American Journal of Medical Genetics 35:546-551 (1990)
Johanson-Blizzard Syndrome: Clinical Spectrum and Further Delineation of the Syndrome Ruth Gershoni-Baruch, Aaron Lerner, Jacob Braun, Yossef Katzir, Theodore C. Iancu, and Avraham Benderly Departments of Genetics (A.B., R.G.B.), Neonatology (Y.K.),and Diagnostic Radiology (J.B.), Rambam Medical Center, Department of Pediatrics, Carmel Hospital (A.L., T.C.I.), and Faculty of Medicine, Technion-Israel Institute of Technology (A.B., A.L., T.C.I.), Haifa, Israel ~~~
We report on 2 patients with Johanson Blizzard syndrome and review the literature, in an attempt to further characterize the clinical spectrum of this disorder. KEY WORDS: pancreatic insufficiency, imperforate anus, hypothyroidism, sensory neural deafness, ectodermal dysplasias, autosomal recessive inheritance INTRODUCTION Johanson and Blizzard [1971] described 3 unrelated girls with midline scalp defects, aplasia of nasal alae, sparse hair, deafness, microcephaly, mental retardation, hypothyroidism, absent permanent teeth, malabsorption, and failure to thrive (JBS). Genitourinary, cardiac, and anorectal malformations may also be part of this autosomal recessive condition.To our knowledge, 26 cases have been reported to date. These include 2 girls reported as cases of trypsinogen deficiency disease [Morris and Fisher, 1967; Townes, 19691, a patient with 47,XXY karyotype [Grand et al., 19661, and 2 sibs with hypoplasia ofthe exocrine pancreas, one of whom had an imperforate anus [Lumb and Beautyman, 19521. We report on 2 children with JBS and review the literature in an attempt to further delineate the clinical spectrum of this disorder. CLINICAL REPORTS Patient 1 A.Z., (Fig. la,b), was born at term after an uncomplicated pregnancy, labor, and delivery. Parents were young, healthy, and consanguineous Arabs (double first cousins). Birthweight (BW) was 2,545 g, length 52 cm, and head circumference (OFC)34 cm. Apgar scores were Received for publication July 3,1989; revision received September 25, 1989. Address reprint requests to Ruth Gershoni-Baruch, M.D., Department of Genetics, Rambam Medical Center, Haifa 35254, Israel.
0 1990 Wiley-Liss, Inc.
9 a t one minute and 10 at 5 minutes. The baby appeared well and alert. On examination she had a small beaked nose with absent nasal alae, small upslanting palpebral fissures with cutaneous lacrimal duct fistulae, a 2 x 3 cm scalp defect over the anterior fontanelle, sparse hair with frontal upsweep, mid-facial hypoplasia, a long upper lip with thin vermillion border and down-turned corners to the mouth, a small chin with a horizontal groove, and a portwine haemangioma in the left inguinal area. She had an imperforate anus and a rectovaginal fistula (Fig. 2). Her hemoglobin was 17 gidl. She had total serum protein of 6.7 gidl and albumin of 4.5 gidl and normal levels of calcium, phosphorus, creatinine, urea, glucose, and electrolytes. Neonatal levels of T4 and TSH were normal. She was started on cow’s milk formula and developed foul, bulky stools with a high fat content and absent trypsin activity. At age 2 days PregestamiP feeds were instituted. Hearing tests documented bilateral hearing loss. Ultrasonograms of kidneys were normal. A computed tomographic (CT) scan of the brain demonstrated mild symmetrical hypodensity of the cerebral white matter with normal ventricles. The petrous bones showed dilated vestibules and cochleas. The baby was alert and ate well but failed to gain weight. A colostomy was performed and the child was released home at age one month. A week later she was readmitted with cold injury and died. Hemoglobin was 8 gldl, total serum protein 5.4 gldl, and albumin 4.1 gldl. Thyroid function tests were normal.
Family History A.Z., brother ofpatient 1,died a year earlier at age 7% hours. The mother, who was then 22 years old, had had a previous miscarriage. Pregnancy, complicated by polyhydramnios, ended in the delivery at term of an asphyxiated male infant. BW was 2,440 g, length 52 cm, and OFC 34 cm. Aplasia of the nasal alae was noted. He had central cyanosis not relieved by mechanical ventilation. Chest film showed an enlarged left atrium. Echocardiography demonstrated a normal heart. He died of cardiorespiratory failure. Permission for autopsy was not granted.
Johanson-Blizzard Syndrome
547
Fig. 1. Patient 1. Facial manifestations and general appearance.
Patient 2 tration varied between 10 and 8 g/dl. The serum iron M.D. (Fig. 31, a 10-year-old girl, was the first child concentration was 34 ng/dl. The total serum protein born a t term to a young, healthy, and consanguineous level was 4.2 g/dl(2.9 g/dl albumin) and the serum choArab (first cousins) couple. Pregnancy, labor, and deliv- lesterol level was 140 mg/dl. The levels of prolactin, ery were normal. Birth weight was 2,420 g, length 48 growth hormone, cortisol, FSH, and LH and the thyroid cm, and OFC 34 cm. Apgar scores were 9 at one minute function tests were normal. and 10 at 5 minutes. At age 2 months she was hospiSweat test, immunoelectrophoresis of serum proteins, talized because of failure to gain weight. Her weight was barium enema, upper gastrointestinal roentgenograms, 2,850 g. Cutaneous scalp defects 1 x 1 cm over the and I.V.P. were normal. Results of liver needle biopsy, anterior and posterior fontanelles were noted. She had jejunal biopsy, bone marrow aspirate, electroencephalohypoplasia of the nasal alae, a small pointed chin, multi- gram, electrocardiogram, and thyroid gland scans were ple cafe-au-lait spots (Fig. 41, and hirsutism. The anus normal. Stools were foul and bulky and had a high fat was anteriorly placed (Fig. 5). The nipples were tiny content and no trypsin activity. Duodenal aspirates had with a very small areola and widely spaced. Genitalia negligible lipase activity and no chemotrypsin. were normal. Hearing tests documented bilateral senThe child was started on PregestamilB feeds and pansory neural deafness. creatic granules. Weight gain was slow. Psychometric Results of BUN, glucose, creatinine, calcium, phos- tests showed marked developmental delay. Physical phorus, transminase, bilirubin, electrolytes, and white findings (at 10 years) were as follows: weight 17.5 kg, count determination were normal. Hemoglobin concen- height 116 cm, and OFC 49 cm (below the 3rd centile).
Fig. 2. Patient 1.Anal atresia.
Fig. 3. Patient 2. Facial manifestations.
Gershoni-Baruch et al.
548
TABLE I. Summarv of JBS Cases* Authors ~
Lumb & Beautyman [I9521
Grand et al. f19661
Fisher 119671
Townes 119691 and Townea & White 119811
1
1
1
Morris &
~
Johanson & Blizzard 119711
Schussheim et al. 119761
Day & Israel [19781
Mardini et al. 119781
Daentl et al. 119791
1
1
Reichart et al. 119791
Sismanis et al. 119791
~
Trait
1
2
1
2
1
1
2
~
Sex Low birth weight Consanguinity Microcephaly Mental retardation Hypotonia Deafness Pancreatic insufficiency Failure to thrive or growth retardation Delayed bone age Scalp defect Small deciduous andior absent permanent teeth Hypoplasiaiaplasia alae nasi Cutaneolacrimal fistulae Abnormal hair pattern Hypothyroidism Imperforate anus Recto-ureteral or rectovaginal fistula GU anomalies Congenital heart defect
1
2
1
~
F
+ -
+
F
XXY
-
-
+
+
+ + +
+ + + + + -
-
+ +
+ + -
F
-
+ + + + + -
F
F
-
-
+ + + + P +
+ + + + + + + A,P +
+ + +
+
+
+ +
+ +
-
-
-
-
-
+
F
+
F
-
_
-
+ + + + + + + P +
+ + + + + + + A +
+ + + + + + + + + + - + + + + + + + -
-
_
M
M
M
-
-
-
+
+
+ + + + + +
+ +
A,P
+ + + -
Family History A second child born subsequently had cystic fibrosis and meconium ileus. At operation, an atretic proximal ileum and a malrotated microcolon were found. A third child also had cystic fibrosis and a 4th child was normal. No other relative had manifestations of the JBS. DISCUSSION Children with JBS have a distinct appearance and can be easily recognized. The small, beaklike nose with aplastic or hypoplastic nasal alae is peculiar and unique-so much so, that authors have failed to describe other common facial characteristics shared by patients with JBS, namely, malar hypoplasia, a mouth with down-turned corners, a long and narrow upper lip, an
+ + +
M
F
F
M
-
-
-
-
+
-
+ + + +
-
+
+ +
+ + + + +
P
A,P
A,P
+
+
+ +
+
-
+ +
+
-
A s -
-
-
+ -
-
+
+ -
+ +
+ + A +
+ + + A
A,P
+
+
+
+
+
-
-
+
+ +
+ +
-
+ + - + = absent; + = present; A = scalp defect over the anterior
-
* Key: Low birth weight =
Johanson-Blizzard Syndrome: Clinical Spectrum and Further Delineation of the Syndrome Ruth Gershoni-Baruch, Aaron Lerner, Jacob Braun, Yossef Katzir, Theodore C. Iancu, and Avraham Benderly Departments of Genetics (A.B., R.G.B.), Neonatology (Y.K.),and Diagnostic Radiology (J.B.), Rambam Medical Center, Department of Pediatrics, Carmel Hospital (A.L., T.C.I.), and Faculty of Medicine, Technion-Israel Institute of Technology (A.B., A.L., T.C.I.), Haifa, Israel ~~~
We report on 2 patients with Johanson Blizzard syndrome and review the literature, in an attempt to further characterize the clinical spectrum of this disorder. KEY WORDS: pancreatic insufficiency, imperforate anus, hypothyroidism, sensory neural deafness, ectodermal dysplasias, autosomal recessive inheritance INTRODUCTION Johanson and Blizzard [1971] described 3 unrelated girls with midline scalp defects, aplasia of nasal alae, sparse hair, deafness, microcephaly, mental retardation, hypothyroidism, absent permanent teeth, malabsorption, and failure to thrive (JBS). Genitourinary, cardiac, and anorectal malformations may also be part of this autosomal recessive condition.To our knowledge, 26 cases have been reported to date. These include 2 girls reported as cases of trypsinogen deficiency disease [Morris and Fisher, 1967; Townes, 19691, a patient with 47,XXY karyotype [Grand et al., 19661, and 2 sibs with hypoplasia ofthe exocrine pancreas, one of whom had an imperforate anus [Lumb and Beautyman, 19521. We report on 2 children with JBS and review the literature in an attempt to further delineate the clinical spectrum of this disorder. CLINICAL REPORTS Patient 1 A.Z., (Fig. la,b), was born at term after an uncomplicated pregnancy, labor, and delivery. Parents were young, healthy, and consanguineous Arabs (double first cousins). Birthweight (BW) was 2,545 g, length 52 cm, and head circumference (OFC)34 cm. Apgar scores were Received for publication July 3,1989; revision received September 25, 1989. Address reprint requests to Ruth Gershoni-Baruch, M.D., Department of Genetics, Rambam Medical Center, Haifa 35254, Israel.
0 1990 Wiley-Liss, Inc.
9 a t one minute and 10 at 5 minutes. The baby appeared well and alert. On examination she had a small beaked nose with absent nasal alae, small upslanting palpebral fissures with cutaneous lacrimal duct fistulae, a 2 x 3 cm scalp defect over the anterior fontanelle, sparse hair with frontal upsweep, mid-facial hypoplasia, a long upper lip with thin vermillion border and down-turned corners to the mouth, a small chin with a horizontal groove, and a portwine haemangioma in the left inguinal area. She had an imperforate anus and a rectovaginal fistula (Fig. 2). Her hemoglobin was 17 gidl. She had total serum protein of 6.7 gidl and albumin of 4.5 gidl and normal levels of calcium, phosphorus, creatinine, urea, glucose, and electrolytes. Neonatal levels of T4 and TSH were normal. She was started on cow’s milk formula and developed foul, bulky stools with a high fat content and absent trypsin activity. At age 2 days PregestamiP feeds were instituted. Hearing tests documented bilateral hearing loss. Ultrasonograms of kidneys were normal. A computed tomographic (CT) scan of the brain demonstrated mild symmetrical hypodensity of the cerebral white matter with normal ventricles. The petrous bones showed dilated vestibules and cochleas. The baby was alert and ate well but failed to gain weight. A colostomy was performed and the child was released home at age one month. A week later she was readmitted with cold injury and died. Hemoglobin was 8 gldl, total serum protein 5.4 gldl, and albumin 4.1 gldl. Thyroid function tests were normal.
Family History A.Z., brother ofpatient 1,died a year earlier at age 7% hours. The mother, who was then 22 years old, had had a previous miscarriage. Pregnancy, complicated by polyhydramnios, ended in the delivery at term of an asphyxiated male infant. BW was 2,440 g, length 52 cm, and OFC 34 cm. Aplasia of the nasal alae was noted. He had central cyanosis not relieved by mechanical ventilation. Chest film showed an enlarged left atrium. Echocardiography demonstrated a normal heart. He died of cardiorespiratory failure. Permission for autopsy was not granted.
Johanson-Blizzard Syndrome
547
Fig. 1. Patient 1. Facial manifestations and general appearance.
Patient 2 tration varied between 10 and 8 g/dl. The serum iron M.D. (Fig. 31, a 10-year-old girl, was the first child concentration was 34 ng/dl. The total serum protein born a t term to a young, healthy, and consanguineous level was 4.2 g/dl(2.9 g/dl albumin) and the serum choArab (first cousins) couple. Pregnancy, labor, and deliv- lesterol level was 140 mg/dl. The levels of prolactin, ery were normal. Birth weight was 2,420 g, length 48 growth hormone, cortisol, FSH, and LH and the thyroid cm, and OFC 34 cm. Apgar scores were 9 at one minute function tests were normal. and 10 at 5 minutes. At age 2 months she was hospiSweat test, immunoelectrophoresis of serum proteins, talized because of failure to gain weight. Her weight was barium enema, upper gastrointestinal roentgenograms, 2,850 g. Cutaneous scalp defects 1 x 1 cm over the and I.V.P. were normal. Results of liver needle biopsy, anterior and posterior fontanelles were noted. She had jejunal biopsy, bone marrow aspirate, electroencephalohypoplasia of the nasal alae, a small pointed chin, multi- gram, electrocardiogram, and thyroid gland scans were ple cafe-au-lait spots (Fig. 41, and hirsutism. The anus normal. Stools were foul and bulky and had a high fat was anteriorly placed (Fig. 5). The nipples were tiny content and no trypsin activity. Duodenal aspirates had with a very small areola and widely spaced. Genitalia negligible lipase activity and no chemotrypsin. were normal. Hearing tests documented bilateral senThe child was started on PregestamilB feeds and pansory neural deafness. creatic granules. Weight gain was slow. Psychometric Results of BUN, glucose, creatinine, calcium, phos- tests showed marked developmental delay. Physical phorus, transminase, bilirubin, electrolytes, and white findings (at 10 years) were as follows: weight 17.5 kg, count determination were normal. Hemoglobin concen- height 116 cm, and OFC 49 cm (below the 3rd centile).
Fig. 2. Patient 1.Anal atresia.
Fig. 3. Patient 2. Facial manifestations.
Gershoni-Baruch et al.
548
TABLE I. Summarv of JBS Cases* Authors ~
Lumb & Beautyman [I9521
Grand et al. f19661
Fisher 119671
Townes 119691 and Townea & White 119811
1
1
1
Morris &
~
Johanson & Blizzard 119711
Schussheim et al. 119761
Day & Israel [19781
Mardini et al. 119781
Daentl et al. 119791
1
1
Reichart et al. 119791
Sismanis et al. 119791
~
Trait
1
2
1
2
1
1
2
~
Sex Low birth weight Consanguinity Microcephaly Mental retardation Hypotonia Deafness Pancreatic insufficiency Failure to thrive or growth retardation Delayed bone age Scalp defect Small deciduous andior absent permanent teeth Hypoplasiaiaplasia alae nasi Cutaneolacrimal fistulae Abnormal hair pattern Hypothyroidism Imperforate anus Recto-ureteral or rectovaginal fistula GU anomalies Congenital heart defect
1
2
1
~
F
+ -
+
F
XXY
-
-
+
+
+ + +
+ + + + + -
-
+ +
+ + -
F
-
+ + + + + -
F
F
-
-
+ + + + P +
+ + + + + + + A,P +
+ + +
+
+
+ +
+ +
-
-
-
-
-
+
F
+
F
-
_
-
+ + + + + + + P +
+ + + + + + + A +
+ + + + + + + + + + - + + + + + + + -
-
_
M
M
M
-
-
-
+
+
+ + + + + +
+ +
A,P
+ + + -
Family History A second child born subsequently had cystic fibrosis and meconium ileus. At operation, an atretic proximal ileum and a malrotated microcolon were found. A third child also had cystic fibrosis and a 4th child was normal. No other relative had manifestations of the JBS. DISCUSSION Children with JBS have a distinct appearance and can be easily recognized. The small, beaklike nose with aplastic or hypoplastic nasal alae is peculiar and unique-so much so, that authors have failed to describe other common facial characteristics shared by patients with JBS, namely, malar hypoplasia, a mouth with down-turned corners, a long and narrow upper lip, an
+ + +
M
F
F
M
-
-
-
-
+
-
+ + + +
-
+
+ +
+ + + + +
P
A,P
A,P
+
+
+ +
+
-
+ +
+
-
A s -
-
-
+ -
-
+
+ -
+ +
+ + A +
+ + + A
A,P
+
+
+
+
+
-
-
+
+ +
+ +
-
+ + - + = absent; + = present; A = scalp defect over the anterior
-
* Key: Low birth weight =
