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Minimal focal dermal hypoplasia in a man: A case of father-to-daughter transmission
JOURNAL of the
AmeRICaN ACaDemy OF
DerMaTOLOGY VOLUME 25
NUMBER 5
PART 2
NOVEMBER 1991
Minimal focal dermal hypoplasia in a man: A case of father-to-daughter transmission Antoine Mabe, MD,a Jerome Couturier, MD,b Claire Mathe, MD,a Frederic Lebras, MD,a Alain Bruet, MD,a and Jean-Pierre Fendler, MDa Poissy and Paris, France Focal dermal hypoplasia is a rare genetic disorder characterized by diffuse and specific cutaneous lesions. Multiple visceral abnormalities are frequently associated. A minimal form ofthe disease (only cutaneous and localized to one thigh) is reported in the father of a woman who had typical focal dermal hypoplasia. (J AM ACAD DERMATOL 1991;25:879-81.) Focal dermal hypoplasia (FDH), often referred to as Goltz syndrome, is a rare disorder characterized by specific cutaneous and osseous lesions. I, 2 Multiple visceral abnormalities are common. The condition is thought to be genetic; most cases involve women. We report the case of a woman with FDH whose father had mild cutaneous lesions, which we believe to be a minimal, localized form of the disease.
CASE REPORTS Case 1. Since birth this 23-year-old woman had had disseminated areas of atrophic and hyperpigmented skin on which scattered telangiectases and rare soft nodules were present. The skin lesions were principally distributed in a linear and serpiginous pattern on the arms and legs. The patient had digital and perianal papillomas. The nails were missing on the left hand. The patient was short and had scoliosis, prognathism, a claw-shaped left hand, and syndactyly of both feet. An anterior tibial transposition procedure had been performed in 1986. Her teeth were irregular. Results of an intelligence quotient test and ophthalmologic examination were normal. Biopsy specimens from the hypoplastic cutaneous lesions showed marked hypoplasia of the dermis with superficially located subcutaneous fat (Fig. 1). Radiologic examination showed hypoplasia ofthe left collarbone and aplasia ofleft
From the Department of Internal Medicine and Dermatology, Centre Hospitalier Intercommunal de Poissy,· and Structure et Mutagenese chromosomiques, Institut Curie, Paris. b Reprint requests: Antoine Mahe, Service de M6decine Interne, Centre Hospitalier Intercommunal de Poissy, 78303 Cedex, Poissy, France.
16/1/29970
Fig. 1. Case 1. Photomicrograph of biopsy specimen of skin lesion from arm shows atrophy of dermis with superficially located subcutaneous fat. (Hematoxylin-eosin stain; XIOO.) upper ribs. There were longitudinal striations in the metaphyseal regions of both lower limbs that were characteristic of osteopatha striata. The patient had a history of multiple lower and upper urinary tract infections. Intravenous pyelography and abdominal ultrasonography showed a solitary normal right kidney. Retrograde cystography ruled out reflux. Case 2. The father ofthe patient described in case 1was seen at 53 years of age. Since birth he had mild skin lesions on the left thigh only. There was a linear pattern of small plaques of erythematous, slightly hyperpigmented, and atrophicskin on the anterior and medial aspects ofthe thigh (Fig. 2). Askin biopsy specimen (Fig. 3) showed the dermis to be of normal thickness, with rare ectopic adipocytes and marked attenuation ofthe collagen fibers in the papillary dermis. Cicatrization ofthe site of punch biopsy
879
Journal of the American Academy of Dermatology
880 Mahe et al.
'.3 Fig. 2. Case 2. Linear erythematous plaques along left thigh. was delayed. X-ray films of both femurs yielded normal findings. There was no other cutaneous, osseous, or visceral abnormalities. Family history. Patient 1 was the only daughter of patient 2. Her mother's family were all healthy, without evidence of FDH. Her father had a son from another marriage. His mother had another son from a previous marriage. Except for patients 1 and 2, all members of the family were healthy. Genetic study. No chromosome abnormalities were found by high-resolution karyotypic analysis in patients 1 and 2 and in the mother of patient 1. DISCUSSION
We report two cases of FDH of different severity. The propositus had typical features of the disease with severe cutaneous, osseous, and visceral involvment. J, 2 Her father had only minimal, cutaneous lesions. Mild forms of FDH have rarely been reported, principally in relatives of patients with typical disease. Wechsler et al,3 reported the case of a 63-yearold woman whose daughter and granddaughter had typical FDH. A 2 x 2 cm circular area of scarring with alopecia of the scalp was the only possible sign of FDH in her. Godin et a1. 4 described a family in which five members from different generations presented cutaneous lesions similar to those observed in FDH but without any obvious visceral involvement. Burgdorf et a1. 5 reported a family in which the
Fig. 3. Case 2. Rare ectopic adipocytes in papillary dermis and attenuation ofcollagen fibers. (Hematoxylineosin stain; xSO.)
propositus presented a typical picture of FDH. Her father had only linear cutaneous lesions on the extremities. We are not aware of other cases of the limited form of the disease we observed in case 2. The genetics of FDH are not fully elucidated. 2 Approximately 95% of cases are sporadic but an inherited form of the disease is documented by the existence of familial cases with affected members in successive generations. Ninety percent of the patients are female. These features suggest X-linked dominant inheritance with lethality in hemizygous male patients. In this mode of inheritance, female patients are heterozygous for the condition and viable, whereas hemizygous male patients are usually too severely affected to survive. 6 According to the Lyon hypothesis,? random X chromosome inactivation could result in functional mosaicism and account for the linear pattern of skin and borte lesions. Autosomal dominant inheritance with sex limitation in the male is less probable. Although rare, male cases have occurred8 and two other cases of father-to-daughter transmission have been reported. 5, 9 In the two cases in which detailed clinical data are available, the fathers exhibited mild signs of the disease. These findings do not exclude X-linked dominant inheritance because hemizygous male patients could be the result of gametic half-
Volume 25 Number 5, Part 2 November 1991
chromatid mutations (i.e., on one chromosomal DNA strand only), which leads to viable mosaicism in the embryo.6, 10 Early mutation may affect the germ line and explain father-te-daughter transmission. In keeping with this hypothesis, reported male patients have always been the first affected members in their families. An alternate mode of inheritance, that is, autosomal dominant, should also be considered in these families. No recurrent karyotypic abnormality has been found in FDH and no genetic linkage is known at present. Because of the subtlety, mild FDH, such as that reported herein, may be easily misdiagnosed or overlooked. These forms may occur more often than the rarity of reported cases suggests. Nevertheless, we believe that their appearance is characteristic enough to allow a definite diagnosis of FDH, even without visceral involvement, at least in families with otherwise typical FDH. Without a suggestive familial background, the possibility of a minimal form of FDH should be considered in the differential diagnosis of congenital linear dermatoses. Recognition of these forms may be of great importance in genetic counseling.
Focal dermal hypoplasia 881 REFERENCES
1. Goltz RW. Henderson RR, Hitch JM, et at. Focal dermal hypoplasia syndrome. A review of the literature and report of two cases. Arch Dermatol 1970;101:1-11. 2. Temple IK, MacDowall P, Baraitser M, eta!. Focal dermal hypoplasia (Goltz syndrome). J Med Genet 1990;27:180-7. 3. Wechsler MA, Papa eM. Haberman F, et al. Variable expression in focal dermal hypoplasia. Am J Dis Child 1988; 142:297-300. 4. Gorlin RJ, Meskin LH, Peterson WC, et al. Focal dermal hypoplasia syndrome. Acta Derm Venereol (Stockh) 1963; 43:421-40. 5. Burgdorf WHC, Dick GF, Soderberg MD, et al. Focal dermal hypoplasia in a father and daughter. J AM ACAD DERMATOL 1981;4:273-7. 6. Wettke-Shafer R, Kantner G. X-linked dominant inherited diseases with lethality in hemizygous males. Hum Genet 1983;64:1-23. 7. Lyon ME Sex chromatin and gene action in the mammalian X-chromosome. Am J Hum Genet 1962;14:135-48. 8. Hall EH. Terezhalmy GT. Focal dermal hypoplasia syndrome. JAM ACAD DERMATOL 1983;9:443-51. 9. Larregue M, Michel Y, Maroteaux J, et al. L'hypoplasie dermique en aires. Considerations sur I'osteopathie striee et sur Ie probleme genetique. Ann Dermatol Syph 1971; 98:491-500. 10. Gartler SM, Francke U. Half chromatid mutations: Transmission in humans? Am J Hum Genet 1975;27:218-23.
AmeRICaN ACaDemy OF
DerMaTOLOGY VOLUME 25
NUMBER 5
PART 2
NOVEMBER 1991
Minimal focal dermal hypoplasia in a man: A case of father-to-daughter transmission Antoine Mabe, MD,a Jerome Couturier, MD,b Claire Mathe, MD,a Frederic Lebras, MD,a Alain Bruet, MD,a and Jean-Pierre Fendler, MDa Poissy and Paris, France Focal dermal hypoplasia is a rare genetic disorder characterized by diffuse and specific cutaneous lesions. Multiple visceral abnormalities are frequently associated. A minimal form ofthe disease (only cutaneous and localized to one thigh) is reported in the father of a woman who had typical focal dermal hypoplasia. (J AM ACAD DERMATOL 1991;25:879-81.) Focal dermal hypoplasia (FDH), often referred to as Goltz syndrome, is a rare disorder characterized by specific cutaneous and osseous lesions. I, 2 Multiple visceral abnormalities are common. The condition is thought to be genetic; most cases involve women. We report the case of a woman with FDH whose father had mild cutaneous lesions, which we believe to be a minimal, localized form of the disease.
CASE REPORTS Case 1. Since birth this 23-year-old woman had had disseminated areas of atrophic and hyperpigmented skin on which scattered telangiectases and rare soft nodules were present. The skin lesions were principally distributed in a linear and serpiginous pattern on the arms and legs. The patient had digital and perianal papillomas. The nails were missing on the left hand. The patient was short and had scoliosis, prognathism, a claw-shaped left hand, and syndactyly of both feet. An anterior tibial transposition procedure had been performed in 1986. Her teeth were irregular. Results of an intelligence quotient test and ophthalmologic examination were normal. Biopsy specimens from the hypoplastic cutaneous lesions showed marked hypoplasia of the dermis with superficially located subcutaneous fat (Fig. 1). Radiologic examination showed hypoplasia ofthe left collarbone and aplasia ofleft
From the Department of Internal Medicine and Dermatology, Centre Hospitalier Intercommunal de Poissy,· and Structure et Mutagenese chromosomiques, Institut Curie, Paris. b Reprint requests: Antoine Mahe, Service de M6decine Interne, Centre Hospitalier Intercommunal de Poissy, 78303 Cedex, Poissy, France.
16/1/29970
Fig. 1. Case 1. Photomicrograph of biopsy specimen of skin lesion from arm shows atrophy of dermis with superficially located subcutaneous fat. (Hematoxylin-eosin stain; XIOO.) upper ribs. There were longitudinal striations in the metaphyseal regions of both lower limbs that were characteristic of osteopatha striata. The patient had a history of multiple lower and upper urinary tract infections. Intravenous pyelography and abdominal ultrasonography showed a solitary normal right kidney. Retrograde cystography ruled out reflux. Case 2. The father ofthe patient described in case 1was seen at 53 years of age. Since birth he had mild skin lesions on the left thigh only. There was a linear pattern of small plaques of erythematous, slightly hyperpigmented, and atrophicskin on the anterior and medial aspects ofthe thigh (Fig. 2). Askin biopsy specimen (Fig. 3) showed the dermis to be of normal thickness, with rare ectopic adipocytes and marked attenuation ofthe collagen fibers in the papillary dermis. Cicatrization ofthe site of punch biopsy
879
Journal of the American Academy of Dermatology
880 Mahe et al.
'.3 Fig. 2. Case 2. Linear erythematous plaques along left thigh. was delayed. X-ray films of both femurs yielded normal findings. There was no other cutaneous, osseous, or visceral abnormalities. Family history. Patient 1 was the only daughter of patient 2. Her mother's family were all healthy, without evidence of FDH. Her father had a son from another marriage. His mother had another son from a previous marriage. Except for patients 1 and 2, all members of the family were healthy. Genetic study. No chromosome abnormalities were found by high-resolution karyotypic analysis in patients 1 and 2 and in the mother of patient 1. DISCUSSION
We report two cases of FDH of different severity. The propositus had typical features of the disease with severe cutaneous, osseous, and visceral involvment. J, 2 Her father had only minimal, cutaneous lesions. Mild forms of FDH have rarely been reported, principally in relatives of patients with typical disease. Wechsler et al,3 reported the case of a 63-yearold woman whose daughter and granddaughter had typical FDH. A 2 x 2 cm circular area of scarring with alopecia of the scalp was the only possible sign of FDH in her. Godin et a1. 4 described a family in which five members from different generations presented cutaneous lesions similar to those observed in FDH but without any obvious visceral involvement. Burgdorf et a1. 5 reported a family in which the
Fig. 3. Case 2. Rare ectopic adipocytes in papillary dermis and attenuation ofcollagen fibers. (Hematoxylineosin stain; xSO.)
propositus presented a typical picture of FDH. Her father had only linear cutaneous lesions on the extremities. We are not aware of other cases of the limited form of the disease we observed in case 2. The genetics of FDH are not fully elucidated. 2 Approximately 95% of cases are sporadic but an inherited form of the disease is documented by the existence of familial cases with affected members in successive generations. Ninety percent of the patients are female. These features suggest X-linked dominant inheritance with lethality in hemizygous male patients. In this mode of inheritance, female patients are heterozygous for the condition and viable, whereas hemizygous male patients are usually too severely affected to survive. 6 According to the Lyon hypothesis,? random X chromosome inactivation could result in functional mosaicism and account for the linear pattern of skin and borte lesions. Autosomal dominant inheritance with sex limitation in the male is less probable. Although rare, male cases have occurred8 and two other cases of father-to-daughter transmission have been reported. 5, 9 In the two cases in which detailed clinical data are available, the fathers exhibited mild signs of the disease. These findings do not exclude X-linked dominant inheritance because hemizygous male patients could be the result of gametic half-
Volume 25 Number 5, Part 2 November 1991
chromatid mutations (i.e., on one chromosomal DNA strand only), which leads to viable mosaicism in the embryo.6, 10 Early mutation may affect the germ line and explain father-te-daughter transmission. In keeping with this hypothesis, reported male patients have always been the first affected members in their families. An alternate mode of inheritance, that is, autosomal dominant, should also be considered in these families. No recurrent karyotypic abnormality has been found in FDH and no genetic linkage is known at present. Because of the subtlety, mild FDH, such as that reported herein, may be easily misdiagnosed or overlooked. These forms may occur more often than the rarity of reported cases suggests. Nevertheless, we believe that their appearance is characteristic enough to allow a definite diagnosis of FDH, even without visceral involvement, at least in families with otherwise typical FDH. Without a suggestive familial background, the possibility of a minimal form of FDH should be considered in the differential diagnosis of congenital linear dermatoses. Recognition of these forms may be of great importance in genetic counseling.
Focal dermal hypoplasia 881 REFERENCES
1. Goltz RW. Henderson RR, Hitch JM, et at. Focal dermal hypoplasia syndrome. A review of the literature and report of two cases. Arch Dermatol 1970;101:1-11. 2. Temple IK, MacDowall P, Baraitser M, eta!. Focal dermal hypoplasia (Goltz syndrome). J Med Genet 1990;27:180-7. 3. Wechsler MA, Papa eM. Haberman F, et al. Variable expression in focal dermal hypoplasia. Am J Dis Child 1988; 142:297-300. 4. Gorlin RJ, Meskin LH, Peterson WC, et al. Focal dermal hypoplasia syndrome. Acta Derm Venereol (Stockh) 1963; 43:421-40. 5. Burgdorf WHC, Dick GF, Soderberg MD, et al. Focal dermal hypoplasia in a father and daughter. J AM ACAD DERMATOL 1981;4:273-7. 6. Wettke-Shafer R, Kantner G. X-linked dominant inherited diseases with lethality in hemizygous males. Hum Genet 1983;64:1-23. 7. Lyon ME Sex chromatin and gene action in the mammalian X-chromosome. Am J Hum Genet 1962;14:135-48. 8. Hall EH. Terezhalmy GT. Focal dermal hypoplasia syndrome. JAM ACAD DERMATOL 1983;9:443-51. 9. Larregue M, Michel Y, Maroteaux J, et al. L'hypoplasie dermique en aires. Considerations sur I'osteopathie striee et sur Ie probleme genetique. Ann Dermatol Syph 1971; 98:491-500. 10. Gartler SM, Francke U. Half chromatid mutations: Transmission in humans? Am J Hum Genet 1975;27:218-23.