| Abstract|| |
NeuLaxova syndrome (NLS) is a rare congenital abnormality involving multiple systems. Until date, only 60 cases of this syndrome have been reported in the literature. A stillborn fetus from a 23-year-old female with bad obstetrics history and consanguinity marriage, presented at 41 weeks gestation and not appreciating fetal movements for the past 3 days. Ultrasound examination revealed the absence of fetal cardiac activity and features of growth retardation. The fetus was sent for pathological examination. At autopsy, fetus had ichthyosis over the scalp and face, depressed nasal bridge, low set ears, microcephaly, slopping forehead, wide interdigital spaces, edema of hands and feet, hypoplastic penis, right leg showed congenital talipes equinovarus and left leg showed rocker bottom foot. On dissection, all organs were in situ. Both lungs were hypoplastic, brain was atrophied, and heart showed right ventricle hypertrophied. A diagnosis of NLS was made. Genetic counseling and early serial ultrasound examination should be performed at high-risk families because of its autosomal recessive mode of inheritance. Early diagnosis of the disease may offer termination of the pregnancy as an option. The prognosis is poor, and the affected newborns are either stillborn or die immediately after birth.
Keywords: Congenital multiple abnormalities, ichthyosis, Neulaxova syndrome
|How to cite this article:|
Dwivedi T, Gosavi M. Neu Laxova syndrome. Indian J Pathol Microbiol 2019;62:149-52
| Introduction|| |
Neu–laxova syndrome (NLS) is an extremely rare congenitally inherited disorder with only about 60 cases being reported in the literature., Prevalence is <1/10,00,000. It is mostly lethal and autosomally inherited which has a strong association with consanguinity. No sex preponderance is seen. Fetuses affected with this disorder display multisystem involvement with intrauterine growth retardation (IUGR), ichthyosis, microcephaly, and abnormal facial features constituting the main anomalies., We present here a case report of this syndrome.
| Case Report|| |
A 23-year-old woman presented with a history of 9 months amenorrhea and inability to appreciate fetal movements. There was no history of per vaginal leak or bleed, abdominal pain, or fever. There was no history of diabetes or hypertension. She had not taken folic acid. History, personal history, family history, and menstrual history were unremarkable. History of first-degree consanguinity was present. There was a bad obstetric history (gravida 3, para 2, and living 0) with previous two pregnancies being terminated for congenital anomalies. Ultrasonography (USG) performed during the present pregnancy at 20 weeks had also revealed that the present fetus had multiple congenital anomalies [Figure 1]a. The details of the USG findings of all the three pregnancies showed similarities and is presented in [Table 1]. During the present pregnancy, several tests conducted like HIV as well as the venereal disease research laboratory were nonreactive and other tests such as routine urine examination, hematological profile, thyroid function tests, lupus anticoagulant, and cardiolipin antibodies-IgM, IgG, and IgA, were found to be within normal limits. Furthermore, both the parents underwent genetic testing and were found to be of a normal karyotype without any evidence of any numerical or structural abnormalities of chromosomes [Figure 1]c and [Figure 1]d. Given the increased nuchal thickness, an amniocentesis was performed at 21 weeks. With the GTG banding (Giemsa banding) technique, an impression of a normal karyotype was reported [Figure 1]e. Karyotyping of the mother as well as the father was also normal [Figure 1]a and [Figure 1]b. Parents refused to terminate the present pregnancy even after abnormal anomaly scan. Hence, at 41 week, a stillborn fetus was sent for autopsy. Infantogram of the fetus was done to rule any skeletal abnormalities which showed only subcutaneous swelling and no skeletal abnormalities [Figure 1]b. The fetus weighed 1500 g and placenta weighed 350 g. External examination revealed microcephaly, fusion of posterior fontanelle, ichthyosis over the face and scalp, absent eyebrow, proptosis, depressed nasal bridge, thick lips with an open mouth, short neck wide interdigital spaces with flexure contracture in all limbs, right rocker bottom foot, left-sided congenital talipes equinovarus, and a rudimentary penis [Figure 1]f, [Figure 1]g, [Figure 1]h, [Figure 1]i, [Figure 1]j, [Figure 1]k. On dissection, the fetus showed a thick deposition of fat beneath the skin over the chest wall and abdomen, a partially autolyzed, but atrophic brain and hypoplastic lungs [Figure 1]l, [Figure 1]m, [Figure 1]n]. The heart, liver, spleen, and kidneys were partially autolyzed. The umbilical cord showed three vessels. Microscopic study revealed partial autolysis of all organs. The ichthyoid skin over the scalp and face showed hyperkeratosis, orthokeratosis with autolytic changes [Figure 1]o. Placenta showed areas of hemorrhage with arteriosclerosis of the vessels. A diagnosis of NLS was made.
|Figure 1: (a) Ultrasonography at 20 weeks increased nuchal thickness with intrauterine growth retardation and multiple anomalies. (b) X-ray of the fetus showing subcutaneous swelling. (c-e) Normal karyotyping of the mother, father, and fetus, respectively. (f-k) External examination of the fetus showing ichthyosis over the scalp and face, characteristic facies, short and broad neck, edema of hand and feet, foot showing CTEV and rocker bottom foot, hypoplastic penis. (l) On dissection showing thick deposition of fat beneath the skin over the chest wall and abdomen. (m and n) Hypoplastic lung and atrophied brain. (o) Microscopy of ichthyosis over scalp and face showing hyperkeratosis, orthokeratosis with autolytic changes (H and E, ×40)|
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| Discussion|| |
NLS was first described by Dr. Richard Neu in 1971 and Dr. Renata Laxova in 1972. This syndrome is characterized by severe IUGR with multiple congenital malformations and generalized edema. Other systemic manifestations which are seen in this syndrome are characteristic facies (receding forehead, exophalthalmus, cataract, hyperthelorism, flat nasal bridge, deformed ear, cleft lip/palate, thick lips, and micrognathia), microcephaly, cerebellum hypoplasia, corpus callosum agenesis, decreased gyri, dilatation or abnormal ventricle, dandy walker abnormalities, choroid plexus cyst, short broad necks, cystic hygroma, small thorax, hypoplastic or atelectatic lungs, ichthyosis and increase in skin thickness, the absence of hair, short webbed digits, syndactyly of fingers and flexions of the joints, rocker bottom feet, and ambiguous genitalia.
Tos et al. had classified NLS into three groups according to the severity of the disease. Group I: joint contractures, partial syndactyly, thin scaly skin, mild ichthyosis and poor mineralization of bones. Group II: massive swelling of hand and feet, ichthyosis, undermineralized bones and Group III: hypoplastic digits, severe ichthyosis, short limbs and stick-like long bones. Our case belongs to Group III.
Tos et al. described that affected fetus had ichthyotic skin lesions with increased fatty tissue beneath the epidermis, which is a prominent characteristic feature of this syndrome. Kniffin CL et al. also found the same finding of the ichthyotic skin lesions in an affected infant born of consanguineous south Indian parents. Both features of ichthyotic skin lesions as well as increased fatty tissue beneath the epidermis were seen in our case. According to Tos et al. characteristic features of NLS resemble “restrictive dermopathies.” Ichthyotic skin changes lead to protein loss which in turn causes hypoproteinemia and polyhydramnios, generalized edema, and swollen limbs in utero. In fact, limb deformities and flexion contractures are also a consequence of these dermatopathies. The tight skin of the fetus reduces fetal movement leading to failure of swallowing and contractures are development.
The exact cause for this condition has not been established, but various theories have been postulated. Earlier in 1981, Scot et al. reported NLS as a cerebroarthrodigital syndrome complex with the severe central nervous system (CNS) developmental defect. Another theory postulated by Acuna-Hidalgo et al. is that this disorder is a metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. They classified NLS into NLS 1 and two according to mutation of genes. NLS 1 is caused by mutation of gene PHGDH gene (1p12) and in NLS 2 mutation of gene PSAT1 (9q21.2) was noted. Both syndromes had overlapping clinical features, but in clinical course, NLS 2 is less severe. Shaheen et al. reported that NLS is an inborn error of serine metabolism, is caused by mutations in PHGDH. All these genes are essential for cell proliferation [Figure 2].,
|Figure 2: Mutation pathway of PHGDH gene and PSAT1gene responsible for Neu–Laxova Syndrome|
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The inheritance pattern in NLS is autosomal recessive. Consanguinity has been reported in most of the cases. Hence, as in our case also. Karyotyping of affected cases has been reported to be normal on majority cases. Karyotyping was normal in our case also.
USG is useful in the monitoring of “at risk” pregnancies as well in identifying this syndrome. Aslan H et al. suggested that USG findings of marked ocular proptosis in a growth-restricted, edematous fetus should be considered as the diagnosis of NLS.
Prenatal ultrasound and postnatal findings are the only modalities to diagnose this entity. Hence, all the high-risk pregnancies should be carefully monitored by USG: 6–8 weeks (accurate dating), 12–16 weeks (analysis of active fetal limb movements), and 16–24 weeks (detection of facial and skeletal anomalies and polyhydramnios). Postnatal finding for diagnosis is CNS anomalies, poor formation of the cortical bone and dermatological features (ichthyosis, massive fat with hypertrophy of fat cells, and edema).
Differential diagnosis of NLS include Cerebro-oculo-facio-skeletal syndrome (does not include short neck, ichthyosis, subcutaneous swelling or syndactyly, less retardation of development of the brain, and less lethal than NLS), Bowen Hutterite syndrome (malformations and of the brain and spinal cord and do not have short neck, ichthyosis, subcutaneous swelling or syndactyly), Pena-Shokeir syndrome type I (no short neck, ichthyosis or subcutaneous swelling), restrictive dermopathy, multiple pterygium syndrome, Trisomy 18 syndrome (no ichthyosis or subcutaneous swelling seen in the past three conditions).
The prognosis is poor, affected newborns either are stillborn or die immediately after birth with the longest survival of reported in the literature is of 134 days.
| Conclusion|| |
NLS is a rare disorder with poor prognosis; therefore, the prenatal diagnosis of NLS is extremely important. Parents should be informed about the inheritance of this disease, which makes genetic counseling and early-serial ultrasound examination mandatory for the high-risk families.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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Department of Pathology, KLE University's Jawaharlal Nehru Medical College, Belagavi - 590 010, Karnataka
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]