such as very dysplastic, large ears, high
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Limb/pelvis-hypoplasia/aplasia syndrome
Table 1 Clinical findings in our patients compared with the cases reported by Al-Awadi et al2 and Raas-Rothschildet al.'
Our cases Al-Awadi et al Raas-Rothschild et al
Clinical findings Case Case Case Case Case Fetus Fetus1 2 1 2 1 1 2
FaceAsymmetrical + + - - -Elongated - - + + -Broad nasal bridge + + + + -Epicanthic folds + + + - -Dysplastic ears + + - - -Long ears + + - - + ? ?Pointed chin + + - - + ? ?
ThoraxBarrel shaped chest + + + + -Prominent sternum - - + + -Pectus carinatum + + - - -Hypoplastic nipples + + - - -
Upper limbsFlexion contracture of elbow joint + + + + + +Shortened forearm + + + + + + +Mobile wrist + + - - + ? ?Malformed digits + + + + + + +
PelvisSeverely malformed + + + + + + +
External genitaliaSex M F F M M F MHypospadias + NR NR - - NR ?Hypoplastic scrotum + NR NR - + NR ?Inguinal testes + NR NR + + NR ?Upwardly displaced genitalia + + - + + + +
Lower limbsStick-like projections + + + + + + +Hypoplastic feet + + + + + + +
OtherBroad neck + + + + - - +Short neck + + - - - - +Hairy pigmented naevus - - - - + - -Pilonidal sinus + + - - +Deep anal pit - - - +High and narrow palate + +Occipital meningocele - - - - - - +Occipital neck tissue mass - - - - - +
+ = present; - = not present or not mentioned; ? = too early to know; NR = not relevant.
Table 2 Radiographicalfindings in our patients compared with the cases reported by Al-Awadi et al2 andRaas-Rothschild et al.'
Clinical findings
Our cases Al-Awadi et al Raas-Rothschild et al
Case Case Case Case Case Fetus Fetus1 2 1 2 1 1 2
Skull
Poorly ossified calvarium
Upper limbsShortened and bowed radii
Aplasia of ulna
Aplasia of carpal bones
Hypoplasia/aplasia of metacarpals andphalanges
Pelvis
Hypoplasia of pelvic bones
Lower limbs
Short, bowed/separated hypoplastic/aplasticfemur
Aplasia of fibula
Hypoplasia/aplasia of tarsals, metatarsals, andphalanges
Thorax
Pseudarthrosis of clavicleBroad claviclesBroad ribs
+±
+ + + +±+ + + + + + +
+ + -± + +
+ + + + + + +
+ + + + ?
+ + + + + + ++ + + + + + +
+ + + + + +
~~~+
+ + +
+ =present; - = not present or not mentioned; ? = too early to know.
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Camera, Ferraiolo, Leo, Spaziale, Pozzolo
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Figure 4 Case 2. (A,B,C) patient's appearance, (D) low set dysplastic ear,(E) malformed upper limb and hand, (F) anteverted external genitalia and stick-likeappendages with malformed feet.
and narrow palate, and pseudarthrosis of theright clavicle. Ultrasonographic examinationshowed no defects of the internal organs. Age-nesis of a kidney, meningocele, and hypoplasiaof the cerebellum have been associated withlimb/pelvis-hypoplasia/aplasia syndrome. Thiscondition shows autosomal recessive inherit-ance. The patients described by Al-Awadi etall and those reported by Raas-Rothschild et
all had consanguineous parents. The two sibsreported here are a further confirmation ofautosomal recessive inheritance. It has beensuggested that the gene responsible for thisrare syndrome could be confined to the MiddleEast gene pool.' However, these two Italianneonates affected with the limb/pelvis-hypo-plasia/aplasia syndrome argue against this.The parents of our patients and those of the
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Limb/pelvis-hypoplasia/aplasia syndrome
Figure S Case 2. Pseudarthrosis of clavicle, bowed radius, absent ulna, andfourmalformed digits.
other patients are healthy and show no defects,so that the heterozygous state is impossible todetect.We propose that this syndrome should
be called the Al-Awadi/Raas-Rothschild syn-drome.
We thank Dr M Baraitser, London, for hishelpful criticism.
1 Raas-Rothschild A, Goodman RM, Meyer S, et al. Patholo-gical features and prenatal diagnosis in the newly recog-nised limb/pelvis-hypoplasia/aplasia syndrome. J MedGenet 1988;25:687-97.
2 Al-Awadi SA, Teebi AS, Farag T, Naguib KM, El-KhalifaMY. Profound limb deficiency, thoracic dystrophy,unusual facies, and normal intelligence: a new syndrome.JMed Genet 1985;22:36-8.
3 Aitken GT. Proximal femoral focal deficiency: definition,classification, and management. In: Aitken GT, ed. Proxi-malfemoral deficiency: a congenital anomaly. Washington,DC: National Academy of Sciences, 1969:1-22.
4 Kuhne D, Lenz W, Petersen D, Sehonenberg H. Defekt vonfemur und fibula mit amelie, peromelie oder ulnarenstrahldefekten der arme. Ein syndrom. Humangenetik1967;3:244-63.
5 Daentl DL, Smith DW, Scott CI, Hall BD, Gooding CA.Femoral hypoplasia-unusual facies syndrome. JT Pediatr1975;86: 107-1 1.
Figure 6 Case 2. Hypoplasia of pelvic bones,hypoplastic femora, short and slender tibiae, and absentfibulae.
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