Hum Genet (199(I) 86:7-13
9 Springer-Verlag1990
Identification of functioning sweat pores and visualization of skin temperature patterns in X-linked hypohidrotic ectodermal dysplasia by whole body thermography R. P. Clark t, M. R. G o f f I, and K. D . M a c D e r m o t 2
~Thermal Biology Unit, King's College. Campden Hill Road, London, W8 7AH, UK 2Clinical Genetics, Royal Free Hospital School of Medicine. Rowland Hill Street. London NW3 2PF, UK Received July 10, 1989 / Revised March 29. 1990
Summary. In this preliminary study, non-invasive infrared thermography has been used to visualize individual sweat pores and whole body skin temperature patterns in subjects with X-linked hypohidrotic ectodermal dysplasia (XHED) and normal controls, The findings in eight obligate heterozygotes and four affected males were compared to six normal female controls and to six non-manifesting females at risk for carrier status. Sweat secretion from individual pores in circumscribed areas was imaged using a high spatial resolution SPRITE infrared detector system working in the 8-141am band. In seven out of eight obligate heterozygotes, skin areas devoid of active sweat glands were found on the face, the hands or the trunk. Tear front movement over the cornea was also visualized and abnormal patterns were identified in obligate heterozygotes. Whole body skin temperature patterns, obtained with an Agema 780 Medical Thermovision system, identified abnormal skin temperature distributions, including characteristic aberrant "'cascade" back patterns, in obligate carriers. Two out of six "'at risk" females had skin temperature patterns comparable with obligate heterozygotes and we have tentatively concluded that they are carriers. Thermal imaging may be used for the examination of "at risk" non-manifesting females in families with a single affected male. The results of this study suggest that the random X-inactivation in females with XHED, as well as producing relatively large skin areas with sweat pore aplasia, is also associated with abnormal temperature patterns that are consistent with altered peripheral vascular perfusion.
Introduction
X H E D is a complex ectodermal dysplasia/malformation syndrome, characterized in affected males by oligodonOffprint requests to: R. P. Clark
tia, sparse hair, hypohidrosis due to sweat pore aplasia, and characteristic facial clinical signs. Pinheiro and FreireMaia (1979) showed, in a study of large Brazilian kindred, that 70% of obligate carrier females manifest clinical signs of XHED. However, in the absence of severe oligodontia, teeth malformation or breast aplasia, the remaining signs may be too subtle for a diagnosis to be made. Objective measurement of sweat production over the body is difficult but, under test, males with X H E D produce sub-normal amounts of sweat. In carrier females a mosaic pattern of sweat pore aplasia has been demonstrated on finger tips and palms (Passarge and Fries 1973: O'Leary et al. 1986). However. as these areas constitute only 5-6% of body surface area such limited tests cannot be regarded as providing a reliable assessment of sweating from the body as a whole. Considerable data on the normal distribution of sweat glands is available (Kuno 1956). Weiner (1945) studied thermal sweating in healthy male volunteers and subdivided regions of the body surface according to the amount of sweat produced and, importantly, noted great individual variability, Kerr et al. (1966) were the first to produce whole body surface sweating patterns in four obligate carriers for XHED and in two normal controls. Their method had the disadvantage of the cumbersome application of a quinazarin/iodine solution which was painted over the body during thermal induction of sweating. The thermographic techniques used in this study have the advantage of easy application, are non-invasive and are tolerated well by patients of all ages. Whole body skin temperature patterns can be obtained and individual functioning sweat pores can be visualized in circumscribed areas (Clark et al. 1987: Goff and Clark 1985: Ring and Hughes 1986). The aim of this study was to evaluate thermographic scanning in relation to the mosaic distribution of sweating and to identify abnormal skin temperature patterns
in f e m a l e s h e t e r o z y g o u s f o r X H E D , normal controls.
w h e n c o m p a r e d to
Patients and methods
Patients Obligate carrier females and those "'at risk'" for being carriers were recruited from "~-3 ~,enerations of families with X H E D ascertained during a family linkage study with polymorphic D N A markers as previously reported (MacDermot et al. 1986). The age range was 19-65 years. All family members were examined by one of the authors (K. MacD) and the clinical diagnosis in carrier females was made when the following were present: characteristic dysmorphic facial signs, sparse eyebrows/eyelashes, oligodontia and/or abnormal tooth shape in both dentitions and/or sparse scalp hair. Cases 1-8 were obligate carriers as judged by the pedigree structure. Each had at least one affected son and one or more affected family members in the same and/or previous generations, confirming the vertical transmission of the gene for X H E D . Out of eight obligate carriers, two (cases 4 and 6) showed no clinical signs of XHED. The pedigree of case 6 was unusual. This non-manifesting female, had an affected grandson and three affected daughters, according to the clinical criteria used in this study. The father of these three affected daughters was clinically unaffected at the age of 63 years and after active army service m India had no doubt about his normal sweating and heat tolerance, In this family, no evidence of non-paternity was found with five polymorphic D N A markers (MacDermot et al. 1987). Parental gonadal mosaicism could not be excluded at this stage of the study. Cases 9-14, were females with no abnormal physical signs, but who were "'at risk" for X H E D as judged by the pedigree structure. The age range was 8-65 years. Sparsity of scalp hair as an isolated clinical sign was difficult to cvaluate. Case 13. a 65 year old female had sparse hair which was judged to be normal for age. Case 14, a 17 year old, had a receding frontal hairline and a visible scalp (in the posterior view} which was judged to be abnormal and represented a sin,,le~ clinical sign of XHED. Cases 15-18 were males affected with X H E D aged 18 months to 22 years. They wcrc screened in order to detect abnormal thermal pancrns, and to identify arcas of reduced sweating, for subsequenl comparison with thermal patterns produced by hetcrozygous tenla[es, Case 19 was a 10 year old fcmale. ,aith heat intolerance sincc birth and subnormal productkm of sweat which had been confirmed bv sweat tests. In addition, she had proportionately short stature, retinitis pigmcntosa, short ridged nails, worn down teeth: at present she remains undiagnoscd. Cases 20-25 were normal control heahhy females, aged 3-58 years, with no subjective sweating impairment, skin disorders or famih history of XHED. These were recruited from hospital personnel and their families.
Thermographic equipment Infra-red thermography ix the technique in which radiation in the inira-red portion of the clcctromagnctic spectrum, coming fronl the skin surface, is collected by a special scanner and focussed on to infra-red scnsitivc dctectors to produce an electrical output Woportional to thc intensity of the radiation in the scanned scene. Electronic processing of the scanner signal produces a TV image where particular colours, or grey levels, represent specific temperatures. The thcrmal imagcs produced are directly related to the temperature of the skin surface and can bc accurately calibrated by ~111 Jlllil~ analysis ctlnlputcr. Two thermographic systems wcrc used in this study. The first was an Agema 78(I Medical Thermovision system sensitive to radiation m the 2-6 t.lm waveband (shortwave) and employing a single
detector element of indium antimonide. The scanner was coupled to a digital tape storage system and to a Pericolor image analysis computer to facilitate numerical characterization of thermal images. This system was used to determine absolute temperature levels and patterns over the whole body. The second system was a high spatial resolution scanner based on a multi-element SPRITE detector of cadmium mercury telluride operating in the 8-14 pm waveband, The longer wavelength and high spatial resolution of this scanner allowed visualization of the insensible evaporation from individual functioning sweat pores. The emissivity of the surface of the fluid film at the end of the sweat pore is different from that of the surrounding skin and this. coupled with the cooling produced by the evaporating sweat, enabled the sweat pores to be visualised by the scanner. Thermal images were again recorded on magnetic tape and numerical analysis was achieved using an image analysis computer.
Methods The thermographic examinations were carried out in a temperature controlled room maintained at 28-30~ (just above thermoneutrality where, with subjects at rest, frank sweating with "'wet" skin did not occur). Patients equilibrated for 20rain before being scanned whilst wearing a two-piece swimming suit or swimming trunks. Oral temperature for all subjects was taken every 10rain throughout the examination, which lasted about 1 h. The Agema system was used to visualize and store temperature patterns over the whole body. Sweat pore distributions of the bands, face and selected areas of the trunk were next determined using the high resolution scanner. When visualizing sweat pore activity over the face, patients were asked to perform a "'touch toes" manoeuvre with thermal images being taken immediately before and after this procedure. In warm conditions, with normal controls, touching the toes provides a short-lived increase of sweat secretion, particularly from the skin around the lips. nose and chin, Uniformity of tear production was also observed by scanning the "'wettcdness'" of the cornea after repeated blinking.
Results F o r the r e s t i n g p a t i e n t s , t h e e n v i r o n m e n t a l c o n d i t i o n s in t h e t h e r m o g r a p h i c e x a m i n a t i o n r o o m w e r e n o t h o t e n o u g h to c a u s e f r a n k s w e a t i n g a n d t h e r e b y s i g n i f i c a n t l y m o d i f y a v e r a g e skin t e m p e r a t u r e by e v a p o r a t i v e c o o l ing. It is c o n v e n i e n t to d e s c r i b e t h e r e s u l t s in t w o sections. T h e first b e i n g t h e t h e r m o g r a p h i c i d e n t i f i c a t i o n o f i n d i v i d u a l a n d g r o u p s o f s w e a t p o r e s and t h e s e c o n d t h e o v e r a l l skin t e m p e r a t u r e p a t t e r n s o b s e r v e d .
Direct visualization of sweat pores I n d i v i d u a l l y f u n c t i o n i n g s w e a t p o r e s w e r e v i s u a l i z e d by the high r e s o l u t i o n l o n g w a v e i n f r a - r e d d e t e c t o r s y s t e m . T h e y a p p e a r e d as b l a c k c o l d s p o t s d u e to the l o c a l i z e d e f f e c t o f c o o l i n g by e v a p o r a t i o n a n d t h e c h a n g e d e m i s sivity o f the fluid film itself (Fig. 1). T h i s v i s u a l i z a t i o n therelk~re p r o d u c e d an u n e q u i v o c a l r e c o r d o f t h e dist r i b u t i o n o f s w e a t p o r e s in any p a r t i c u l a r a r e a . S u c h high r e s o l u t i o n s c a n n i n g c a n n o t , at p r e s e n t , v i s u a l i z e t h e w h o l e p r o j e c t e d a r e a o f t h e b o d y in o n e s c e n e . Serial ima g e s h a v e to be t a k e n o f c i r c u m s c r i b e d a r e a s o f t h e b o d y e a c h a b o u t s o m e 30 c m d i a m e t e r . T h e s w e a t i n g p a t t e r n s o b t a i n e d o n t h e h a n d s , face a n d axilla a r e i l l u s t r a t e d h e r e . F i g u r e 2 s h o w s t h e d o r s a l
Fig.1. The functioning sweat pores at the base of the nails in a healthy control show as discrete black dots Fig. 2a, b. A comparison of sweating over the fingers for a normal control and a male with XHED. a The dorsal surface-control subject to the left and b the palmar surface-control to the right Fig. 3. The distribution of functioning sweat pores over the chin and upper lip of a healthy control subject as visualized with the SPRITE infra-red detector system Fig. 4a, b. Examples of the patchy sweating patterns seen in obligate carriers for XHED. The subject in a has asymmetrical patchy sweating on the upper lip only and a more sparse sweat pattern is seen over the subject in b (note that the dark eyes in a were due to the presence of contact lenses)
Axillary sweating was found to be absent in several obligate carrier females and this is illustrated in Fig. 5a and b and c o m p a r e d with the characteristic cool axillary regions (due to cooling by the evaporation of sweat) in warm environmental conditions (Fig. 5c). After repeated blinking, the tear front over the cornea in healthy subjects shows a uniform fluid layer moving across the surface. In a n u m b e r of the heterozygous females and affected males there was a patchy or mosaic pattern over the cornea indicating asymmetry of tear flow which produced considerable thermal gradients over the cornea (Fig. 6).
Skin temperature patterns surface (Fig. 2a) and palmar surface (Fig. 2b) of digits from an affected male with X H E D and a normal control. The expected absence of sweat pores in affected males and the high density of these in normal controls confirms the sensitivity and selectivity of this scanning method. In several obligate carrier females, patchy distribution of sweat pores was found over the palms of the hands. The flat areas of the face, skin of the upper and lower lip, forehead and chin produced clear sweat pore images and were found to be informative areas. Fig. 3 shows a normal pattern of sweating over the face. As before, affected males showed no sweating over these areas. Figure 4a and b demonstrate patchy sweating in two obligate carriers. Several carriers had unilateral absence of sweating of the upper lip, from the philtrum laterally, with clear demarcation at the mid-line. All obligate females (except case 4) showed areas of absent facial sweating not seen in normal controls.
The A g e m a 780 Medical Thermovision system, operating in the short infra-red wavelength, recorded the overall t e m p e r a t u r e paterns on the skin which result from the interaction of environmental conditions, the direct conduction of heat from deep structures, heat transported to the skin by the cutaneous blood flow and the insensible evaporation of sweat. Considerable information exists as to the "normal" thermographic patterns in healthy subjects, particularly regarding t e m p e r a t u r e distributions and their individual variability in different situations (Clark and Edholm 1985). It was against this experience that abnormal patterns found in this study were judged. The most informative areas of the body, which show clear differences between obligate carriers and normal controls, were the front and back of the trunk, the axilla and the eyes. The normal symmetry over the right and left halves of the front trunk was modified in six females. In one obligate carrier, a large hot area was seen on the left half of the abdomen extending from the rib margin to the iliac crest (Fig. 7).
10 Fig. 5. a Axillary thermogram for an obligate carrier for X H E D showing this area to be hot with no sign of sweating; b is a colour thermograrn showing this area as white, red and yellow. This patient is contrasted with a healthy control in warm conditions seen in c where the axillary region is cold due to the evaporation of secreted sweat. In all of the colour thermograms, the colour code shows white to be the warmest colour and black the coolest with adjacent colours differing by 0.5~ In the monochrome images, the range from black to white is 5~ Fig. 6. a An example of the patchy or mosaic distribution of tear flow over the cornea following repeated blinking in an obligate carrier for X H E D . This is contrasted with the more uniform horizontal tear front found in control subjects (b)
Fig. 7. a Shows a colour thermogram of the asvmmetrical temperature distribution over the front of the trunk of an obligate X H E D carrier and b shows a linescan thermal profile through the trunk (along the green line) which characterizes the asymmetrical temperature differences and indicates a clear mid-line separation Fig.& The normal "V"" shaped warm area over spine and top of the shoulders seen in healthy lean control subjects
Fig. 9. Two examples (a and b) of the abnormal "'cascade temperature pattern found over the backs of some obligate carrier females. The normal warm "'V'" is absent and temperatures fall in relatively horizontal striations along the length of the spine
11 T h e n o r m a l t e m p e r a t u r e p a t t e r n over the b a c k in healthy l e a n subjects is s h o w n in Fig. 8 where there is a characteristic "V" or " T " warm area c e n t r e d o n the spine. T e n f e m a l e s showed different t h e r m a l back p a t t e r n s . In four obligate carriers and two "at risk" females the thermal p a t t e r n was m o d i f i e d to a "'cascade" p a t t e r n with horizontal striations of t e m p e r a t u r e falling along the length of the spine (Fig. 9). T h e r e m a i n i n g six females with different back p a t t e r n s had m i n o r changes, also f o u n d in two n o r m a l controls, a n d these were i n t e r p r e t ed as n o t specific in the c o n t e x t of this study. U n u s u a l l y p r o m i n e n t vasculature was seen in the peri-orbital area in all four affected males. T a b l e 1 shows a s u m m a r y of the clinical a n d t h e r m o graphic findings for the 25 subjects of this study.
Discussion
This p r e l i m i n a r y study provides e v i d e n c e that a b n o r m a l skin t e m p e r a t u r e p a t t e r n s a n d the mosaic d i s t r i b u t i o n of sweat pores can be visualised in females h e t e r o z y g o u s for X H E D by high r e s o l u t i o n i n f r a - r e d t h e r m o g r a p h y . I n s e v e n out of eight obligate h e t e r o z y g o t e s studied, skin areas devoid of sweat pores were visualised o v e r the face, t r u n k , h a n d s and axilla. N o r m a l controls s h o w e d symmetrical high density d i s t r i b u t i o n of sweat pores over these sites. T h e size of these sweating defects was e s t i m a t e d to be b e t w e e n 0 . 5 - 1 0 c m 2. O n e h e t e r o z y g o u s female showed large u n i l a t e r a l sweating defects over her entire a b d o m e n . A r e a s of sweat p o r e aplasia m e a s u r i n g b e t w e e n 0 . 1 - 2 . 0 c m 2 were d o c u m e n t e d o n f i n g e r p r i n t s
Table 1. A summary of the clinical and the thermographic findings Patients
Clinical signs"
Thermographic findings
Abnormal dentition
Dysmorphic clinical signs
Subjective sweating impaired
Facial sweating h Upper Lower Nose lip lip
Thermal back pattern ~
Thermal front pattern r
Obligate heterozygotes
1
+
-
-
3
3
1
C
A
2
+
+
-
2
2
2
A
A
3
+
+
+
3
3
1
C
C
4
-
-
-
1
1
1
B
A
5
+
+
-
3
3
2
C
B
6
-
-
-
3
3
3
A
A
7
+
+
-
1
3
1
C
B
8
+
+
+
3
3
1
B
B
Females at risk o f being carriers 9
-
-
-
1
1
1
A
A
10
-
-
-
1
1
1
B
A
11
-
-
-
1
1
1
C
B
12
-
+
-
1
1
1
B
A
1
1
1
B
B
1
1
1
C
B
+ + + +
+ + + +
+ + + +
3
3
3
A
A
3
3
3
A
A
3
3
3
A
A
3
3
3
A
A
+
-
+
1
1
1
B
A
-
-
-
t
1
1
A
A
1
I
1
A
A
1
1
1
B
A
1
1
1.
B
B
1
1
1
A
A
1
1
I
A
A
13 14 A f f e c t e d males
15 16 17 18 Undiagnosed case
19 N o r m a l f e m a l e controls"
20 21 22 23 24 25
+, Present: - , absent b 1. Normal: 2, reduced: 3. absent c A, Normal: B, non-specific: C. characteristic "'cascade" on back, "'asymetry" on front
12
Fig. 10. A reproduction of Blaschko's original drawing (1901) showing the "'system of lines on the surface of the human bodv which the linear nevi and dermatoses follow"
of heterozygous females by Passarge and Fries (1973). In our study the extent of sweating defects ranged from patchy distribution to complete absence of sweating over the face or axilla. In obligate carriers for X H E D , similar asymetrical sweating patterns over the face+ trunk and axilla were observed by Kerr et al. (1966). The infra-red thermographic method offers better resolution and is considerably easier to perform. The whole body thermography performed with the Agema 780 Thermovision system produced back patterns in six out of fourteen females consisting of a +'cascade" of horizontal striations with falling temperatures along the spine. This +'cascade" pattern was not seen in over 200 thermographic examinations in other conditions (R. P. Clark, unpublished data). The non-random pattern along which many skin lesions develop (Blaschko 1901) was recognised as being clearly different to, and independent of, the spinal ganglia system of dermatomes (which represent areas of skin associated with sensation) (Happle 1985). The lines of Blaschko (Fig. 10) are only visualised when clonal proliferation of two functionally different cell populations takes place. Happle and Frosch (1985) were able to demonstrate, in females with XHED+ that hypohidrotic areas over the back followed the lines of Blaschko and revealed a "'V" shaped area over the spine devoid of active sweat pores. In the present study a notable feature of the temperature patterns in female carriers, leaving aside any effect of sweating, was the lack of a normal "V" shaped warm area over the spine. It is therefore paradoxical that with classical sweat testing a "V "+shaped pattern can be produced on the
back of female carriers, but not in normal subjects whereas with skin temperature imaging, a '+V" shaped pattern can be produced in normal subjects, but not in female carriers. The origin of the normal "V" shaped warm area over the backs of healthy subjects is unknown but could be associated with cell development in the areas occupied by the Blaschko lines. In female carriers, the Blaschko lines are areas that are highlighted because of the absence of sweat pores in a "V" shaped pattern. If these same areas are also deficient in the superficial vasculature and/or the neurological control of the microcirculation, the normal +'V" shaped temperature pattern may well be absent. It is tempting to speculate that this abnormal back pattern in carriers of X H E D also reflects functional Xchromosome mosaicism. The presence of two functionally different cell clones could disrupt the normal caudal migration of the primitive streak (Hamilton et al. t964) with normal vasculature in the mid-line (normal "V'" or " T +"pattern). This would result in abnormal distribution of superficial vasculature over the shoulders without normal caudal extension over the spine. The lines of Blaschko, paradoxically, may be a common link in abnormal vascular and sweat patterns (both of which are important in thermoregulatory control) and both may be manifestations of X-chromosome mosaicism. However, it is clear that, in carrier females, the sweat pore distribution is by no means congruent with the temperature patterns identified by thermography. Functional X-chromosome mosaicism producing a linear arrangement of two different cutaneous cell populations has been shown by Happle (1985) to be present in heterozygous females with a range of X-dominant disorders: incontinentia pigmenti (Haber 1952), focal dermal hypoplasia (Champion 1975), chondrodysplasia punctata (Edidin et al. 1977) and X linked recessive disorders such as Menkes syndrome (Votpintesta 1974). In this latter disorder the author observed a patchy pattern of skin hypopigmentation with a sharp mid-line separation in an otherwise healthy sister of a black boy affected with Menkes syndrome. This mid-line change of pigmentation is comparable to the asymmetry in temperature pattern found in one of the obligate carrier females for X H E D in this study. Unusually prominent orbital vasculature was also seen in males with X H E D and in several carrier females: diminished tear production occurred in these patients. It is possible that abnormal superficial vasculature in the orbit is a further manifestation of the X H E D gene. In this study, one out of eight obligate carrier females (case 4) was an exception in that she had unequivocal normal density of sweat pores over her face and normal thermographic patterns over her body. She had normal dentition and no abnormal clinical signs. Fingerprint patterns were not examined. From this West Indian pedigree there is no doubt that she is an obligate carrier and her affected son shows clear clinical expression of XHED. Her mother and three sisters were manifesting carriers one of which had an affected son. It is possible, there-
13 fore, that in this female the distribution inactivation of the X - c h r o m o s o m e bearing the X H E D mutation was such as to prevent clinically detectable expression, including obvious sweat aplasia. Case 6, a non-manifesting female f r o m a pedigree where parental mosaicism could not be excluded (see Patients and methods) showed absent facial sweating and was classed as a carrier. The present comparison of sweating patterns in obligate h e t e r o z y g o t e s for X H E D and normal controls allowed assessment of the "'possible h e t e r o z y g o t e " group of females. Case 11 showed a characteristic "cascade" back pattern, seen only in heterozygous females. As this is the only abnormality detected in this patient, clarification of her carrier status has to await confirmation of the significance of this finding in a larger n u m b e r of patients. Case 14 had sparse hair and an a b n o r m a l "'cascade" back pattern and we have tentatively concluded that she is a carrier. N o n e of the subjects in this study experienced a rise in b o d y t e m p e r a t u r e above 38~ H o w e v e r , all affected males, five h e t e r o z y g o u s females and two females (+'at risk") experienced some discomfort after about 30rain of the p r o c e d u r e and had to leave the t e m p e r a t u r e controlled r o o m . In this preliminary study, our conclusions regarding t e m p e r a t u r e and sweating patterns specific for obligate h e t e r o z y g o t e females were obtained by c o m p a r i s o n with those for normal controls. D o u b l e blind t h e r m o g r a p h i c studies o f a larger group o f patients are needed to confirm our results and should include sweat pore counts on fingerprints and the use of the recently r e p o r t e d closely linked D N A markers ( Z o n a n a et al. 1988). Sequential horizontal scanning of the back patterns of heterozygous females with the high resolution scanner to determine sweat pore distributions in detail is indicated to see whether the routes of Blaschko lines can be demonstrated. The wider availability of high resolution thermal scanners, t o g e t h e r with i m p r o v e m e n t s in image capture and analysis techniques, will enable such studies to be possible.
Acknowledgements. The authors are grateful to the Rank Prize Funds for making the high resolution scanner available for this work and especially to the former Chairman of the Opto-electronics Committee, the late Dr.F.E.Jones. MBE, FRS, for his constant encouragement and enthusiasm. This project was approved by tile Clinical Research Centre/Northwick Park Hospital Ethical Committee.
References Blaschko A (1901) Die Nervenverteitung in der Haut in ihrer Beziehung zu den Erkrankungen der Haut. Braum011er, Wien Leipzig Champion RH (1975) Focal dermal hypoplasia. Br J Dermatol 93 [Suppl 2] :70-71 Clark RP, Edholm OG (1985) Man and his thermal environment. Arnold, London Clark RP, Goff MR, MacDermot KD (1987) High resolution thermography and X-linked hypohidrotie ectodermal dysplasia (XED). J Physiol 384:5P Edidin DV, Esterly NB, Bamzai AK, Fretzin DF (1977) Chondrodysplasia punctata (Conradi-Hunerman syndrome). Arch Dermatol 113 : 1431-1434 Goff MR, Clark RP (1985) Computerized infra-red thermography in medicine and physiology. J Phot Sci 33 : 6(I-67 Haber H (1952) The Bloch-Sulzberger syndrome (incontinentia pigmenti). Br J Dermatol 64: 129-140 Hamilton WJ, Boyd JD, Mossman HW (1964) Human embryology (prenatal development of form and function), 3rd edn. Heffer. Cambridge, pp 121-122 Happle R (1985) Lionization and the lines of Blaschko. Hum Genet 70: 200-2(}6 Happle R+ Frosch PJ (1985) Manifestation of the lines of Blaschko in women heterozygous for X-linked hypohidrotic ectodermal dysplasia. Clin Genet 27:468-471 Kerr CB, Wells RS, Cooper KE (1966) Gene effect in carriers of anhidrotic ectodermal dysplasia. J Med Genet 3:169-176 Kuno Y (1956) Human perspiration. Thomas, Springfield, 111 MacDermot KD. Winter RM, Malcolm S (1986) Gene localisation of X linked hypohidrotic ectodermal dysplasia (C-S-T syndrome). Hum Genet 74:172-173 MacDermot KD, Morgan SH, Cheshire JK+ Wilson TK, Kaitilla I. Soderholm AL, Chapelle A de la, Kolvraa S. Bolund L. Kruse T (1987) X-linked hypohidrotic ectodermal dysplasia. Multipoint linkage analysis from 3 centers using five polymorphic DNA markers (abstract). (gth International Workshop on Human Gene Mapping) Cytogenet Cell Genet 46:627 O'Leary E, Slaney J, Bryant DG, Fraser FC (1986) A simple technique for recording and counting sweat pores on the dermal ridges. Clin Genet 29: 122-128 Passarge E. Fries E (1973) X chromosome inactivation in X linked hypohidrotic ectodermal dysplasia. Nature New Biol 245:5859 Pinheiro M, Freire-Maia N (1979) Christ-Siemens-Touraine syndrome - a clinical and genetic analysis of a large Brazillian kindred. I. Affected females. Am J Med Genet 4:113-122 Ring EFJ, Hughes H (1986) Real-time video thermography. In: Clark RP+ Golf MR (eds) Recent developments in medical and physiological imaging. Taylor & Francis+ London, pp 86-89 Volpintesta EJ (1974) Menkes kinky hair syndrome in a black infant. Am J Dis Child 128:244-246 Weiner JS (1945) The regional distribution of sweating. J Physiol 104:32-40 Zonana J, Clarke A, Sarfarazi M, Thomas NST, Roberts K, Marrymee K, Harper PS (1988) X linked hypohidrotic ectodermal dysplasia: localisation within the region Xgl 1-21.1 by linkage analysis and implications for cancer detection and prenatal diagnosis. Am J Hum Genet 43 : 75-85
