96945 JHS39510.

1177/1753193413496945The Journal of Hand SurgeryAl-Qattan

Full length article

JHS(E)
The Journal of Hand Surgery

Central and ulnar cleft hands: a review of (European Volume)

2014, Vol. 39E(5) 510­–519
© The Author(s) 2013
concurrent deformities in a series of 47 Reprints and permissions:
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patients and their pathogenesis DOI: 10.1177/1753193413496945

jhs.sagepub.com

M. M. Al-Qattan

Abstract
Two main types of cleft hands have been described. The ulnar cleft hand deformity is very rare and is
characterized by two constant features: a deep cleft radial to the little finger and hypoplasia of the ulnar
digits. The pathogenesis of ulnar clefts is unknown. The second type is the central cleft hand deformity,
which is characterized by a soft tissue/bone defect in the hand centrally. Patients with central clefts also
have several concurrent deformities in the remaining digits. This paper reviews the clinical features of
three cases with ulnar cleft hands and 44 cases of central cleft hands, with special emphasis on concurrent
deformities. The author’s hypothesis of pathogenesis for both types of clefts and their concurrent deformities
is then offered.

Keywords
Cleft hand, congenital, split hand
Date received: 19th March 2013; revised: 15th May 2013; accepted: 9th June 2013

Historically, cleft hands used to be classified into typi- known to cause isolated central osseous syndactyly
cal and atypical types (Barsky, 1964). However, it is or polysyndactyly (Shamseldin et al., 2012). The sec-
now agreed that the atypical type is part of the terato- ond theory is popular in the genetics literature and
logic sequence of symbrachydactyly (Ogino, 1990a). states that the central hand cleft deformity is a unique
Currently, two types of cleft hands are described in entity caused by degeneration of the central part of
the literature. The ulnar cleft hand deformity is the apical ectodermal ridge (AER) secondary to loss
extremely rare and less than 20 cases have been of function of certain genes that are expressed spe-
reported (Al-Qattan et al., 2010; Kato et al., 1983; cifically in that part of the AER (Shamseldin et al.,
Miura, 1988; Tonkin et al., 2002). The embryological 2012). However, this does not explain the frequent
basis of ulnar clefts has not been described. The sec- occurrence of concurrent deformities in the remain-
ond type of cleft hand deformity is uncommon and has ing digits in patients with central hand clefts.
been given different names such as “typical’ cleft One way to examine these theories in the clinical
hand, “central” cleft hand, “central” ray deficiency, setting is to investigate the prevalence of syndactyly,
“Lobster-claw” deformity, “central ectrodactyly”, polydactyly, synostosis, and other deformities in a
“central oligodactyly”, “cleft hand complex”, and large series of central hand clefts. A study of concur-
“split-hand-foot” malformation” (Barsky, 1964; rent deformities in patients with central and ulnar
Shamseldin et al., 2012). Two main theories of patho- hand clefts may also help in understanding the patho-
genesis of the central cleft hand deformity have been genesis of these deformities.
offered. Ogino (1990a; 2007) states that the central In this paper, the clinical features of 44 cases with
cleft hand deformity is part of a spectrum, which central hand clefts and three cases with ulnar hand
starts with central osseous syndactyly, progressing to
central polysyndactyly, and ends with central ray defi- Division of Plastic Surgery, King Saud University, Riyadh, Saudi
ciency. Hence, all three deformities are caused by the Arabia
same insult or teratogenic event. Ogino’s theory was
Corresponding author:
based on animal experiments (Ogino, 1990b). In M. M. Al-Qattan, Division of Plastic Surgery, King Saud University,
humans, however, several genes causing central Riyadh, PO Box 18097, Riyadh 11415, Saudi Arabia.
hand clefts have been identified, and none of them are Email: moqattan@hotmail.com

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Al-Qattan 511

Table 1.  The distribution of non-syndromal versus syndromal cases in 44 patients with central hand clefts.

Type of cases Number of patients Positive family history

A Non-syndromal 10 0
B Syndromal cases:  
  Split hand–foot malformation 30 26
  Split hand–foot malformation with ectodermal dysplasia* 1 0
  Split hand–foot malformation with ectodermal dysplasia 3 2
and cleft lip/palate (EEC syndrome)

*Ectodermal dysplasia is manifested by evidence of abnormal development of ectodermal structures such as dry skin, sparse/brittle hair,
enamel defects, hypodontia, and hypohidrosis.
EEC: ectrodactyly-ectodermal dysplasia-clefting.

Table 2.  The number of missing rays in 10 non-syndromal patients (n = 10 hands) and 34 syndromal patients (n = 59 hands)
with central hand clefts.

Missing rays Number of hands with missing rays in

  Non-syndromal cases Syndromal cases

No missing rays (only central soft-tissue cleft) 1 2
One missing ray 1 6
Two missing rays 5 27
Three missing rays 3 22
Four missing rays (little finger monodactyly) 0 2

Table 3.  Concurrent deformities in 10 non-syndromal patients (n = 10 hands) and 34 syndromal patients (n = 59 hands) with
central hand clefts.

Concurrent deformities of the remaining digits Number of hands with deformity

  Non-syndromal cases Syndromal cases

Polydactyly 1 1
Simple syndactyly 2 30
Complex syndactyly 0 1
Hypoplasia 3 36
Radiological evidence of synostosis(carpal/metacarpal/phalangeal) 5 10
Cross-phalanx across the cleft 0 6

clefts are reviewed with special emphasis on concur- Results

rent deformities. The author’s hypothesis of patho-
physiology for both types of clefts and their concurrent There were a total of 44 cases with central hand clefts.
deformities is then offered. Age at time of presentation ranged from 1 month to
60 years (mean 5 years). There were 20 males and
22 females. The distribution of non-syndromal ver-
Methods sus syndromal cases is shown in Table 1. All non-
The clinical and radiological features of all patients of syndromal cases (n = 10 patients) had involvement of
central and ulnar hand clefts seen by the author over a single hand with no involvement of the feet. The miss-
the last two decades (1993–2013) were reviewed with ing rays and concurrent deformities of the remaining
particular attention to the presence of syndromes/positive digits of affected hands are shown in Tables 2 and 3.
family history, number of missing rays, and presence Illustrative examples are shown in Figures 1–3.
of concurrent polydactyly/syndactyly/hypoplasia/ Syndromal cases had clefting of both hands in
synostosis and other deformities in the remaining 25 cases, and hence a total of 59 hands were avail-
digits in the hand. able for examination. The feet were involved in all

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512 The Journal of Hand Surgery (Eur) 39(5)

Figure 1.  Non-syndromal central cleft with synostosis of second and third metacarpals forming a wide metacarpal with a
bifid base.

number of missing rays and concurrent deformities

are shown in Table 4.

Discussion
The development of the AER and its interactions with
the limb bud mesoderm is the key to understand the
pathophysiology of hand clefts and their concurrent
deformities. Therefore, the basic embryology of the
AER will be discussed first before the pathophysiol-
ogy is explained.

Basic AER embryology

In humans, the limb bud appears as an ectodermal
bulge at intrauterine day 26 (IUD26). The AER passes
through four stages: induction/early development,
maturation, maintenance, and finally, regression
(Fernandez-Teran and Ross, 2008).
The first stage includes both induction and early
development of the AER, and this occurs during
IUD26–32 (Figure 9). Induction of the AER is mainly
through the engrailed-1(EN-1) pathway, and early
development is mainly through a loop between two
fibroblast growth factors known as the FGF10-FGF8
loop. Bone morphogenetic proteins 4 and 7 (BMP4
Figure 2.  Non-syndromal central cleft with first web syndac-
tyly and index hypoplasia. There is also central polydactyly. and 7) act via their receptor BMPR1A to induce the
expression of EN-1, which results in the induction of
the AER (Fernandez-Teran and Ross, 2008).
syndromal cases. The number of missing rays and Mesodermal FGF10 induces WNT3 in the overlying
concurrent deformities of affected hands are shown ectoderm. WNT3 then induces FGF8 in the ectoderm.
in Tables 2 and 3, and illustrative examples are shown FGF8 is essential for the early development of the
in Figures 4 and 5. AER and also acts to maintain the expression of FGF10
There were three cases with ulnar hand clefts in the mesoderm. This reciprocal relationship is
(Figure 6–8). There were two females and one male. known as the FGF10-FGF8 loop (Liu et al., 2002).
The patient in Figure 6 had bilateral ulnar clefts, and The second stage of maturation of the AER (Figure 10)
hence a total of four hands were examined. The occurs during IUD33–46 and is manifested by the

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Al-Qattan 513

Figure 3.  Non-syndromal central cleft with proximal absence of rays and distal complex syndactyly.

Figure 4.  A syndromal case (familial split hand–foot malformation) with no concurrent deformities. The patient was clas-
sified as “syndromal” because he had bilateral central feet clefts and a positive family history.

Figure 5.  A syndromal case (familial split hand–foot malformation), which is of interest for the current paper. One hand
has a central cleft and simple syndactyly of the first web; and the other hand has isolated simple central syndactyly. The
proximal phalanx of the right ring finger is wide and deformed, and one may argue it has fused with the proximal phalanx
of the middle finger.

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514 The Journal of Hand Surgery (Eur) 39(5)

Figure 6.  Case 1 with ulnar-sided cleft. Note the dorsal dimelia (palmar nail). There is hypoplasia and camptodactyly of the
ring finger (from Al-Qattan et al., 2010).

Figure 7.  Case 2 with ulnar sided cleft. Note the polydactyly radial to the cleft and hypoplastic biphalangeal little finger
ulnar to the cleft.

Figure 8.  Case 3 with ulnar-sided cleft. Note the deformed little finger.

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Al-Qattan 515

Figure 10.  Maturation of the AER. The three loops medi-

ating maturation (see text) are drawn with three different
coloured arrows.

Figure 9.  Induction/development of the AER.

development of a thickened AER with very high levels

of FGF8 along the entire AER, as well as the expres-
sion of FGF4 in the posterior aspect of the AER. The
hand “paddle” (IUD33) and digital metacarpal rays
(IUD41) appear during this period, which continues to
IUD46 (Al-Qattan et al., 2009). It is important to note
that up to IUD46, interdigital apoptosis has not started
yet. Maturation of the AER also coincides with the
appearance of Sonic Hedgehog (SHH) in the posterior
mesenchyme (within the zone of polarizing activity).
The maturation of the AER is mediated by three loops
between the mesoderm and ectoderm (Figure 10). (1) Figure 11.  Maintenance of the AER
The FGF10-FGF8 loop (Liu et al., 2002) is still active
and ensures high FGF8 levels in the AER. (2) SHH
induces FGF4 in the posterior part of the AER; FGF4 The third or maintenance stage of the AER (IUD47–
also helps maintain SHH. This is known as the SHH- 56) coincides with the formation of the phalanges and
FGF4 loop (Laufer et al., 1994; Niswander et al., 1994). separation of the digits. During the maintenance
(3) The third loop is the epithelial mesenchymal loop phase, the AER still has a high level of FGF4 posteri-
(Panman et al., 2006): SHH stimulates high levels of orly and a high level of FGF8 anteriorly, but a rela-
GREMLIN 1 (GREM 1) in the mesoderm. GREM 1 is a tively low level of FGF8 centrally (Figure 11).
BMP inhibitor, and hence the mesoderm has very low Explanation of the high level of FGF4 posteriorly:
levels of BMP 2, 4, and 7 during the maturation phase WNT7A (from the dorsal ectoderm) is the main main-
of the AER. The low BMP level leads to a high level of tainer of SHH activity during this phase (Al-Qattan,
FGF8 in the overlying ectoderm. Finally, FGF8 dif- 2011). SHH (via the SHH-FGF4 loop described above)
fuses (as a gradient) into the mesoderm, and this low- maintains high FGF4 activity in the posterior AER
ers the activity of retinoic acid in the mesoderm (Laufer et al., 1994; Niswander et al., 1994).
(Hernandez-Martinez et al., 2009). Retinoic acid is the Explanation of the relatively low level of FGF8 cen-
key molecule mediating interdigital apoptosis, and trally: During the maintenance phase, the hand pad-
hence there is no apoptosis during the maturation dle grows and cells that leave the zone of polarising
phase of the AER. activity, but no longer express SHH, spread anteriorly.

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516 The Journal of Hand Surgery (Eur) 39(5)

This increases the gap between SHH signal and and several protein ligands, including members of the
GREM-1 expressing cells. Hence, SHH is no longer transforming growth factor-beta super family, Indian
able to stimulate GREM1 in the central mesoderm hedgehog gene products, and parathyroid hormone-
(Panman et al., 2006). This leads to the up-regulation related peptide (Al-Qattan et al., 2009).
of BMP 2/4/7 (along with their downstream transcrip-
tion factors MSX1/2) in the central mesoderm. BMPs Pathophysiology of cleft hand
then suppress FGF8 in the central AER (Panman et al., deformities and their concurrent
2006). However, formation of the phalanges of the
central digits requires the presence of a “sufficient”
deformities
FGF8 level centrally. The maintenance of a “sufficient” Ectodermal FGFs and their mesenchymal interac-
FGF8 level centrally is mediated by the specific expres- tions are essential for induction of proximo-distal
sion of several proteins in the central AER, such as outgrowth of the limb, mesenchymal cell survival,
P63, DLX 5/6, and WNT10B (Le Lacono et al., 2008; facilitation of SOX9 function to ensure progressive
Shimomura et al., 2008; Witte et al., 2009). The rela- establishment of chondrogenesis, facilitation of the
tively low level of FGF8 centrally leads to an increased formation of phalanges within the PFR (just under the
activity of retinoic acid in the mesoderm. Retinoic acid AER), and maintenance of SHH activity (Yu and Ornitz,
diffuses through the entire mesoderm and initiates 2008). Therefore, it is no surprise that when both
digital separation by apoptosis (Hernandez-Martinez FGF4 and 8 are removed completely, the proximo-
et al., 2009). Mesodermal BMPs and ectodermal FGFs distal growth is arrested and the entire hand paddle
will also direct the formation of the phalanges (which will fail to form (Boulet et al., 2004). However, when
are added to the metacarpal rays) within the “phalanx- only FGF4 is removed, FGF8 can usually take over its
forming region” (also known as the PFR) under the function (Lu et al., 2006). The ulnar cleft hand deform-
AER (Suzuki et al., 2008). ity is probably caused by a primary defect in FGF4,
Finally, an explanation of the high level of FGF8 ante- which is expressed in the posterior part of the AER
riorly: Panman et al. (2006) have shown that GREM1 is (Figure 11). Normally, FGF8 will take over its function,
always up-regulated in mesodermal cells located dis- and hence ulnar hand clefts are extremely rare.
tal to the SHH source and acts on FGF8 levels in the Rarely, FGF8 will not be able to do so and the deform-
overlying AER. Normally, SHH does not reach the ity will manifest. As mentioned before, one main func-
most anterior part of the mesoderm (Lettice et al., tion of FGF4 is maintenance of SHH activity via the
2002). Hence, this most anterior part of the hand pad- FGF4-SHH loop. Therefore, if our hypothesis is cor-
dle will still have high mesodermal GREM1, low mes- rect, then all patients with ulnar hand clefts will have
odermal BMPs, and high ectodermal FGF8 levels. to have a degree of ulnar ray deficiency because defi-
Suzuki et al.’s (2008) experiments also confirmed that ciency of SHH results in ulnar ray deficiency. A review
the most anterior part of mesoderm has the lowest of our cases (Table 4) and all reported cases of ulnar
BMP activity during phalanx formation. In fact, nor- hand clefts in the literature (Al-Qattan et al., 2010;
mal thumb morphology and development will occur Kato et al., 1983; Miura, 1988; Tonkin et al., 2002)
only in the presence of low BMP activity/high FGF8 revealed that 100% of cases had hypoplasia of the lit-
activity, as well as the absence of SHH activity anteri- tle + ring finger, which indicate SHH insufficiency.
orly (Tickle, 2006). The remaining digits require a Furthermore, the family reported by Horii et al. (1994)
graded SHH activity to develop: the little finger supports our hypothesis. In that family, the father and
requires the highest SHH activity and the index finger his first baby had an ulnar hand cleft; and his second
requires the lowest SHH activity (Tickle, 2006). baby had severe ulnar ray deficiency manifested by
The fourth and final stage of embryology of the AER complete absence of the ulna and the ulnar three dig-
is regression of the AER, which occurs after IUD56. its. The proposed pathogenesis of ulnar hand clefts is
IUD56 is the end of the embryonic life and the crown to shown in Figure 12.
rump length is about 3 cm. By this time, all digits have Several animal experiments have confirmed that
formed and have been separated by normal webs. The the main defect in the central hand cleft deformity is
hand paddle will only increase in size with no further reduced FGF8 in the AER (Krakower et al., 1998;
events directing “identity.” This coincides with the Naruse et al., 2007). Similarly, human mutations (such
attenuation of SHH expression and regression of the as P63, DLX5, 7q21, and 10q24 mutations) leading to
AER (along with its FGF8/4). The actual stimulus for phenotypes with central hand clefts also lead to
AER regression is unknown (Fernandez-Teran and reduced FGF8 levels in the AER during the mainte-
Ross, 2008). The main event occurring in the hand nance phase (Elliot and Evans, 2006). It should be
paddle after IUD56 is the ossification of metacarpals noted that FGF8 is expressed along the entire AER,
and phalanges via several SOX transcription factors i.e., centrally, anteriorly, and posteriorly (Mariani

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Al-Qattan 517

Table 4.  Clinical features of the three cases with ulnar hand clefts (n = 4 hands).

Number of missing rays Concurrent deformities of the remaining digits

No missing rays (n = 3 hands) (only a cleft radial to the little finger) Polydactyly (n = 1 hand)
  Simple syndactyly (n = 1 hand)
  Complex syndactyly = (nil)
One missing ray (n = 1 hand) (ring finger) Hypoplasia of the little + ring finger (n = 4 hands)
  Synostosis (nil)
  “Cross phalanx” across the cleft (nil)
  Dorsal dimelia* (n = 2 hands)
  Camptodactyly (n = 2 hands)

* Dorsal dimelia is diagnosed if either an ectopic palmar nail or dorsalisation of the palmar skin is present.

Primary defect in FGF4 in posterior AER

Most cases Rare cases

FGF8 takes over the function of FGF4 FGF8 rescue is not sufficient

Ulnar cleft Decreased SHH activity

Normal phenotype

Ulnar ray deficiency manifests

usually as hypoplasia of the
little + ring fingers

Figure 12.  The pathogenesis of ulnar hand clefts.

et al., 2008). So, what are the effects of FGF8 reduction cleft deformity, which has been observed by hand sur-
along the AER? Centrally, the degree of FGF8 reduc- geons for several decades and is referred to in the lit-
tion will determine the severity of the central cleft, erature as Maisels’ centripetal sequence. Maisels
which may vary from a deep central soft tissue cleft (1970) noted that in the central hand cleft deformity,
(without bony loss) progressing to variable loss of the digital ray suppression starts centrally and then pro-
bones of the middle finger ray and ending with loss of gresses in a radial direction, so that in the most severe
multiple central rays. Anteriorly, the reduction of FGF8 monodactylous form, the most ulnar digit is preserved.
is known to result in various grades of thumb hypo- The high normal FGF4 expression in the posterior AER
plasia (Mariani et al., 2008; Sun et al., 2002). Therefore, is expected to preserve the little finger even with
it is of no surprise that the central hand cleft deformity severe FGF8 suppression, and this has been shown
is associated with thumb hypoplasia (Falliner, 2004; experimentally (Lu et al., 2006).
Manske and Halikis, 1995; Miura et  al., 1992). Suppressed FGF8 then results in a secondary
Posteriorly, the suppression of FGF8 is not expected to event in the AER: induction of an ectopic over-
cause any defects because FGF4 is highly expressed expression of FGF4 in the central and anterior parts
posteriorly and FGF4 is capable of replacing the func- of the AER (Lu et al., 2006). This ectopic over-expres-
tion of FGF8 (Lu et al., 2006). This explains the hand sion of FGF4 occurs after a variable “lag period.” If
phenotype of the most severe form of the central hand the lag period is short, FGF4 can completely rescue

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518 The Journal of Hand Surgery (Eur) 39(5)

Primary insult: Suppression of FGF8 in AER

Suppressed FGF8 in central + /- anterior AER Suppressed FGF 8 in posterior AER

Central cleft +/- thumb hypoplasia The little finger is preserved by the
normally expressed FGF4 in posterior AER

Variable lag period

Secondary insult: ectopic over-expressin of FGF 4 in the AER

Variable degree of “rescue” Syndactyly

of skeletal defects Polydactyly
Polysyndactyly
Synostosis

Figure 13.  The pathogenesis of central hand clefts.

the skeletal defects that would have resulted from phalanges, and this manifested as “tip” complex syn-
loss of FGF8 function (Lu et al., 2006). With longer lag dactyly. The proposed pathogenesis for central hand
periods, central clefts will occur. Another manifesta- clefts is shown in Figure 13.
tion of ectopic over-expression of FGF4 is the occur- The current paper supports Ogino’s theory that
rence of polydactyly, syndactyly, polysyndactyly, and polydactyly, syndactyly, and central hand clefts occur
synostosis (Lu et al., 2006). This clearly explains the secondary to the same insult to the AER. We explain
frequent occurrence of these concurrent deformities this by defining the primary insult as suppression of
in our and other series in the literature (Baluth and ectodermal FGF8, which then leads to a secondary
Falliner, 1986; Falliner, 2004). The patient shown in insult of ectopic over expression of FGF4. The final
Figure 5 shows an absent central ray in the right phenotype depends on three factors: severity of the
hand and simple syndactyly in the left hand. Compared primary insult, lag period for ectopic FGF4 expres-
with the right, the left hand phenotype indicates a sion, and degree of FGF4 over expression. Finally,
milder FGF8 suppression or shorter lag period for this paper offers a hypothesis for the pathogenesis of
FGF4 over expression, or both. The same explanation ulnar hand clefts based on a primary event of FGF4
may be given to the variable phenotype of syndactyly, suppression followed by a secondary event of SHH
polydactyly, and central cleft hand reported by Satake suppression.
et al. (2009) in different members of a single family.
In contrast, the hand phenotype in Figure 3 and cases Conflict of interests
reported by Elliott et al. (2009) indicate that there None declared.
was severe FGF8 suppression with a long lag period
for FGF4 over expression. By the time this over Funding
expression came to the rescue, it was too late to res- This work was supported by the College of Medicine
cue the central metacarpals and proximal phalan- Research Center, Deanship of Scientific Research, King
ges. Instead, FgF4 attempted to rescue the distal Saud University, Riyadh, Saudi Arabia.

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Al-Qattan 519

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