Fucosidosis Type 2

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Fucosidosis

Type 2

Boris G. Kousseff, M.D., Nicholas G. Beratis, M.D., Lotte Strauss, M.D., Paula W. Brill, M.D., Richard E. Rosenfield, M.D., Beatrice Kaplan, M.D., and Kurt Hirschhorn, M.D.

From the Departments of Pediatrics, Pathology, Radiology, and Rehabilitation Medicine, Mount Sinai School of Medicine of the City University of New York, New York

ABSTRACT. Two siblings, 9 and 4#{189}years old, had a-i-fucosida.se deficiency, angiokeratoma, progressive

psycho-motor retardation, neurologic signs, coarse facial features,

and dysostosis multiplex. It appears that genetic hetero-geneity is present in fucosidosis; there are at least two types. In type 1, patients have no vascular lesions, but have rapid psychomotor regression, severe and rapidly progressing neurologic signs, elevated sodium and chloride excretion in the sweat, and fatal outcome before the sixth year. In type 2, patients have angiokeratoma, milder psychomotor retarda-tion and neurologic signs, longer survival, and normal salinity in the sweat.

Quantitative studies on erythrocytes and in saliva

disclosed severely increased expressions of Lea and Le. Biopsies of skin and gingiva showed alterations as seen in angiokeratoma. There was also evidence of lysosomal storage in vascular endothelium, eccrine sweat gland epithelium, and fibroblasts of the skin. Pediatrics, 57:205-213, 1976,

FUCOSIDOSIS, GENETIC HETEROGENEITY, LYSOSOMAL STORAGE

DISEASES, MUCOLIPIDOSES.

In 1966, Durand et a!.’ described a new muco-polysaccharide lipid storage disease in two siblings with progressive psychomotor regression. Later, Van Hoof and Hers2 demonstrated a-i-fucosidase deficiency in the liver and brain of the patients, and the term fucosidosis was coined.3 In several tissues of patients with fucosidosis, fucose-rich glycolipids, glycoproteins, and mucopolysac-charides have been identified.2-4 Lewis and H blood-group activity have been found in the stored material3 and increased amounts of Le’ have been de:.ionstrated on the erythrocytes and serum of the two patients.1’ In addition to the two cases we report in this paper, there are nine well documented cases of fucosidosis in the litera-ture.’4’ Five patients47 had rapidly progressive psychomotor retardation, severe neurologic signs, and skeletal abnormalities. Three of these had coarse facial features. In three other patients, the

disease was manifested by milder neurologic

signs, longer survival, and skin lesions defined as angiokeratoma corporis diffusum .‘ In addition,

one unusual patient had normal mentality, severe growth retardation, and skeletal abnormalities characterized as

spondyloepiphyseal-metaphy-seal dysplasia.’#{176} We now report detailed studies of the two siblings affected with fucosidosis, previously briefly described,’ ‘ as well as

enzy-matic studies on their parents.

CASE REPORTS

Case 1

A boy (RM220864), born August 22, 1964, was first seen by

US at the age of 9 years. He appeared normal at birth, and his birthweight was 3,660 gm. He sat up at 6 months, walked at 12 months, and started to say single words at 15 months. Around the age of 18 months, the parents became aware that his psychomotor development did not progress, and he soon stopped talking. During the first four years of life, his features gradually became coarse. He had frequent tipper respiratory tract infections and two episodes of pneumonia. Growth retardation was noticed at the age of 5 years, and a few purplish skin lesions were seen on the scrotum and penis. Within the next four years, the lesions gradually increased in number and spread over the buttocks, the abdomen, and the thighs. Gradually he became clumsy, with a stiff gait and

posturing of both arms. He had no difficulty in controlling his body temperature. At the age of 9 years, his height was 1 10 CIII and his weight was 22 kg, both well below the third

percentile. His head circumference was 51.2 cm (40th

(Received March 25; revision accepted for publication May 15, 1975.)

This work was supported in part by Public Health Service

grants HD 02552 and GM 19443. The patients were studied in the USPHS Clinical Research Center (RR-71).

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.

I

FIG. 1. Angiokeratoma corporis diffusum on the penis and

scrotum of patient 1.

206 FUCOSIDOSIS TYPE 2

percentile). During one week of hospitalization, his temper-attire remained between 36 and 37.2 C. He had no

intelli-gible speech, but he appeared to follow some simple

instructions given by the parents. His gait was unstable,

broad-based with tiptoeing and posturing of the arms in

flexion. Muscle tone was increased in all extremities, with both spasticity and rigidity. There was restriction in the motion of both wrists, elbows, and shoulders. All deep tendon reflexes were increased, and the plantar reflexes were

upward bilaterally. His skin was thick and there were

increased subcutaneous markings, particularly on the chest, the palms, and the soles. No evidence of hyperhidrosis or hypohidrosis was noted. Lanugo-like hypertrichosis was on the extremities and along the thoracic spine. On the scrotum and penis there were several pinhead-sized, purplish, raised lesions (Fig. 1), which did not coalesce and did not blanch on diascopy. The same type of lesions, but lighter in hue and less in number, were scattered over the abdomen, the buttocks, and the thighs. Some of the lesions appeared as streaks up to 3 ml long. His face was coarse, and there were discrete dilated vessels on the gums perpendicular to the roots of the

teeth. The anterioposterior diameter of the thorax was

increased, and kyphoscoliosis was present. There was no

evidence of hepatosplenomegaly or corneal opacities, and the salivary glands were not enlarged. Psychological evalua-tion showed severe mental retardation, and the IQ could not be measured.

Results of routine hematologic studies and urinalysis were normal, but the bleeding time was slightly prolonged to 5#{189}

minutes (normal, 2 to 5 minutes). Ten percent of the

peripheral lymphocytes were vacuolated. Electrolytes, urea, creatinine, bilirubin, immunoglobulins, lipoproteins, serum alkaline phosphatase, serum and urine amino acids, and bone marrow smears were normal. The total amount of urinary acid mucopolysaccharides excreted in 24 hours was 6 mg.

The levels of glucose, protein, and lactate dehdrogenase were normal in the cerebral fluid. Results of a sweat test

were normal, with sodium values of 43 mEq/hter, and

chloride values of 38 mEq/liter. Results of ECC and EEG

were normal. Nerve conduction velocities were within

normal limits, except for the right median nerve where the velocity was decreased to 35 msec/m (normal range, 45 to 68).

When the patient was reexamined at the age of 10 years, new angiokeratoma lesions were found at the umbilicus.

Case 2

The younger brother (GM150269) of patient 1 was normal

at birth. His birthweight was 3,700 gm. When he was 6 months old a red streak was noted on the upper gum. He sat up at 7 months, walked at 18 months, and said a few single words at the same time. Soon after, he stopped talking and

his psychomotor functions ceased to develop. He had

frequent respiratory tract infections. A few more red streaks appeared on the gums within the next four years. Coarsening

of the face also became apparent. No inability to control body temperature was noted. At age 4#{189}years, the patient’s weight was 19 kg (30th percentile), and his height was 97.5 cm (3rd percentile). Head circumference was 50 cm (40th

percentile). His body temperature during one week of

hospitalization was between 36.2 and 37.1 C. His face was

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TABLE I

ALPHA-L-FUCOSIDASE ACTIVITY IN CULTURED SKIN

FIBROBLASTS

clear.

The patient’s salivary glands were not enlarged. His gait was broad-based. Muscle tone was slightly increased in all extremities, the deep tendon reflexes were generally brisk, and the plantar reflexes were upward l)ilaterally. Psycholog-ical evaluation showed an age quotient of 42.

While results of routine hematologic studies were normal, bleeding time was prolonged to eight minutes. No vacuoles

were seen in the peripheral lymphocytes. There was no

abnormal mucopolysacchariduria or aminoaciduria. Serum electrolytes, urea, creatinine, lipoproteins, and alkaline

phos-phatase were normal. Bone marrow smear, urine, and

cerebrospinal fluid were normal. Results of a sweat test were normal, with sodium values of 50 mEq/liter and chloride

values of 20 mEq/hter. Results of EEC and ECG were

normal. Nerve conduction velocities were within normal limits, except for the right median nerve where the velocity was decreased to 34.3 msec/m.

When we reexamined the patient at the age of 5 years 9 nionths, he had developed typical angiokeratoma lesions on the scrotum and thighs. According to the mother, these lesions first appeared at the age of 5 years 2 Inonths.

Both parents were of German-Italian extraction, but no history of consanguinity could be elicited.

#{176}Nmolof p-nitrophenol per milligram of protein per hour.

tMean ± SD.

coarse with puffy eyelids similar to that of his brother. His teeth were widely spaced, with dilated vessels on the gums perpendicular to the roots of the teeth. The vessels did not blanch on diascopy. His skin was thick; and there were increased subcutaneous markings all over the body, particu-larly on the palms (Fig. 2), soles, and chest. The extremities had lanugo-like hair. A mild right scoliosis was present.

There was no hepatosplenomegaly, and the corneas were

SPECIAL STUDIES Enzymatic Studies

Heparinized blood was obtained from the patients, their parents and grandparents, as well

as from nine normal donors. The erythrocytes were sedimented with 6% dextran in saline and the supernatant leukocyte-rich fraction was centrifuged. The erythrocytes present in the leukocyte pellet were lysed in 2.5 ml of 0.83% ammonium chloride. After five minutes at room temperature, the cell suspension was centrifuged and the leukocytes were washed three times with normal saline.

Fibroblasts were grown from skin biopsies obtained from the inner surface of the forearms of the two patients, the patients’ parents, and 15 normal subjects. The skin fibroblasts were cultured in RPMI 1640 medium, supplemented with 20% fetal calf serum, penicillin (100 U/mi),

streptomycin (100 mg/ml), and 1% 200 mM L-glutamine. Cells were always harvested at the early confluent stage, 24 hours after the last change of medium. Long-term lymphoid cell lines were established from the patients using

gg’

Peripheral leukocytes, cultured skin fibroblasts, and long-term lymphoid line cells were lysed in distilled water by eight cycles of freezing and

Subjects No. Stud-led No. of Prepar-ations Studied Enzyme Activity0 Mean Range

Patients 2 8 0.0 0.0

Case 1 4 0.0 0.0

Case 2 4 0.0 0.0

Heterozygotes 2 8 23.7 13.6 to 30.8

Father 4 25.2 18.4 to 29.5

Mother 4 22.2 13.6 to 30.8

Controls 15 30 70.4 ± 25.4t 40.7 to 109.5

thawing. The lysates were centrifuged at 1,800 g for five minutes, and the supernatant fractions were used for enzymatic determination. The activity of a-L-fucosidase was measured using a modification of the method of Zielke et al.’3 The concentration of the substrate p-nitrophe-noi-a-L-fucoside was increased to 3.0 mM. The acetate buffer used had a pH of 5.7, and the incubation time was reduced to two hours. For cultured skin fibroblasts, four preparations were studied from each of the patients and the patients’ parents, and two from each of the 15 controls.

No activity of a-L-fucosidase was detected in the peripheral leukocytes of patient 2. The activity in the leukocytes of patient 1 was 16 nmol of p-nitrophenol per milligram of protein

per hour. In the leukocytes of the nine control subjects, the activity (mean ± SD) was 184.1 ± 80.3, with a range of 116.9 to 380.9. Accurate identification of heterozygotes using leukocytes was not possible because of occasional overlap with normal values. However, since het-erozygote values in the family were generally lower than those of normals, it was possible to identify the Italian grandparent in each side of the family as the probable carrier.

Absence of a-L-fucosidase activity was demon-strated in the cultured skin fibroblasts of the patients. The enzymatic activity in the fibroblasts of the obligate heterozygous parents was 33.6% of the activity found in the normal controls (Table I). The activities of the lysosomal enzymes aryl-sulfatase A and B, a-glucosidase, a-galactosidase, a-iduronidase, 13-galactosidase, f3-glucosidase,

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208 FUCOSIDOSIS TYPE 2 TABLE II

BLOOD GROUPING

Factor Father Mother Case 1 Case 2

ABO 0 A, 0 0

Rh 1,2,3,4, 5,-6,7 (R,R2) 1,2,-3,4, 5,6,7 (R2r) 1,2,-3,-4, 5,-6,7 (R,R,) 1,2,-3,-4, 5,-6,7 (R,R,) Kell 1,2,-3,4,-6 (Kk) 1,2,-3,4,-6 (kk) 1,2,-3,4,-6 (Kk) 1,2,-3,4,-6 (Kk)

Kidd b b b b

Duffy ab b b ab

Lua - -

-P, + + + +

MN MNss MNss Mss Nss

Ge + + + +

Yta + + + +

Lewis a b ab ab

Saliva Lewis,

noH

Lewis, H,A

Lewis, H Lewis, H

a-L-fucosidase was also demonstrated in the two long-term lymphoid cell lines established from the patients.

Blood Grouping

Erythrocytes were typed quantitatively by the method of Berkman et al.’4 This method was easily adaptable for quantitative inhibition of agglutination and allowed assay of saliva speci-mens for Lea, Leb, H, and A antigens. The relation between relative concentration of salivary anti-gen and degree of inhibition could be linearized by log-.probit transformation.

Qualitative blood grouping data pertaining to red cell and saliva are given in Table II. Assay of

H

and A agglutinability of erythrocytes and of A

and H agglutination inhibition by saliva showed that specimens from the patients and their parents failed to differ significantly from speci-mens from the controls. Other erythrocytic antigens were also within normal quantitative lits.

In contrast, Lewis activity on red cells and in saliva was expressed to an unusually high degree

in the patients, when compared to that found in the parents and to that in the controls. Neither of the specimens from the parents was significantly

different from those from the normal controls.

Quantitative erythrocyte Lewis agglutination in the H nonsecretor father was 47.5 units Le (expressed as Mog,0 OD

x 100,

adjusted for actual cell count and instrument performance);

and in the H secretor mother, 58.3 units Leb.

Both patients were H secretors. Patient 2 showed 64.9 units Le’ and 81.2 units L&. Patient 1 showed 73.5 units Le” and 106 units Leb. Clearly, both patients displayed Le (a + b +

)

red cell phenotypes. Both displayed more Le’ activity

than Lea activity, consistent with their H secre-tory status. However, both patients displayed unusually high degrees of Lewis agglutinability. This is particularly apparent for the Le’ “minor” component of their phenotypes. Their Lea expres-sion alone is the highest ever observed in tests of

Le(a + b +

)

phenotypes, and their Le’ activity is also the highest observed among normal H-Le secretors.

Quantitative salivary Lewis agglutination inhi-bition in the father was 67 units Le’ (expressed as reciprocal of salivary dilution required for 50% inhibition of Le-anti--Le agglutination); and in the mother, 6 units Le’ and 23 units Leb. Patient 2 showed 17 units Le” and 133 units Le’. Patient 1 showed 6 units Le” and 123 units Leb. Therefore, the patients showed approximately 5#{189}times higher Lewis activity in their saliva than did the mother, who was of the same phenotype.

Radiologic Findings

The skeletal findings may be characterized as a dysostosis multiplex less severe than that of Hurl-er’s syndrome. The pelvis, hips, and spine were the sites of the most striking abnormalities. In general the findings were quite similar in the two brothers.

The iliac wings were flared, and the acetabular roofs were elongated and scalloped. Coxa valga

and flattening and irregularity of the femoral heads were present. The femoral head flattening was more severe in patient 1. There was lumbar vertebral breaking with inferior beaking of some vertebrae and central beaking of others. The odontoid was hypoplastic. The sinuses and mastoid air cells were underpneumatized. In patient 2, the teeth were widely spaced. The medial portion of the distal radial metaphysis was deficient. There was slight metacarpal widening

and cortical thinning. The bone age15 was four years less than the chronological age in patient 1,

and one year less in patient 2. The clavicles were widdened medially. The glenoid fossae of the scapulae were flattened. The ribs, heart, and lungs were normal.

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, I

.‘‘.,

.

. . . . 0 #{149} ,#{149} #{149},

-.. . l ---: ‘ #{149}. ‘ ‘#{149}- #{149}

FIG. 4. Osmium-fixed semi-thin section of eccrine sweat gland showing diffuse enlargement and discrete vacuoliza-tion of epithelial cells. Nucleus is often displaced to cell

periphery. A small blood vessel, cut longitudinally, between two segments of the gland shows vacuolated endothelial cells. The large, dark cells are fat cells (toluidine blue, x 450

[original magnification]).

with uranyl acetate and lead citrate were

exam-FIG. 5. Electronmicrograph (micron marker = 1i) of part of a subepidermal capillary lined by

enlarged endothelial cells (E), the cytoplasm of which contains numerous “vacuoles” with mostly empty appearance except for some electron-dense granular material. Some of the storage

material appears accumulated within the cytoplasm, possibly secondary to rupture of the

limiting membranes. The involvement of the endothelial cells varies, to judge from the more normal appearance of the cell with the nucleus. A pericyte in the specimen is not involved. FIG. 3. Paraffin secretion of skin showing telangiectatic,

thin-walled subepidermal vascular channels hugged by elongated epidermal ridges. Segments of a normal sweat duct are seen to the left (hematoxylin-cosin, x 160 [original

magnifica-tion]).

Detailed description and illustration of the radiographic findings are the subject of another

16

Histopathologic Studies

A biopsy of skin taken from a lesion on the thigh of patient 1 was processed for light and electron microscopy. Formalin-fixed

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.0.

--..

4-s, ,

L

med with an RCA EMU-3G electron microscope. Paraffin secretions of the gingival biopsies of both brothers were prepared for microscopic examina-tion.

Light Microscopic Findings-The epidermis

showed slight hyperkeratosis with irregular elon-gation of the rete ridges. The superficial dermis, in close proximity to the epidermis, contained dilated thin-walled, endothelial-lined vascular

spaces (Fig. 3). Several nondistended small blood vessels appeared narrowed by swollen endothelial cells with a finely vacuolated PAS-negative cyto-plasm. An eccrine sweat gland showed swelling and diffuse fine cytoplasmic vacuolization of the epithelial cells of the secretory coil (Fig. 4). Dark and clear cells could not be differentiated. The myoepithelial cells did not appear to participate in this alteration. The vacuoles were PAS-nega-tive and unstained by toluidine blue. The sweat duct epithelium did not show vacuolization. The gingival biopsies were similar in the two patients. Immediately beneath the mucosal epithelium there was an abundance of capillaries lined by swollen endothelial cells showing a fine vacuoli-zation of their cytoplasm. Rare telangiectatic vessels were present in patient 1, superficially and in the submucosa. The deeper connective tissue

contained abundant basoph ilic ground substance. In patient 2, the vascular lesion was more exten-sive and angioniatous.

Electronnsicroscopic Firidings-Endothelial

cells of dermal capillaries were enlarged; their cytoplasm was occupied by numerous electronlu-cent, membrane-lim ited vacuoles containing scant, finely granular or flocculent material in the

otherwise ‘empty ITnatrix (Fig. 5). These

vacuoles measured up to 2ji in diameter. Rupture

of membranes seemingly caused formation of

larger vacuoles by coalescence or discharge of their contents into the cytoplasm. Pericytes did not appear to be involved. Endothelium of the overdistended capillaries abutting on the epider-mis was attenuated and apparently devoid of vacuoles. Fibroblast contained cvtoplasmic vacu-oles.

The eccrine sweat gland epithelium contained two distinct types of storage material (Fig. 6). The myoepithelial cells were not significantly en-larged and contained minute vesicles filled with

lamellated osmiophilic nate rial, presum ably lipid. The secretory epithelial cells by contrast were diffusely enlarged; their cytoplasm was packed with innumerable larger inclusions, bounded by a unit membrane and containing

210 FUCOSIDOSIS TYPE 2

. ‘p

.: ‘ - / v

,:4##{247}

:

l

FIG. 6. Electronmicrograph (micron marker = 3) of eccrine sweat gland showing notal)le

enlargement of epithelial cells with accumulation of storage vacuoles throughout their

cytoplasm. The membrane-bound vacuoles contain reticulogranular material consistent with polysaccharide storage. One of the cells is almost completely filled by a single large vacuole displacing organelles to the periphery of the cell. None of the cells contains secretion granules characteristic of dark cells. Myoepithelial cells (M) contain smaller storage granules with

osmiophilic laminated material indicative of lipid (L = lumen)

(

x 3.500).

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TABLE III

MAJOR CLINICAL AND LABORATORY FINDINGS IN FUc0SIDOSIS TYPES 1 AND 2

Findings

T ype 1 Typ e 2

k

Present Cases

Unclassified

-Durand at a!.’ #{149}

Loeb et

Voets et aL’

Matsuda et al.4

Pate! et al.’

,-Borrone et al.’

Schafer et a!.

National origin Italy Italy Italy Germany Japan USA Italy Italy Italy, Italy,

Germany Germany

USA

Consanguinity + + + - + - + + - - 0

Sex M F M M F M M F M M M

Age 3 yr 5 yr

9mot 2mot

5 yrt 4 yr 4 yr

2mo

20 yr 17 yr 5 yr 9 yr 4 yr

6mo

9 yr

Age of onset of psychomotor regression

1 yr 1 yr 1 yr

4 mo

1 yr 1 yr 1 yr

2 mo

2 yr 1 yr 1 yr 1 yr

6 mo 6 mo

-Coarse features NM NM + + + + + + + + NM

Angiokeratoma - - - + + + + +

-Growth retardation

+ + + + - + + + + + +

Skeletal abnormalities

+ + + + + + + + + + +

Kyphosis and scoliosis

+ + + + - + + - + + NM

Progressive neurologic signs

+ + + + + + + + + +

-Seizures NM NM NM NM + + - - - - NM

Hepatomegaly - - + + + - - -

-Splenomegaly - - + - - - - + - -

-Cardiomegaly + + - NM - - - + - -

-Frequent respiratory infections

+ + - + + + NM NM + + NM

Na and Cl in sweat

High High NM High High A Normal Normal Normal Normal NM

Vacuolated lymphocytes

+ + + + + NM + + + - NM

Abnormal ECG + + NM NM NM NM - - - - NM

#{176}NM= Not Mentioned.

tDeceased. A = Anhidrotic.

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212 FUCOSIDOSIS TYPE 2

features of “clear” and “dark” cells were nearly obliterated, making their differentiation virtually impossible. Limited sampling of a sweat duct showed only a rare cytoplasmic vacuole.

DISCUSSION

The major clinical and laboratory findings of the reported cases of fucosidosis are listed in Table III. It seems that there are at least two forms of the disease-type 1 and type 2. The one patient reported by Schafer et al.’#{176}differs from all other patients with fucosidosis reported so far,

and is, therefore, listed separately.

Angiokeratoma corporis diffusum, a skin lesion considered characteristic of Fabry’s disease, is the cardinal clinical finding that distinguishes the two

types of fucosidosis. The distribution of the angio-keratoma lesions resembles that seen in Fabry’s disease’7: it is localized on the genitalia, thighs, lower abdomen, and buttocks. However, it

appears that the onset of the cutaneous and mucosal lesions is earlier in fucosidosis. It is not known if the lack of angiokeratoma lesions in patients with type 1 is due to their shorter life span. The onset of angiokeratoma was observed in patient 2 at the age of 6 months; and in four other patients with type 2, skin lesions were noted between the ages of 4 and 5 years. Loonen and others” recently reported the case of a 29-year-old patient with angiokeratoma corporis

diffusuin and /3-galactosidase deficiency in pe-ripheral leukocytes and cultured skin fibroblasts. It seems, therefore, that angiokeratoma lesions may develop later in life in certain lysosomal storage diseases.

The onset of psychomotor regression occurs slightly earlier in type 1 than in type 2. The mean age of the onset in the reported cases of type 1 was 12.8 months; in type 2 mean age was 17.2 months. Type 1 also appears to be rapidly fatal. Three patients out of five reported so far died before the age of 6 years. The other two were severely affected by 4 years of age. All patients with type 2 survived longer and were alive when reported. The oldest was 20 years old.

Splenomegaly is not a consistent finding in fucosidosis and has been observed in only two patients-one with type i,! and one with type 2.6

No evidence of renal involvement was found in the two patients reported here. Renal impairment leading to chronic renal insufficiency occurs in Fabry’s disease. It is not known on the basis of the few available observations whether renal involve-ment may also develop in type 2 fucosidosis.

The radiologic findings of dysostosis multiplex included vertebral beaking, odontoid hypoplasia,

pelvic deformity, widening of the shafts of tubular bones, and sinus hypoaeration. Although not as severe as the skeletal abnormalities of Hurler’s syndrome, the presence of these findings is compatible with the diagnosis of a storage disease.

Although patients with type 2 have a milder course of the disease than patients with type 1, no a-L--fucosidase activity was detected in several preparations of cultured skin fibroblasts. The production of a labile enzyme by the mutant cells or the use of an artificial substrate may cause this apparent absence of activity. The apparent residual enzymatic activity observed in the pe-ripheral leukocytes in patient 1 may be nonspe-cific.

Abnormal sweat has been reported in several cases of fucosidosis. In the four patients with type

1 studied by sweat test,4-57 there were increased amounts of sodium and chloride in the sweat; four patients with type 2,6 1 1 including our patients,

had normal sweat electrolytes. The fifth patient with type 2 developed anhidrosis and inability to control body temperature.1 Hyperhidrosis has also been observed in two patients with type 1’ Involvement of sweat glands has not been previously reported in this lysosomal disorder. It has been described in mucopolysaccharidoses2

with and without demonstrable abnormalities of sweating at the time of examination. Ultrastruc-tural studies of the skin in the 20-year-old man with angiokeratoma did not include sweat glands but revealed storage in vascular endothelium and fibroblasts. The development of anhidrosis in that patient raises the possibility that sweat glands may in time become damaged to the extent of interfering with sweat production and secretion. Investigations of more patients with this disorder

are needed before structural-functional correla-lions can be attempted.

Our finding of electron-lucent vacuoles in vascular endothelium and fibroblasts confirm those of Patel et al.9 The relationship between endothelial storage and the development of angiokeratoma is not understood. Since the cuta-neous lesions do not blanch on pressure, it is

thought unlikely that the telangiectasias are caused by obstruction of the lumen of venules and capillaries resulting from swelling and damage of the endothelium, although this cannot be ruled out. Observations on the ultrastructure of vascular endothelium in type 1 fucosidosis have not been reported.

Lewis A and B antigens were notably elevated in both the erythrocytes and saliva of our patients. The result of salivary Lewis was 5#{189}times that

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found in the parents, while red-cell Lewis was the highest ever observed on red cells. However, the H specificity did not show a significant increase. Because Lewis-specific a-fucose is bound in a-i

-8 4 linkage to fl-N-acetyl-D-glucosamine and

H-specific a-fucose is bound in a-i - 2 linkage

to $-galactose, the deficient fucosidase may be primarily a fucosidase specific for 1 -* 4 linkage to fl-N-acetyl-D-glucosamme. The findings also imply that Lewis structures reflect the result of

continuous enzymatic synthesis and degradation.

It is not known at this time why Lewis activity has been found to be normal in the saliva of the two patients described by Borrone et al.,6 unless the difference was insufficient to be noted by

semiquantitative manual methods.

In view of the finding that the majority of cases of fucosidosis derive from Italy (Table III), it is of interest that we have presumptive evidence that the fucosidosis gene in the family in our study was derived on both paternal and maternal sides from Italian grandparents.

The clinical differences between the two types indicate the heterogeneity present in fucosidosis. The similarity between the two siblings described here, as well as within one pair of siblings with type P and another pair with type 26 reported in the literature, indicates that the clinical differ-ences are genetically determined.

SUMMARY

Two brothers with fucosidosis had

angiokera-toma corporis diffusum, coarse features, mental

and growth retardation, and neurologic signs. Both siblings had radiologic findings of dysostosis multiplex. Alpha-L-fucosidase deficiency was

demonstrated in peripheral leukocytes, cultured

skin fibroblasts, and long-term lymphoid cell lines

of the patients. Morphologic changes were observed in cutaneous and gingival biopsies. Ultrastructurally these suggested lysosomal

stor-age in endothelial cells, fibroblasts, and sweat gland epithelium. Quantitative studies of A, B, H,

[ga, and Le6 antigens on erythrocytes and in

saliva disclosed normal expressions of A, B, and H,

but notably increased expressions of Lea and Le’. These results imply that this type of fucosidosis involves a-i - 4 /3-N-acetyl-D-glucosamine and

not a-i -3 2 f3-galactose linkages, and that Lewis

expression reflects the result of continuous enzy-matic synthesis and degradation.

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ultrastructural studies in a case of mucopolysac-charidosis “F” (fucosidosis). Helv Pediatr Acta 36:519, 1969.

8. Voelz C, Tolksdorf M, Freitag F, Spranger J: Fucosi-dose. Monatsschr Kinderheilkd 1 19:352, 1971.

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ACKNOWLEDGMENT

We wish to thank Dr. Ruben Matalon, University of

Chicago, for the estimates of the mucopolysaccharide levels; Mr. Norman Katz for the preparation of the

electronmicro-graphs; Charlene Heller, Roberta Weiss, and Shirley

(10)

1976;57;205

Pediatrics

Rosenfield, Beatrice Kaplan and Kurt Hirschorn

Boris G. Kousseff, Nicholas G. Beratis, Lotte Strauss, Paula W. Brill, Richard E.