journal of Medical Genetics (1973). 10, 346.

Lip Pits and Congenital Absence of Second Premolars:Varied Expression of the Lip Pits Syndrome*

EDWARD L. SCHNEIDERtDepartment of Pediatrics, University of California-San Francisco; San Francisco, California 94122, USA

Summary. A family with the lip pits syndrome is described in which nine ofthe 11 affected members have hypodontia involving the second premolars.

The familial occurrence of lower lip pits (fistulas,sinuses) was first described by Dermarquay in 1845.Family studies indicate that this congenital malfor-mation is inherited as an autosomal dominant traitwith high penetrance (80%) and with expressionwhich varies from a single barely noticeable lowerlip depression to upper cleft lip and/or palate(Cervenka, Gorlin, and Anderson, 1967). Themost common lesions are two fistulas which appearas pits on the vermilion part of the lower lip,equidistant from the midline. In addition to cleftlip and/or palate, other less frequently associatedanomalies include syndactyly of the hands, poly-thelia, ankyloglossia, and symblepharon (Cervenkaet al, 1967).The family reported here prominently displays an

association of lower lip pits and hypodontia, involv-ing the mandibular and maxillary second premolars.Since missing third molars are extraordinarily com-mon (25%) in the general population, the hypo-dontia under discussion concerns the remaining 28teeth (Werther and Rothenberg, 1939).

Materials and MethodsFamily B came to our attention when an unaffected

member of the family (III.12) came to our clinic forgenetic counselling on an unrelated matter. Subse-quently, 27 members of family B were personally ex-amined and information on 11 other members was ob-tained by a questionnaire. Of the latter group, threeare deceased and one is institutionalized with Down'ssyndrome. Full mouth x-rays were done on three

Received 7 June 1973.* This work was aided by grants from the National Foundation-

March of Dimes, Maternal and Child HIealth Service (USPHS),and the National Institute of General Medical Sciences, USPHS.

t Present address: Mammalian Genetics Section, Laboratory ofCellular and Comparative Physiology, Gerontology Research Center,Baltimore City Hospitals, Baltimore, Maryland 21224, USA.

346

family members. Red blood cell and serum sampleswere obtained from 16 family members, including ninewith lip pits. The following red blood cell antigensystems were analysed: A, B, 0, Rh(C,D,E,c), Lewis(Lea, Leb), MNSs, Duffy (Fya), Kidd (JKa), Kell, and P(Giblet, 1969). Electrophoresis was performed on redblood cells for haemoglobin, glucose-6-phosphate de-hydrogenase, and phosphoglucomutase types and serumfor haptoglobin types (Sparkes, Baluda, and Townsend,1969; Petrakis, Lee, and Mossberger, 1973).

ResultsInheritance. The pedigree of family B is

shown in Fig. 1. Eleven of the 27 (41%) membersexamined had either unilateral (Cervenka et al, 1967)or bilateral (Brechkus, Oliver, and Montelius, 1944)pits in the anterior paramedian vermilion portion ofthe lip (Figs. 2a and 2b). The presence of lip pits intwo deceased family members, was documented byphotographs. The high incidence of lip pits in off-spring of affected members (12 of 21 or 57%), thevertical transmission through three generations andfather to son transmission indicate autosomal domi-nant inheritance.

Associated Hypodontia. As is shown inTable I, nine of the 11 examined family memberswith lip pits had less than 28 teeth present (thirdmolars excluded). By contrast, none of the 12family members without lip pits but with perma-nent dentition had missing teeth. That this is not afortuitous association is indicated by chi-squaretesting, which reveals a highly significant correla-tion between lip pits and hypodontia (less than 28teeth). Of the nine patients with lip pits and hypo-dontia, four have missing maxillary and mandibu-lar second premolars while five have missing man-dibular second premolars only. One patient (11.3)with missing mandibular second premolars also had

copyright. on O

ctober 19, 2020 by guest. Protected by

http://jmg.bm

j.com/

J Med G

enet: first published as 10.1136/jmg.10.4.346 on 1 D

ecember 1973. D

ownloaded from

Lip Pits and Congenital Absence of Second Premolars: Varied Expression of the Lip Pits Syndrome 347

8 15 16 17

00(3 Lip pits only aLip pits and hypodontia e0

OJ® Examined, neither li pitsI ~~~nor hypoTontia

22

Deceosed, lip pits by history

Questionnaire reveals neitherlip pits nor hypodontia

FIG. 1. Pecigree of family B.

TABLE IPRESENCE OF HYPODONTIA IN PATIENTS WITH

LIP PITS

Normal Dentition* Hypodontia*(> 28 teeth) ( 28 teeth)

Affected individualsLip pits only

Unilateral 0 2Bilateral 2 5

Lip pits and cleft lip andpalate 0 2

Total 2t 9 +

Unaffected individuals 12t 0+

* Excluding third molars.t x2 = 12 9, p< 001.

one missing upper lateral incisor (Fig. 3a). Oralradiology of this patient's son (III.19) revealed themore commonly observed pattern of missing mandi-bular second premolars only (Fig. 3b).

Other Malformations. Cleft lip and palatewere observed in two family members (II.4 andIII.16) with both lip pits and hypodontia. Ptyer-gia, syndactyly, ectodermal dysplasia, or other mal-formations were not observed in affected familymembers. One person without lip pits had Down'ssyndrome and another died of congenital heartdisease (tetralogy of Fallot).

Red Blood Cell Antigen and Other GeneticStudies. The results of red blood cell antigen

FIG. 2b. Unilateral lip pit observed in III.17.

I

II

IVI

el

..

FIG. 2a. Bilateral lip pits observed in III.19.

copyright. on O

ctober 19, 2020 by guest. Protected by

http://jmg.bm

j.com/

J Med G

enet: first published as 10.1136/jmg.10.4.346 on 1 D

ecember 1973. D

ownloaded from

Edward L. Schneider

FIG. 3a. Full mouth radiograph of II.3 revealing absent bilateral mandibular second premolars and right lateral maxillary incisor (arrows).

FIG. 3b. Full mouth radiograph of III.18 revealing absent bilateral permanent mandibular second premolars with only deciduous mandibularsecond premolars present (arrows).

348

copyright. on O

ctober 19, 2020 by guest. Protected by

http://jmg.bm

j.com/

J Med G

enet: first published as 10.1136/jmg.10.4.346 on 1 D

ecember 1973. D

ownloaded from

Lip Pits and Congenital Absence of Second Premolars: Varied Expression of the Lip Pits Syndrome 349

analysis as well as electrophoretic studies on hapto-globin, glucose-6-phosphate-dehydrogenase, phos-phoglucomutase, and haemoglobin revealed noapparent linkage to either lip pits or missing teeth.

DiscussionCongenital missing teeth is not an uncommon

finding with an incidence, if third molars are ex-cluded, of between 3 and 6% (Breckhus et al, 1944;Gates, 1946; Grahnen, 1962). The most fre-quently involved teeth, excluding third molars, arethe maxillary incisors and the maxillary and mandi-bular premolars (Breckhus et al, 1944; Gates, 1946;Grahnen, 1962). Families have been described withapparent autosomal dominant transmission of miss-ing maxillary lateral incisors, maxillary canines,maxillary central incisors, and various other lessconsistent combinations (Breckhus et al, 1944;Gates, 1946; Grahnen, 1962). Erwin and Corkern(1949) described a family with dominant transmis-sion of absent maxillary and mandibular secondpremolars. This family differs from family B inthat three of the four members affected had variousadditional missing teeth including lateral maxillaryincisors, mandibular central incisors and maxillaryfirst bicuspids.

Cases of hypodontia have occurred in conjunctionwith ectodermal dysplasia, but lip pits have notbeen observed (Grahnen, 1962). Conversely, re-views of the syndrome of congenital lip pitsdo not mention hypodontia (Watanabe, Igaku-Hakushi, and Tomida, 1951; Neuman and Shulman,1961; Cervenka et al, 1967; Hoffman, 1971).Cervenka et al (1967) in their review noted con-siderable heterogeneity in the expression of the lippit syndrome, with some families having a higherfrequency of cleft lip and/or palate. The familydescribed in this report may represent another as-pect of this heterogeneity. In this case, hypodontiamay have high expression (81 %) and cleft lip and/orpalate low expression (<20%"). Hypodontia there-fore may be a feature of this syndrome which hasbeen overlooked in previous families.

Another possibility is that this family has twoseparate, dominantly inherited disorders, the syn-

drome of lip pits and a syndrome of congenitalabsence of the second premolars (mandibular withor without maxillary). Pedigree analysis wouldsuggest that if this is the case, there is close linkagebetween these two genes. There is a possibility thatlip pits in association with missing second premolarrepresents a new syndrome with autosomal domi-nant inheritance. In either case, one clinicallyimportant observation is the low risk of recurrence(< 10%) for the more severe associated condition,cleft lip and/or palate.

I would like to thank Dr Merle Morriss for dentalconsultation, Drs R. Mossberger and N. Petrakis for theelectrophoretic studies, Mrs E. B. for help in arrangingexaminations of family B, Dr. D. P. Hause for use of hisphotographs, and Drs C. J. Epstein and Bryan Hall foreditorial assistance.

REFERENCES

Breckhus, P. J., Oliver, C. P., and Montelius, G. (1944). A study ofthe pattern and combinations of congenitally missing teeth in man.Journal of Dental Research, 23, 117-131.

Cervenka, J., Gorlin, R. J., and Anderson, V. E. (1967). The syn-drome of pits of the lower lip and cleft lip and/or palate. Geneticconsiderations. American Journal of Human Genetics, 19, 416-432.

Demarquay, J. N. (1845). Quelques considerations sur le bec-de-lievre. Gazette Medicale de Paris, 13,52-54.

Erwin, W. G. and Corkern, R. W. (1949). A pedigree of partialanodontia. Journal of Heredity, 40, 215-218.

Gates, R. R. (1946). Human Genetics. Macmillan, New York.Giblet, E. R. (1969). Genetic Markers in Human Blood. Black-

well Scientific, London.Grahnen, H. (1962). Hereditary factors in relation to dental cariesand congenital missing teeth. In Genetics and Dental Health, ed.by J. Witcop, Jr. McGraw-Hill, New York.

Hoffman, S. (1971). Congenital lip sinuses: hereditary aspects andtheir relationship to cleft lip and palate. British Journal of PlasticSurgery, 24, 241-246.

Neuman, Z. and Shulman, J. (1961). Congenital sinuses of thelower lip. Oral Surgery, Oral Medicine and Oral Pathology, 14,1415-1420.

Petrakis, N., Lee, R., and Mossberger, R. (1973). Cellulose acetateelectrophoresis of human red cell phosphoglucomutase and poly-acrylamide gel electrophoresis of human haptoglobins. (Unpub-lished data.)

Sparkes, R. S., Baluda, M. C., and Townsend, D. E. (1969). Cellu-lose acetate electrophoresis of human glucose-6-phosphate de-hydrogenase. Journal of Laboratory and Clinical Medicine, 73,531-534.

Watanabe, Y., Igaku-Hakushi, M. O., and Tomida, K. (1951). Con-genital fistulas of the lower lip. Oral Surgery, Oral Medicine andOral Pathology, 4, 709-722.

Werther, R. and Rothenberg, F. (1939). Anodontia: a review of itsetiology with presentation of a case. American Journal of Ortho-dontics, 25, 61-81.

copyright. on O

ctober 19, 2020 by guest. Protected by

http://jmg.bm

j.com/

J Med G

enet: first published as 10.1136/jmg.10.4.346 on 1 D

ecember 1973. D

ownloaded from