American Journal of Medical Genetics 53:29-32 (1994)

On the Inheritance of the Split Hand/Split Foot Malformation

Joel Zlotogora Department of Human Genetics, Hadassah Medical Center, Hebrew Uniuersity, Jerusalem, Israel

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Analysis of families with non-syndromal split handsplit foot (SHSF) confirms the ex- istence of 2 distinct entities, most probably caused by at least 2 different autosomal dominant genes. In the families in which the SHSF malformation is non-syndromal and limited to the hands and feet (type I), the pattern of inheritance is of a regular auto- soma1 dominant gene with a high pene- trance (96%). In families in which at least one individual has other limb malforma- tions and SHSF (type 11), the transmission is often unusual. In most families, the gene is non-penetrant, sometimes for generations, before the birth of the first affected individ- ual. Thereafter, among the descendants of affected individuals, the penetrance is re- duced (66%), suggesting the possible exis- tence of another gene which controls the ap- pearance of the clinical manifestations. The possibility that SHSF associated with other limb malformations is a disorder caused by trinucleotide repeat instability is raised. 0 1994 Wiley-Liss, Inc.

KEY WORDS: germinal mosaicism, limb malformations, penetrance, premutation, split handsplit foot

INTRODUCTION The split handkplit foot (SHSF) anomaly has been

observed as isolated or associated with other malfor- mations as part of various syndromes. Among non-syn- dromal SHSF one may distinguish 2 different entities: one in which the malformation is limited to the hands and feet and the second, in which other limb malfor- mations are present, in particular tibia1 hypoplasia

Received for publication December 16, 1993; revision received April 25, 1994.

Address reprint requests to Joel Zlotogora, Department of Hu- man Genetics, Hadassah Hospital, POB 12,000, Jerusalem il 91120 Israel.

0 1994 Wiley-Liss, Inc.

[McKusick, 19921. In some of the reported families all the affected individuals had one type of malformation, while in other families both types of malformations may appear in different individuals. The clinical mani- festations in the affected individuals are variable and in most cases the inheritance appears to be autosomal dominant, with a relatively large number of pedigree displaying incomplete penetrance and often other un- usual characteristics. This has been explained on the basis of germinal mosaicism or unstable premutations [David, 1972; Spranger and Schapera, 19881. In addi- tion, Genuardi et al. [1993] suggested that, according to a mouse model of SHSF [Chay, 19811, the dominant gene for SHSF is controlled by another gene which is recessive. The same model was proposed in order to explain the existence of families in which SHSF ap- peared to be inherited as an autosomal recessive trait [Zlotogora and Nubani, 19891. However, this model does not explain most of the peculiarities in the trans- mission pattern of SHSF and in order to understand it better, an analysis of the pattern of inheritance in families with SHSF was done.

METHODS All the reports on non-syndromal familial SHSF

available were included in this analysis. Two types of families were distinguished: one in which the malfor- mation in all the affected individuals was limited to the hands and feet and the other where at least one individual had other limb defects.

Definition of the Penetrance Two different types of obligatory carriers were distin-

guished: one, the obligatory carriers among the descen- dants of an affected individual; the other, the obligatory carriers among the ancestors of the first affected indi- vidual in the family. In the last group, the healthy par- ent of more than one affected child may be unaffected because of non-penetrance or because of germinal mo- saicism for a new mutation. Penetrance was calculated among the descendants of the first affected individual in each family as the ratio between the number of oblig- atory carriers presenting with a clinical sign of the syndrome to the total number of obligatory carriers.

30 Zlotogora

TABLE I. Families With Non-Syndromal Isolated SHFH (Tvpe I) Which Was Present in at Least 2 Generations*

Reference" Total

Obligatory carriers Descendants Healthy - ancestors in generation-

Affected Total IV

David [19721

Emery [19771 Hedgekatti [19391 Johnston and Davis [19531 MacKenzie and Penrose [19511

Ray [19701

Sommer and Hines [19921 Stevenson and Jennings [19601 Temtamy and McKusick [19781

Viljoen and Beignton [19841 Warkany [19711 Wightman L19371 Anders (1) Bechet (1) Bindseil(1) Burger (1) Jaworska (1) Neugebauer (1) Perhtes (1) Scheffen (1) Schmidt (1) Schultze (1) Tilanus (1) Total

Scott*[l9331

3 9

12 4 8 3

16 2 1 8 4

19 2 3 4 3 4 1 1 - - -

2 - - - 1 3

113

2 2 8 8

11 11 3 4 8 8 1 3

16 16 1 1

7 8 3 3

19 19 2 2 2 2 4 4 2 2 4 4 1 1 1 1

- -

- - - - - - - - - - - - - - 1 1 3 3

99 103

I11 I1

*The obligatory carriers have been separated in 2 groups: the descendants of the first affected individuals and their healthy ances- tors. Each line in the table represent a different family. "The articles marked (1) were cited in Bujdoso and Lenz [1980].

RESULTS Isolated SHSF: Type I (Table I)

Penetrance among the descendants of an af- fected individual. In most of the pedigrees re- ported, many including more than 4 generations, all of the obligatory carriers were affected. Non-penetrant in- dividuals were documented in very few families, such as those reported by Scott [19331 and Emery [19771, each with one non-penetrant obligatory carrier, and by Johnston and Davis [19531, in which 2 obligatory carri- ers were unaffected. The penetrance was calculated to be 96% (99/103).

In 7 of the families analyzed both parents of multiple affected sibs appeared to be unaffected. In only one family was an obligatory carrier also unaffected in a previous gener- ation.

Penetrance among the ancestors.

SHSF Associated With Other Limb Defects: Type I1 (Table 11)

Penetrance among the descendants of affected individuals. In many of the pedigrees analysed un- affected obligatory carriers were reported. The pene- trance was calculated to be 66% (35153).

Penetrance among the ancestors. In 21 of the families analyzed, both parents of more than one oblig-

atory carrier were unaffected. In addition, in many cases, obligatory carriers were also found in the second (271, third (131, or fourth generation (4) before the healthy parents of the first symptomatic obligatory carrier.

DISCUSSION From the analysis of families reported with isolated

SHSF malformation it seems that at least 2 different autosomal genes are involved. Even though the distinc- tion between the 2 types is made in McKusick's cata- logue [McKusick, 19921, it is not made in many reports, leading to confusion. One gene which is responsible €or isolated SHSF limited to the hands and feet (type I) (McKusick, 183600) has a very high penetrance (96%). The variability of the clinical malformations among the affected individuals is such that if all the obligatory carriers were examined in detail, it may be that the penetrance would be even closer to 100% [Emery, 19771. As reported for many other autosomal dominant genes, some of the new mutations in this gene may appear as germinal mosaicism in one of the healthy parents of more than one obligatory carrier. It should be noted that inclusion of families as type I SHSF was based on the absence of individuals with other limbs malforma- tions and that some of the families may in fact belong to SHSF type 11. For instance, the family reported by

Split Handsplit Foot Malformation 31

TABLE 11. Families With Non-Syndramal SHSF Associated With Limb Defects (Type 11) Which Was Present in a t Least 2 Generations*

Obligatorv carriers Descendants Healthy ancestors in generation-

Total Affected Total IV I11 I1 I Reference"

Bailey [1938] der Kalousian and Mnaymneh [1973] Graham and Badgley [19551 Genuardi et al. [19931 Hoyme et al. 119871

8 4 5 6 6 6 8 5

10 2 2 2 3 1 1 5 5

10 4 1

6

2 6 2 2 2 2

10

- 1 1 1

1 1 1 1

1 1 1 1 1 1 1

1 1 1

1 1

-

-

-

-

- -

1 1

21

1 2 2

3 2 2 1

1 1 1 2

-

-

- 1

-

1 1 1 - Majewski et al. El9851

Mufti and Wood [19871 Richieri-Costa et al. [19871

- 1 5 1 -

- 5 6 3

- 1

3 2

-

- 1

5 1

-

- 2

Sener et al. [19891 Spranger and Shapera 119881 Temtamy and McKusick [19781 Birch Jensen (1) Schade (1) Schawarzweller (1) Takahashi (1) Total

5 12

- 3

4 - - 1 1

117 -

53 - 27

- 13

- 4

~~ ~

*The obligatory carriers have been separated in 2 groups: the descendants of the first affected individuals and their healthy ancestors. Each line in the table represent a different family. "The articles marked (1) were cited in Bujdoso and Lenz [19801.

Neugebauer [cited by Bujdoso and Lenz, 19801 which includes 2 affected individuals related through healthy ancestors in 2 generations, appears as an exception in type I SHSF and may belong to SHSF type 11.

SHSF type I1 (McKusick, 119100) is also character- ized by a wide range of clinical manifestations. Some of the affected individuals may present with isolated SHSF, but the most severe manifestations also include involvement of other limbs, in particular tibial apla- siahypoplasia. The penetrance is reduced and was calculated to be 66%. In many cases the obligatory carriers of this gene are unaffected, sometimes for generations, before the appearance of affected individ- uals. This has been referred to as a premutation [Spranger and Schapera, 19881 and is very similar to the observations made in other disorders such as frag- ile X syndrome, myotonic dystrophy, or Huntington dis- ease, in which trinucleotide repeat expansions within or close to the gene are the basis of the mutation. The reduced penetrance may be, as previously suggested, due to the existence of an autosomal recessive gene which controls the clinical expression of the SHSF gene [Genuardi et al., 1993; Zlotogora and Nubani, 19891. In the family reported by Genuardi et al. [19931 individu- als with SHSF had a balanced translocation including 7q22.1. In one of the children, tibial hypoplasia was

associated with SHSF and it is likely that one of the genes for SHSF type I1 is located in the region 7q22.1, being disrupted by the translocation or co-segregating with it.

While a trinucleotide expansion is the most common etiology of the fragile X syndrome, deletions and muta- tions has also been reported [de Boulle et al., 19931. Similarly, it may be that SHSF malformation with other limb defects (type 11) may be caused by expansion of a repeat sequence as well as in some cases by muta- tions or deletions which disrupt the gene as it was ob- served in some sporadic individuals with chromosomal aberrations in the 7q22.1 region. Soon it will be possi- ble to test these hypotheses since mapping for the gene responsible for SHSF on chromosome 7 is in progress.

REFERENCES Bailey S (1938): A pedigree of syndactylism. J Hered 29:467468. Bujdoso G, Lenz W (1980): Monodactylous splithand-splitfoot. A mal-

formation occurring in three distinct genetic types. Eur J Pediatr 133:207-215.

Chay CK (1981): Dactylaplasia in mice. A two-locus model for devel- opmental anomalies. J Hered 72:234-237.

David TJ (1972): Dominant ectrodactyly and possible germinal mo- saicism. J Med Genet 9:316-320.

de Boulle K, Verkerk AJMH, Reyniers E, Vits L, Hendrickx J, van Roy B, van den Bos F, de Graaff E, Oostra BA, Willems PJ (1993):

32 Zlotogora

A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nature Genet 3:31-35.

der Kaloustian VM, Mnaymneh WA (1973): Bilateral tibial aplasia with lobster claw hands. A rare genetic entity. Acta Paediatr Scand 62:77-78.

Emery AEH (1977): A problem for genetic counselling-split hand de- formity. Clin Genet 12:125-127.

Graham JB, Badgley CE (1955): Split hand with unusual complica- tions. Hum Genet 7:44-50.

Genuardi M, Pomponi MG, Sammito V, Bellussi A, Zollino M, Neri G (1993): Split hand/split foot anomaly in a family segregating a bal- anced translocation with breakpoint on 7q22.1. Am J Med Genet 47:823-831.

Hegdekatti RM (1939): Congenital malformation of hands and feet in man. J Hered 30:191-196.

Hoyme HE, Jones KL, Nyam WL, Pauli RM, Robinow M (1987): Auto- soma1 dominant ectrodactyly and absence of long bones of upper and lower limbs: Further delineation. J Pediatr 111:538-543.

Johnston 0, Davis RW (1953): On the inheritance of hand and foot anomalies in six families. Am J Hum Genet 5:35&366.

MacKenzie HJ, Penrose LS (1951): Two pedigrees of ectrodactyly. Ann Eugen London 16:88-96.

McKusick VA (1992): “Mendelian Inheritance in Man. Catalogs of Au- tosomal Dominant, Autosomal Recessive, and X-Linked Pheno- types.” Baltimore: John Hopkins, 10th edition.

Majewski F, Kuster W, ter Haar B, Goecke T (1985): Aplasia of tibia with split handsplit foot deformity. Report of six families with 35 cases and considerations about variability and penetrance. Hum Genet 70:136-147.

Mufti MH, Wood SK (1987): Ectrodactyly in sisters and half sisters. J Med Genet 24:220-224.

Ray AK (1970): Another case of split-foot mutation in two sibs. J Hered

Richieri-Costa A, Masiero D, da Silva CRM (1987): Tibia1 hemimelia: report on 37 new cases, clinical and genetic considerations. Am J Med Genet 27:867-884.

61:169-170.

Scott W (1933): Syndactylism with variations. J Hered 24:239-244.

Sener RN, Isikan E, Diren HB, Sayli BS, Sener F (1989): Bilateral split hand with bilateral tibial aplasia. Pediatr Radio1 19:258-260.

Sommer A, Hines SJ (1992): Brief clinical report. Autosomal dominant inheritance of tetramelic monodactyly. Am J Med Genet 425-54.

Spranger M, Schapera J (1988): Anomalous inheritance in a kindred with split hand, split foot malformation. Eur J Pediatr 147: 202-205

Stevenson AC, Jennings LM (1960): Ectrodactyly-evidence in favour of a disturbed segregation in the offspring of affected males. Ann Hum Genet 24:89-96.

Temtamy SA, McKusick VA (1978): The genetics of hand malforma- tions. New York: Alan R. Liss, Inc., for the National Foundation- March of Dimes. BD:OAS XIV(3):3&40.

Viljoen DL, Beighton P (1984): The split hand and split foot anomaly in a central african negro population. Am J Med Genet 19: 545-552.

Warkany J (1971): “Congenital Malformations. Notes and Com- ments.” Chicago: Year Book Medical Publishers.

Wightman J C (1937): A pedigree of syndactyly. J Hered 28:421423.

Zlotogora J , Nubani N (1989): Is there an autosomal recessive form of the split hand and split foot malformation? J Med Genet 26: 138-140.