Neu-Laxova Syndrome

Disease Overview

Neu-Laxova syndrome (NLS) is a rare genetic disorder characterized by severe growth delays before birth, low birth weight and length, and distinctive abnormalities of the head and facial region, including a small head, widely shaped eyes and other malformations.^1,2 Babies with NLS can have a wide variety of symptoms that affect nearly every part of their development and they often die before birth.² A baby with NLS that survives birth will typically die shortly after due to respiratory, infectious, or neurological complications.²  The longest surviving child with NLS lived to be 10 months old.³

NLS is inherited in an autosomal recessive pattern. There are two forms of NLS, Neu-Laxova syndrome 1 and Neu-Laxova syndrome 2, which are caused by variants in different genes but are very similar overall.¹ As of 2022, there were 88 reports of individuals affected with NLS worldwide.²

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Synonyms

• NLS

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Signs & Symptoms

Babies with NLS may have distinctive abnormalities that can be seen before birth. These may include severely delayed growth (intrauterine growth delay)⁴; excessive fluid in the thin-walled membrane (amniotic sac) surrounding the fetus during pregnancy (polyhydramnios)⁵; abnormally reduced fetal movements; a short umbilical cord and an abnormally small placenta. There are distinctive differences of the head and facial (craniofacial) region associated with NLS. These may include a markedly small head (microcephaly)⁶, sloping of the forehead, widely spaced eyes and other malformations, resulting in a distinctive facial appearance. Other common features include abnormal accumulations of fluid in tissues throughout the body (generalized edema)⁶, permanent flexion and immobilization of multiple joints (flexion contractures), as well as other limb malformations and/or abnormalities of the brain, skin, genitals, kidneys and/or heart. Overall, multiple organ systems are affected by Neu-Laxova syndrome.^{1, 2}

Nervous System ^{1, 2, 4, 5, 7, 8, 9, 10, 11, 12, 13}

Very Frequent:

• Unusual structure of the nervous system (abnormal nervous system morphology)
• Small head size (microcephaly) ^{6, 14}
• Forehead that slopes backward (sloping forehead)

Frequent:

• Abnormal structure of the central part of the cerebellum, the part of the brain that helps coordinate movement (cerebellar vermis)
• Unusual brain folding patterns (abnormal cortical gyration)
• Improper movement of brain cells during development (abnormality of neuronal migration)
• Missing part of the brain structure that separates the fluid-filled cavities called lateral ventricles (absent septum pellucidum)
• Poor development of the cerebellum (cerebellar hypoplasia), a structure that controls movement and balance (cerebellar hypoplasia)
• Brain abnormality characterized by absence or underdevelopment of the cerebellar vermis and enlargement of the fluid-filled cavity between the brainstem and the cerebellum (the fourth ventricle) and the part of the skull that contains the cerebellum and the brainstem (the posterior fossa), known as Dandy-Walker malformation^8*
• Smooth brain surface due to lack of folds (lissencephaly)^15,16
• Abnormally large brain folds (macrogyria)
• Abnormal posture with severe backward arching of the body (opisthotonus)
• Abnormally thick brain folds (pachygyria)
• Excessive and small brain folds (polymicrogyria)
• Permanent and involuntary contractions of the jaw muscles impairing the opening of the mouth (trismus)

Occasional:

• Calcium deposits in the brain (cerebral calcification)
• Enlarged fluid cavities in the brain (ventriculomegaly)

Skin and Hair  ^{1, 2, 5}

Very Frequent:

• Dry, scaly skin (ichthyosis) ^{7, 9, 16}
• Loose or sagging skin (lack of skin elasticity)

Occasional:

• Abnormal shape or growth of eyelashes
• Abnormal shape of the eyelids
• Unusual hair structure or appearance (abnormal hair morphology)

Craniofacial Features^{1, 2, 5, 16}

Very Frequent:

• Thick edge of the lips (thick vermilion border)

Frequent:

• Abnormality of the mouth
• Unusual groove between the nose and upper lip (abnormality of the philtrum)
• Flattened nose bridge (depressed nasal ridge)
• Turned-out lower lip (everted lower lip vermilion)
• Widely spaced eyes (hypertelorism)
• Large ears (macrotia)
• Bulging eyes (proptosis)

Occasional:

• Issues with tear drainage system
• Split or forked uvula (bifid uvula)
• Clouding eye lens (cataract) ⁴
• Opening in the roof of the mouth (cleft palate) ^{4, 7}
• Small jaw (micrognathia) ^{4, 6, 7}
• Protruding back of the head (prominent occiput)
• Receding chin or jaw (retrognathia)
• Partial opening in the hard part of the roof of the mouth (submucous cleft hard palate)

Musculoskeletal System ^{1, 2, 17}

Frequent:

• Underdeveloped or absent muscles (aplasia/hypoplasia involving the skeletal musculature)
• Wasting away of muscles (skeletal muscle atrophy) ^{6, 11}
• Involuntary muscle contractions (muscle spasm)
• Progressive muscle weakness (muscular dystrophy)
• Wide foot structure (broad foot)
• Permanent bending of joints (flexion contracture)
• Unusually large hands (large hands)

Occasional¹⁸:

• Joint stiffness or limited movement at birth (arthrogryposis multiplex congenita)
• Shortened limbs (micromelia)
• Softening of bones (osteomalacia)
• Low bone density (osteopenia)
• Weak, brittle bones (osteoporosis)
• Webbing or extra skin in joints (pterygium)
• Bone softening in children, usually due to lack of vitamin D (rickets)
• Curved spine (scoliosis)
• Spinal cord not fully closed at birth (spina bifida)

Genitourinary and Reproductive System^{16, 18}

Frequent:

• Genitalia that don’t appear clearly male or female (ambiguous genitalia)
• Underdeveloped genitalia (external genital hypoplasia)
• Reduced function of the sex glands (hypogonadism)

Cardiovascular and Respiratory System ²

Occasional:

• Unusual heart or blood vessel structure (abnormality of cardiovascular system morphology)
• Underdeveloped lungs (pulmonary hypoplasia)

Prenatal Features ^{8, 24, 1, 2, 19}

Very Frequent:

• Poor growth of the fetus during pregnancy (intrauterine growth retardation)

Frequent:

• Reduced movement in the womb (decreased fetal movement)
• Excess amniotic fluid during pregnancy (polyhydramnios)

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Causes

Neu Laxova syndrome is caused by changes (variants) in one of three different genes: PHGDH, PSAT1 or PSPH.² Neu Laxova syndrome type 1 is caused by variants in the PHGDH gene and Neu Laxova syndrome type 2 is caused by variants in the PSAT1 gene. Other cases are caused by variants in the PSPH gene. These genes code for proteins that are needed for an important pathway (serine synthesis pathway) in prenatal development. This pathway produces brain lipids and other important building blocks that are needed for proper brain development in the developing fetus.² Variants in these genes prevent the creation of L-serine, which impacts overall fetal development and leads to the wide variety of symptoms.² 

Inheritance

NLS follows an autosomal recessive inheritance pattern.^{2, 9, 10, 12, 14} Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.  

The parents of several individuals with NLS have been closely related by blood (consanguineous). Consanguineous relationships increase the risk of autosomal recessive genetic disorders. This is because closely related people are more likely to share recessive genes from a common ancestor.

A few people have also been reported in which NLS has appeared to occur randomly for unknown reasons (sporadically).

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Affected populations

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), 88 affected individuals have been reported as of 2022.² Researchers suggest that the disorder may have a higher frequency in Pakistanis than in other geographic or ethnic populations.

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Disorders with Similar Symptoms

Symptoms of the following disorders may be similar to those of Neu-Laxova syndrome. Comparisons may be useful for a differential diagnosis. ^20,21,22

Cerebro-oculo-facio-skeletal (COFS) syndrome is a rare genetic disorder that some researchers think may be related to NLS. Both conditions cause severe growth delays, small head size, brain abnormalities, distinct facial features, eye problems and musculoskeletal issues such as joint contractures. However, COFS syndrome is progressive, meaning the nervous system worsens over time due to nerve degeneration, whereas NLS is a condition presenting from birth without progressive nerve loss. Babies with COFS syndrome often survive longer than those with NLS, which is usually fatal before or shortly after birth.

Fetal akinesia deformation sequence 1, also known as Pena-Shokeir syndrome type I, shares similarities with NLS including poor movement in the womb, growth restriction, joint contractures and distinctive facial features. However, unlike NLS, fetal akinesia can result from many different causes and is not always a genetic disorder. Additionally, it does not typically cause major brain malformations, while NLS is associated with severe structural abnormalities in the brain. Skin webbing is another key feature of fetal akinesia that is not present in NLS.

Restrictive dermopathy is another genetic condition that causes severe growth restriction before birth, breathing difficulties, stiff joints and distinct facial features. A major difference from NLS is that restrictive dermopathy is characterized by extremely tight, rigid skin that does not stretch properly, whereas NLS is associated with dry, scaly skin. A short umbilical cord is also common in restrictive dermopathy but not in NLS. Skull and facial abnormalities in NLS tend to be more severe, including a sloping forehead and microcephaly.

Bowen-Conradi syndrome (or Bowen-Hutterite syndrome) primarily affects individuals of Hutterite descent and shares features with NLS, such as poor growth before and after birth, small head size, distinct facial features and joint abnormalities. Unlike NLS, which is almost always fatal at birth, some babies with Bowen Hutterite syndrome survive longer.

Multiple pterygium syndrome is characterized by growth delays, stiff joints, spinal curvature and facial differences. Unlike NLS, it is associated with webbing of the skin in different areas of the body, a key feature that is not present in NLS. While both conditions cause joint contractures, multiple pterygium syndrome does not typically involve major brain abnormalities like NLS. Additionally, it can occur sporadically, whereas NLS follows an autosomal recessive inheritance pattern.

Trisomy 18, also known as Edwards syndrome, is characterized by growth restriction, small head size, facial differences, hand and foot deformities and brain abnormalities. Unlike NLS, trisomy 18 is caused by an extra copy of chromosome 18. It is more commonly associated with severe heart and kidney defects, which are not defining features of NLS. Some infants with trisomy 18 survive longer, whereas NLS is almost always fatal at or before birth.

Other conditions such as Walker-Warburg syndrome, Smith-Lemli-Opitz syndrome, and Miller-Dieker syndrome share some symptoms with NLS but lack the full combination of brain, skull, skin  and joint abnormalities seen in NLS.

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Diagnosis

A diagnosis of NLS may be suggested before birth (prenatally) based upon specialized testing, such as repeated fetal ultrasonography.² During fetal ultrasonography, sound waves are used to create an image of the developing fetus. Fetal ultrasound around 20 weeks may reveal characteristic findings that suggest NLS, especially intrauterine growth restriction.² Other findings include, 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.^{2, 5, 18} Severe central nervous system malformations have been consistently seen in babies with NLS on ultrasound and/or neuropathological examination. During neuropathological examination, tissue analysis of the brain, spinal cord and nerves are done to look for signs of the disease. Once findings typical of NLS are observed, genetic testing is recommended to confirm the diagnosis.²

Genetic testing for variants in genes associated with NLS can be done on a sample of amniotic fluid obtained from an amniocentesis, which involves extracting a small sample of the amniotic fluid surrounding the fetus.²

The diagnosis of NLS may also be made after birth based upon a thorough clinical evaluation and characteristic physical findings followed by genetic testing that shows two disease-causing variants in the PHGDH, PSAT1 or PSPH genes.

Specialized testing may also be done to detect certain conditions that may be associated with the disorder (e.g., congenital heart defects).

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Standard Therapies

Treatment

Specific therapies for the treatment of NLS are limited. If a baby survives birth, there are options for symptomatic, supportive and life sustaining therapies. There are no current FDA approved treatments for people with NLS.

Genetic counseling is recommended for affected families.

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Clinical Trials and Studies

A proposed treatment is serine supplementation, however this would require early in utero diagnosis due to early impact of the condition on development. 

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

1. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Neu Laxova Syndrome. Entry No: 256520. Last Edited 02/27/2024. Available at: https://omim.org/entry/256520. Accessed March 4, 2025.
2. Serrano Olave A, López AP, Cruz MM, Rodríguez SM, Narbona Arias I, López JSJ. Prenatal Diagnosis of Neu–Laxova Syndrome. Diagnostics. 2022; 12(7):1535.
3. Ozcan D, Derbent M, Seçkin D, et al. A collodion baby with facial dysmorphism, limb anomalies, pachygyria and genital hypoplasia: a mild form of Neu-laxova syndrome or a new entity?. Ann Dermatol. 2013;25(4):483-488. doi:10.5021/ad.2013.25.4.483
4. 4.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.
5. 5.Curry CJR. Further comments on the Neu Laxova syndrome[letter]. Am J Med Genet. 1982;13:441-444.
6. 6.Hirota T, et al. A Japanese case of Neu-Laxova syndrome. J Dermatol. 1998;25:163-166.
7. 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.
8. 8.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.
9. Abdel Meguid N, et al. Neu Laxova syndrome in two Egyptian families. Am J Med Genet. 1991;41:30-31.
10. Broderick K, et al. Neu Laxova syndrome: a case report. Am J Obstet Gynecol. 1988;158:574-575.
11. 11.Karimi-Nejad MH, et al. Neu Laxova syndrome: report of a case and comments. Am J Med Genet. 1987;28:17-23.
12. 12.Ejeckam GG, et al. Neu Laxova syndrome: report of two cases. Pediatr Pathol. 1986;5:295-306.
13. Neu-Laxova Syndrome. Orphanet, Last update: Oct 2006. https://www.orpha.net/en/disease/detail/2671. Accessed March 5, 2025.
14. 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.
15. 15.Silengo MC, et al. The Neu-COFS (cerebro-oculo-facio-skeletal) syndrome. Clin Genet. 1984;25:201-204.
16. 16.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.
17. 17.Ostrovskaya TI, et al. Cerebral abnormalities in the Neu Laxova syndrome. Am J Med Genet. 1988;30:747-756.
18. 18.Lazjuk GI, et al. Brief clinical observations: the Neu-Laxova syndrome–a distinct entity. Am J Med Genet. 1979;3:261-267.
19. Turkel SB, et al. Additional manifestations of the Neu Laxova syndrome. J Med Genet. 1983;20:227-229.
20. Silengo MC, et al. The Neu-COFS (cerebro-oculo-facio-skeletal) syndrome. Clin Genet. 1984;25:201-204.
21. Suzumura, H., Arisaka, O. (2010). Cerebro-Oculo-Facio-Skeletal Syndrome. In: Ahmad, S.I. (eds) Diseases of DNA Repair. Advances in Experimental Medicine and Biology, vol 685. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6448-9_19
22. Viraraghavan VR, Sanke S, Mendiratta V, Dewan A, Kumar A, Pangti R. Restrictive Dermopathy – A Rare Congenital Skin Disorder. Indian J Dermatol. 2020;65(6):519-521. doi:10.4103/ijd.IJD_554_18

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