Neu-Laxova Syndrome 1

A number sign (#) is used with this entry because Neu-Laxova syndrome-1 (NLS1) is caused by homozygous mutation in the PHGDH gene (606879) on chromosome 1p12.

See also PHGDH deficiency (601815), an allelic disorder with a less severe phenotype.

Description

Neu-Laxova syndrome is an autosomal recessive lethal multiple malformation syndrome characterized by ichthyosis, marked intrauterine growth restriction, microcephaly, short neck, central nervous system anomalies (lissencephaly, cerebellar hypoplasia and/or abnormal/agenesis of the corpus callosum), limb deformities, hypoplastic lungs, edema, and abnormal facial features including severe proptosis with ectropion, hypertelorism, micrognathia, flattened nose, and malformed ears (summary by Manning et al., 2004).

Genetic Heterogeneity of Neu-Laxova Syndrome

NLS2 (616038) is caused by mutation in the PSAT1 gene (610936) on chromosome 9q21.

Clinical Features

Neu et al. (1971) described 3 sibs with intrauterine growth retardation and multiple congenital anomalies, including microcephaly and abnormal limbs, skin, external genitalia, and placenta. Two girls were stillborn and a boy died at 7 weeks. Laxova et al. (1972) likewise reported 3 sibs. The parents were first cousins. Povysilova et al. (1976) reported 3 affected sibs. Lazjuk et al. (1979) reported a sporadic case. Autopsy showed a brain that weighed only 19.8 gm, the smallest recorded weight for brain in a 39-week fetus.

Winter et al. (1981) described 2 patients with Neu-Laxova syndrome and 1 patient with cerebrooculofacioskeletal (COFS) syndrome (214150) and discussed possible genetic relationships of the 2 disorders.

Scott et al. (1981) reported additional cases of Neu-Laxova syndrome, bringing the total to 13. They summarized as follows: 'The Neu-Laxova syndrome is a lethal dysplasia-malformation syndrome with abnormalities of placentation, severe intrauterine growth retardation, edema, ectodermal dysplasia, and the CAD complex with severe CNS developmental defect.' CAD is the acronym for cerebroarthrodigital syndrome (Spranger et al., 1980). Scott et al. (1981) concluded that the patients of Spranger et al. (1980) did not have the Neu-Laxova syndrome, but a possibly teratogenic malformation syndrome with better prognosis than in the Neu-Laxova syndrome.

Fitch et al. (1982) reported parental consanguinity and discussed further the differentiation from the COFS syndrome. The classic COFS syndrome does not include short neck, ichthyosis, subcutaneous swelling or syndactyly; retardation of development of the brain is much less severe than in the Neu-Laxova syndrome and neonatal lethality is not a feature. See also review by Curry (1982). Prominence of the eyes (exophthalmos) is a conspicuous feature of the Neu-Laxova syndrome; absence of the eyelids exaggerates the exophthalmos. Curry (1982) suggested that there may be two types of this syndrome, each caused by mutation in a separate gene. Group 1 cases, represented by patients such as that of Fitch et al. (1982), have no edema and no increased fat layer, whereas those of group 2, represented by the patient reported by Muller et al. (1987), among others, show an increased layer of subcutaneous adipose tissues with hypertrophy of fat cells.

Karimi-Nejad et al. (1987) emphasized ichthyotic skin lesions as a prominent characteristic change and called attention to the increased fatty tissue beneath the epidermis and the atrophic muscles embedded therein. Naveed et al. (1990) described the ichthyotic skin lesions in an affected infant born of consanguineous South Indian parents.

Ostrovskaya and Lazjuk (1988) reviewed cerebral abnormalities on the basis of 3 cases.

Meguid and Temtamy (1991) reported an affected female from 2 different families in each of which 4 other members were affected. Severe microcephaly with slanting forehead and protuberant eyes, generalized edema, contractures of the limbs, and generalized ichthyotic skin lesions were features.

Kuseyri et al. (1993) described an affected newborn female, the offspring of consanguineous Turkish parents.

Rouzbahani (1995) described an affected male infant of a nonconsanguineous Iranian couple; in addition to typical manifestations, the infant had cleft lip and palate, short limbs with hypoplastic forearms, recognizable thumbs and 3 fingers, 3 recognizable toes, and atrial and ventricular septal defects.

In a review of the literature, Manning et al. (2004) found reports of 61 purported cases of NLS. Although most were sporadic, a number of cases had been reported in consanguineous families. At least 10 families with multiple affected children had been described. The families were from diverse ethnic backgrounds. Manning et al. (2004) concluded that the data from these patients suggested that NLS represents a heterogeneous phenotype.

Manar and Asma (2010) reported a Jordanian girl, born of consanguineous parents, with Neu-Laxova syndrome. The patient presented at 31 weeks' gestation with severe intrauterine growth retardation. Ultrasound showed severe microcephaly, large mouth, decreased fetal movement, fixed flexion of upper and lower limbs with clubfeet, and kyphosis. At birth, the infant had poor respiration requiring mechanical ventilation. There were significant dysmorphic features, including proptotic eyes with extremely hyperemic conjunctivae and hazy cornea, closed fontanels, hypertelorism, depressed nose, and high-arched palate. The skin was thick, shiny, and very tight with fissuring at the flexion areas, abdomen, and chest, consistent with ichthyosis. The hips were in fixed flexion, the digits were short, and the hands and feet were edematous. She had no spontaneous movement, no spontaneous eye movement, and the pupils were small and nonreactive. Brain CT revealed a very small brain with lissencephaly and intraventricular and intracerebral hemorrhages. She died on day 4 of life.

Acuna-Hidalgo et al. (2014) reported 4 fetuses from 3 unrelated families with NLS1. Clinical features included intrauterine growth retardation, decreased fetal movements, microcephaly, facial dysmorphism, limb and digital deformities, rocker-bottom feet, swollen hands or feet, and ichthyosis.

Inheritance

Consanguinity and multiple affected sibs support autosomal recessive inheritance of Neu-Laxova syndrome (Manning et al., 2004).

Diagnosis

Muller et al. (1987) demonstrated the usefulness of ultrasonography in the monitoring of 'at risk' pregnancies. Shapiro et al. (1992) made the diagnosis of presumed NLS by ultrasonography in a 32-week fetus. The findings included intrauterine growth retardation, Dandy-Walker anomaly, choroid plexus cysts, receding forehead and microcephaly, bilateral cataract without prominent eyes, scalp edema with no generalized edema, retrognathia, curved penis, and flexion deformities of the limbs. Massive swelling of hands and feet seen in classic cases was missing; edema was noted only in the scalp.

Kainer et al. (1996) also pointed out the usefulness of ultrasonographic demonstration of abnormal fetal movement patterns in the prenatal diagnosis of this disorder. At 34, 35, and 36 weeks' gestation, no breathing movements, no sucking, and no swallowing were observed. Also there were no hiccups or normal isolated arm or leg movements. Already at that time the diagnosis was evident from extensive edema of hands and ocular hypertelorism with protruding eyes. The lips were thick with a round, gaping mouth.

Manning et al. (2004) presented 2 patients with Neu-Laxova syndrome with striking prenatal diagnostic findings and described the detailed postmortem examinations. They suggested that prenatal ultrasound findings of marked ocular proptosis in a growth-restricted, edematous fetus should prompt consideration of the diagnosis.

Molecular Genetics

In 3 patients from unrelated consanguineous Saudi families with NLS, Shaheen et al. (2014) identified 2 different homozygous missense mutations in the PHGDH gene (G140R, 606879.0007 and R163Q, 606879.0008). The mutations were found by a combination of autozygosity mapping and exome sequencing. Both substitutions occurred at highly conserved residues within the NAD(P)-binding domain and at the PHGDH dimer interface, suggesting that they would interfere with enzyme function. In vitro studies of the variants were not performed. In addition to manifesting classic features of the disorder, 1 of the patients had a dried blood spot that showed low concentrations of serine and glycine, consistent with a biochemical diagnosis of PHGDH deficiency. Shaheen et al. (2014) suggested that the severe phenotype observed in these patients reflects the extreme end of the inborn error of serine metabolism.

Acuna-Hidalgo et al. (2014) identified biallelic mutations in the PHGDH gene (see, e.g., 606879.0009 and 606879.0010) in affected individuals from 3 unrelated families with NLS1. Functional studies of the variants were not performed.

Associations Pending Confirmation

See 172480.0003 for discussion of a possible association between variation in the PSPH gene and Neu-Laxova syndrome.