NORD gratefully acknowledges Phillip L. Pearl, MD, Chief of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital, Harvard Medical School, for assistance in the preparation of this report.
Neu-Laxova syndrome (NLS) is a rare genetic disorder that is inherited as an autosomal recessive trait. The syndrome is characterized by severe growth delays before birth (intrauterine growth retardation); low birth weight and length; and distinctive abnormalities of the head and facial (craniofacial) region. These may include marked smallness of the head (microcephaly), sloping of the forehead, widely spaced eyes (ocular hypertelorism), and other malformations, resulting in a distinctive facial appearance. NLS is also typically characterized by abnormal accumulations of fluid in tissues throughout the body (generalized edema); permanent flexion and immobilization of multiple joints (flexion contractures); other limb malformations; and/or abnormalities of the brain, skin, genitals, kidneys, and/or heart.
NLS is associated with distinctive abnormalities before birth. These may include severely delayed growth (intrauterine growth retardation); excessive fluid in the thin-walled membrane (amniotic sac) surrounding the fetus during pregnancy (polyhydramnios); abnormally reduced fetal movements; a short umbilical cord; and an abnormally small placenta. (The placenta is the organ within the uterus that joins the blood supplies of the mother and the developing fetus.) In addition, in some cases, the umbilical cord may have only two blood vessels. (The umbilical cord, which is the flexible structure that connects the fetus with the placenta, normally has two umbilical arteries as well as a larger umbilical vein.)
Newborns with NLS typically have an abnormally low birth weight and length as well as marked smallness of the head (microcephaly). Additional malformations of the head and facial (craniofacial) area are also usually present, resulting in a characteristic appearance. Such abnormalities include a sloping forehead; a flattened nose with a broad nasal bridge; full cheeks; and a small, underdeveloped jaw (micrognathia). Affected newborns may also have large, low-set, malformed (dysplastic) ears; a round, gaping mouth with thick lips; a short neck; and widely set, unusually prominent eyes. In addition, the eyelids are underdeveloped (hypoplastic) and turned outward (ectropion), causing them to appear absent. Additional eye (ocular) abnormalities may also be present, such as unusually small eyes (microphthalmia) and loss of transparency of the lenses of the eyes (cataracts). Some affected newborns may also have incomplete closure of the roof of the mouth (cleft palate) and a vertical groove in the upper lip (cleft lip).
NLS is also associated with musculoskeletal abnormalities, including permanent flexion and immobilization of major joints (flexion contractures), such as the elbows, wrists, hips, knees, and ankles, with skin webbing across certain immobilized joints (e.g., elbows and knees). In addition, the arms and legs are unusually short, and the hands and feet may be swollen. Affected newborns may also have overlapping fingers; webbed or fused fingers and toes (syndactyly); and a deformity in which the feet appear shaped like the rocker of a rocking chair (rocker-bottom feet). In addition, there may be “underossification” of bones in the hands and feet and other abnormalities of bone formation. (Ossification refers to the conversion of fibrous tissue or cartilage into bone.)
The disorder is also typically characterized by an abnormal accumulation of fluid in tissues throughout the body (generalized edema). In addition, some infants may have abnormal (i.e., myxomatous) proliferation of connective tissue or excessive fatty deposits beneath the outermost layer of skin (epidermis), with degeneration (atrophy) of surrounding muscles. Less commonly, edema may not be present or may be restricted to the scalp. Some affected infants may also have yellowish, dry, scaling (“ichthyotic”) skin.
NLS may also be associated with malformations of the brain. In many cases, there is incomplete development of the folds (gyri) of the outer region of the brain (cerebral cortex), causing the brain’s surface to appear unusually smooth (agyria). Additional malformations may include absence of the thick band of nerve fibers that connects the two hemispheres of the brain (agenesis of the corpus callosum) or underdevelopment (hypoplasia) of the cerebellum, which is the region of the brain that plays an essential role in coordinating voluntary movements and maintaining proper posture. In addition, in some instances, there may be cystic malformation of the fourth cavity (ventricle) of the brain (Dandy-Walker malformation) and associated hydrocephalus. Hydrocephalus is a condition in which there is impaired flow or absorption of the fluid that circulates through the ventricles of the brain and the spinal canal [cerebrospinal fluid (CSF)], potentially leading to increasing fluid pressure in the brain, a rapid increase in head size, or other associated findings. In some cases, NLS may also be associated with additional abnormalities of the brain and spinal cord (central nervous system).
Some affected newborns may also have additional physical abnormalities, such as underdevelopment of the genitals; absence of one of the kidneys (unilateral renal agenesis) or other renal defects; underdevelopment of the lungs (pulmonary hypoplasia); or structural abnormalities of the heart (congenital heart defects). Congenital cardiac malformations may include an abnormal opening in the fibrous partition (septum) that separates the upper or lower chambers of the heart (atrial or ventricular septal defects); persistence of the fetal opening between the two major arteries (aorta, pulmonary artery) emerging from the heart (patent ductus arteriosus); or a heart defect in which the aortic and pulmonary arteries are in one another’s normal positions (transposition of the great arteries). Infants with NLS may be stillborn or develop life-threatening complications shortly after birth.
NLS is transmitted as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
The parents of several individuals with NLS have been closely related by blood (consanguineous). In recessive disorders, if both parents carry the same gene for the same disease trait, there is an increased risk that their children may inherit the two genes necessary for development of the disease.
A few cases have also been reported in which NLS has appeared to occur randomly for unknown reasons (sporadically).
There has been one reported case of NLS that has occurred for no apparent reason (sporadically). Several cases of this disorder have been associated with “blood” related parents.
NLS appears to affect males and females in relatively equal numbers. Since the disorder was originally described in three siblings in 1971 (Neu, RL) as well as three siblings in another family in 1972 (Laxova, R), over 30 additional cases have been reported. Investigators suggest that the disorder may have a higher frequency in Pakistanis than in other geographic or ethnic populations.
A diagnosis of NLS may be suggested before birth (prenatally) based upon specialized testing, such as repeated fetal ultrasonography. During fetal ultrasonography, sound waves are used to create an image of the developing fetus. Such testing may reveal characteristic findings that suggest NLS, such as weak fetal activity, restricted limb movement, excessive fluid in the membranous sac surrounding the developing fetus (polyhydramnios), a small placenta, and intrauterine growth retardation. Additional findings seen on ultrasound that may suggest NLS include an abnormally small head, receding forehead, prominent eyes, joint contractures, and/or generalized edema.
The diagnosis of NLS may also be made or confirmed after birth (postnatally) based upon a thorough clinical evaluation and characteristic physical findings. Specialized testing may also be conducted to detect certain conditions that may potentially be associated with the disorder (e.g., congenital heart defects).
The treatment of NLS is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; physicians who diagnose and treat neurological disorders (neurologists); physicians who diagnose and treat heart abnormalities (cardiologists); and/or other health care professionals.
Specific therapies for the treatment of NLS are symptomatic and supportive. In addition, genetic counseling will be of benefit for affected families.
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Jones KL. Smith’s Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders Company; 1997:174-183.
Buyse ML. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, Inc.; 1990:1226-1227, 1471-1472.
Gorlin RJ, et al., eds. Syndromes of the Head and Neck. 3rd ed. New York, NY: Oxford University Press; 1990:512-513, 621-629.
Shreedhara Avabratha K, et al. Neu-Laxova syndrome. Indian Pediatr. 1999;36:328.
Hirota T, et al. A Japanese case of Neu-Laxova syndrome. J Dermatol. 1998;25:163-166.
Kainer F, et al. Qualitative analysis of fetal movement patterns in the Neu Laxova syndrome. Prenatal Diag. 1996;16:667-669.
Rouzbahani L. New manifestations in an infant with Neu Laxova syndrome [letter]. Am J Med Genet. 1995;56:239-240.
King JA, et al. Neu Laxova syndrome: pathological evaluation of a fetus and review of the literature. Pediatr Pathol Lab Med. 1995;15:57-79.
Kuseyri F, et al. Neu Laxova syndrome: report of a case from Turkey. Clin Genet. 1993;43:267-269.
Shapiro I, et al. Neu Laxova syndrome: prenatal ultrasonographic diagnosis, clinical and pathological studies, and new manifestations. Am J Med Genet. 1992;43:602-605.
Abdel Meguid N, et al. Neu Laxova syndrome in two Egyptian families. Am J Med Genet. 1991;41:30-31.
Russo R, et al. Neu Laxova syndrome: pathological, radiological, and prenatal findings in a stillborn female. Am J Med Genet. 1989;32:136-139.
Ostrovskaya TI, et al. Cerebral abnormalities in the Neu Laxova syndrome. Am J Med Genet. 1988;30:747-756.
Broderick K, et al. Neu Laxova syndrome: a case report. Am J Obstet Gynecol. 1988;158:574-575.
Sulli N, et al. Review of the Pena-Shokeir syndrome I, Pena-Shokeir II and Neu-Laxova. Clinical and interpretative contribution. Minerva Pediatr. 1988;40:191-194.
Karimi-Nejad MH, et al. Neu Laxova syndrome: report of a case and comments. Am J Med Genet. 1987;28:17-23.
Tolmie JL, et al. The Neu Laxova syndrome in female sibs: clinical and pathological features with prenatal diagnosis in the second sib. Am J Med Genet. 1987;27:175-182.
Muller LM, et al. A case of the Neu Laxova syndrome: prenatal ultrasonographic monitoring in the third trimester and the histopathological findings. Am J Med Genet. 1987;26:421-429.
Ejeckam GG, et al. Neu Laxova syndrome: report of two cases. Pediatr Pathol. 1986;5:295-306.
Silengo MC, et al. The Neu-COFS (cerebro-oculo-facio-skeletal) syndrome. Clin Genet. 1984;25:201-204.
Mueller RF, et al. Neu Laxova syndrome: two further case reports and comments on proposed subclassification [letter]. Am J Med Genet. 1983;16:645-649.
Fitch N, et al. Comments on Dr. Curry’s classification of the Neu Laxova syndrome [letter]. Am J Med Genet. 1983;15:515-518.
Turkel SB, et al. Additional manifestations of the Neu Laxova syndrome. J Med Genet. 1983;20:227-229.
Curry CJR. Further comments on the Neu Laxova syndrome[letter]. Am J Med Genet. 1982;13:441-444.
Fitch N, et al. The Neu-Laxova syndrome: comments on syndrome identification. Am J Med Genet. 1982;13:445-452.
Winter RM, et al. Syndromes of microcephaly, microphthalmia, cataracts, and joint contractures. J Med Genet. 1981;18:129-133.
Lazjuk GI, et al. Brief clinical observations: the Neu-Laxova syndrome–a distinct entity. Am J Med Genet. 1979;3:261-267.
Laxova R, et al. A further example of a lethal autosomal recessive condition in sibs. J Ment Defic Res. 1972;16:139-143.
Neu RL, et al. A lethal syndrome of microcephaly with multiple congenital anomalies in three siblings. Pediatrics. 1971;47:610-612.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. NLS; NLS. Entry No: 256520. Last Edited December 21, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed September 24, 2012.
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