Clfnicnl Genetics 1976: 9: 513-526
Analbuminemia in an American Indian girl H. BOMAN,* M. HERMODSON, C. A. HAMMOND, AND A. G. MOTULSKY
Departments of Medicine and Genetics and the Center for Inherited Diseases, University of Washington, Seattle, Washington, U.S.A. Analbuminemia was fortuitously detected in a nonedematous 12-year-old American Indian girl with atopic dermatitis, mild bronchial asthma, a mild seizure disorder, and hyperlipoproteinemia with a corneal arcus. Immunologic methods revealed trace amounts (17 mg/100 ml) of apparently normal serum albumin. The patient’s parents were remotely related. The pedigree and clinical findings were compatible with autosomal recessive transmission of analbuminemia. Heterozygotes had subnormal levels of serum albumin. The Gc-locus is closely linked to the structural albumin locus. Gc-protein levels were normal in the patient and together with normal chromosomal banding studies make it unlikely that a chromosomal deletion caused analbuminemia. Gc-types in the family were compatible with, but did not prove, linkage of analbuminemia to the Gc-locus. These findings suggest a “tha1assemia”-like mutation for this disorder. Received 10 October, accepted f o r publication 17 November 1975
Since Bennhold and co-workers first reported analbuminemia in 1954, a total of 1 3 patients with this disorder have been reported. Twelve of these cases were reviewed by Ott (1974a), and the thirteenth case was recently published (Cormode et al. 1975). Analbuminemia is an extraordinary “experiment of nature” aiding our understanding of the role of albumin in normal physiology. We report here studies on the biochemical genetics of an American Indian girl with analbuminemia. Case Report
The patient (J.D.S.) has been followed from birth by one of us (C.A.H.). She was born at term in 1961 after an uncomplicated pregnancy. No abnormality (including edema or icterus) was noted at birth or in
the postnatal period. Length at birth was 48 cm; head circumference was 34 cm (50th percentile). Growth was normal but motor development was slightly delayed. At age 3?h years her height was 96 cm and weight 19.5 kg; at 5% years these measurements were 106 cm and 22 kg, respectively. At age 18 months she had pneumonia, treated at home. After repeated throat infections and serous otitis, enlarged tonsils and adenoids were removed at age 6 years without complications and with subsequent clinical improvement. At age 3% years she had generalized small patches of eczema, developing into a widespread itching dermatitis and generally xerotic skin. Local treatment with steroids, tar, emolients, and dietary changes proved unsuccessful. Peas, corn, potatoes, and salmon were found to worsen the skin
* Present address: Institute of Medical Genetics, University of Oslo, Oslo
3, Norway.
514
BOMAN. HERMODSON, HAMMOND. AND MOTULSKY
taking doxicycline 100 mg every morning for 5 days for an upper respiratory infection. After being out in hot weather all day, she went to bed as usual in the evening. At midnight her parents heard her fall and found her unconscious on the floor. She was not spastic and did not have epileptiform movements; there was no tongue biting, and she was fully continent. She woke after approximately 30 min without sequelae before being seen by a physician, and had no recollection of the episode. During the ensuing work-up for epilepsy, paper electrophoresis of serum revealed absence of albumin. On the basis of several definitely abnormal electroencephalograms she was given pheno-
lesions. A biopsy of the skin lesions at age 9 showed lichen nitidus and chronic non-
specific dermatitis. She also suffered from mild bronchial asthma and rhinitis, and had been treated with hyposensibilization since age 6 years with injections of house dust allergens. Her asthma was made worse by exercise, but she was able to participate in normal physical activity. A maternal aunt had mild asthmatic symptoms; otherwise no asthma or allergies were known in the family. The patient attended regular school and received average grades. Her only fainting episode occurred in July 1973. Before the episode she had been
I I
lI
m m I
I
12
P
3
5
4
6
m
m
f
0 Analbuminemia @ Hypoalbuminemia- presumed heterozygous
a
Normal serum albumin level
Fig. I.The S podigree.
9
10
ANALBUMINEMIA IN AN AMERICAN INDIAN GIRL
barbital 15 mg four times daily, which she has been taking without side effects. She was later admitted to the Clinical Research Center ward at the University of Washington Hospitai for further studies of her serum protein abnormality. Family History The patient belongs to an American Northwest Indian tribe with ancestors from the shores of Puget Sound, Washington. A family pedigree is given in Fig. 1. The parents (V-5 and V-6) of the patient (VI-2) were related two ways as third cousins (coefficient of inbreeding 1/128), since the maternal grandparents (IV-10 and IV-11) themselves were second cousins. The father of 111-3 was a white man, otherwise no Caucasian admixture was recorded. Both parents, the older sister, and the brother of the patient were clinically normal with an essentially noncontributing past medical history. The younger sister (VI-4) of the patient died in infancy. Hospital records of this infant were obtained. At the time of delivery, the mother referred to a full-term pregnancy but the infant's birth weight was only 1930 g. The course of pregnancy and birth were uncomplicated; no structural abnormalities were noted in the newborn. During the first night the infant became cyanotic and was given oxygen. The infant was unusually active and irritable. The possibility of neonatal tetany arose and intramuscular calcium gluconate was administered. Chest X-ray examination revealed a normal cardiac silhouette and thymus, and no gross pulmonary abnormalities. The baby expired on the fifth day of life. No blood analyses were done, and an autopsy was not performed.
Clinicul Findings The patient gave the impression of generally good health. She had eczematous dermatitis
515
with thickening and xerosis of the skin, affecting the trunk, the extensor surfaces of arms and legs, the face and the scalp. Molluscurn contagiosum on one eyelid, the neck, and the forearms was also detected. Blood pressure measurements ranged between 130/80 and 110/70 mm Hg. Her weight was 51.5 kg, height 144 cm (midparental height, 167.5 cm), and head circumference, 55 cm. She had no pedal or ankle edema. Liver, spleen, and lymph nodes were not palpable. She had a short first toe consistent with brachydactyly type D, but
Table 1 Hematological and clinical chemistry values in patient J.D.S. with analbuminemia. (Some normal values from this laboratory are given in brackets) Hemoglobin 12.4 g/100 ml Hematocrit 37 Qh Red blood cells 5.02 milllmm3 6,600 /mmf White blood cells Eosinophilic cells 11 Qh Erythrocyte sedimentation rate 77 mrnlh Serum iron 78 ,Ug/lOO ml TlBC 555 ,pg/100 m l Na 139 rnEq/l K 4.0 rnEqlt CI 107 rnEqll Ca 7.8 mgllOO mi Po4 4.8 mgI100 ml BUN 6 mg/lOO ml 0.6 mg/lOO ml Creat i n i ne Total bilirubin 0.03 mg/l00 ml Alkaline phosphatase 287 U (60-260) SGOT 25 U (
Analbuminemia in an American Indian girl H. BOMAN,* M. HERMODSON, C. A. HAMMOND, AND A. G. MOTULSKY
Departments of Medicine and Genetics and the Center for Inherited Diseases, University of Washington, Seattle, Washington, U.S.A. Analbuminemia was fortuitously detected in a nonedematous 12-year-old American Indian girl with atopic dermatitis, mild bronchial asthma, a mild seizure disorder, and hyperlipoproteinemia with a corneal arcus. Immunologic methods revealed trace amounts (17 mg/100 ml) of apparently normal serum albumin. The patient’s parents were remotely related. The pedigree and clinical findings were compatible with autosomal recessive transmission of analbuminemia. Heterozygotes had subnormal levels of serum albumin. The Gc-locus is closely linked to the structural albumin locus. Gc-protein levels were normal in the patient and together with normal chromosomal banding studies make it unlikely that a chromosomal deletion caused analbuminemia. Gc-types in the family were compatible with, but did not prove, linkage of analbuminemia to the Gc-locus. These findings suggest a “tha1assemia”-like mutation for this disorder. Received 10 October, accepted f o r publication 17 November 1975
Since Bennhold and co-workers first reported analbuminemia in 1954, a total of 1 3 patients with this disorder have been reported. Twelve of these cases were reviewed by Ott (1974a), and the thirteenth case was recently published (Cormode et al. 1975). Analbuminemia is an extraordinary “experiment of nature” aiding our understanding of the role of albumin in normal physiology. We report here studies on the biochemical genetics of an American Indian girl with analbuminemia. Case Report
The patient (J.D.S.) has been followed from birth by one of us (C.A.H.). She was born at term in 1961 after an uncomplicated pregnancy. No abnormality (including edema or icterus) was noted at birth or in
the postnatal period. Length at birth was 48 cm; head circumference was 34 cm (50th percentile). Growth was normal but motor development was slightly delayed. At age 3?h years her height was 96 cm and weight 19.5 kg; at 5% years these measurements were 106 cm and 22 kg, respectively. At age 18 months she had pneumonia, treated at home. After repeated throat infections and serous otitis, enlarged tonsils and adenoids were removed at age 6 years without complications and with subsequent clinical improvement. At age 3% years she had generalized small patches of eczema, developing into a widespread itching dermatitis and generally xerotic skin. Local treatment with steroids, tar, emolients, and dietary changes proved unsuccessful. Peas, corn, potatoes, and salmon were found to worsen the skin
* Present address: Institute of Medical Genetics, University of Oslo, Oslo
3, Norway.
514
BOMAN. HERMODSON, HAMMOND. AND MOTULSKY
taking doxicycline 100 mg every morning for 5 days for an upper respiratory infection. After being out in hot weather all day, she went to bed as usual in the evening. At midnight her parents heard her fall and found her unconscious on the floor. She was not spastic and did not have epileptiform movements; there was no tongue biting, and she was fully continent. She woke after approximately 30 min without sequelae before being seen by a physician, and had no recollection of the episode. During the ensuing work-up for epilepsy, paper electrophoresis of serum revealed absence of albumin. On the basis of several definitely abnormal electroencephalograms she was given pheno-
lesions. A biopsy of the skin lesions at age 9 showed lichen nitidus and chronic non-
specific dermatitis. She also suffered from mild bronchial asthma and rhinitis, and had been treated with hyposensibilization since age 6 years with injections of house dust allergens. Her asthma was made worse by exercise, but she was able to participate in normal physical activity. A maternal aunt had mild asthmatic symptoms; otherwise no asthma or allergies were known in the family. The patient attended regular school and received average grades. Her only fainting episode occurred in July 1973. Before the episode she had been
I I
lI
m m I
I
12
P
3
5
4
6
m
m
f
0 Analbuminemia @ Hypoalbuminemia- presumed heterozygous
a
Normal serum albumin level
Fig. I.The S podigree.
9
10
ANALBUMINEMIA IN AN AMERICAN INDIAN GIRL
barbital 15 mg four times daily, which she has been taking without side effects. She was later admitted to the Clinical Research Center ward at the University of Washington Hospitai for further studies of her serum protein abnormality. Family History The patient belongs to an American Northwest Indian tribe with ancestors from the shores of Puget Sound, Washington. A family pedigree is given in Fig. 1. The parents (V-5 and V-6) of the patient (VI-2) were related two ways as third cousins (coefficient of inbreeding 1/128), since the maternal grandparents (IV-10 and IV-11) themselves were second cousins. The father of 111-3 was a white man, otherwise no Caucasian admixture was recorded. Both parents, the older sister, and the brother of the patient were clinically normal with an essentially noncontributing past medical history. The younger sister (VI-4) of the patient died in infancy. Hospital records of this infant were obtained. At the time of delivery, the mother referred to a full-term pregnancy but the infant's birth weight was only 1930 g. The course of pregnancy and birth were uncomplicated; no structural abnormalities were noted in the newborn. During the first night the infant became cyanotic and was given oxygen. The infant was unusually active and irritable. The possibility of neonatal tetany arose and intramuscular calcium gluconate was administered. Chest X-ray examination revealed a normal cardiac silhouette and thymus, and no gross pulmonary abnormalities. The baby expired on the fifth day of life. No blood analyses were done, and an autopsy was not performed.
Clinicul Findings The patient gave the impression of generally good health. She had eczematous dermatitis
515
with thickening and xerosis of the skin, affecting the trunk, the extensor surfaces of arms and legs, the face and the scalp. Molluscurn contagiosum on one eyelid, the neck, and the forearms was also detected. Blood pressure measurements ranged between 130/80 and 110/70 mm Hg. Her weight was 51.5 kg, height 144 cm (midparental height, 167.5 cm), and head circumference, 55 cm. She had no pedal or ankle edema. Liver, spleen, and lymph nodes were not palpable. She had a short first toe consistent with brachydactyly type D, but
Table 1 Hematological and clinical chemistry values in patient J.D.S. with analbuminemia. (Some normal values from this laboratory are given in brackets) Hemoglobin 12.4 g/100 ml Hematocrit 37 Qh Red blood cells 5.02 milllmm3 6,600 /mmf White blood cells Eosinophilic cells 11 Qh Erythrocyte sedimentation rate 77 mrnlh Serum iron 78 ,Ug/lOO ml TlBC 555 ,pg/100 m l Na 139 rnEq/l K 4.0 rnEqlt CI 107 rnEqll Ca 7.8 mgllOO mi Po4 4.8 mgI100 ml BUN 6 mg/lOO ml 0.6 mg/lOO ml Creat i n i ne Total bilirubin 0.03 mg/l00 ml Alkaline phosphatase 287 U (60-260) SGOT 25 U (
