American Journal of Medical Genetics 98:330±335 (2001)
Brief Clinical Report
Peculiar Facial Appearance and GeneralizedBrachydactyly in a Patient With CongenitalOnychodysplasia of the Index Fingers(Iso-Kikuchi Syndrome)
P. Franceschini,1* D. Licata,1 A. Guala,1 G. Di Cara,1 and D. Franceschini2
1Dipartimento di Scienze Pediatriche e dell'Adolescenza, Servizio di Genetica Clinica, UniversitaÁ di Torino, Italy2II Divisione Ortopedia e Traumatologia ASO CTO-CRE-M.Adelaide, Torino, Italy
We report on a patient with clinical mani-festations consistent with a diagnosis ofcongenital onychodysplasia of the index®ngers (COIF). This syndrome has beenfound mainly in Japan, and as far as weknow, this is the ®rst case reported in Italy.In addition to the typical bilateral split nailof the second ®nger, the patient showedbilateral inguinal hernia, a peculiar face,and short hands. The metacarpophalangealpro®le showed a generalized brachydactylywith all the hand long bones below �3 SD.The patient's father showed a peculiar kindof micronychia on both the ®fth toes, sug-gesting a possible autosomal dominanttransmission of the syndrome. In uteroischemia of the palmar digital artery and adysplastic change in the crescent-shapedcap of the distal phalanx are the two maincandidate pathogenetic mechanisms thathave been proposed. In our opinion, thegradual broadening of the spectrum of thissyndrome brings support to the hypothesisof a basal dysplastic pathogenetic mechan-ism involving not only the index ®ngers butalso perhaps other tissues outside. We thinkthat for the moment the de®nition of COIFfor this syndrome should be maintained, thealternative proposed term ``congenital ony-chodysplasia'' being too inde®nite.# 2001 Wiley-Liss, Inc.
KEY WORDS: Iso-Kikuchi syndrome; COIF;nail dysplasia; brachydac-tyly
INTRODUCTION
Congenital onychodysplasia of the index ®ngers(COIF), or Iso-Kikuchi syndrome, is a rare clinicalentity characterized by various nail dysplasias com-monly involving the index ®ngers, but not infrequentlythe contiguous middle ®ngers and thumbs [Ohtsu,1989; Kikuchi, 1991]. The nail dysplasia may consist ofirregular lunula, malalignment, micronychia, polyoni-chia, and anonychia. X-ray examination may show theterminal phalanx to be slightly hypoplastic with nar-rowing of the distal end and with a Y-shaped terminalsplitting visible only in lateral projections [Kikuchiet al., 1985]. The ®rst picture of a COIF patient waspublished in 1964 by Onizuka and Soeda [1964],without mention of its diagnosis. Kamei [1966] reporteda case of polyonychia congenita without polydactyly,not attaining the de®nitive COIF diagnosis. Iso [1969a,1969b] ®rst described a defect as ``congenital nail defectof the index ®ngers'' and Kikuchi et al. [1974] proposedits present name (COIF). Although COIF has beenmainly reported in Japan, some cases have been alsoreferred in USA [Millman and Strier, 1982; Baran andStroud, 1984], in England [Harper and Weber, 1985], inFrance [Baran, 1980; Claudy, 1980], and in Korea[Youn et al., 1996].
We report a boy with congenital onychodysplasiawhose main features were splitting of nails of bothindex ®ngers and generalized brachydactyly. To ourknowledge, this is the ®rst case of COIF so far reportedin Italy.
CLINICAL REPORT
A 10-year-old Italian boy presented to our clinic withabnornal nail plates on both index ®ngers. He was the
*Correspondence to: Dr. Piergiorgio Franceschini, Dipartimentodi Scienze Pediatriche e dell'Adolescenza, Servizio di GeneticaClinica, UniversitaÁ di Torino, Piazza Polonia 94, I-10126 Torino,Italy. E-mail: [email protected]
Received 12 April 2000; Accepted 17 October 2000
Published online 11 January 2001
ß 2001 Wiley-Liss, Inc.
®rst born to non-consanguineous parents after 40 weeks'gestation with a body weight of 2.7 kg. Cesarean sectionwas performed for face presentation. At age two years,the patient was treated for bilateral inguinal hernia. Atnine years and 11 months, he had a generalized tonic-clonic seizure without fever. EEG showed a left frontalfocus and treatment with anticonvulsants was startedthereon. Neuropsychiatric evaluation showed moderatemental retardation. Orthopedic examination at 10 yearsbecause of limping, followed by a radiological study ofthe feet, demonstrated left calcaneal osteochondrosis.
At physical examination, the boy showed relativemacrocephaly (head circumference 54.6 cm, 75th-90thcentile), medial ¯are of left eyebrow, left eye esotropia,long palpebral ®ssures, malar hypoplasia (Fig. 1), higharched palate, dental crowding, a single 2�2 cm cafeÁ aulait spot and two white spots on dorsal region, slightindication of shawl scrotum, short hands (hand length13.5 cm,<3rd centile), middle ®nger length 5.5 cm(< 3rd centile) (Fig. 2a), clinodactyly of ®fth ®ngers, andbilateral simian crease. Striking features were marked®nger nail hypoplasia and a peculiar splitting of thenail of both index ®ngers (Fig. 2b). Other features wereslight genu varum, short feet (foot length 76.5 cm,< 3rdcentile) with hypoplastic nails and wide space between®rst and second toes (Fig. 2c). X-ray pictures of thehands showed only a hypoplastic terminal tuft of bothindex ®ngers (Fig. 3a). Roentgenogram of the feetshowed bilateral irregular density of the calcanealapophysis and cone shaped epiphyses of the second,third, and fourth proximal phalanges (Fig. 3b). Themetacarpophalangeal pro®le con®rmed the signi®cantdiffuse shortness of the hand long bones (Fig. 4).Chromosome examination gave normal results.
The patient's father was affected with bilateralexternal micronychia of ®fth toes (Fig. 5), and thepaternal grandmother was referred to bear an unspe-ci®ed bilateral ®fth ®nger malformation (clinodactyly,hypoplasia, or camptodactyly?). A mother's brother wasaffected with epilepsy and the same pathology wasprobably present in a maternal uncle, his son, andgrandson.
Fig. 1. Patient's face. Note medial ¯are of left eyebrow, long palpebral®ssures, left eye esotropia, and malar hypoplasia.
Fig. 2. (a) Patient's hands with short ®ngers, clinodactyly of ®fth®ngers and hypoplastic nails. (b) Patient's index ®ngers with split nails andasymmetric micronychia. (c) Patient's feet. Note short ®ngers withhypoplastic nails and increased distance between ®rst and second toes.
Iso-Kikuchi Syndrome 331
DISCUSSION
Splitting of the index ®nger nail with unequal growthof the two components seems to be the main character-istic of COIF [Iso, 1969a; Murakoa et al., 1977], but thefull spectrum of the nail dysplasia include irregularlunula, malalignment, micronychia (hypoplastic andrudimental), polyonychia (split rudimental), and ano-nychia [Baran, 1980; Kikuchi et al., 1981; Baran andStroud, 1984] (Table I). In polyonychia, there are twosmall incomplete nails on one index ®nger, with theradial one being smaller than its ulnar counterpart. Inmicronychia, a small nail is seen on the ulnar aspect of
the index ®nger, as if the smaller part on the radialaspect of polyonychia had disappeared. According toKikuchi et al. [1981], this kind of micronychia in COIFis different from the usual form which is located on thecentral part of the ®nger. Besides mild forms of COIFwhere mild nail anomalies, such hemionychogriphosisor nail malalignment, have been reported, severe formshave also been described with anonychia on both index®ngers. Additional ®ndings have been reported in somepatients: cutaneous or osseous syndactyly, congenitalrestriction of the distal interphalangeal joint of index®nger, and ear anomaly (two patients) [Kitayama andTsukada, 1983]. Brachymesophalangy of little ®ngers
Fig. 3. (a) X-rays of the patient's hands. Note the hypoplastic terminal tuft of both index ®ngers. (b) X-rays of the patient's feet. Note short toes andcone shaped epiphyses of the second, third and fourth proximal phalanges.
Fig. 4. Patient's metacarpophalangeal pro®le: note diffuse shortness of all the hand long bones.
332 Franceschini et al.
has been described in six patients [Kikuchi et al., 1974;Kinoshita and Nagano, 1976; Kitayama and Tsukada,1983] (Table II).
In addition to the pathognomonic feature of COIF(polyonichia, split nail variant), our patient shows apeculiar face quite dissimilar to those of his parents,brachydactyly involving all the hand long bones asshown by the metacarpophalangeal pro®le, and bilat-eral inguinal hernia. Brachydactyly has never beenexpressly reported in COIF, but in two of the ®vepatients studied by Millman and Strier [1982], thehands were described as ``broad with shortened digits''.In no case did the hands seem to have been measured.As regards the face, we do not have any terms ofcomparison and, since no ``particular'' face has everbeen related to COIF, our observation may be coin-cidental. The same reasoning could also hold foringuinal herniae. The mild mental retardation of ourpatient may be related to epilepsy, probably inheritedfrom the mother. We think that, for the present, thereare no grounds to keep isolated COIF forms separatedfrom those with associated malformations.
The kind of micronychia present in the feet of ourpatient's father deserves some consideration. In ouropinion, this is not the usual toe nail hypoplasia/dysplasia frequently seen in the ®fth toe of adults,sometimes representing a familiar variant. The nailcon®guration in this case is quite peculiar, lacking the
TABLE I. Distribution of Index Finger Anomalies in 90 PatientsWith COIF*
Number of®ngers %
Type of nail Anonychia 16 10.8anomalies Micronychia 78 52.7
Polyonychia 45 30.4Hemionychogriphosis 5 3.4Malalignement 4 2.7
*Bilateral involvement, 58; monolateral, 32.From: Millman and Strier [1982]; Samman [1983]; Kitayama and Tsukada[1983]; Baran [1984]; Samman [1984]; Harper and Beer [1985]; Miura andNakamura [1990]; Youn et al. [1996]; present case.
Fig. 5. Micronychia of ®fth toes of the patient's father.
TABLE II. Familiarity and/or Associated Anomalies in COIF
Authors Family recurrences Number of patients with associated defects
Kikuchi et al. [1974] ± 2 - Brachymesophalangy of 5th ®ngersMaeda [1975] 1 (brother & sister) ±Kinoshita and Nagano [1976] ± 2 - Brachymicromesophalangy of 5th ®ngers
± 1 - Cutaneous II-III ®ngers syndactylySamman [1978] 1 (?) ±Claudy [1980] 1 (father & son) ±Millman and Strier [1982] 1 (9 patients) 1 - Broad hands with short ®ngers � 5th ®ngers clinodactyly
± 1 - 5th ®ngers' clinodactyly± 1 - Broad hands with short ®ngers
Kitayama and Tsukada [1983]
±
1 - Onychodysplasia of right 3rd ®nger � brachymetacarpia of left 5th®nger � cutaneous syndactyly of right 2nd-3rd-4th ®ngers � osseoussyndactyly of left 2nd-4th ®ngers
±
1 - Cutaneous syndactyly of both 3rd-4th ®ngers� cutaneous syndactyly ofright 2nd-3rd and left 4th-5th toes � brachymesophalangy of left 5th ®nger� incontinentia pigmenti of Bloch-Sulzberger � ear anomaly
± 1 - Ear anomaly± 1 - Restriction of distal interphalangeal joint of left 2nd ®nger
±1 - Cutaneous syndactyly of left 2nd-3rd ®ngers � restriction of distalinterphalangeal joint of left 2nd ®nger
± 1 - Simian creaseSamman [1984] 1 (2 sisters)? ±Koshimizu et al. [1984] 1 (identical twins) ±Amano et al. [1985] 1 (2 siblings) ±Miura and Nakamura [1990] 1 (mother & son) ±
± 2 - Brachymesophalangy of 5th ®nger
±1 - Osseous syndactyly of 3rd-4th ®ngers � brachymesophalangy of 5th®ngers
± 1 - Microtia with meatal atresiaYoun et al. [1996] ± 1 - Abnormal nail on left II toe � left cryptorchidism.
Present case 1 (father & son)
1 - Macrocephaly � medical ¯are of left eyebrow � malar hypoplasia �arched palate � short ®ngers � hypoplastic nails � bilateral inguinalhernia
Iso-Kikuchi Syndrome 333
third medial part, and the remaining two-thirds beingsomewhat thickened. Toenail hypoplasia in COIF hasalready been reported in the literature [Youn et al.,1996] and is present in all toes of our patient,paticularly in the ®fth. Based on these considerations,we are inclined to think that the patient inherited thesyndrome from his father. This kind of ®fth toemicronychia could be a minor sign for the presence ofthe mutation. Moreover, the unspeci®ed bilateral ®fth®nger malformation of the patient's paternal grand-mother brings slight but consistent support to theautosomal dominant inheritance of this syndrome. Oneshould remember that in some cases the Y splitting ofthe distal phalanx of the second ®nger peculiar of COIFhas been found also in digits without any nailabnormality (another cryptic minor anomaly thatshould be looked for and that could be very useful forthe purpose of genetic counselling) [Kikuchi et al., 1974;Kitayama and Tsukada, 1983; Miura and Nakamura,1990; Pappert et al., 1991]. The genetics of COIF is stillunsettled. Koshimizu et al. [1984] found COIF in iden-tical twins. An autosomal dominant mode of inheri-tance has been proposed by Claudy [1980] (father andson), by Millman and Strier [1982] (nine family mem-bers in ®ve generations), and by Miura and Nakamura[1990] (mother and son). The family reported by Harperand Beer [1985] (13 patients spanning four genera-tions), is not convincing for COIF. The syndrome hasalso been found in siblings by Maeda [1975], Amanoet al. [1985], and possibly by Samman [1984], suggest-ing an autosomal recessive fashion of inheritance.Genetic heterogeneity is the most likely explanation.Local disruption due to vascular changes may possiblybe an additional cause. The statement that ``sincehereditary and familial cases of this disease are rare,hereditary factors may not be involved'' [Kitayama andTsukada, 1983] sounds nonsense. Sporadic cases maybe interpreted as de novo mutations or expression ofautosomal recessive inheritance.
The pathogenesis of COIF is still unknown, anddifferent explanations for this syndrome have beensuggested. Atavism has been proposed by Egawa[1977], and by Iso and Kikuchi [1984], based on theobservation made by Spearman [1978], who noted thatamong the prosimians, the tarsiers have nails on all ofthe digits except the second and the third, which haveclaws. In this context the COIF syndrome couldrepresent a particular throwback. Some authors pro-posed a theory that in uterus ischaemia of the palmardigital artery might be an important role in the cause ofCOIF [Kikuchi et al., 1981]. The ischaemic damagewould mainly be seen on the radial side of the affected®nger due to the smaller calibre of the artery on thatside [Edwards, 1960], which should be more protectedthan the ulnar one. Kikuchi [1985] suggested thatCOIF could occur ``from a peculiar grip of the ®ngers ofthe fetus in utero, the thumbs pressing the index®ngers.'' Polyonychia in COIF really has been inter-preted as a central anonychia. This theory does notaccount for the frequent association between the nailand the corresponding phalangeal bone splitting alongtwo perpendicular planes. A hypothesis that a dysplas-
tic change in the crescent-shaped cap of the distalphalanx could be the cause of COIF has been putforward by Miura and Nakamura [1990]. According tothese authors, if COIF is not the result of ectodermaldysplasia, it might be associated with the condition ofthe underlying distal phalanx which is a mesodermalderivative and whose typical changes (Y shapedbifurcation), when present, are not reminiscent of apartially necrotic phalanx. In our opinion, this hypoth-esis is the most convincing and is compatible with thepresence of frequent abnormalities (20%), such asbrachydactyly, syndactyly, ear anomalies or, as in ourpatient, inguinal herniae, found in COIF (Table II) andhardly explainable with a mere ischaemia.
On the basis of our observation and of 89 patientsfound in the literature [Millman and Strier, 1982;Samman, 1983, Samman, 1984; Kitayama and Tsu-kada, 1983; Baranand Stroud, 1984; Harper and Beer,1985; Miura and Nakamura, 1990; Youn et al., 1996],the diagnostic criteria of COIF may be summarizedin the following ®ve points: 1) bilateral or unilateralindex ®ngernail involvement; 2) congenital occurrence;3) onychodysplasia characterized with decreasingfrequency by micronychia, polyonychia (split nail:pathognomonic when present), anonychia, hemionicho-gryposis, and malalignment; 4) underlying bony pha-lanx anomalies (mainly bifurcation of distal phalanxonly evident in lateral projection); and 5) hereditary(autosomal dominant transmissions demonstrated in15 patients from four independent families, andpossibly autosomal recessive modes described in threefamilies) (Table III).
We do think that the de®nition of COIF should bemaintained, and the term ``congenital onychodysplasia''suggested by Kitayama and Tsukada [1983] is inde®-nite. Although it is true that the index ®nger is notalways affected, the involvement of such ®nger, insingle (not familial) patients, seems to be an almostessential prerequisite for the diagnosis.
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TABLE III. Diagnostic Criteria of COIF
1) Index ®nger nail involvement; mono or bilateral (radial sitemore involved than ulnar)
2) Congenital occurrence3) Onychodysplasia with variable aspects
MicronychiaPolyonychiaAnonychiaHemionychogriphosis (variant: malalignement)
4) Underlying distal bony phalanx anomalies5) Hereditary (autosomal dominant; autosomal recessive)
334 Franceschini et al.
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Iso-Kikuchi Syndrome 335
