disorganisation: a model for 'early amnion rupture'? · developing amnion, caused involvement of...

Journal of Medical Genetics 1989, 26, 421-425

Disorganisation: a model for 'early amnion rupture'?D DONNAL* AND R M WINTERtFrom *the Regional Genetic Centre, St Mary's Hospital, Manchester M13 OJH; and tthe Kennedy GaltonCentre, Northwick Park Hospital, Harrow, Middlesex HAI 3UJ.

SUMMARY The hypothesis of an intrinsic defect of germ plasma put forward by Streeter toexplain the abnormalities observed in 'amniotic bands sequence' (ABS) was not supported byTorpin, who suggested that the bands derived from early amnion rupture, with formation ofmesodermal strings and naked chorion, which then constricted or adhered to fetal parts.Recently, several authors have recorded and discussed possible mechanisms for 'non-bandrelated' malformations in patients with otherwise typical limb constrictions and amputations.The mouse mutant disorganisation (Ds) is a semidominant with 72% of heterozygotes

manifesting abnormalities, which include cranioschisis, limb duplications and deficiencies,gastro/thoracoschisis, and papillae protruding from other parts of the body. We report similarabnormalities including papillae in five fetuses and one newborn with ABS and, based on theseobservations and published reports, we suggest that a human homologue for Ds may be the causeof at least some examples of ABS.

Streeter' examined embryos and concluded that ringconstrictions are localised areas of imperfectlyformed tissue owing to defective areas of germplasma which, because of the proximity to thedeveloping amnion, caused involvement of thisstructure too. Later, Torpin2 suggested that pre-mature rupture of the amnion was responsible forcongenital ring constrictions and amputations. Themechanism suggested was that, after rupture of theamnion and separation from the chorion,mesodermal strings formed which constricted fetalparts, the naked chorion acting as a site to whichfetal parts could adhere, this process being helpedby amniotic fluid leakage. This latter hypothesis hasbeen generally accepted and observations of anoma-lies not easily explained by amniotic band disruptionhave been attributed to either vascular interferenceor mechanical teratogenesis. We report five fetusesand one newborn, all with anomalies commonlyseen in ABS, and in addition anomalies difficult toexplain by amniotic band disruption. The mousemutant disorganisation (Ds) has anomalies whichare very similar to those observed in ABS fetusesand we suggest that a human homologue of Dsmay be responsible for some cases of ABS andmay explain the rare familial reports of apparentABS.

Received for publication 7 February 1989.Accepted for publication 9 February 1989.

Case reports

CASE 1

This was a female fetus aborted at 21 weeks'gestation by a 29 year old primigravid mother whohad raised serum a fetoprotein (AFP) and amnioticfluid AFP. The fetus had a large encephalocele inthe frontoparietal area and clefting of the left side ofthe face with an exophthalmic right eye. There weremultiple amputations of the digits of the hands andfeet with terminal syndactyly. The umbilical cord, atthe insertion into the abdomen, contained threevessels, but 3-5 cm distally it divided, sending twovessels to the placenta and one vessel to themeninges covering the encephalocele. There werethree skin tags containing cartilage 05 cm long overthe left shoulder and upper cervical region (fig 1).

CASE 2This was a female fetus aborted by a 28 year oldprimigravid woman after the detection of highserum and amniotic fluid AFP levels. The fetus hada huge right sided thoraco/gastroschisis; membranebands extended from the cord and fetal surface ofthe placenta to the back of the abdominal defect andto the liver. There were amputations of the fingerswith distal syndactyly. There was a right primarycleft lip and palate and a short, thick neck, but notissue bands observed in the facial region. There wasa blister over the back. A skin spur projected from

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the left calf and there was angulation of the righttibia and fibula. The right hallux was duplicated witha deep cleft between it and the second toe. The leftkidney was absent and there was a single umbilicalartery (fig 2).

FIG 1 Case 1; note distal amputations, divided umbilicalcord, and skin tag on left shoulder.

CASE 3This was a female fetus aborted at 18 weeks'gestation in the first pregnancy of a 20 year oldwoman. There was a large defect involving the rightparietal and occipital bone, a primary bilateral cleftlip and palate, and a skin spur over the mid thoracicregion posteriorly. There were amputation deformi-ties with terminal syndactyly of the fingers. Therewas complete syndactyly of the fourth and fifth toesof both feet.

CASE 4This was a male fetus aborted at 18 weeks' gestationby a 22 year old normal woman, whose older son hasunilateral renal agenesis. Ultrasound scan in thepregnancy had shown a lack of liquor and severefetal distortion. The placenta was attached to anabdominal wall defect in the fetus and no umbilicalcord was identified. The trunk was rotated through1000 and the legs compressed against the back. Theright arm was hypoplastic with very short upper andlower segments, with webbing across the antecubitalfossa. The hand was represented by a nub of tissue.There was hydrocephalus and an occipital skulldefect. There appeared to be three nostrils present,two on the right separated by a groove from one onthe left (fig 3).

CASE 5This was a female fetus aborted by a 18 year oldprimigravida after ultrasound scan diagnosis ofhydrocephalus. There were amputations of thefingers of both hands with terminal syndactyly withtissue strands. Both frontal bones were deficient as

FIG 2 Case 2; note primary cleftlip, amputation of fingers on lefthand blister on back, skin spur onleft calf, and preaxial polydactylyof right foot.

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Disorganisation: a model for 'early amnion rupture'?

was the ethmoid plate. The anterior falx was absentand there was wide separation of the nostrils with agroove extending upwards to a skin spur projectingfrom the region of the anterior fontanelle (fig 4).There was bilateral microphthalmos.

CASE 6This girl is the offspring of unrelated Caucasianparents. The family and pregnancy history wereunremarkable. At birth she was noted to have apapilla over the left temporal region that appeared

FIG 4 Case 5; note separated nostrils, widely spaced eyes,and skin spur over anterior ntanelle.

to be tethered to the underlying muscle, because itwas retractile when she cried (fig 5). There was asimilarly tethered sinus over the right temporalregion. A small occipital encephalocele was notedand a CT scan of the brain showed hydrocephalus.There were absent fingers with a remaining thumband index finger on the right hand (fig 6) and a ringconstriction of the thumb of the left hand. A renalultrasound scan showed a possible unilateral cystic

FIG 3 Case 4; note presence of three nostrils. kidney. The hand abnormalities appeared to be

FIG 5 Case 6 with papilla on the left temple.

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FIG 6 Case 6; amputation of digits 3 to 5 on right hand.

secondary to amniotic bands, but the craniofacialabnormalities and the renal defect cannot be ex-plained on this basis.

Discussion

There are many published reports of fetuses andinfants with ABS who in addition have anomaliesdifficult to explain by band disruption. Higginbot-tom et at3 described a study where two of the caseshad primary cleft lip and palate, one an absent arm,shoulder girdle, and subclavian artery, and anotherchoanal atresia and microphthalmos. It was sug-gested that these findings supported very earlyamnion rupture, that is, before fusion of themaxillary and median nasal processes and beforelimb budding. Graham et at4 described two babieswith preaxial polydactyly as well as other bandrelated defects. They suggested that the super-numerary digits resulted from compression of thedeveloping foot plate before 42 days of develop-ment. Pagon et al, 5 reporting 15 patients withlimb/body wall defects, described abnormalitiesdifficult to explain by band disruption, includingabsent limbs and kidneys, imperforate anus, micro/anophthalmos, primary cleft lip and palate, lobsterclaw, and skin tags containing cartilage.

Recently, Hunter and Carpenter' described fourcases of ABS with malformations not resulting fromamniotic bands and discussed previously suggestedmechanisms; they concluded that the most likelyhypothesis was an extrinsic insult or perhaps occa-sionally a familial susceptibility leading to loss offetal vascular integrity. This in turn leads to superfi-cial haemorrhage and denudation with adhesions

causing syndactyly and constrictions, and also to theobserved internal anomalies.The mouse mutant disorganisation (Ds) has been

described by Hummel.7 It arose as a spontaneousmutation in an inbred strain of mice and has beenstudied in heterozygotes. It appears to be a semi-dominant, lethal in homozygotes, and with incom-plete penetrance in heterozygotes, 72% of whichmanifest anomalies. The effects of the mutation,while they affect development of structures derivedfrom all germ layers and appear to be active duringthe whole period of embryogenesis, do seem tooperate after the establishment of the primary axis.In 500 abnormal mouse fetuses, known by parentalgenotype to be heterozygotes, 67% had multipledefects and the rest single defects: 53% had cra-nioschisis or exencephaly; 40%/o had hamartomasrepresented by papillae of variable size and shapeprotruding from the body,.some containing cartil-age; and 33% had limb abnormalities, usually singleand consisting of duplications or reductions, andsometimes separate but imperfect accessory limbs ordigits. About 20% of affected fetuses had gastro- orthoracoschisis and 20% a facial abnormality, such asseparation of the nasal processes. A smallerproportion had anal atresia, bladder exstrophy, andabsent kidneys.Our patients have anomalies which have been

assumed to be the result of disruption by amnioticbands, and we suggest that these cases and thosepublished cases with apparent ABS, in addition toanomalies difficult to explain by band disruption,may result from a mutant gene, the homologue ofthe mouse mutant disorganisation.There are a few published reports of familial

amniotic bands. Etches et at8 described a mother,child, and great aunt who all had amputationssimilar to those seen in ABS, and Lubinsky et at9described two further families.These familial instances could be explicable by the

effects of a semidominant gene, such as Ds. Whilenot suggesting that all cases of ABS are caused by amutant gene homologous to Ds, the possibilityshould be borne in mind and an appropriate familyhistory taken, specifically noting craniofacial, limb,and genitourinary anomalies.

References

Streeter GL. Focal deficiencies in fetal tissues and their relationto intrauterine amputation. Contr Embryol Carneg Instn 1930;22:1-44.

2 Torpin R. Amniochorionic mesoblastic fibrous strings andamniotic bands. Associated constricting fetal malformations orfetal death. Am J Obstet Gynecol 1965;91:65-75.Higginbottom MC, Jones KL, Hall BD. Smith DW. Theamniotic band disruption complex: timing of amniotic rupture

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and variable spectra of consequent defects. J Pediatr 1979;95:544-9.

4 Graham JM, Higginbottom MC, Smith DW. Preaxial poly-dactyly of the foot associated with early amnion rupture:evidence for mechanical teratogenesis? J Pediatr 1981;98:943-5.Pagon RA, Stephans TD, McGillivray BC, et al. Body walldefects with reduction limb anomalies: a report of fifteen cases.Birth Defects 1979;15(5A):171-85.

6 Hunter AGW, Carpenter BF. Implications of malformations notdue to amniotic bands in the amniotic band sequence. Am J MedGenet 1986;24:691-700.

7 Hummel KP. Developmental anomalies in mice resulting fromaction of the gene Disorganization, a semi-dominant lethal.Pediatrics 1959;23:212-21.

8 Etches PL, Stewart AR, Ives EJ. Familial congenital amputa-tions. J Pediatr 1982;101:448-9.

9 Lubinsky M, Sujansky E, Sanger W, Salyards P, Severn C.Familial amniotic bands. Am J Med Genet 1983;14:81-7.

Correspondence to Dr D Donnai, Regional GeneticCentre, St Mary's Hospital, Manchester M13 OJH.

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