American Journal of M e d i c a l Genetics U374-377 (1992)
Ectodermal Dysplasia, Lipoatrophy, Diabetes Mellitus, and Amastia: A Second Case of the AREDYLD Syndrome E.J. Breslau-Siderius, J. Toonstra, J.A. Baart, H.P.F. Koppeschaar, J.A. Maassen, and F. A. Beemer Clinical Genetics Center Utrecht (E.J.B.-S.,F.A.B.),Department of Endocrinology, University Hospital (HP.FX.), and University Children’s Hospital the Netherlands ( F A.B.), Utrecht; Hospital Maarschalksbos, Baarn (J.T.); Department of Oral and Maxillo-facial Surgery, Academic Hospital Free University, Amsterdam (J.A.B.); Medical Biochemistry, Sylvius Laboratories, Leiden (J.A.M.) A 19-year-old female with ectodermal dysplasia, lipoatrophy, diabetes mellitus, and amastia is described. This complex of symptoms is very similar to that of a case published by Pinheiro et al [19831 under the acronym of AREDYLD syndrome. o 1992 Wiley-Liss, Inc. KEY WORDS: ectodermal dysplasia, lipoatrophy, diabetes mellitus, amastia, AREDYLD syndrome INTRODUCTION In 1983 Pinheiro et al. reported a presumably new ectodermal dysplasialacrorenal syndrome with lipoatrophic diabetes and other manifestations, for which they suggested the name of AREDYLD (AcroRenal-Ectodermal-DYsplasia-Lipoatrophic-Diabetes) syndrome. The proband, a 22-year-old woman, was moderately developmentally retarded. She had anodontia, hypotrichosis, typical facial features, a generalized deficiency of subcutaneous fat, hepatosplenomegaly, amastia, hypoplasia of labia minora, hypertrophy of the clitoris, and a small vaginal introitus. At age 15 years she appeared to have a nonketotic insulin-resistant diabetes. Radiographic examination of the skeleton showed shortening of the fourth and fifth right metacarpal bones, bowing of the tibia, and scoliosis. There was a dysfunction of the right ureter and hypoplasia of the middle right major renal calyx. The parents were consanguineous, and an autosomal recessive mode of inheritance was proposed. The patient we describe has an almost identical clini-
Received for publication December 12, 1990;revision received January 20, 1992. Address reprint request to Dr. F. A. Beemer, Clinical Genetics Center Urecht, P.O. Box 18009 3501 CA Utrecht, The Netherlands.
0 1992 Wiley-Liss, Inc.
cal picture, including ectodermal dysplasia, lipoatrophy, diabetes, and amastia, and to the best of our howledge represents the second published case of the AREDYLD syndrome. CLINICAL REPORT The proposita is a 19-year-oldfemale, the second of 3 children. Her parents and sibs are healthy. For many years she had medical treatment because of dry skin and slow growing thin hair. The development of her teeth was not complete and required surgical treatment. Her fingernails were normal in early infancy but subsequently developed an irregular surface with transverse as well as longitudinal grooves. Sweating was minimal. Only in hot weather was some sweat noted on the forehead. Breast budding, normal pubertal breast development, and pubic hair growth did not occur. The age of menarche was 13 years, but subsequently she had amenorrhea for 6 months. She then had oligomenorrhea, once in every 6-8 weeks a menses with a duration of 5 days. Her psychomotor development was reported normal. On physical examination at age 19, her height was 1.77 m and weight 55 kg. She was slender and had sparse, slow-growing scalp hair. On the lateral sides of the eyebrows hair growth was diminished. There was sparse axillary and pubic hair. Her nails showed transverse as well as longitudinal grooves (Fig. 1).Her skin felt dry. There was a shortage of subcutaneous fat. Breasts were absent (Fig. 2). The labial development was normal; there was no clitoromegaly. On intraoral examination she appeared to have hypodontia (Fig. 3). At age 19 years, 2 deciduous dentition and 14 permanent teeth were present. Two mesiodentes were impacted and the 22 was not vital because of dens invaginatus. Crown sizes of the 15, 12, and 22 were reduced. The combination of hypodontia and reduced crown sizes resulted in frontal diastema, deep bite, and shortness of face. From age 19 years she has had diabetes mellitus. She is treated with an intermediate active insulin regimen of 56 U insulin daily.
AREDYLD Syndrome
375
Fig. 1. Nails of the proposita, showing transverse as well as longitudinal grooves.
Fig. 3. X-ray of upper and lower jaw. Note the mesiodentes and nonvital 22 on the tracing.
Fig. 2. The chest of the proposita, showing amastia.
Laboratory Investigations Laboratory determinations disclosed normal values for serum creatinine (76 pmol/L), sodium (139 mmol/L1, potassium (4.5 mmol/L), alkaline phosphatase (81 IU/L), gammaglutamyltransferase (15 IU/L), cholesterol (5.0 mmol/L), HDL (1.4 mmolh), LDL (2.6 mmoV L), and triglycerides (0.6 mmol/L). Endocrine investigations in serum: total Thyroxine (T4) 92 nmol/l (n = 64-1541, Thyroid Stimulating Hor-
mone (TSH) 1.3 IU/ml (n = 0.1-5.0), antimicrosomal antibodies: negative, luteinizing hormone (LH) 66 IU/L (adult female: n = 5-22 in follicular or luteal phase, 30-250 in midcycle peak), follicle stimulating hormone (FSH) 16 IU/L (adult female: n = 5-20 in follicular or luteal phase, 30-59 in midcycle peak), prolactine 0.47 Uh,testosteron 3,6 NMOLL (n = 0-2.0). The binding of (l25)l-insulin to cultured skin fibroblasts [Maassen et al., 19881 was elevated (0.20 fmol/106 cells, controls 0.07-0.15 fmol). This insulin binding was done at an insulin concentration of 30 pmol/L giving high affinity binding sites for insulin. The insulin stimulated uptake of 2-deoxyglucose by fibroblasts showed a high basal uptake, which was hardly stimulated by 50 nM insulin or 50 nM Insulinlike Growth Factor 1 (IGF-1). Basal autophosphorylation of the insulin receptor was slightly elevated, whereas 50 nM insulin stimulated receptor autophosphorylation to a normal level. Her IGF-1 level was 138 ng/ml, which is below 2 SD according to her age. The IGF-2 level was normal. An histologic examination of a skin biopsy of the axilla showed the presence of eccrine as well as apocrine sweat glands. Chromosome study (GTG banding) showed a normal female karyotype 46, XX. Hand X-ray showed a short ( - 2 SD)middle and proximal phalanx of the fifth finger. She had normal size kidneys on ultrasound examination. A parenchyal bridge in the left kidney indicated a
376
Breslau-Siderius et al.
double pyelum system. Ultrasound of the pelvis was normal.
DISCUSSION Ectodermal dysplasia associated with other malformations gives a broad spectrum of syndromes [FreireMaia and Pinheiro, 19841 divided in subgroups according to the presence or absence of the following signs: trichodysplasia, dental abnormalities, onychodysplasia, and a dyshidrosis. The manifestations of the patient described by Pinheiro et al. [1983], and the one we present, are summarized in Table I. Pinheiro et al. [1983] coined the acronym AREDYLD syndrome for this complex of symptoms. Because their proband had only hair and dental anomalies, the syndrome was considered to be a tricho-odonto-ectodermal dysplasia [F’reire-Maia and Pinheiro, 19841.Our patient displayed hair, dental as well as nail dysplasia, and reduced sweating. Therefore her ectodermal dysplasia can be classified in the tricho-odonto-onychialsubgroup of Freire-Maia and Pinheiro [1984]. The dental anomalies anomalies seen originate early in fetal life (6th-14th week), during the development of teeth buds. The patient described by Pinheiro et al. [1983] showed malformations of the hand skeleton and the urinary tract. To a minor degree these were also found in the present case. In contrast, short stature and scoliosis were absent in our patient. As our patient has menses, though oligomenorrhea, it is conceivable that to some degree ovarian activity is present. A high LH value in combination with a high normal FSH value is a normal finding in the preovulatory period in normally ovulating woman. As in this patient we could not obtain pertinent evidence of ovulation by means of basal body temperature measurements and/or serum progesterone, other explanations should be considered. First, early ovarian failure due to depletion of primordial follicles or maybe autoantibodies. Second, polycystic ovarian disease (PCO) cannot be ruled out. The slightly elevated testosterone value may be in agreement with PCO; however, a LH elevation as found in this patient makes PCO less likely.
TABLE I. Summary of Clinical Manifestations of the Patient described by Pinheiro et al. U9831 and Present Case Symptoms Hypotrichosis Alhypodontia Nail dysplasia Hypohydrosis Diabetes mellitus Ahypomastia Reduced subcutaneous fat Hepatosplenomegaly Abnormal external genitalia Renal abnormality General shortness Scoliosis Hand shortness (4-5 ray)
Patients Pinheiro Resent
+
+-
-
+ + + + + + + +
+
+
+ + + + + +-
+-
+
Pinheiro et al.’s [19831 patient had an insulin-resistant diabetes, a generalized deficiency of subcutaneous fat, and hepatosplenomegaly. Insulin receptor studies in erythrocytes gave normal results. Studies of the fibroblasts were not done. An abdominal subcutaneous fat biopsy demonstrated virtual absence of fat tissue, with only a few adypocytes visualized [B. Liberman, personal communication, 19901. Lipoatrophic diabetes is characterized by a complete or partial lack of subcutaneous fat, abnormalities of carbohydrate and lipid metabolism, and resistance to insulin. The spectrum of lipoatrophic diabetes ranges from severe generalized forms t o milder partial forms. In several cases of lipoatrophic diabetes, a defect in insulin binding to erytrocytes or fibroblasts has been demonstrated [Wachslicht-Rodbardet al., 1981; Magre et al., 19881. Our patient has a partial lipoatrophy. Her diabetes mellitus is responding well to 56 units insulin daily. We do not know whether this is due to an insufficient insulin production or to insulin resistance. She has normal serum lipids. Because of the combined occurrence of diabetes and lipoatrophy, insulin receptor studies were undertaken. To differentiate an insulin-receptor defect from a postreceptor defect in the signaling pathway inside the cell, the capacity of fibroblasts to take up 2-deoxyglucoseafter stimulation by insulin and insulinlike growth factor 1 (IGF-l), respectively, was determined. The receptors for insulin and IGF-1 are distinct gene products, which activate the same signaling pathway with respect to glucose transport [Maassen and van der Zon, 19901. A defect in the insulin receptor affects only insulin but not IGF-1 action, whereas a postreceptor defect affects the action of both hormones. In vitro studies of fibroblasts of our patient make an insulin resistance due to a defect in the postreceptor signal transduction likely, since neither insulin nor IGF-1 could fully stimulate the 2-deoxyglucose uptake. The biochemical data on our patient indicate a postreceptor defect, which affects both insulin and IGF-1 action. The clinical abnormalities in AREDYLD patients agree with a situation of both decreased insulin and IGF-1 action. A decreased action of insulin, resulting from a postreceptor defect, can lead to impaired glucose homeostasis and to a loss of the antilipolytic activity of insulin. The knowledge of in vivo IGF-1 effects is insufficient to ascribe directly some ofthe AREDYLD abnormalities to impaired IGF-1 action. However, it can be argued that the lack of hair growth and the hypotrophy of breast and clitoris results from defective IGF-1 action. In patients with leprechauism, the insulin receptor has lost its function due to mutations in the receptor [Kadowaki et al., 19901. IGF-1 receptor functioning seems normal [Maassen et al., 19901.Plasma insulin concentrations in these patients are often extremely elevated, resulting in cross-binding of insulin to IGF-1 receptors. It is expected that this situation results in an overactivation of the IGF-1 receptor signalling pathway. Characteristic dysmorphic features of leprechaun patients (who die before puberty) are hirsutism, hypertrophy of the external genitals [Rosenberg et al., 19801. These abnormalities
AREDYLD Syndrome are suggested to result from the enhanced stimulation of IGF-1 receptors. A decreased signaling via IGF-1 receptors is expected to yield the opposite effects as observed in AREDYLD patients. As far as we know this is the second case described of an association of ectodermal dysplasia, diabetes mellitus, amastia, and lipoatrophy. It confirms the assumption of Pinheiro et al. [19831that ectodermal dysplasia, lipoatrophy, and diabetes could have the same cause, which remains unknown at the moment. Because of the consanguinity of the parents of the patient described by Pinheiro et al. [1983] and the fact that she had a sister with similar features, these authors suggested that the syndrome is due to an autosomal recessive gene. We cannot contribute to this assumption. No parental consanguinity could be demonstrated (6 generations back) and the proposita is the only affected in the family. The parents do not have (partial) symptoms. Neither patient has reproduced. A new dominant mutation or uniparental disomy cannot be excluded.
ACKNOWLEDGMENTS We thank Drs. J.M. Deurloo and E. Janssen for referring the patient. The IGF studies were done by Dr. J.M. Wit and Mr. H.F. Oltmans in the Wilhelmina Children’s
377
Hospital, Utrecht. We are grateful for the information from Dr. B. Liberman, Medical University, Sao Paulo, Brasil.
REFERENCES Freire-Maia N, Pinheiro M (1984):Ectodermal dysplasias. New York: Alan R Liss, pp 25-27, 149-151. Kadowaki T, Kadowaki H, Rechler MM, Serraro Rios M, Roth J , Gordon P, Taylor SI (1990):Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance. J Clin Invest 86254-264. Maassen JA, Klinkhamer MP, Odink RJH, Sips H, Zon van der GCM, Wieringa Tj, Krans HMJ, Moller W (1988):Improper expression of insulin receptors on fibroblasts from a leprechaun patient. Eur J Biochem 172325-729 Maassen J A, vander Zon GCM (1990):Coupling of insulin responsive glucose transport to receptors for insulin like growth factor 1 in primary human fibroblasts. Eur J Biochem 190:553-557. Magre J, Reynet Ch, Capeau J, Blivet M-J, Picard J (1988):In vitro studies of insulin resistance in patients with lipoatrophic diabetes. Diabetes 37:421-428. F’inheim M, Freire-Maia N, Chautard-Freire-Maia E A, Araujo L M B, Liberman B (1983):AREDYLD: A syndrome combining an acrorenal field defect, ectodermal dysplasia, lipoatrophic diabetes and other manifestations. Am J Med Genet 16:29-33. Rosenberg AM, Hawordth JC, de Groot GW, CL Treverer, MM Rechler (1980):A case of leprechaurism with severe hyperinsulinemia. Am J Dis Child 134,170-175. Wachslicht-Rodbard H, Muggeo M, Kahn R, Saviolakis G A, Harrison L C, Flier J S (1981):Heterogeneity of the insulin-receptor interaction in lipoatrophic diabetes. J Clin Endoc and Metab 52:416-425.
Ectodermal Dysplasia, Lipoatrophy, Diabetes Mellitus, and Amastia: A Second Case of the AREDYLD Syndrome E.J. Breslau-Siderius, J. Toonstra, J.A. Baart, H.P.F. Koppeschaar, J.A. Maassen, and F. A. Beemer Clinical Genetics Center Utrecht (E.J.B.-S.,F.A.B.),Department of Endocrinology, University Hospital (HP.FX.), and University Children’s Hospital the Netherlands ( F A.B.), Utrecht; Hospital Maarschalksbos, Baarn (J.T.); Department of Oral and Maxillo-facial Surgery, Academic Hospital Free University, Amsterdam (J.A.B.); Medical Biochemistry, Sylvius Laboratories, Leiden (J.A.M.) A 19-year-old female with ectodermal dysplasia, lipoatrophy, diabetes mellitus, and amastia is described. This complex of symptoms is very similar to that of a case published by Pinheiro et al [19831 under the acronym of AREDYLD syndrome. o 1992 Wiley-Liss, Inc. KEY WORDS: ectodermal dysplasia, lipoatrophy, diabetes mellitus, amastia, AREDYLD syndrome INTRODUCTION In 1983 Pinheiro et al. reported a presumably new ectodermal dysplasialacrorenal syndrome with lipoatrophic diabetes and other manifestations, for which they suggested the name of AREDYLD (AcroRenal-Ectodermal-DYsplasia-Lipoatrophic-Diabetes) syndrome. The proband, a 22-year-old woman, was moderately developmentally retarded. She had anodontia, hypotrichosis, typical facial features, a generalized deficiency of subcutaneous fat, hepatosplenomegaly, amastia, hypoplasia of labia minora, hypertrophy of the clitoris, and a small vaginal introitus. At age 15 years she appeared to have a nonketotic insulin-resistant diabetes. Radiographic examination of the skeleton showed shortening of the fourth and fifth right metacarpal bones, bowing of the tibia, and scoliosis. There was a dysfunction of the right ureter and hypoplasia of the middle right major renal calyx. The parents were consanguineous, and an autosomal recessive mode of inheritance was proposed. The patient we describe has an almost identical clini-
Received for publication December 12, 1990;revision received January 20, 1992. Address reprint request to Dr. F. A. Beemer, Clinical Genetics Center Urecht, P.O. Box 18009 3501 CA Utrecht, The Netherlands.
0 1992 Wiley-Liss, Inc.
cal picture, including ectodermal dysplasia, lipoatrophy, diabetes, and amastia, and to the best of our howledge represents the second published case of the AREDYLD syndrome. CLINICAL REPORT The proposita is a 19-year-oldfemale, the second of 3 children. Her parents and sibs are healthy. For many years she had medical treatment because of dry skin and slow growing thin hair. The development of her teeth was not complete and required surgical treatment. Her fingernails were normal in early infancy but subsequently developed an irregular surface with transverse as well as longitudinal grooves. Sweating was minimal. Only in hot weather was some sweat noted on the forehead. Breast budding, normal pubertal breast development, and pubic hair growth did not occur. The age of menarche was 13 years, but subsequently she had amenorrhea for 6 months. She then had oligomenorrhea, once in every 6-8 weeks a menses with a duration of 5 days. Her psychomotor development was reported normal. On physical examination at age 19, her height was 1.77 m and weight 55 kg. She was slender and had sparse, slow-growing scalp hair. On the lateral sides of the eyebrows hair growth was diminished. There was sparse axillary and pubic hair. Her nails showed transverse as well as longitudinal grooves (Fig. 1).Her skin felt dry. There was a shortage of subcutaneous fat. Breasts were absent (Fig. 2). The labial development was normal; there was no clitoromegaly. On intraoral examination she appeared to have hypodontia (Fig. 3). At age 19 years, 2 deciduous dentition and 14 permanent teeth were present. Two mesiodentes were impacted and the 22 was not vital because of dens invaginatus. Crown sizes of the 15, 12, and 22 were reduced. The combination of hypodontia and reduced crown sizes resulted in frontal diastema, deep bite, and shortness of face. From age 19 years she has had diabetes mellitus. She is treated with an intermediate active insulin regimen of 56 U insulin daily.
AREDYLD Syndrome
375
Fig. 1. Nails of the proposita, showing transverse as well as longitudinal grooves.
Fig. 3. X-ray of upper and lower jaw. Note the mesiodentes and nonvital 22 on the tracing.
Fig. 2. The chest of the proposita, showing amastia.
Laboratory Investigations Laboratory determinations disclosed normal values for serum creatinine (76 pmol/L), sodium (139 mmol/L1, potassium (4.5 mmol/L), alkaline phosphatase (81 IU/L), gammaglutamyltransferase (15 IU/L), cholesterol (5.0 mmol/L), HDL (1.4 mmolh), LDL (2.6 mmoV L), and triglycerides (0.6 mmol/L). Endocrine investigations in serum: total Thyroxine (T4) 92 nmol/l (n = 64-1541, Thyroid Stimulating Hor-
mone (TSH) 1.3 IU/ml (n = 0.1-5.0), antimicrosomal antibodies: negative, luteinizing hormone (LH) 66 IU/L (adult female: n = 5-22 in follicular or luteal phase, 30-250 in midcycle peak), follicle stimulating hormone (FSH) 16 IU/L (adult female: n = 5-20 in follicular or luteal phase, 30-59 in midcycle peak), prolactine 0.47 Uh,testosteron 3,6 NMOLL (n = 0-2.0). The binding of (l25)l-insulin to cultured skin fibroblasts [Maassen et al., 19881 was elevated (0.20 fmol/106 cells, controls 0.07-0.15 fmol). This insulin binding was done at an insulin concentration of 30 pmol/L giving high affinity binding sites for insulin. The insulin stimulated uptake of 2-deoxyglucose by fibroblasts showed a high basal uptake, which was hardly stimulated by 50 nM insulin or 50 nM Insulinlike Growth Factor 1 (IGF-1). Basal autophosphorylation of the insulin receptor was slightly elevated, whereas 50 nM insulin stimulated receptor autophosphorylation to a normal level. Her IGF-1 level was 138 ng/ml, which is below 2 SD according to her age. The IGF-2 level was normal. An histologic examination of a skin biopsy of the axilla showed the presence of eccrine as well as apocrine sweat glands. Chromosome study (GTG banding) showed a normal female karyotype 46, XX. Hand X-ray showed a short ( - 2 SD)middle and proximal phalanx of the fifth finger. She had normal size kidneys on ultrasound examination. A parenchyal bridge in the left kidney indicated a
376
Breslau-Siderius et al.
double pyelum system. Ultrasound of the pelvis was normal.
DISCUSSION Ectodermal dysplasia associated with other malformations gives a broad spectrum of syndromes [FreireMaia and Pinheiro, 19841 divided in subgroups according to the presence or absence of the following signs: trichodysplasia, dental abnormalities, onychodysplasia, and a dyshidrosis. The manifestations of the patient described by Pinheiro et al. [1983], and the one we present, are summarized in Table I. Pinheiro et al. [1983] coined the acronym AREDYLD syndrome for this complex of symptoms. Because their proband had only hair and dental anomalies, the syndrome was considered to be a tricho-odonto-ectodermal dysplasia [F’reire-Maia and Pinheiro, 19841.Our patient displayed hair, dental as well as nail dysplasia, and reduced sweating. Therefore her ectodermal dysplasia can be classified in the tricho-odonto-onychialsubgroup of Freire-Maia and Pinheiro [1984]. The dental anomalies anomalies seen originate early in fetal life (6th-14th week), during the development of teeth buds. The patient described by Pinheiro et al. [1983] showed malformations of the hand skeleton and the urinary tract. To a minor degree these were also found in the present case. In contrast, short stature and scoliosis were absent in our patient. As our patient has menses, though oligomenorrhea, it is conceivable that to some degree ovarian activity is present. A high LH value in combination with a high normal FSH value is a normal finding in the preovulatory period in normally ovulating woman. As in this patient we could not obtain pertinent evidence of ovulation by means of basal body temperature measurements and/or serum progesterone, other explanations should be considered. First, early ovarian failure due to depletion of primordial follicles or maybe autoantibodies. Second, polycystic ovarian disease (PCO) cannot be ruled out. The slightly elevated testosterone value may be in agreement with PCO; however, a LH elevation as found in this patient makes PCO less likely.
TABLE I. Summary of Clinical Manifestations of the Patient described by Pinheiro et al. U9831 and Present Case Symptoms Hypotrichosis Alhypodontia Nail dysplasia Hypohydrosis Diabetes mellitus Ahypomastia Reduced subcutaneous fat Hepatosplenomegaly Abnormal external genitalia Renal abnormality General shortness Scoliosis Hand shortness (4-5 ray)
Patients Pinheiro Resent
+
+-
-
+ + + + + + + +
+
+
+ + + + + +-
+-
+
Pinheiro et al.’s [19831 patient had an insulin-resistant diabetes, a generalized deficiency of subcutaneous fat, and hepatosplenomegaly. Insulin receptor studies in erythrocytes gave normal results. Studies of the fibroblasts were not done. An abdominal subcutaneous fat biopsy demonstrated virtual absence of fat tissue, with only a few adypocytes visualized [B. Liberman, personal communication, 19901. Lipoatrophic diabetes is characterized by a complete or partial lack of subcutaneous fat, abnormalities of carbohydrate and lipid metabolism, and resistance to insulin. The spectrum of lipoatrophic diabetes ranges from severe generalized forms t o milder partial forms. In several cases of lipoatrophic diabetes, a defect in insulin binding to erytrocytes or fibroblasts has been demonstrated [Wachslicht-Rodbardet al., 1981; Magre et al., 19881. Our patient has a partial lipoatrophy. Her diabetes mellitus is responding well to 56 units insulin daily. We do not know whether this is due to an insufficient insulin production or to insulin resistance. She has normal serum lipids. Because of the combined occurrence of diabetes and lipoatrophy, insulin receptor studies were undertaken. To differentiate an insulin-receptor defect from a postreceptor defect in the signaling pathway inside the cell, the capacity of fibroblasts to take up 2-deoxyglucoseafter stimulation by insulin and insulinlike growth factor 1 (IGF-l), respectively, was determined. The receptors for insulin and IGF-1 are distinct gene products, which activate the same signaling pathway with respect to glucose transport [Maassen and van der Zon, 19901. A defect in the insulin receptor affects only insulin but not IGF-1 action, whereas a postreceptor defect affects the action of both hormones. In vitro studies of fibroblasts of our patient make an insulin resistance due to a defect in the postreceptor signal transduction likely, since neither insulin nor IGF-1 could fully stimulate the 2-deoxyglucose uptake. The biochemical data on our patient indicate a postreceptor defect, which affects both insulin and IGF-1 action. The clinical abnormalities in AREDYLD patients agree with a situation of both decreased insulin and IGF-1 action. A decreased action of insulin, resulting from a postreceptor defect, can lead to impaired glucose homeostasis and to a loss of the antilipolytic activity of insulin. The knowledge of in vivo IGF-1 effects is insufficient to ascribe directly some ofthe AREDYLD abnormalities to impaired IGF-1 action. However, it can be argued that the lack of hair growth and the hypotrophy of breast and clitoris results from defective IGF-1 action. In patients with leprechauism, the insulin receptor has lost its function due to mutations in the receptor [Kadowaki et al., 19901. IGF-1 receptor functioning seems normal [Maassen et al., 19901.Plasma insulin concentrations in these patients are often extremely elevated, resulting in cross-binding of insulin to IGF-1 receptors. It is expected that this situation results in an overactivation of the IGF-1 receptor signalling pathway. Characteristic dysmorphic features of leprechaun patients (who die before puberty) are hirsutism, hypertrophy of the external genitals [Rosenberg et al., 19801. These abnormalities
AREDYLD Syndrome are suggested to result from the enhanced stimulation of IGF-1 receptors. A decreased signaling via IGF-1 receptors is expected to yield the opposite effects as observed in AREDYLD patients. As far as we know this is the second case described of an association of ectodermal dysplasia, diabetes mellitus, amastia, and lipoatrophy. It confirms the assumption of Pinheiro et al. [19831that ectodermal dysplasia, lipoatrophy, and diabetes could have the same cause, which remains unknown at the moment. Because of the consanguinity of the parents of the patient described by Pinheiro et al. [1983] and the fact that she had a sister with similar features, these authors suggested that the syndrome is due to an autosomal recessive gene. We cannot contribute to this assumption. No parental consanguinity could be demonstrated (6 generations back) and the proposita is the only affected in the family. The parents do not have (partial) symptoms. Neither patient has reproduced. A new dominant mutation or uniparental disomy cannot be excluded.
ACKNOWLEDGMENTS We thank Drs. J.M. Deurloo and E. Janssen for referring the patient. The IGF studies were done by Dr. J.M. Wit and Mr. H.F. Oltmans in the Wilhelmina Children’s
377
Hospital, Utrecht. We are grateful for the information from Dr. B. Liberman, Medical University, Sao Paulo, Brasil.
REFERENCES Freire-Maia N, Pinheiro M (1984):Ectodermal dysplasias. New York: Alan R Liss, pp 25-27, 149-151. Kadowaki T, Kadowaki H, Rechler MM, Serraro Rios M, Roth J , Gordon P, Taylor SI (1990):Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance. J Clin Invest 86254-264. Maassen JA, Klinkhamer MP, Odink RJH, Sips H, Zon van der GCM, Wieringa Tj, Krans HMJ, Moller W (1988):Improper expression of insulin receptors on fibroblasts from a leprechaun patient. Eur J Biochem 172325-729 Maassen J A, vander Zon GCM (1990):Coupling of insulin responsive glucose transport to receptors for insulin like growth factor 1 in primary human fibroblasts. Eur J Biochem 190:553-557. Magre J, Reynet Ch, Capeau J, Blivet M-J, Picard J (1988):In vitro studies of insulin resistance in patients with lipoatrophic diabetes. Diabetes 37:421-428. F’inheim M, Freire-Maia N, Chautard-Freire-Maia E A, Araujo L M B, Liberman B (1983):AREDYLD: A syndrome combining an acrorenal field defect, ectodermal dysplasia, lipoatrophic diabetes and other manifestations. Am J Med Genet 16:29-33. Rosenberg AM, Hawordth JC, de Groot GW, CL Treverer, MM Rechler (1980):A case of leprechaurism with severe hyperinsulinemia. Am J Dis Child 134,170-175. Wachslicht-Rodbard H, Muggeo M, Kahn R, Saviolakis G A, Harrison L C, Flier J S (1981):Heterogeneity of the insulin-receptor interaction in lipoatrophic diabetes. J Clin Endoc and Metab 52:416-425.
