Neu–Laxova syndrome

Overview

Neu–Laxova syndrome (NLS) is a rare, severe, autosomal recessive congenital disorder characterized by profound developmental abnormalities affecting the central nervous system, skin, and skeletal system. First described in the 1970s by Drs. Richard L. Neu and Renata Laxova, this syndrome is associated with prenatal growth restriction, microcephaly, facial dysmorphism, limb anomalies, and ichthyosis-like skin changes. It is considered a lethal condition, with most affected infants being stillborn or dying shortly after birth.

Due to its extreme rarity and severity, Neu–Laxova syndrome presents a significant diagnostic and genetic counseling challenge. The disorder reflects defects in serine biosynthesis, a pathway critical for cellular proliferation, differentiation, and brain development.

Causes

Neu–Laxova syndrome is caused by mutations in genes involved in the serine biosynthesis pathway. The most commonly implicated genes are:

• PHGDH (phosphoglycerate dehydrogenase)

• PSAT1 (phosphoserine aminotransferase 1)

• PSPH (phosphoserine phosphatase)

These genes are essential for the production of L-serine, a non-essential amino acid critical for brain development, protein synthesis, and cell signaling. Mutations in any of these genes impair L-serine production, leading to the severe congenital abnormalities seen in NLS.

The syndrome follows an autosomal recessive inheritance pattern. This means both parents must carry one mutated copy of the gene, and their child must inherit both mutated copies to develop the condition.

Symptoms

Neu–Laxova syndrome presents with a constellation of prenatal and postnatal findings. Most cases are diagnosed in utero or at birth due to the distinctive clinical features.

Neurological and Craniofacial Features

• Microcephaly: Severely small head circumference due to impaired brain growth

• Lissencephaly or brain malformations: Smooth brain surface, underdeveloped cerebral cortex

• Hydrocephalus or ventriculomegaly: Accumulation of fluid in the brain

• Facial dysmorphism: Including proptosis (bulging eyes), micrognathia (small jaw), low-set ears, and flat nasal bridge

Skin and Limb Abnormalities

• Ichthyosis-like skin: Thickened, dry, scaly skin similar to congenital ichthyosis

• Edema: Generalized swelling, particularly of the face and limbs

• Joint contractures (arthrogryposis): Fixed joint positions due to abnormal development

• Absent or underdeveloped fingers/toes: Limb hypoplasia or deformities

Other Features

• Intrauterine growth restriction (IUGR): Poor fetal growth during pregnancy

• Hypoplastic or underdeveloped genitalia

• Polyhydramnios: Excessive amniotic fluid observed during pregnancy

• Premature delivery or stillbirth

Diagnosis

Diagnosis of Neu–Laxova syndrome can occur prenatally or postnatally through a combination of imaging, clinical assessment, and genetic testing.

Prenatal Diagnosis

• Ultrasound: Detects microcephaly, limb contractures, facial anomalies, and polyhydramnios

• Fetal MRI: Offers detailed imaging of brain abnormalities such as lissencephaly

Postnatal Diagnosis

• Physical examination: Observation of the characteristic phenotype

• Skin biopsy: May reveal hyperkeratosis consistent with ichthyosis

• Neuroimaging (CT or MRI): Confirms brain malformations

• Genetic testing: Confirms biallelic mutations in PHGDH, PSAT1, or PSPH genes

Carrier testing and prenatal genetic diagnosis are important in families with a history of NLS to inform reproductive choices.

Treatment

There is currently no curative treatment for Neu–Laxova syndrome. Management is supportive and palliative due to the lethal nature of the condition. For fetuses diagnosed prenatally, families may be offered counseling about the prognosis and the option of pregnancy termination, depending on local laws and ethical considerations.

Supportive Management (Postnatal)

• Respiratory support for neonates with breathing difficulties

• Skin care to manage ichthyosis and prevent infection

• Hydration and temperature regulation due to skin barrier dysfunction

• Palliative care focusing on comfort and quality of life

In rare, milder cases potentially associated with partial enzyme deficiencies, experimental treatments such as serine supplementation have been explored, though efficacy in classic NLS is limited due to the severity of genetic mutations.

Prognosis

The prognosis for Neu–Laxova syndrome is extremely poor. Most affected infants are stillborn or die within hours or days of birth due to severe neurological and systemic abnormalities. Survivors beyond the neonatal period are exceptionally rare and typically have profound developmental delays and severe disabilities.

For families with a history of NLS, genetic counseling is crucial to assess carrier status and discuss reproductive options. Early prenatal diagnosis through chorionic villus sampling (CVS) or amniocentesis with targeted genetic analysis may help in planning and decision-making for future pregnancies.

Although NLS remains a lethal condition, advancements in genetic testing and prenatal imaging have improved early detection and family support, allowing for informed care pathways and emotional preparation.