J. med. Genet. (I966). 3, I7.

Sex-linked Cleft Palate*Report of a Family and Review of 77 Kindreds

E. DAVID WEINSTEINt and MAIMON M. COHEN+

From the Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, U.S.A.

Cleft palate, with or without cleft lip, is one ofthe more common congenital malformations inman (Fraser and Calnan, I96I). The frequencyof facial clefts in Caucasians is about I-5 per I000live births (Fogh-Andersen, I942, I963; Van derWoude, 1954; Neel, I958; Rank and Thomson,I960; Loretz, Westmoreland, and Richards, I96I;Milham, I963; Kraus, Kitamura, and Ooe, I963;Greene, I963; Woolf, Woolf, and Broadbent, I963;Greene, Vermilion, Hay, Gibbens, and Kersch-baum, I964), and this condition comprises 7 5%of all congenital defects noted at birth (Kraus et al.,I963). Using these figures, Greene (I963) esti-mated that in the United States nearly 6ooo newcases of lip and palatal clefts occurred annually.The incidence of clefts of the lip and palate varies

among the different races. Mitani (I943) and Neel(1958) found the frequency to be higher in theJapanese (I-89-2-68 per I000 live births). Ivy(I962) and Greene et al. (I964) found the frequencyof facial clefts to be lower among American Negroes(0-22-0-55 per I000 live births).This paper describes the first reported family

with cleft palate that manifests an apparent sex-linkedpattern of inheritance. This study also includes ananalysis of 77 other families studied in the HeredityClinic ofthe University ofMichigan from December194I through December I964; they were ascertainedthrough a facial cleft in the propositus.

Case ReportThe N family (HC 9046, Fig. i) was referred to the

Heredity Clinic at the University of Michigan after thebirth, on May 8, I964, of the propositus, IV.4. At birth

Received May io, I965.*This work was supported in part by U.S. Public Health Service

Grants 5F2 HD-is, 919-03 and GM-o9252-03.tPresent Address: Department of Community Medicine, Uni-

versity of Kentucky Medical Center, Lexington, Kentucky, U.S.A.tPresent Address: Division of Human Genetics, Department of

Pediatrics, Children's Hospital, Buffalo, New York, U.S.A.

-MG2

it was noted that this male child had a wide midlinecleft of both the soft and hard palate extending to theincisor foramen (Fig. 2). Other anomalies observed atthis time included hypertelorism, strabismus, a medianfrontal prominence, an occipital protuberance, and low-set posteriorly rotated ears (Fig. 3A and 3B). An inclu-sion cyst of the penile meatus was also noted.The older brother of the propositus (IV.3) born on

August 26, I96I, also had a large midline cleft palatethat was repaired surgically at I7 months of age. At32 months of age contrast radiographs of the genito-urinary system in this youngster revealed urethralobstruction. Vesical neck surgery was performed forurethral valves on April 27, I964. Fig. 3C and 3Dreveal the same phenotypic defects as noted above inhis younger brother.The mother (III.2) exhibited similar hypertelorism

and the median frontal prominence seen in her sons(Fig. 3E and 3F). She manifested a prominent occiputand also had a soft cystic lesion of the scalp (3 x 3 x2 cm.) at the occiput. Both the father (III.i) and anolder female sib (IV.2) were normal. There was noknown parental consanguinity. A maternal great-uncle(II.3) was found to have a repaired midline palatal cleftand also showed hypertelorism and a median frontalprominence. These findings led to the conclusion that

N FAMILY (HC 9046)

3FNCNC |~

NC NC NC

7 4154718N

21-22* CLEFT PALATE * ABORTION*CLEFT LIP

AND PALATE A 7 ABORTIONS® CONGENITAL NC NORMAL CH-ROMOSOMES

HEART DISEASE/ PROPOSITUS

FIG. I. Pedigree of family with apparent sex-linked recessivre cleftpalate.

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i8

FIG. 2. Propositus, IV.4 (age 8 months), demonstratingpalate.

the great-uncle had a facial cleft probably basame genotypic constitution as the propositbrother.A male second cousin (IV.20) was found

repaired unilateral (left) cleft lip and palate ahave similar facies to the 3 affected individualiabove. He may represent a coincidental casclefts. However, his anomalies may also besame gene (as his great-uncle (II.3) andcousins (IV.3 and IV.4)) but influenced b'modifier' genes. Since he is related to the otiindividuals through 2 female ancestors (III.6the latter hypothesis is suggested.

Glucose-6-phosphate dehydrogenase (G61in II.3, III.i, IV.4, and IV.2o, showed normenzyme activity. Blood grouping studies,Xga, were performed on 11.2, II.3, III.i, I]

IV.2, IV.3, IV.4, and IV.20. Electrophoretiof the red cell enzymes G6PD and acid phoswell as haemoglobin of these family mernormal. The blood grouping and electropG6PD and acid phosphatase revealed no paresion.

It was not possible to demonstrate any linka,the above genetic markers and the clefts segthe family. Cytogenetic studies of the chronthe peripheral leucocytes in these 9 subjects

Weinstein and Cohen

III.i, III.2, II1.6, IV.2, IV.3, IV.4, and IV.20: 4 affectedand 5 normal) revealed numerically and morphologicallynormal karyotypes. No apparent X autosome trans-location could be discerned. Colour vision was nottested because of the young ages of the two affectedbrothers.

Review of Heredity Clinic KindredsFrom more than gooo kindreds recorded in the

Heredity Clinic of the University of Michigan, 83were found to have one or more individuals withfacial clefts. In 5 of these kindreds the facial cleftswere found to be associated with lip pits and the

midline cleft

ised on the,us and his

al -I-1

to have and did not,sdescribedse of facialdue to the2 second

y differentier affectednd 11.5),

?D) assaysial levels ofincluding

11.2, 111.6,

icmoidlinecety! '

phatase, asnbers, wasuhoresis ofntoavealexclu- FIG. 3. A and B, propositus, IV.4 (age 5 months), demonstrating

hypertelorism, strabismus, median fronal prominence, occipitalprotuberance, and low-set posteriorly rotated ears; C and D, older

ge between brother of propositus, IV.3 (age 31 years), demonstrating hypertelor-regating in ism, strabismus, median frontal prominence (mild), occipital pro-tiosomes of tuberance, and low-set posteriorly rotated ears; E and F, mother of

propositus, 111.2 (age 23 years) demonstrating hypertelorism and(II.2, 11.3, median frontal prominence.

1:11%.

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Sex-linked Cleft Palate

TABLESEX OF PROPOSITI AND AFFECTED RELATIVES IN 77KINDREDS WITH CLEFT LIP, WITH OR WITHOUTCLEFT PALATE (CL(P)), AND WITH CLEFT PALATE

ALONE (CP)

Male Female Total

52 Propositi with CL(P)Sporadic cases 14 3 27Cases with affected relative(s) I6 9 25Relatives with CL(P) 33 22 55Relatives with CP alone 2 I 3

25 Propositi with CP aloneSporadic cases 9 9 I8Cases with affected relative(s) 3 4 7Relatives with CL(P) 2 3Relatives with CP alone 4 2 6

Ir44Affected Individuals in 77 KindredsCL(P) 64 46 InoCP alone i8 I6 34

Total 82 62 144

syndrome inherited in an autosomal dominantfashion (Van der Woude, I954). These 5 kindredsand the present family (HC 9046) are excludedfrom this review of the Heredity Clinic Kindreds.The remaining 77 kindreds are summarized in theTable.Of the propositi with cleft lip with or without

cleft palate, 49% (25/52) had a positive familyhistory of facial clefts. In his study of 703 families,Fogh-Andersen (I96I) found 37% of cleft lip withor without cleft palate propositi to have a positivefamily history. Similarly, 28% (7/25) of the pro-

positi with cleft palate alone in the present reporthad a positive family history in contrast to the i9%found by Fogh-Andersen. The higher incidencesof positive family histories in the present cases

probably represents the ascertainment bias of a

heredity clinic.Cleft lip with or without cleft palate accounts

for approximately 75% of the facial clefts in thegeneral population and cleft palate alone for 25%(Spriestersbach, Spriestersbach, and Moll, I962).Spriestersbach et al. (I962) have shown that cleftsin the relatives of affected individuals are of thesame type as the propositus more often than wouldbe expected from the general population figures.In the present study 95% (55/58) of the affectedrelatives of the cleft lip, with or without cleftpalate, propositi had either cleft lip alone or cleftlip and palate. Of the 9 affected relatives of thecleft lip propositi, 6 (67%) had cleft palate alone.Although these numbers are too small for significantconclusions, the results are consistent with thefindings of others.

Cleft lip, with or without cleft palate, is usually

found more commonly in males (65-70%), whilecleft palate alone is more often reported in females(6o-65%) (Fogh-Andersen, I942; Greene, I963).Among the present 77 kindreds, 58% of the iocases with cleft lip, with or without cleft palate,were males, while 47% of the 34 with cleft palateonly were females. The alteration in the sex ratioin the cases with cleft lip, with or without cleftpalate, is consistent with the findings of others butthat of the cases with cleft palate alone is not.Again, however, the numbers are small.

Fig. 4 and 5 illustrate the pedigrees of the 32kindreds with familial cases of facial clefts. HeredityClinic cases HC 266, 366, and 8569 (Fig. 4) couldbe due to a sex-linked recessive mutant gene, as ispostulated for the family reported above (HC 9046).Cases HC 309 (Fig. 5) 3I5, 593, and 6943 (Fig. 4)could represent sex-linked dominant inheritancewith variable penetrance, though autosomal domi-nance cannot be ruled out.At birth about I5-25% of all patients with facial

cleftswillhave other associated malformations (Krauset al., i963; Greene et al., i964). Spriestersbachet al. (I962), Jaworska and Poradowska (i963), andGreene et al. (i964) found that the associated mal-formations in facial cleft patients were signficantlymore numerous in patients with isolated cleftpalate. In the present study 35 of i44 patients(24%) were found to have one or more associatedanomalies. Of the iiO patients with cleft lip, withor without cleft palate, 20 (i8%) were so affectedwhile 44% (I5 of 34) of the patients with cleft palateonly had other malformations. Although thenumber of associated malformations is significantlyhigher in the cleft palate group (X2 = 9-055, d.f. =I, p < O OI), a review of the types of malformationsin the two groups did not appear to be different.Included in both groups were malformations in theskeletal, muco-cutaneous, central nervous, respira-tory, and endocrine systems, as well as congenitalheart disease. The group with cleft palate onlyincluded one patient with possible D or E trisomysyndrome, and the group with cleft lip, with orwithout cleft palate, included one chromosomally-proven trisomy D. Of the 20 patients of the lattergroup, with an associated anomaly, IO were sporadicclefts and io familial (4 sibs, 2 sibs, 4 separate).In the group with cleft palate only, ii of the I5patients with an associated malformation weresporadic clefts and the remaining 4 familial (twosib pairs). The congenital urethral valves foundin the brother of the propositus are in keeping withthe high incidence of associated malformations inpatients with facial clefts, especially those patientswith cleft palate only.

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Weinstein and Cohen

HEREDTY CLINIC PEDIGREES. CL1PROPOSITUS WITH CL (P)

IIIII

IVIlVv

II11III

IV

(HC 366)

(eOCT( Tr

IV '(HC 7652) 66Q 6

V (HC792)0 (HC CM

III QWOC OT 6OJ(HCI411) HC653) '(HCI952)

II

::I (-190io (CQ 46)I-Vi()tfC H C 4048)

IV 48(HC6943) (HC8569)

I NO ISSUE

(OCLEFT PALATE 0 SEX UNKNOWN

( CLEFT UP * ABORTION0 C-LEFT UP AND ) PROPOSITUS

PALATE

FIG. 4. Heredity clinic pedigrees, male propositi with cleft lip, withor without cleft palate (CL(P)) showing familial cases of facial clefts.

DiscussionNumerous studies have attempted to elucidate

the role of heredity in the formation of humanfacial clefts (Fogh-Andersen, 1942, I96I; Metrakos,Metrakos, and Baxter, I958; Rank and Thomson,1960; Ramsey and Wynn-Williams, I960; Loretzet al., I96I; Spriestersbach et al., I962; Ivy, I962;Greene, I963; Greene et al., I964; Cervenka, I963;Jaworska and Poradowska, I963; Tretsven, I963,Woolf et al., I963; Woolf, Woolf, and Broadbent,1964). Generally it is concluded that both groupsexibit different degrees of familial aggregation andthat heredity is apparently much more significantin the group with cleft lip, with or without cleftpalate, than in the group with cleft palate only.Little has been added to the genetics of facial cleftssince Fogh-Andersen (1942) suggested that cleft lip,with or without cleft palate, was transmitted as anincomplete recessive trait with sex limitation tothe male. In incomplete recessive traits the gene

generally occurs as a recessive, but under certainconditions the heterozygote is manifested. Fogh-Andersen states that the predominance of males isprobably not due to the occurrence of sex-linkedcases. Further, Fogh-Andersen felt that cleft palatealone was inherited as a simple autosomal dominantwith decreased penetrance and sex limitation to thefemale. Only one Japanese study (Fujino, Tanaka,and Sanui, I963) has found a significant increase inconsanguinity, suggesting that recessive genes mayplay a role in facial clefts. Schull (i958), however,found no clear suggestion of recessive factors inthe aetiology of facial clefts among offspring ofconsanguineous Japanese marriages.

Fraser (I955) suggested that specific genetictypes of facial clefts should be sorted out from theheterogeneous categories. Van Der Woude (1954)described several families in which facial cleftsassociated with lip pits were inherited in an auto-somal dominant fashion. Fraser and Calnan (I96I)

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Sex-linked Cleft Palate

HEREDITY CLINIC PEDIGREES. 9 PROPOSITA WITH CL (P)

~ ~ LiQ~~~~~~(Q Q0

gp c 4(i 4*U" fw-

(HC137) (HC245)

-Q (HC743)

CI11 fit}O~~II b (4)(y t (r (r

IV (7y'(HC4859)

IV6IV ( HC637)

/(HC 6619)t-,8

(HC 8486)

HEREDITY CLINIC PEDIGREES, PROPOSITUS WITH CP

(9) i (b -(HC701)HC 688)

HEREDITY CLINIC PEDIGREES, 9 PROPOSITA WITH CP

(HC633) (HCI277)

"f7A( HC 7579 )

'( HC7210)1 NO ISSUE

OD CLEFT PALATE 0 SEX UNKNOWN

O1 CLEFT UP 0 ABORTION

* CLEFT LIP AND , PROPOSITUSPALATE

FIG. S. Heredity clinic pedigrees, female propositi with cleft lip,with or without cleft palate (CL)(P), male and female propositi withcleft palate only (CP), showing familial cases of facial clefts.

pointed out that cleft palate seemed to occur witha remarkable frequency as a part of autosomaldominant syndromes, including those of Pierre-Robin and Treacher-Collins as well as in ectro-dactyly.The finding of facial clefts and chromosomal

anomalies has been reported several times; howeverthe only consistent association is noted in the D1-trisomy syndrome. In 9 of 13 cases, both cleftpalate and lip were manifested, while one additionalpatient exhibited cleft palate alone (Smith, Patau,Therman, Inhorn, and DeMars, I963). Cellscultured from the palatal mucosa of a patient withcleft lip and palate showed a modal number of 72chromosomes (Gropp, Jussen, and Odunjo, I964).No diploid or tetraploid cells were found and the

modal karyotype of this tissue was a triploid com-plement plus a triplicated supemumerary memberof Group F. DeMyer, Zeman, and Palmer (I963)report a pair of sibs with alobar holoprosencephalyand median clefts ofthe lip and palate. The chromo-somes ofone ofthese sisters as well as another patientwith the syndrome were normal. Numerous otherkaryotypic investigations of individuals with facialclefts have revealed no chromosomal aberrations.The present family represents the first reported

occurrence of human facial clefts exhibiting a

probable sex-linked recessive mode of inheritance.In the 3 affected sibships there are 5 males, 4 ofwhom are affected, and 5 females, none of whomare affected (Fig. i). If the inheritance patternwere autosomal recessive, the prior probability of

Iv11

II111III

IV

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Weinstein and Cohen

having 4 affected males, I unaffected male, and 5unaffected females, among IO offspring, 5 of whomare male, is 0-0034I. The analogous probabilityif inheritance were sex-linked recessive is 0OI54.The facial clefts in this family could also be the

result of an autosomal dominant gene with muchreduced penetrance (50%), as proposed by Fogh-Andersen. One would also have to postulate asex limitation in the male rather than in the female,as suggested by previous studies It is felt that asex-linked recessive gene is the most likely cause ofthe clefts in this family.The hypertelorism, median frontal prominence,

and occipital protuberance seen in the 2 affectedmales, their mother, and their affected great-unclemay be phenotypic expressions of pleiotropic effectsof the abnormal gene. The failure of the palate tojoin and fuse in the midline may be secondary toan underlying bony abnormality of the skull. Theskull, in effect, may be too wide. Fraser (I955)and F. C. Fraser (I965, personal communication)mentions the association between facial clefts and awide head.

SummaryA family is presented with an apparent sex-linked

recessive form of facial cleft. Chromosome studieson the 4 affected individuals and 5 normal familymembers were normal. Cases of clefts of the lipand palate seen in a heredity clinic from I94I toI964 are reviewed with an analysis of 77 kindreds.

The authors would like to thank Dr. M. SamuelAdams for referring this family to the Heredity Clinicand Dr. William J. Schull for his statistical advice. Theywould also like to thank Drs. Margery W. Shaw andWilliam J. Schull for their assistance in the preparationof the manuscript.

REFERENCESv

Cervenka, J. (I 963). Harelip and cleft palate-genetic contribution.Acta Chir. plast. (Praha), 5, I87.

DeMyer, W., Zeman, W., and Palmer, C. G. (i963). Familial alobarholoprosencephaly (archinencephaly) with median cleft lip andpalate. Neurology (Minneap.), IX, 913.

Fogh-Andersen, P. (1942). Inheritance of harelip and cleft palate.Op. Domo Biol. hered. hum., Kbh., 4.

- (I96I). Inheritance patterns for cleft lip and cleft palate. I:Congenital Anomalies of the Face and Associated Structures,ed. S. Pruzansky, pp. 123-I33. Thomas, Springfield, Illinois.- (I963). Vital statistics of cleft lip and palate-past, present,

future. Acta Chir. plast. (Praha), 5, I69.Fraser, F. C. (I955). Thoughts on the etiology of clefts of the palateand lip. Acta genet. (Basel), 5, 358.

Fraser, G. R., and Calnan, J. S. (I96I). Cleft lip and palate: Seasonalincidence, birth weight, birth rank, sex, site, associated malforma-tions and parental age. A statistical survey. Arch. Dis Childh.,36, 420.

Fujino, H., Tanaka, K., and Sanui, Y. (I963). Genetic study ofcleft-lips and cleft-palates based upon 2,828 Japanese cases.KyushuJ. med. Sci., 14, 3I7.

Greene, J. C. (I963). Epidemiology of congenital clefts of the lipand palate. Pubi. Hlth Rep. (Wash.), 78, 589.

, Vermillion, J. R., Hay, S., Gibbens S. F., and Kerschbaum,S. (I964). Epidemiologic study of cleft lip and cleft palate in fourstates. J. Amer. dent. Ass., 68, 387.

Gropp, A., Jussen, A., and Odunjo, F. (I964). Near-triploidchromosome constitution in epithelial-cell cultures of p.latalmucosa from a case of cleft palate. Lancet, I, II67.

Ivy, R. H. (I962). The influence of race on the incidence of certaincongenital anomalies, notably cleft lip-cleft palate. Plast. reconstr.Surg., 30, 58I.

Jaworska, M., and Poradowska, W. (I963). Cleft lip and cleftpalate: a summarized statistical survey. Acta Chir. plast. (Praha),5, i8i.

Kraus, B. S., Kitamura, H., and Ooe, T. (I963). Malformationsassociated with cleft lip and palate in human embryos and fetuses.Amer. j. Obstet. Gynec., 86, 32I.

Loretz, W., Westmoreland, W. W., and Richards, L. F. (I96I). Astudy of cleft lip and cleft palate births in California, I955.Amer. 7. publ. Hith, Si, 873.

Metrakos, J. D., Metrakos, K., and Baxter, H. (I958). Clefts ofthe lip and palate in twins. Plast. reconstr. Surg., 22, 1O9.

Milham, S., Jr. (I963). Underreporting of incidence of cleft lipand palate. Amer. J. Dis. Child., Io6, i85.

Mitani, S. (1943). Malformations of newborns. Obstet. Gynec.,Tokyo, II, 345.

Neel, J. V. (I958). A study of major congenital defects in Japaneseinfants. Amer. J. hum. Genet., 10, 398.

Ramsey, P. A., and Wynn-Williams, D. (I960). Discordant defor-mities of lip and palate in monozygotic twins. Brit. J. plast.Surg., 13, IO.

Rank, B. K., and Thomson, J. A. (I960). Cleft lip and palate inTasmania. Med. J. Aust., 2, 68 I.

Schull, W. J. (I958). Empirical risks in consanguineous marriages:Sex ratio, malformation and viability. Amer. 7. hum. Genet., IO,294.

Smith, D. W., Patau K., Therman, E., Inhorn, S. L., and DeMars,R. I. (I963). The D1 trisomy syndrome. J. Pediat., 62, 326.

Spriestersbach, D. C., Spriestersbach, B. R., and Moll, K. L. (I962).Incidence of clefts of the lip and palate in families with childrenwith clefts and families with children without clefts. Plast. reconstr.Surg., 29, 392.

Tretsven, V. E. (I963). Incidence of cleft lip and palate in MontanaIndians. J7. Speech Dis., 28, 52.

Van Der Woude, A. (I954). Fistula labii inferioris congenita andits association with cleft lip and palate. Amer. J. hum. Genet., 6,244.

Woolf, C. M., Woolf, R. M., and Broadbent, T. R. (I963). Agenetic study of cleft lip and palate in Utah. ibid., IS, 209.-,- , and (I964). Cleft lip and heredity. Plast. reconstr.

Surg-, 34, II-

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