Skewed sex ratios in familial holoprosencephalyand in people with isolated single maxillary centralincisor

Graeme Suthers, Scott Smith, Sue Springbett

AbstractAutosomal dominant holoprosencephalyis a rare but well documented entity and itcan be the result of mutations in the SonicHedgehog gene (SHH). The transmittingparent may be normal or have a singlemaxillary central incisor.

We describe a skewed sex ratio amongthe transmitting parents with SHH muta-tions, with more mothers than fathershaving the mutation (p=0.002). The mech-anism underlying this skewed sex ratio isnot clear; the SHH mutations do notinvolve triplet repeats, imprinting is plau-sible but untested, and there is no evi-dence that the risk of holoprosencephaly isgreater among males carrying such amutation (p=0.15). We considered thepossibility that males with such a muta-tion are at greater risk of other malforma-tions outside the central nervous system,which could reduce their reproductive fit-ness.

To avoid ascertainment bias in identify-ing children with various malformationsin kindreds with familial holoprosen-cephaly, we reviewed the reports of peoplewith single maxillary central incisor andno other congenital malformations. Of the16 cases identified, 13 were female(p=0.0085).

We suggest that boys with mutationsassociated with autosomal dominant holo-prosencephaly may be at greater risk ofmajor malformations outside the centralnervous system than girls.(J Med Genet 1999;36:924–926)

Keywords holoprosencephaly; single central maxillaryincisor; sex ratio

Holoprosencephaly represents the partial orcomplete failure of the cephalic neural tube todivide into right and left lobes. It can be chro-mosomal, multifactorial, or monogenic inorigin and may be associated with othermidline malformations.

Autosomal dominant (AD) holoprosen-cephaly is uncommon but well documented.The transmitting parent may have a single cen-tral maxillary incisor as the only manifestationof a midline abnormality. There are at least 12genetic loci responsible for holoprosencephaly1

and the Sonic Hedgehog gene (SHH) at 7q36has been identified as one of the genesresponsible.2 3

AD holoprosencephaly resulting from muta-tions in SHH exhibits preferential maternaltransmission. In nine families with docu-mented SHH mutations2 3 there were 16 trans-mitting parents, 14 of whom were female(p=0.002). Preferential maternal transmissionwas not evident in one large kindred with ADholoprosencephaly that is not linked to 7q36(pedigree 1 in reference 4) or in four familiesthat have not been genotyped (pedigrees f, l, n,and o in reference 5); of the total of 12transmitting parents, four were female(p=0.12).

What could account for the skewed sex ratioamong parents who are carriers of documentedor presumptive SHH mutations? There are anumber of possibilities.

First, triplet repeat mutations can show sexspecific preferential expansion during trans-mission, but the SHH mutations identifiedwere missense, nonsense, and deletions.2 3

Second, imprinting of 7q36 could accountfor the skewed ratio. There is indirect evidencethat portions of chromosome 7 are imprinted.Maternal uniparental disomy of this chromo-some is associated with short stature and theRussell-Silver syndrome.6 In particular, theregion 7q35-qter is probably imprinted andthis would encompass the SHH gene. Thereare limited data to explore this possibility inrelation to AD holoprosencephaly. In one fam-ily with a documented SHH mutation, a manand his sister each had a child with holoprosen-cephaly (pedigree 3 in reference 4; see also ref-erence 7). This would argue against imprintingof the SHH gene.

A third possibility is that the expression ofSHH mutations in the developing brain is moresevere in males than females and hence thereproductive fitness is selectively reduced inmales. In the seven families with documentedSHH mutations and published phenotypes,4

nine of the 15 children with holoprosencephalywere male (p=0.15). These data do not supportthe suggestion that there is a sex specific eVectof SHH mutations on the developing brain.This conclusion is reinforced by the generalobservation that the sex ratio for non-chromosomal holoprosencephaly is close toone.8

A fourth possibility is that males with muta-tions causing AD holoprosencephaly are morelikely than females to have other midlinemalformations outside the central nervous sys-tem. As a result, males with the mutation wouldhave reduced reproductive fitness. It is diYcultto assess this reliably in the families described.

J Med Genet 1999;36:924–926924

South AustralianClinical GeneticsService, Centre forMedical Genetics,Women’s & Children’sHospital, NorthAdelaide, SA 5006,AustraliaG Suthers

Dental Clinic,Women’s & Children’sHospital, NorthAdelaide, SA 5006,AustraliaS Smith

Adelaide DentalHospital, University ofAdelaide, SA,AustraliaS Springbett

Correspondence to:Dr Suthers

Revised version received7 June 1999Accepted for publication5 August 1999

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The process of identifying the families intro-duces an ascertainment bias and there wereusually insuYcient data reported to determinewhether the reproductive fitness of malescarrying a presumptive or proven mutation wasindeed reduced.

In view of the diYculty of testing thishypothesis directly by examining families withAD holoprosencephaly, we took an alternativeapproach. A single central maxillary incisor is arare finding, occurring in approximately1:50 000 people,9 but it is well documented insome carriers of AD holoprosencephaly.7 10

The presence of a single maxillary central inci-sor as an isolated finding would not aVectreproductive fitness, and such a feature in theabsence of any family history of midlinecongenital malformations could represent mildexpression of an AD holoprosencephaly muta-tion or be the result of some other mechanism.If males with mutations causing AD holopros-encephaly are more likely than females to havemidline malformations outside the centralnervous system that reduce their reproductivefitness, one might expect to find more femaleswith an isolated single maxillary central incisorthan males. In other words, are single maxillarycentral incisors in otherwise healthy peoplemore common in men or women? A skewed sexratio in favour of women would suggest thatthere is a link between isolated single maxillarycentral incisor and being a carrier of AD holo-prosencephaly.

We defined a single maxillary central incisoras a maxillary tooth that was symmetrical in themidline and which lacked a clearly definedcentral notch which is often used to infer adouble tooth. We excluded reports of peoplewith agenesis of one central incisor and associ-ated asymmetry of the dental arch, holoprosen-cephaly or other congenital malformations(including choanal atresia) that would compro-mise reproductive fitness, short stature, Men-delian disorders, or chromosome abnormali-ties. We avoided an ascertainment bias byexcluding people with a family history of holo-prosencephaly. We also excluded cases de-scribed in population surveys of oligodontia asinsuYcient detail was presented.

We identified articles describing 15 peoplewith an isolated single maxillary central incisorand no other congenital abnormalities thatwould have reduced their reproductive fitness(table 1). We also identified a child withisolated single maxillary central incisor throughour Dental Clinic. Of the 16 cases identified,13 were female (p=0.0085), indicating askewed sex ratio among those with isolatedsingle maxillary central incisor. It is intriguingto note that the only published familial caseswe noted were a mother and daughter, and thattwo of the girls were reported to have sibs withcleft lip; one sib was male and the gender of theother was not stated.

It is clear that transmitting carriers of ADholoprosencephaly resulting from SHH muta-tions are more likely to be female than male. Asimilar skewed sex ratio is evident amonghealthy people with a single maxillary centralincisor. This concordance suggests that such

people might represent the mildest phenotypeof an SHH mutation; this possibility could onlybe evaluated by examining the SHH gene inpeople with a single maxillary central incisor. Italso raises the possibility that the preferentialmaternal transmission of SHH mutations infamilies with AD holoprosencephaly may bebecause of milder expression of the causativemutation outside the central nervous system inwomen. This is not to suggest that all maleswith such mutations are phenotypically abnor-mal; two clinically normal males with SHHmutations have been identified.2 3

We have some anecdotal evidence consistentwith the suggestion that the reproductivefitness of boys with a single maxillary centralincisor may be less than that of girls. We iden-tified two boys with single maxillary centralincisors through our Dental Clinic in additionto the girl mentioned above. The boys were ofnormal height and intelligence, lacked dysmor-phic features, and had been ascertainedthrough the Dental Clinic rather than througha medical service. However, both boys had hadcorrection of major midline malformations ininfancy, imperforate anus in one and doubleoutlet right ventricle in the other.

There is a slight female excess amongchildren with the syndrome of solitary maxil-lary central incisor, short stature, and choanalatresia (F:M=1.6).9 The female excess is lessmarked than among people with isolated singlemaxillary central incisor, and this is similar tothe loss of sex ratio distortion with more severeexpression of the AD holoprosencephaly phe-notype.

Skewed sex ratios have been observed inother midline malformations as well. Neuraltube defects occur in male and female babieswith equal frequency, but in kindreds with twoor more aVected children there are more trans-mitting mothers than fathers.11 12 It is welldocumented that cleft lip occurs more fre-quently in boys,11 13 with a predominance offathers among normal transmitting parents. Onthe other hand, the schisis association occursmore commonly in female babies,14 but it is not

Table 1 Reported cases of isolated single central maxillaryincisor

Year ReferenceCaseNo Gender Additional clinical data

1970 16 5 Male1986 17 1 Male1991 18* 1 Male1958 19 1 Female1967 20 1 Female Daughter of next case1967 20 2 Female Mother of preceding case1970 16 1 Female1970 16 2 Female1974 21 1 Female1977 22 5 Female Also had Graves’ disease1978 23 2 Female Also had unilateral absent

cochlea1979 24 1 Female Had sib with cleft lip1983 25 1 Female1991 18* 2 Female Had brother with cleft lip1991 18* 3 Female

1 Female Present case

*These cases were described as having single maxillary centralincisors that were morphologically right (or left) maxillary cen-tral incisors. These teeth were centred in the midline with nodistortion of the maxillary arch or gaps in the maxillarydentition.

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clear if this reflects more severe expression infemales or a higher risk of early prenatal lossamong males.

The underlying reasons for these various sexratios are not known. On the other hand, thereare some preliminary data that implicateabnormal SHH expression in the formation ofa single central incisor. A number of genes inthe Sonic Hedgehog signalling pathway (in-cluding SHH itself) are expressed in specifictemporal and spatial patterns during earlytooth development in the mouse.15

In preparing this report we struggled withthe terminology. The term “central incisor”usually refers to paired teeth that are inparamedian locations and are morphologicallyright and left sided. The same term is also used(as we have in this report) for a single abnormaltooth that is symmetrical about the midline. Asa small step towards more precise nomencla-ture, we would follow Hall9 and suggest that a“single maxillary central incisor” as defined forthis study would be described more appropri-ately as a “single maxillary median incisor”.

Finally, this analysis raises the possibility thata healthy woman with a single maxillarymedian incisor and no family history of midlinemalformations may be at increased risk of hav-ing a baby with holoprosencephaly. There areno data to suggest the magnitude of this riskand, as noted above, it would be interesting toexamine the SHH genes of such people for evi-dence of mutations.

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