Clinical Genetics 1990: 38: 128-138 Case Report

lncontinentia pigmenti: XXY male with a family history

J. GARC~A-DORADO, P. DE UNAMUNO, E. FERNANDEZ-L6PEZ, J. SALAZAR VELOZ' AND M. ARMIJO

Department of Dermatology, 'Genetics Section, General Hospital, Salamanca, Spain

We report on the case of a male who from the start of life displayed vesicular lesions; on the trunk these were clustered and on the limbs they adopted a linear configuration. After biopsy of one such lesion, the histopathological study was compatible with a diagnosis of incontinentia pigmenti (IP). In the following months, hyperkeratotic lesions appeared which later became 'pigmented. The mother and other female members of the family also showed different degrees of alteration related to the same disease. The karyotype study showed the existence of 47,XXY (Klinefelter syndrome). The exceptional nature of this case is that although it is the third case reported in the literature of a male affected by incontinentia pigmenti with a previous family history, it is the only one combining this characteristic with the presence of a 47,XXY karyotype.

Received 23 August, revised 7 November, accepted for publication 9 December 1989

Key wordr: Block-Sulzberger disease; incontinentia pigmenti; Klinefelter syndrome; X-linked dermatosis; XXY chromosomes.

The term incontinentia pigmenti (IP), known also as Block-Sulzberger disease, is used to refer to a genodermatosis manifest- ed as a characteristic dermatological poly- morphism with three different stages. It is sometimes accompanied by systemic dys- functions of diverse nature which are reflec- tions of the ecto- and mesodermic poly- dysplasia underlying the disease (Delgado et al. 1984, Dupri et al. 1978). The skin lesions are unimportant regarding the quality of life of the patient since they generally disappear spontaneously (Carney & Carney 1970).

There is no doubt that the disease has a genetic origin, which some researchers relate to a failure in immunotolerance (Person 1985). However, one controversial point is the mechanism of hereditary transmission. In the study carried out by Carney (1976), 55% of the patients had a family history of IP. Similar relationships were reported by

other authors (Dulanto & Camacho 1979). Studies have even been carried out over four consecutive generations (Wiklund & Weston 1980). Cases of the disease appearing in women with no previous family history could be accounted for in terms of a spon- taneous mutation. Starting out from the hypothesis that all males phenotypically af- fected by IP were lacking in a family history of the disease, it was proposed that IP would be transmitted through a dominant gene on the X chromosome, thus preferentially af- fecting women and being lethal for males (McKusick 1986). It was also accepted that in males the disease would always be sec- ondary to a spontaneous mutation. Al- though such a hypothesis appears to be con- vincing, two unique cases of males with a family history of the disease appeared; the case reported by Hecht et al. (1982) and that of Kurczynski et al. (1982), thereby

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throwing doubt on the hypothesis that IP inherited by males would lead to intra- uterine death of male foetuses. The present work reports on the appearance of a third case with a family history of the disease who, owing to the occurrence of certain pe- culiar chromosomal features, has survived.

Case Report 1 (Fig. 1, 111-6)

This male was delivered normally after 37 weeks of gestation, with no extraordinary incidents. From birth, the infant exhibited vesicular lesions; on the trunk these adopted a clustered appearance, while they followed a linear disposition along the limbs. During the first few weeks of life the infant began to develop new outbreaks of vesicular lesions that even affected his face. At the same time, he progressively developed hy- perkeratotic lesions on the sites previously occupied by the small vesicles (Fig. 2A and 2B). Over the following months new out- breaks appeared, though with fewer lesions each time; in the zones where the previous lesions had been located an arboriform pig- mentation persisted (Fig. 2D).

The histological study was carried out on vesicular lesions on the thighs. On the epi- dermis, there were foci of spongiotic vesicu- lation with numerous eosinophilic cells in- side. At some points dyskeratotic cells were observed. On the dermis an intense degree of infiltration, above all of eosinophils and

I

I l l 8

Fig. 1. Genealogical tree of family.

some mononuclear cells, was observed (Fig.

Among the analytical data, an important finding was a leucocytosis of 25 700 with 41 % eosinophils. The karyotype study car- ried out with GTG-banding from lympho- cyte cultures (Seabright 1972) revealed cell populations with 47, XXY (Fig. 3).

The general examination of the patient did not show morphological alterations of the genitalia, which were phenotypically masculine. No radiological, neurological or ophthalmological alterations were ob- served.

2C).

Evolution Between the 3rd and 8th month of life, the infant underwent repeated episodes of otitis, tonsillitis, rhinitis and bronchopneumonia, with a clinical picture of diarrhoea requiring hospitalization. After appropriate treat- ment, recovery was complete. However, at that time the leucocytosis accompanied by the eosinophilia persisted. An immunolog- ical study gave the following data: IgG: 590 mg/100 ml (N=427+ -186); IgA: 46 mg/ 100 ml (N=28+ - 18); IgM: 139 mg/100 ml (N = 43 + - 17). The Type IV sensitivity against several antigens was as follows: C. albicans + + +; Tnchophytin +; Sraphylo- coccus + + +; Streptococcus + f ; Man- toux -. The motility of the polymorphonu- clear cells (chemotaxis) was decreased both after the first hour and after 2.5 h; this was also the case with phagocytosis, although the serum candidacidal activity remained unaltered. Components of complement were as follows C3: 94 mg/100 ml (N= 111+ - 12); C4: 24 mg/100 ml (N= 16-39).

Family History After the diagnosis of IP had been'con- firmed, a detailed genealogical study was carried out (Fig. 1). It was established that the parents were not related. They had pre- viously had a healthy son, the miscarriage

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of a daughter (Fig. 1, 111-5) after 3 months of gestation, and then the patient described in Case Report 1. The father had had no previous history of interest. The mother

(Fig. 1, 11-4) did not recall having suffered from any cutaneous lesions and none were present at the time of examination. There were no alterations in the locomotor system,

Fig. 2A. Linearly arranged vesicular lesions. 8. Warty lesions on soles of both feet. C. Incipient vesiculation due to spon- giosis and eosinophilic exocytosis. D. Hy- perpigrnented lesions on trunk together with new vesicular lesions.

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the neurological system or eyes. Panoramic exploration of the dentition of both jaws revealed the presence of some first teeth and the absence of definitive teeth in the lower jaw (molars and premolars).

The obstetric data concerning the ma- ternal grandmother (Fig. 1,I-2) revealed the death at birth of a son (Fig. 1, 11-5), with no cutaneous lesions (we were unable to confirm this), and two miscarriages of sons at 5 and 3 months of gestation (Fig. 1, 11-3 and 11-7). A striking feature in the stomato- logical background was the persistence at 20 years of age of several teeth from her first dentition, and that later only a single molar appeared.

Case 2 (Fig. 1, 11-8) is the maternal aunt of the proband. Recently she has given birth to a daughter affected by IP (Fig. 1, 111-8), with the typical cutaneous lesions in the first months of life.

The rest of the family appearing in the

I 2 3

geneological tree was explored by our team without finding any kind of alteration re- lated to IP.

Case Report 2 (Fig. 1, 11-8)

A woman, 26 years old, who had been born with no kind of cutaneous lesion. Eight days after birth, according to her mother, she had an outbreak of lesions described as wheals. They were apparently elevated lesions but the mother does not remember whether they were vesicular or not. They apparently dis- appeared after approximately 10 days and did not leave any residual lesions. However, for several years the patient has been suffer- ing from small pigmented plaques on her limbs, mainly thighs, that were nummular and principally featured a hyperpigmenta- tion at the level of hair follicles (Fig. 4A). Almost from birth, the parents noticed the appearance of ophthalmological alterations,

4 5

6 7 8 9 10 I I 12 x x

Fig. 3. Karyotype of Case 1 (111-6).

132 G A R C I A - D O R A D O E T A L .

detailed below. The physical development of the patient was normal. She has never had any locomotor defects and the only striking feature has been her hands, which are extremely small. The patient has still not lost all her deciduous teeth; several molars and other teeth remain. Some of these have been extracted but the permanent teeth have still not appeared. Intellectual development seems to have been normal, although the patient's schooling was hindered by her ab- normal vision. The patient has a normal karyotype. We have had access to her medi- cal reports covering the period 1960-1970, and the following aspects of her history are of interest: - Rotary nystagmus. - Congenital bilateral optic atrophy with foci of chorioretinitis (congenital toxoplas- mosis was ruled out according to the sero- logical and radiological studies of the skull, to which we also had access). - EEG. Cortical-subcortical dysrhythmia; this was generalized and pathologic (diffuse slowing with a predominance of theta waves).

Physical exploration revealed the exis- tence of important alterations in the dental structure (Fig. 4B), later confirmed with a radiological study: - Partial anodontia accompanied by the ab- sence of upper incisors. - Very evident conical teeth on both dental arches. - Pronounced morphological anomalies on the upper dental arch with completely de- formed canines, and irregularities, although to a lesser extent, on the lower arch.

Discussion

Sex Ratio and Prevalence IP is a genodermatosis preferentially affect- ing females, with no known ethnic or geo- graphical predominance (Correa et al. 1983). Until 1976, Carney (1976) had re-

viewed 653 cases, of which 593 were women (97%) and only 16 males (3%). Since then, several more cases of women affected with the disease have been described (Correa et al. 1983, Delgado et al. 1984, Dulanto & Camacho 1979, Dupre et al. 1978, Emerit et al. 1977, Gimenez et al. 1987, Grouchy et al. 1985, Hodgson et al. 1985, Kajii et al. 1985, Vissian et al. 1978), and a few males (Dulanto & Camacho 1979, Hecht et al. 1982, Kurczynski et al. 1982), these figures being difficult to quantify with precision since their publication is dispersed among specialist journals on paediatrics, ophthal- mology, genetics and dermatology.

IP is a multisystemic disease manifested in characteristic dermatological lesions, as- sociated with other systemic affectations; the clinical expression of these varies con- siderably.

Dermatologic Picture The typical dermatologic picture (Lorincz 1985) is manifested in three stages that usually follow each other, although they may occur simultaneously, while in other patients not all are observed. In a follow-up of 15 patients over 11 years, Eisenhaure & Feingold (1985) found that the above devel- opmental pattern can vary considerably. Some stages even recur periodically during infancy. The inflammatory stage is usually present at the time of birth, although in some patients the onset of this is delayed and appears after the first few weeks of life or, exceptionally, after 2 months (Bleehen & Ebling 1986).

Only three cases have been described in which the erythematous-vesicular lesions appeared when the patient was 1 year old (Carney 1976). In the case reported by Cor- rea et al. (1983), even at the moment of birth the patient exhibited vesicular, wart- like and pigmented lesions, suggesting a possible intrauterine development of the dis- ease. The wart-like lesions usually appear

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between the second and sixth week of life. The pigmented phase is usually appreciable between weeks 12-26 (Carney 1976). Our patient can be said to fit the normal pattern of the course of the disease since he was affected by the initial phase at birth; he began to develop wart-like lesions after 4 weeks and hyperpigmented lesions after 3 months. Additionally, the lesions were highly typical, regarding both their location and their morphological aspect. The wart- like lesions are usually found on the limbs (Dulanto 8c Camacho 1979), as was ob- served in the case reported here. The pig- mented lesions often have an arboriform morphology, which our patient exhibited on both the trunk and the limbs. Although the normal course is restitutio ad integrum, oc- casionally atrophic, hyperchromic or achro- mic zones are seen. The observation of hy- perpigmented lesions in a child with coil- genital malformations of different types does not always correspond to the existence of IP (Ment et al. 1978). Fulk (1984) re- ported different clinical pictures with

characteristics that might easily be confused with IP.

Mascar6 et al. (1985) emphasised that the residual achromic lesions are extremely use- ful for performing a screening among ap- parently healthy family members of patients with IP. Recent research (Moss & Ince 1987) accepts hypopigmented stria on limbs as being very suggestive late evidence of IP, sometimes accompanied by circumscribed sudoral hypofunction. Also characteristic of later manifestations are the painful subun- gual keratotic tumors (Mascar6 et al. 1985, Piiiol et al. 1973, Simmons et al. 1986).

Histopathologic Features All the foregoing stages have histopatho- logic features and ultrastructural images that have been studied in depth (Guemer & Wong 1974, Schamburg-Lever & Lever 1973, Vissian et al. 1974, Wong et al. 1971). The most usual finding in the inflammatory stage, the time at which we performed the biopsy on our patient, is spongiosis with the formation of intraepidermal vesicles, sur-

Fig. 4A. Hyperpigrnented lesions with perifolicular disposition. B. Dental lesions: partial anodontia and characteristic conical teeth.

134 G A R C I A - D O R A D O E T A L

rounded by numerous eosinophils - also present inside the vesicles - together with others in the underlying dermis (Lever & Schamberg-Lever 1983). There are also iso- lated dyskeratotic cells in the intervesicular epidermis. All these findings were present in the biopsy of our patient.

Exceptionally, basophilic cells have been reported in the initial vesicular lesions of IP (Schmalstieg et al. 1984); these have been assigned a pathophysiological role in the eventual recruiting of eosinophils. Charac- terisation and quantification of the chemo- tactic factors of the eosinophils in the epi- dermis (Takematsu et al. 1986) should also help to clarify the pathogenic mechanisms involved.

Laboratory Data The literature contains many references to an intense leucocytosis with an important degree of eosiniphilia, with values as high as 80% (Dupre et al. 1978). The leucocytosis of 25 700, with 41% eosinophils found in our patient corroborates this. In the last 10 years, immunological alterations associated with the disease have been reported; these have been thought to favour the repeated infections observed in these patients. Among them, the following are out- standing:

a) The above-mentioned altered neutro- philic chemotaxis reported by Dahl et al. (1975), Jessen et al. (1978) and Menni et al. (1 986), the latter case being accompanied by the Behcet syndrome.

b) An increase in immunoglobulins E, also found by Dahl et al. (1975).

c) A depression in lymphocyte stimula- tion, confirmed by Jessen et al. (1 978).

The susceptibility to repeated infections shown by our patient prompted us to per- form a complete immunological study; this allowed us to establish the existence of de- ficient neutrophile chemotaxis and phago- cytosis, together with an alteration at the

level of the lymphocyte subpopulations, confirming the findings of the above-men- tioned authors.

Associated Systemic Alterations The characteristic clinical picture is ac- companied by systemic alterations that Car- ney (1976) found in 79.8% of his patients. Their interest lies in the fact that in many patients who do not show many signs of the disease and who exhibit a somewhat inapparent dermatologic picture owing to the evolution of the disease or its low degree of expressivity, the diagnostic key can be obtained from detailed exploration of one of these associated manifestations. Until now, our Case 1 has not shown any of these alterations; by contrast his maternal aunt (Case 2) shows, or has shown, several simul- taneously, some of them quite characteristic.

Alterations in Dentition These are undoubtedly the most common features observed (Garcia-Bravo et al. 1986). The partial anodontia observed in 43% of these patients (Carney 1976) is the most frequent finding, whereas conical teeth (Wiklund & Weston 1980), observed in 33% of affected patients, are the most character- istic; accordingly, the finding of this feature alone in a relative of a patient affected by IP is sufficient evidence to consider that that relative is also affected (Garcia-Bravo et al. 1986). Other common findings are mal- formed teeth, delay in dentition, early onset of canes and dental weakness. These alter- ations may affect both the first and second stage of dentition. In Case 1, none of these alterations could be evaluated in view of the age of the patient. In contrast, in Case 2 all of them were observed.

Ophthalmological Alterations These are second in frequency, and are ob- served in 35% of the patients in the form of strabismus, a decrease in visual acuity,

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nystagmus (FranGois 1984), microaneurisms of the macular area (Jain & Willets 1978), atrophy of the optic nerve, cataracts, retinal pigmentation, retinoblastoma, pseudogly- oma (Schmidt et al. 1972) and foci of chorioretinitis.

Regarding such findings, it should be noted that our Case 2 was affected with congenital bilateral optic atrophy that has subsequently led to an important decrease in visual acuity close to blindness; during adolescence, this was diagnosed as chorio- retinitis, toxoplasmosis being ruled out. Similarly, the ophthalmological study re- vealed the existence of rotary nystagmus.

Neurological Alterations These are the most serious. Among them are included convulsive seizures, mectal re- tardation, spastic paralysis, microcephaly, ipsisarrhythmias with flexional spasm (LarrCgue et al. 1977, Simonsson 1977) and an abnormal EEG. For certain authors these are characteristic (Garcia-Bravo et al. 1986) and a common finding in them is a diffuse slowing in the EEG-rhythm, with the appearance of theta waves. The EEG alterations found in Case 2 fully coincide with these criteria.

In some studies (Eisenhaure & Feingold 1986), it has been reported that seizures dur- ing the first week of life in IP patients could appreciably worsen the prognosis.

Genetics Because there are very few published case histories of families with several affected members, and owing to the low incidence of the disease in males, there is very little evidence supporting a hereditary pattern linked to the X chromosome. Nonetheless, the hypothesis that this might be the mech- anism of transmission, leading to death in males, is almost universally accepted (McKusick 1986). According to such conjec- ture, one would expect no incidence in

males, except in cases of chromosome aber- ration, whereas in fact about 20 cases in males have been reported. The majority of these were interpreted as spontaneous mu- tations since there was no family history of the disease. The family studied here is compatible with X-linked transmission and could be said to be characteristic if the abor- tions of males occurring in the maternal grandmother are taken into consideration. Our male patient does not correspond to a spontaneous mutation but rather to a moth- er-to-son transmission. Similar cases have previously been described by Hecht et al. (1982) and Kurczynski et al. (1982).

If one accepts X-linked dominant here- dity being lethal for males, the cases of sur- viving males remain to be explained. Di- verse hypotheses have been postulated; in 1975, Lenz suggested that the “half chroma- tid mutation” proposed by Gartler & Franc- ke (1975) could explain the cases of males with IP in which a situation of mosaicism compatible with life would occur. Other theories have been advanced to explain sur- vival in males; these include the “escaper” phenomenon, suggested by Hecht et al. (1 982) for their case reported with mother- child transmission, and that proposed by Langenbeck (1 982)- “half chromatid back mutation” - to explain the case of Hecht et al.

Since 1972, when Grouchy et al. described for the first time chromosomal alterations in patients with IP, several works showing the chromosomal instability underlying the disease have been published (Cantu et al. 1973, Emerit et al. 1977, Vissian et al. 1978). More recently, as a consequence of translo- cations involving band Xpl l in patients with IP, several authors have suggested that the IP gene locus might be located in this juxtacentromenc region of the X chromo- some (Grouchy et al. 1985, Kajii et al. 1985, Hodgson et al. 1985).

Also mentioned as an explanation for the

136 G A R C I A - D O R A D O E T A L .

survival of males with IP is the association with the Klinefelter Syndrome. As far as we know, only three cases with this association concerning a patient without a family his- tory of the disease have been published (Kunze et al. 1977, Ormerod et al. 1987, Prendiville et al. 1989). What is curious about the male patient reported here is that he has both a family history of the disease and an association with Klinefelter Syn- drome. We believe that this is the first time this coincidence has been reported.

It is evident that this chromosomal pa- thology could be a possible explanation for the occurrence of IP in males both with or . without a family history of the disease. We would therefore stress the importance of a detailed chromosomal study of all males with IP.

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