American Journal of Medical Genetics 41:30-31 (1991)
Brief Clinical Report Neu Laxova Syndrome in Two Egyptian Families Nagwa Abdel Meguid and Samia A. Temtamy Human Genetics Department, National Research Center, Cairo, Egypt
We report on 2 Egyptian girls from 2 families with 8 affected relatives, 4 in each family. The 2 propositae had unusual facial appearance, severe microcephaly,generalized edema, contractures of limbs, and generalized ichthyotic skin lesions. Findings in the present 2 patients were compared with those in previously reported cases of Neu Laxova syndrome. In our cases, consanguinity, affected sibs, and affected cousins were noted. Autosomal recessive inheritance and lethality are emphasized. A high frequency of the Neu Laxova syndrome in Egyptians is suspected as a result of the increased consanguinity rate.
KEY WORDS: Neu Laxova syndrome (NLS), microcephaly, ichthyosis, intrauterine growth retardation, consanguinity,joint contracture. INTRODUCTION The Neu Laxova syndrome (NLS) was identified in 1971 by Neu et al., who reported on 3 sibs with a lethal syndrome of microcephaly and multiple congenital anomalies. In 1972,Laxova et al. reported another 3 sibs born to consanguineous parents. Lazjuk et al. [1979] noted a stillborn girl similarly affected and proposed the eponym. The total number of reported cases is around 27, 18 females and 9 males [Neu et al., 1971; Laxova et al., 1972; Povysilova et al., 1976; Lazjuk et al, 1979; Scott et al., 1981;Fitch et al., 1982;Mueller et al., 1983; Turkel et al., 1983; Paes et al., 1985; Nejad et al., 1987; Tolmie et al., 1987;Ostrovskaya and Lazjuk, 1988;Manjunath and Sreenivas, 19903. Here we report our observations of NLS in Egyptians.
CLINICAL REPORTS Patient 1: A 7-day-old girl was referred because of multiple congenital anomalies. She was born to normal first cousin parents. The mother and father at the time of her birth were both 34 years. The mother had a history of 3 spontaneous abortions around 12 weeks of gestation. The patient had 4 normal siblings, 2 sisters and 2 brothers. She had 3 other sibs, 2 sisters and one brother, who were similarly affected and died at ages 4 hours to 3 days. The mother was followed ultrasonographically at 14 and 16 weeks, at which time no fetal abnormality was detected. However, later there was fetal growth retardation. Delivery was normal, but at term the patient’s birth weight was low (1,400 g). On examination, the patient had a weight of 1,250g, a length of 31.5 cm, and a head circumference (OFC) of 22.5 cm. She had an unusual facial appearance (Fig. 11, with sloping forehead, protuberant eyes, micrognathia, flattened nose, high-arched palate, and very short neck with malformed ears. The chest was broad with widely spaced nipples. There were flexion contractures of elbows, wrists, fingers, hips, knees, and ankles, with bilateral rockerbottom feet and syndactyly between toes 2 and 3. The skin over the entire body was thin, scaly, and lemon yellow, with mild ichthyosis. Chromosomes were normal. Skeletal roentgenograms showed poor mineralization. Patient 2: A 2-month-old girl was referred because of multiple congenital anomalies. She was born to normal first cousin parents. The pregnancy was normal and delivery was at term. Her birth weight was 1,500 g. The mother and father were 23 and 32 years old, respec-
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Received for publication June 13,1990; revision received December 14,1990. Address reprint requests to Prof. Dr. Samia A. Temtamy, Human Genetics Department, National &search Center, Tahrir St., Dokki, Cairo, Egypt
0 1991 Wiley-Liss, Inc.
Fig, 1. Note characteristic dysmorphism, ichthyosis, and severe limb contractures.
Neu-Laxova Syndrome in Egyptians tively, at the time of her birth. There was a history of 4 prior spontaneous abortions at about 12-14 weeks of gestation. The patient had 2 normal brothers and a similarly affected sister who died at age 1month, as well as 2 affected first cousins (girls born to the father’s brothers) who died at age 15 days. On examination, her weight was 1,200 g, her length 37.5 cm, and OFC 26 cm. She had an abnormal face (Fig. 2), with sloping forehead, microphthalmia with ectropion, depressed nasal bridge, micrognathia, apparently, low-set overfolded ears, short neck, bilateral, widely spaced hypoplastic nipples, and mild contractures of both upper and lower limbs. Her skin was thin, with severe ichthyosis. Chromosomes were normal. Skeletal radiographs showed poor mineralization.
DISCUSSION The Neu-Laxova syndrome is a rare disorder characterized by severe intrauterine growth retardation, microcephaly, abnormal face, short neck, and abnormal skin and limbs [Turkel et al., 19831. Ichthyosis is a common manifestation [Nejad et al., 19871.The sex ratio is F 18:M 9, including our propositae. The most common findings in the previously reported cases compared to ours are shown in Table I. In 1982, Curry separated this syndrome into 3 groups: group 1 was characterized by joint contractures, partial syndactyly, thin scaly skin, mild ichthyosis, and poor mineralization of bones; group 2 was characterized by massive swelling, ichthyosis, and undermineralized bones; and group 3 was characterized by hypoplastic digits, severe ichthyosis (harlequin-likefetus), short limbs, and sticklike long bones. Despite important similarities among all the previously reported cases and also among our cases, distinctive differences in limbs, skin, and skeletal radiographs suggest that these patients may represent different grades of severity. Ultrasonography in case 1at 14-16 weeks was unable to detect an affected fetus. However, intrauterine growth retardation was noted at 22 weeks. A diagnosis of the Neu Laxova syndrome was made by ultrasonography in the third trimester by Muller et al. U9871. They suggested that an at-risk pregnancy should be monitored carefully by ultrasound at 6-8 weeks for accurate dating, a t 12-16 weeks for active fetal movements, and at 16-24 weeks for facial and skeletal anomalies, detection of intrauterine growth retardation, and polyhydramnios. We recommend fetal skin biopsy, as we consider ichthyosis an obligatory manifestation of the syndrome.
Fig. 2. Note microphthalmia and milder limb contractures.
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TABLE I. Main Findings in the Previously Reported Cases of Neu Laxova Syndrome Compared With Our Cases Characteristics Sex Parental consanguinity Affected Sibs Microcephaly Slanted forehead Protuberant eyes Microphthalmia Flattened nose Deformed ears Cleft palate Micrognathia Short neck Generalized edema Abnormal limbs Abnormal fingers and toes Ichthyosis Increased subcutaneous fat AtroDhic muscles
No. with finding1 No. reDorted 18 F19 M 22125 14125 21/25 24125 12116 5/16 16120 19119 4121 13118 25/25 22125 20124 24/25 19120 717 819
Our 2 cases
2F 212 212 212 212 112 012 212 212 012 2 12 212 212 212 212 212 012 112
From our analysis, the high female to male ratio 18:9, together with increased neonatal abortions, suggests that the NLS is more lethal in males. The observation of 2 familial cases with consanguinity in both and affected first cousins in one suggests that the Neu Laxova syndrome has a high gene frequency in Egypt, as has also been postulated for the Mexican, Mormon, Indian, Pakistan, and other populations.
REFERENCES Curry CJ (1982): Letter to the editor: Further comments on the Neu Laxova syndrome. Am J Med Genet 13:442-444. Fitch N, Resch L (1982): The Neu Laxova syndrome: Comments on syndrome identification. Am J Med Genet 13:445-452. Laxova R, Ohara P, Timothy JAD (1972):A further example of a lethal autosomal recessive condition in sibs. J Ment Defic Res 16:139-143. Lazjuk GL, Lurie IW, Ostrovskaja T, Kirillova KA, Nedzved MK, Usoev S (1979):Brief clinical observations: The Neu Laxova syndrome. A distinct entity. Am J Med Genet 3:261-267. Manjunath NC, Sreenivas V (1990):New manifestations ofNeu Laxova syndrome. Am J Med Genet 35:55-59. Mueller RF, Winter RM, Naylor CP (1983): Letter to the editor: Neu Laxova syndrome: Two further case reports and comments on proposed subclassification. Am J Med Genet 16:645-649. Nejad M, Khajavi H, Gharavi MJ, Nejad R (1987): Neu Laxova syndrome: Report of a case and comments. Am J Med Genet 28:17-23. Neu RL, Kajii T, Gardener L, Nagyfy F, Kings L (1971): A lethal syndrome of microcephaly with multiple congenital anomalies in three siblings. Pediatrics; 47:610-612. Ostrovskaya T, Lazjuk G (1988): Cerebral abnormalities in the Neu Laxova syndrome. Am J Med Genet 30:747-756. Paes B, Tompkins K (1985): Craniofacial and visceral defects with congenital contractures: A variant of the Neu-Laxova syndrome. J Clin Dysmorphol; 31:21-25. Povysilova V, Macek M, Salichova J, Seemanova E (1976): Lethal syndrome or multiple malformations. Cesk Pediatr 31:190-194. Tolmie J , Mortimer G, Doyle D, McKenzie R, McLaurin J , Nielson J (1987): The Neu Laxova syndrome in female sibs: Clinical and pathological features with prenatal diagnosis in the second sib. Am J Med Genet 27:175-182. Turkel S, Ebbin A, Towner J (1983):Additional manifestation of Neu Laxova syndrome. Am J Med Genet 20:227-229.
Brief Clinical Report Neu Laxova Syndrome in Two Egyptian Families Nagwa Abdel Meguid and Samia A. Temtamy Human Genetics Department, National Research Center, Cairo, Egypt
We report on 2 Egyptian girls from 2 families with 8 affected relatives, 4 in each family. The 2 propositae had unusual facial appearance, severe microcephaly,generalized edema, contractures of limbs, and generalized ichthyotic skin lesions. Findings in the present 2 patients were compared with those in previously reported cases of Neu Laxova syndrome. In our cases, consanguinity, affected sibs, and affected cousins were noted. Autosomal recessive inheritance and lethality are emphasized. A high frequency of the Neu Laxova syndrome in Egyptians is suspected as a result of the increased consanguinity rate.
KEY WORDS: Neu Laxova syndrome (NLS), microcephaly, ichthyosis, intrauterine growth retardation, consanguinity,joint contracture. INTRODUCTION The Neu Laxova syndrome (NLS) was identified in 1971 by Neu et al., who reported on 3 sibs with a lethal syndrome of microcephaly and multiple congenital anomalies. In 1972,Laxova et al. reported another 3 sibs born to consanguineous parents. Lazjuk et al. [1979] noted a stillborn girl similarly affected and proposed the eponym. The total number of reported cases is around 27, 18 females and 9 males [Neu et al., 1971; Laxova et al., 1972; Povysilova et al., 1976; Lazjuk et al, 1979; Scott et al., 1981;Fitch et al., 1982;Mueller et al., 1983; Turkel et al., 1983; Paes et al., 1985; Nejad et al., 1987; Tolmie et al., 1987;Ostrovskaya and Lazjuk, 1988;Manjunath and Sreenivas, 19903. Here we report our observations of NLS in Egyptians.
CLINICAL REPORTS Patient 1: A 7-day-old girl was referred because of multiple congenital anomalies. She was born to normal first cousin parents. The mother and father at the time of her birth were both 34 years. The mother had a history of 3 spontaneous abortions around 12 weeks of gestation. The patient had 4 normal siblings, 2 sisters and 2 brothers. She had 3 other sibs, 2 sisters and one brother, who were similarly affected and died at ages 4 hours to 3 days. The mother was followed ultrasonographically at 14 and 16 weeks, at which time no fetal abnormality was detected. However, later there was fetal growth retardation. Delivery was normal, but at term the patient’s birth weight was low (1,400 g). On examination, the patient had a weight of 1,250g, a length of 31.5 cm, and a head circumference (OFC) of 22.5 cm. She had an unusual facial appearance (Fig. 11, with sloping forehead, protuberant eyes, micrognathia, flattened nose, high-arched palate, and very short neck with malformed ears. The chest was broad with widely spaced nipples. There were flexion contractures of elbows, wrists, fingers, hips, knees, and ankles, with bilateral rockerbottom feet and syndactyly between toes 2 and 3. The skin over the entire body was thin, scaly, and lemon yellow, with mild ichthyosis. Chromosomes were normal. Skeletal roentgenograms showed poor mineralization. Patient 2: A 2-month-old girl was referred because of multiple congenital anomalies. She was born to normal first cousin parents. The pregnancy was normal and delivery was at term. Her birth weight was 1,500 g. The mother and father were 23 and 32 years old, respec-
-
Received for publication June 13,1990; revision received December 14,1990. Address reprint requests to Prof. Dr. Samia A. Temtamy, Human Genetics Department, National &search Center, Tahrir St., Dokki, Cairo, Egypt
0 1991 Wiley-Liss, Inc.
Fig, 1. Note characteristic dysmorphism, ichthyosis, and severe limb contractures.
Neu-Laxova Syndrome in Egyptians tively, at the time of her birth. There was a history of 4 prior spontaneous abortions at about 12-14 weeks of gestation. The patient had 2 normal brothers and a similarly affected sister who died at age 1month, as well as 2 affected first cousins (girls born to the father’s brothers) who died at age 15 days. On examination, her weight was 1,200 g, her length 37.5 cm, and OFC 26 cm. She had an abnormal face (Fig. 2), with sloping forehead, microphthalmia with ectropion, depressed nasal bridge, micrognathia, apparently, low-set overfolded ears, short neck, bilateral, widely spaced hypoplastic nipples, and mild contractures of both upper and lower limbs. Her skin was thin, with severe ichthyosis. Chromosomes were normal. Skeletal radiographs showed poor mineralization.
DISCUSSION The Neu-Laxova syndrome is a rare disorder characterized by severe intrauterine growth retardation, microcephaly, abnormal face, short neck, and abnormal skin and limbs [Turkel et al., 19831. Ichthyosis is a common manifestation [Nejad et al., 19871.The sex ratio is F 18:M 9, including our propositae. The most common findings in the previously reported cases compared to ours are shown in Table I. In 1982, Curry separated this syndrome into 3 groups: group 1 was characterized by joint contractures, partial syndactyly, thin scaly skin, mild ichthyosis, and poor mineralization of bones; group 2 was characterized by massive swelling, ichthyosis, and undermineralized bones; and group 3 was characterized by hypoplastic digits, severe ichthyosis (harlequin-likefetus), short limbs, and sticklike long bones. Despite important similarities among all the previously reported cases and also among our cases, distinctive differences in limbs, skin, and skeletal radiographs suggest that these patients may represent different grades of severity. Ultrasonography in case 1at 14-16 weeks was unable to detect an affected fetus. However, intrauterine growth retardation was noted at 22 weeks. A diagnosis of the Neu Laxova syndrome was made by ultrasonography in the third trimester by Muller et al. U9871. They suggested that an at-risk pregnancy should be monitored carefully by ultrasound at 6-8 weeks for accurate dating, a t 12-16 weeks for active fetal movements, and at 16-24 weeks for facial and skeletal anomalies, detection of intrauterine growth retardation, and polyhydramnios. We recommend fetal skin biopsy, as we consider ichthyosis an obligatory manifestation of the syndrome.
Fig. 2. Note microphthalmia and milder limb contractures.
31
TABLE I. Main Findings in the Previously Reported Cases of Neu Laxova Syndrome Compared With Our Cases Characteristics Sex Parental consanguinity Affected Sibs Microcephaly Slanted forehead Protuberant eyes Microphthalmia Flattened nose Deformed ears Cleft palate Micrognathia Short neck Generalized edema Abnormal limbs Abnormal fingers and toes Ichthyosis Increased subcutaneous fat AtroDhic muscles
No. with finding1 No. reDorted 18 F19 M 22125 14125 21/25 24125 12116 5/16 16120 19119 4121 13118 25/25 22125 20124 24/25 19120 717 819
Our 2 cases
2F 212 212 212 212 112 012 212 212 012 2 12 212 212 212 212 212 012 112
From our analysis, the high female to male ratio 18:9, together with increased neonatal abortions, suggests that the NLS is more lethal in males. The observation of 2 familial cases with consanguinity in both and affected first cousins in one suggests that the Neu Laxova syndrome has a high gene frequency in Egypt, as has also been postulated for the Mexican, Mormon, Indian, Pakistan, and other populations.
REFERENCES Curry CJ (1982): Letter to the editor: Further comments on the Neu Laxova syndrome. Am J Med Genet 13:442-444. Fitch N, Resch L (1982): The Neu Laxova syndrome: Comments on syndrome identification. Am J Med Genet 13:445-452. Laxova R, Ohara P, Timothy JAD (1972):A further example of a lethal autosomal recessive condition in sibs. J Ment Defic Res 16:139-143. Lazjuk GL, Lurie IW, Ostrovskaja T, Kirillova KA, Nedzved MK, Usoev S (1979):Brief clinical observations: The Neu Laxova syndrome. A distinct entity. Am J Med Genet 3:261-267. Manjunath NC, Sreenivas V (1990):New manifestations ofNeu Laxova syndrome. Am J Med Genet 35:55-59. Mueller RF, Winter RM, Naylor CP (1983): Letter to the editor: Neu Laxova syndrome: Two further case reports and comments on proposed subclassification. Am J Med Genet 16:645-649. Nejad M, Khajavi H, Gharavi MJ, Nejad R (1987): Neu Laxova syndrome: Report of a case and comments. Am J Med Genet 28:17-23. Neu RL, Kajii T, Gardener L, Nagyfy F, Kings L (1971): A lethal syndrome of microcephaly with multiple congenital anomalies in three siblings. Pediatrics; 47:610-612. Ostrovskaya T, Lazjuk G (1988): Cerebral abnormalities in the Neu Laxova syndrome. Am J Med Genet 30:747-756. Paes B, Tompkins K (1985): Craniofacial and visceral defects with congenital contractures: A variant of the Neu-Laxova syndrome. J Clin Dysmorphol; 31:21-25. Povysilova V, Macek M, Salichova J, Seemanova E (1976): Lethal syndrome or multiple malformations. Cesk Pediatr 31:190-194. Tolmie J , Mortimer G, Doyle D, McKenzie R, McLaurin J , Nielson J (1987): The Neu Laxova syndrome in female sibs: Clinical and pathological features with prenatal diagnosis in the second sib. Am J Med Genet 27:175-182. Turkel S, Ebbin A, Towner J (1983):Additional manifestation of Neu Laxova syndrome. Am J Med Genet 20:227-229.
