Preceded by Multiple Diagnostic. X-Rays One Year Prior to The

A Malformation Complex of Ectrodactyly, Clefting and Hypomelanosis of

RAY E. STEWART, D.M.D., M.S. STEVEN FUNDERBURK, M.D. YOSHIO SETOGUCHI, M.D. Torrance, California 90509

A case is described which, at birth, had a bizarre pattern of Aypopigmentation (incontinentia pigment achromians), ectrodactyly involving all four extremities, and unilateral cleft lip and palate. This patient does not have the seizures or other neurological and developmental anomalies previously described as associated with Aypopigmentation of Ito. This condition is also clearly different from the syndrome of ectrodactyly, ectodermal dysplasia, and clefting (EEC).

We have recently observed four-month-old tone. The child has developed normally, Mexican-American female infant with an in- reaching all of her age-appropriate milestones teresting constellation of anomalies, including with no evidence of neurological or other _ unilateral complete clefts of the lip and pal- problems. The Denver Developmental Scales ate, ectrodactyly of the hands and feet, and yielded an intelligence quotient of 100 at 14 generalized abnormalities in skin pigmenta- months of age. tion. The association of ectodermal changes, Examination of the head and neck revealed ectrodactyly, and oralfacial clefting has been unilateral complete cleft of the lip and palate. well documented in the EEC syndrome (ec- There was mild hypoplasia of the right exter- trodactyly, ectodermal dysplasia, and clefting nal ear (Figure 1). syndrome). However, this patient clearly does Examination of the skin revealed a peculiar not fall into this classification. generalized pattern of hypopigmentation over the entire body, including the head, neck, and Clinical findings face. On the dorsum, the pigmentation as- The child was the product of a full-term, sumed a swirling pattern. There was midline uncomplicated pregnancy of a 33-year-old demarcation of the pigment distribution an- gravida-4, para-4, abortion-0, mother and a teriorly, and there was a linear distribution 34-year-old father. The older siblings are nor- on the arms and legs. Several of the hypopig- mal. There is no family history of congenital mented areas were mildly desquamative. Bi- malformations, and there is no history of con- opsy of these areas showed no histopatholog- sanguinity. There was no known exposure to ical changes. There was a pink discoloration radiation, drugs, or other teratogens at the in the hypopigmented patches of skin over the time of conception or during the pregnancy. left shoulder, on both buttocks, and in both However, the mother had gallstone surgery axillae. There were several small heman- preceded by multiple diagnostic. x-rays one glomas located in the midback and glutial year prior to the pregnancy. _ reglons The affected areas of skin were nor- Birth weight was 8 lbs., 11 oz. The infant mal in texture. Sensation was intact, and was vigorous and alert and had good muscle sweating was normal. The hair and nails were of normal quality and quantity. The eyes were normal and with- Dr. Stewart is affiliated with UCLA/Harbor General out obstruction or defects of the lacrimal Hospital, Torrance, California. ducts. There were "lobster-claw'" deformities Drs. Funderburk and Setoguchi are affiliated W1th the Departments of Pediatrics and Psychiatry UCLA School of both hands and absence of the third digit of Medicine, Los Angeles. bilaterally. There was a bifid thumb on the 358 Stewart, et al., ECTRODACTYLY, CLEFTING AND HYPOMELANOSIS 359

phalanges of the third ray and clinodactyly of the first and fifth rays with no evidence of bony fusion. The left foot showed syndactyly of the phalanges of the third and fourth toes with an absence of ossification of the middle phalanx of the fourth toe. Clinodactyly of the fifth toe was noted with absence of ossification of the distal and middle phalanges of the fifth toe. There was no evidence of bony fusion (Figure 4). The right foot had supernumerary rays between the second and third digits with syndactyly of toes two, three, and four. There was shortening of the third metatarsal and a lack of ossification of the middle phalanx of the fifth toe. Again, there was no evidence of bony fusion.

Discussion

The clinical findings described in this patient closely resemble a condition described

by Ito (1952) which has been variously termed FIGURE 1. Patient at age 8 weeks showing unilat- incontinentia pigmenti achromians, systema- eral complete cleft of lip and palate, hypopigmentation on trunk, arms and face, and ectrodactyly. tized achromic nevus (Coupe, 1975; Cram, 1974) and hypomelanosis of Ito (Jelinek, right, and a rudimentary accessory index fin- 1973). In its classic description, this condition ger on the left. In addition, there was wide is said to consist of macular hypopigmented spacing between the second and third toes on whorls, streaks, and patches in a bilateral or the right foot and between the third and unilateral distribution affecting almost any fourth toes on the left foot. Syndactyly was portion of the body surface. Because of the present between the third and fourth toes on differences in the natural history of the cuta- the right side and between the second and neous defect, the histologic features, and the third toes on the left side (Figure 2). In addi- pattern of inheritance, this condition has been tion, there were deep horizontal plantar regarded as distinct and separate from incon- grooves in the first interdigital spaces bilaterally. The remainder of the physical examination was unremarkable. Trypsin-Giemsa banded chromosome anal- ysis done on peripheral blood lymphocytes was normal.

Radiographic findings Anterior posterior radiographs were done of the hands and feet. The right hand exhibited an absence of the third ray and ossification of the middle phalanx of the fifth digit. There was clinodactyly of the second and fifth rays and nonossification of the distal phalanx of the second ray. Three phalanges were noted in the thumb. There was no evi- FIGURE 2. Feet showing 3-4 syndactyly on right dence of bony fusion. (See Figure 3.) and 2-3 syndactyly on left. Hypopigmentation is also The left hand exhibited an absence of the apparent.

360 Cleft Palate Journal, October 1979, Vol. 16 No. 4

FIGURE 3. Radiographs of hands. tinentia pigmenti which it resembles but as a and delayed development, have been the most negative image (Jelinek, et al., 1973). consequential of these defects, but ocular and Patients with the condition as described by musculoskeletal anomalies also have occurred Ito (1952) either have skin lesions at birth or with significant frequency. develop lesions early in life without a preced- In a report of eight patients by Schwartz et ing bullous or verrucous stage. The lesions are al. (1977), there was a particularly high inci- diagnostic clinically because of the extensive dence of nonspecific abnormalities. Six of the areas of bizarre, whorled, marbled, and eight patients had sufficient developmental streaked hypopigmentation which appear to delay to warrant placement in special educa- be unique to this disorder. Unfortunately, tion classes. Four patients had seizure disor- there are no specific histologic changes. Var- ders of varying degrees of severity. In three, ious reports on sections from hypopigmented onset of seizures occurred prior to the third lesions show only decreased numbers of mel- year of life. All four patients with seizures had anocytes, reduction of pigment production in significant scoliosis, and in three, prominent DOPA preparations, and incomplete melani- asymmetry of the lower limbs was noted. zation of melanosomes on electron microscopy Three of the eight patients had ophthalmo- (Stoebner, 1970). Compared to normally pig- logic abnormalities, which included isolated mented skin, melanosomes in keratinocytes iridal heterochromia, a mild alternating eso- from hypopigmented areas are fewer in num- tropia and myopia, microphthalmia, hyper- ber and are packaged individually (Cram, telorism, and nystagmus. Strabismus has been 1974). frequently reported along with other anoma- Reports of this condition in more than 30 lies, most significantly corneal opacity and affected individuals of various ethnic origins choroidal atrophy (Jelinek, 1973). reveal that it is accompanied by associated Abnormalities of teeth, hair, and nails have abnormalities of varying structures and sever- been reported in incontinentia pigmenti ach- ity in 50% of the cases. Central nervous system romians, but these are apparently not present dysfunction, particularly seizure disorders in the majority of cases. Stewart, et al., ECTRODACTYLY, CLEFTING AND HYPOMELANOSIS 361

It is essential to differentiate and distin- scribed in the absence of the more classic guish incontinentia pigmenti achromian from hyperpigmented lesions. Associated anomalies incontinentia pigmenti (Bloch-Sulzberger) are frequent, most commonly involving the with which it is frequently compared and central nervous system, eyes, musculoskeletal often confused. Although similarities do exist system, hair, and teeth. between the two conditions, there are several important differences. Pathogenesis Incontinentia pigmenti is an X-linked dom- The role of genetics in the pathogenesis of inant trait which is observed most frequently hypopigmentation of Ito is not clear (Ito, in females. The condition is thought to be 1952). The majority of reported cases are lethal for most affected males (Gordon, 1970). sporadic. However, a few instances of familial The paucity of affected males and the in- occurrence have been reported. Grosshans et creased incidence of spontaneous abortions in al. (1971) reported an affected mother with women who carry the IP gene support this three affected daughters. Jelinek et al. (1973) hypothesis. The cutaneous manifestations noted a possible occurrence in a distant rela- usually consist of an erythematous and bul- tive of one of his patients. lous phase in infancy, followed by a verruc- Cram and Fukuyama (1974) reported on a cous phase of variable duration. Pigmented boy with hypopigmentation and seizures. His lesions are rarely present at birth but fre- mother and maternal grandfather were said quently develop during infancy and early to have limited areas of hypopigmentation. childhood. The distinctive histologic feature Rubin (1972) described an affected girl whose of pigment-laden macrophages in the dermis two brothers had macular hypopigmentation (pigmentary incontinence) gives the disease and whose father and paternal uncle were its name (Morgan, 1971). Hypopigmented also said to have had an extensive pigmentary lesions are unusual, and have never been de- disorder.

FIGURE 4. Radiographs of feet. 362 Cleft Palate Journal, October 1979, Vol. 16 No. 4

The preponderance of females affected with patient had no detectable developmental ab- this disorder (4:1) raises a question of a sex- normalities or seizure problems on follow-up linked phenomenon. However, this remains examination at fourteen months of age. The speculative. clinical findings are consistent with a diag- The consistency of multiple malformations nosis of hypomelanosis of Ito (incontinentia involving skin, musculoskeletal, ocular, and pigmenti achromians), which appears to be a central nervous system structures suggests that highly variable disorder of uncertain etiology. this entity should be classified as a malfor- The consistent involvement of structures and mation complex. tissues directly related to neural crest cell A possible explanation of the pathogenesis function suggests that this disorder could rea- of the observed malformations lies in a gen- sonably be classified as a malformation complex. eralized defect in neural crest cell differentia- The nature of genetic influence in this con- tion, migration, or cellular interaction. All of dition is unclear, and like the problem of the structural malformations which were ob- accurate determination of a prognosis for af- served in our patient and those described in fected individuals, the precise etiology awaits the literature could arise secondary to a defect further investigation. in neural crest cell activity. The pigmentation Reprints: Ray E. Stewart, D.M. D. anomalies could be attributed to an abnormal UCLA /Harbor Hospital distribution of melanocytes early in develop- Building E-4 ment. The limb malformations and facial Torrance, CA. 90509 clefting could be explained by a disruption in References the interaction between neural crest cells and CoupPE, R., Unilateral systematized achromic nevus, Der- the underlying mesenchymal precursors of the matologica, 134, 19, 1967. affected structures (e.g., faulty ectodermal- Coupr, R., Hypochromic nevus: The inheritance ques- mesodermal interaction). Certainly the re- tion, Arch. Dermatol., 111, 394, 1975. ported defects in CNS development and ocu- Cram, D. L. and FuKuyamMa, K., Proceedings: Unilateral lar abnormalities could arise from similar systematized hypochromic nevus, Arck. Dermatol., 109, 416, 1974. mechanisms. It is interesting and significant Gorpon, H. and Gorpon, W., Incontinentia pigmenti. to note that malformations similar to those Clinical and genetical studles of two familial cases, observed in this group of patients have been Dermatologica, 140, 150, 1970. experimentally produced, either singly or as GrossHans, E. M., StormnEr, P., Bercornp, H., Incon- tinentia pigmenti achromians (Ito): Etude clinique et clusters, in various animal models by manip- histopathologique, Dermatologica, 142, 65, 1971. ulating or interfering with normal neural crest Hamapa, T., Saro, T., Suca1, T. and Morita, Y., Incon- cell development (Johnson, 1975). tinentia pigmenti achromians (Ito), Arck. Dermatol., 96, _- Hypopigmentation as a discrete entity oc- 673, 1967. curs infrequently in infants and children Hurwitz, S. and Braverman, J. M., White spots in tuberous sclerosis, J. Pediatr., 77, 587, 1970. (Hurwitz, 1970). When the phenomenon is Iro, M., Studies of melanin XI. Incontinentia pigmenti observed with no previous history of inflam- achromians, a singular case of nevus depigmentosus matory processes, it should be regarded as a systematicus bilateralis, Tohoku J. Exp. Med., 55 (Suppl.), harbinger of additional associated problems 57, 1952. JEuingek, J. C., Bart, R. $. and ScHirr, G. M., Hypome- demanding further investigation and exami- lanosis of Ito ("incontinentia pigmenti achromlans 5, nation, meludmg developmental testing, and Arch. Dermatol., 107, 596, 1973. careful inspection for musculoskeletal, ocular, Jounson, M. C. and Pratt, R. M., The neural crest in _ and clefting abnormalities. If scoliosis or llmb normal and abnormal craniofacial development. In asymmetry is present, an electroencephalo- Extracellular matrix influences on gene expression. gram and neurologic assessment are indicated New York: Academic Press, Inc., 1975. Morcan, J. D., Incontinentia pigmenti (Bloch-Sulzber- since the likelihood of seizures with this com- ger syndrome), Am. J. Dis. Child., 122, 294, 1971. bination of defects is high (Schwartz, 1977). Rusin, M. B., Incontinentia pigmenti achromians. Mul- Summary and conclusions tiple cases within a family, Arch. Dermatol., 105, 424, 1972. A four-month-old infant is presented At ScHwARTZz, M. F., Hypomelanosis of Ito (incontinentia birth, she had an unusual array of anomalies pigmenti achromians): A neurocutaneous syndrome, /. meludlng cleft lip and cleft palate, limb ab- - Pediatr., 90, 236-240, 1977. StoEBNER, P. and GrossHans, E. M., Incontinentia pig- normalities, and a bizarre pattern of hypopig- menti achromlans (Ito). Etude ultrastrueturale Arch. mentation. Unlike many reported cases, this Klin. Exp. Derm., 239, 227, 1970.