Key Clinical MessageX-linked hereditary hydrocephalus (XLH) is a common cause of fetal hydrocephalus. L1CAM gene variants are causative, and novel pathogenic variants continue to emerge, making accurate diagnosis and variant evaluation increasingly important.AbstractX-linked hereditary hydrocephalus (XLH) is a congenital form of hydrocephalus caused by variants in the L1CAM gene on the X chromosome. Diagnosis is often made prenatally via ultrasound or magnetic resonance imaging (MRI), but specific features such as adducted thumbs are subtle and easily missed. We report a case in which prenatal MRI at 34 weeks gestation revealed fetal hydrocephalus and adducted thumb, suggestive of XLH. Postnatal genetic testing confirmed a previously unreported frameshift variant in the L1CAM gene, c.2248dup (p.Tyr750LeufsTer36). The male infant required neurosurgical intervention and was also diagnosed with Hirschsprung’s disease. Genetic testing confirmed that the mother was a heterozygous carrier. In a subsequent pregnancy, non-invasive prenatal testing (NIPT) predicted a female fetus with no hydrocephalus. This case highlights the importance of thorough imaging and genetic evaluation in suspected XLH, especially given the increasing discovery of novel pathogenic variants.Case PresentationA 29-year-old Japanese woman, Gravida 1 Para 0, conceived with ovulation induction. Her medical and family history were unremarkable. Routine ultrasound at 20 weeks’ gestation revealed enlargement of the fetal lateral ventricles (posterior horn 16 mm)(Fig1). Follow-up imaging showed progressive ventriculomegaly and cortical thinning, suggesting fetal hydrocephalus.MRI at 34 weeks gestation confirmed enlargement of the lateral and third ventricles, with suspected aqueductal stenosis(Fig2A). Adducted left thumb was also observed(Fig2B). The fetus was male. Given these findings and clinical suspicion of XLH, prenatal genetic testing was offered but declined.Biparietal diameter was significantly enlarged (110.1 mm, +7.15 SD). A cesarean section was planned at 36 weeks 3 days due to breech presentation. A male infant was delivered with Apgar scores of 7 and 9 at 1 and 5 minutes, respectively. Birth weight was 3054 g (+1.94 SD), and head circumference 44.2 cm (+9.5 SD).He was admitted to the NICU. On day 2, elevated intracranial pressure necessitated cerebrospinal fluid reservoir placement. Hirschsprung’s disease was suspected and later confirmed by surgery at 38 days. A ventriculoperitoneal shunt was placed at 48 days. Genetic testing showed a hemizygous c.2248dup (p.Tyr750LeufsTer36) variant in the L1CAM gene. We then conducted another genetic counseling session with the patient and her husband and made a carrier diagnosis for the patient. The patient was found to be heterozygous for the same variant as the child (Fig.3, 4).Two years later, the mother conceived naturally. Non-invasive prenatal testing (NIPT) indicated a female fetus. Ultrasound showed no hydrocephalus. A healthy girl was born by repeat cesarean section at 38 weeks. Although carrier status was unknown, genetic counseling for future testing was planned upon her reaching adulthood.DiscussionX-linked hereditary hydrocephalus (XLH) was first reported in 1949 as a disease characterized by hydrocephalus caused by stenosis of the cerebral aqueduct, neuromotor retardation, spastic paralysis of the lower limbs, and adduction flexion of the thumb1). The L1CAM gene has been identified as the gene responsible for XLH. L1CAM is a neuronal cell adhesion molecule located on X chromosome q28 and has important functions in the development of the nervous system2).With recent improvements in the diagnostic accuracy of ultrasound, the incidence of fetal ventricular enlargement detected during antenatal screening has increased. Recent reports suggest that the incidence of fetal ventriculomegaly is around 1% and is generally defined as a diameter of 10 mm or greater in the posterior horn of the lateral ventricles, regardless of gestational age. Severe ventriculomegaly is more likely than mild ventriculomegaly to cause clinical symptoms such as neurodevelopmental delay. If ventriculomegaly is detected on fetal ultrasound, detailed intracranial assessment is required. MRI is useful for fetal intracranial assessment. MRI for detailed intracranial observation is particularly useful in cases with enlarged ventricles on ultrasound3). Adducted thumbs are reported to be an early sign of neurodevelopmental disorders4). Izumi et al. reported that adducted thumbs are present in only half of patients before 24 weeks’ gestation, but are present in most cases of XLH in the second trimester5). Therefore, the timing of evaluation need to be considered. In our case, the diagnosis of adducted thumbs was made by MRI, but there are no previous reports of adducted thumbs diagnosed by MRI. A more detailed evaluation of the brain by ultrasound and MRI may provide more information.The mode and timing of delivery should be discussed. Increased head circumference may complicate delivery, even by cesarean section, increase the risk of maternal injury, and adversely affect the child’s prognosis and should be considered on a case-by-case basis. There is no established method or timing of delivery in cases of fetal hydrocephalus, but cesarean delivery after confirmation of lung maturity is considered appropriate6). (Fetology, Chapter 16, Hydrocephalus.) Kuller JA et al suggested that caesarean delivery of a hydrocephalic fetus with macrocephaly contributes to a better prognosis7). In our case, we did not perform tests to confirm lung maturity. Although the fetus was delivered prematurely at 36 weeks’ gestation, it was delivered at a time when lung maturity was expected.The molecular mechanism and structure of the L1CAM protein are well understood. It is a plasma membrane protein of 1238 amino acids, with an extracellular portion of 1101 amino acids containing 6 IgG domains and 5 fibronectin III domains. Yamasaki M et al. classified the proteins into three classes according to the nature of these variants8). The variant in our case is class 3, which is the most severe. Michaelis RC et al. reported that the fibronectin domain variant is more severe than the IgG domain variant9). Although the variant in our case is a previously unreported variant, it is a frameshift variant in the L1CAM gene, which is known to be pathogenic due to loss of function according to the American College of Medical Genetics and Genomics (ACMG) guidelines10). The variant is located in the fibronectin III2 portion of the L1CAM gene, which is a highly pathogenic variant. Therefore, the variant is considered to be of very high pathogenicity (PVS1).There were no other XLH cases in the family and the probability of a de novo mutation was estimated to be about 1/3. The probability of the patient being a carrier was estimated to be about 2/3, which should be taken into account when diagnosing carriers of X-linked diseases, as the woman will be screened to see if she is a carrier.Regarding prenatal diagnosis, Serikawa T et al. reported that in families where the first child has XLH and the mother is known to be a carrier, the next and subsequent pregnancies should be sexed by chromosome analysis, followed by L1CAM gene analysis if the child is a boy11). As in this case, using NIPT to diagnose the sex of the fetus may be useful in avoiding invasive tests such as amniocentesis. Preimplantation genetic diagnosis is limited to in vitro fertilization, but can reduce the burden on the mother. We need to offer this couple options based on the latest evidence when they consider their next pregnancy.ConclusionThis case highlights the importance of detailed fetal imaging in diagnosing XLH. MRI findings, particularly adducted thumbs, may raise early suspicion. Identification of novel L1CAM variants is vital for expanding our understanding of this condition. Genetic counseling and testing remain essential for informed family planning.Patient ConsentWritten informed consent was obtained from the patient for publication of this case report and accompanying images.Conflict of InterestThe authors declare no conflicts of interest.Author ContributionsRyosuke Horiuchi: primary author, case management, and manuscript preparation; Hiroshi Sato and Chinami Asai: manuscript preparation, prenatal diagnosis and imaging interpretation; Fumika Hamaguchi and Yu Takaishi: obstetric management; Kensuke Fujiwara and Yukiko Ando: genetic counseling and molecular analysis; Takahito Kawata and Yukari Atsumi: pediatric care; Kazuyo Kakui: case supervision and critical review. All authors reviewed and approved the final manuscript.Figure LegendsFigure 1. Ultrasonography at 20 weeks of gestation revealed an enlargement of the posterior horn of the lateral ventricle to 16 mm.Figure 2. Magnetic resonance imaging (T2-weighted image) at 34 weeks of gestation showed marked enlargement of the fetal lateral ventricles and the third ventricle, but no enlargement of the fourth ventricle (A). Adduction flexion of the left thumb was suspected (B).Figure 3. Pedigree of the patient and her family. Generations are shown in Roman numerals, individuals in Arabic numerals. Solid symbols indicate individuals diagnosed with XLH. The proband is marked by an arrow and the letter P.Figure 4. Nucleotide sequence analysis of the L1CAM gene showing the c.2248dup mutation (arrow). Analysis of peripheral blood revealed a heterozygous germline mutation in the mother.References1. Bickers DS, Adams RD. Hereditary stenosis of the aqueduct of Sylvius as a cause of congenital hydrocephalus. Brain. 1949;72(Pt. 2):246–62.2. Rosenthal A, Jouet M, Kenwrick S. Aberrant splicing of neural cell adhesion molecule L1 mRNA in a family with X-linked hydrocephalus. Nat Genet. 1992;2(2):107–12.3. Di Mascio D, et al. Role of prenatal MRI in fetuses with isolated severe ventriculomegaly: a multicenter study. Eur J Obstet Gynecol Reprod Biol. 2021;267:105–10.4. Ouyang YS, et al. Adducted thumb as an isolated morphologic finding: an early sonographic sign of impaired neurodevelopment. Medicine (Baltimore). 2018;97(38):e12437.5. Izumi R, et al. Adducted thumb may not be mandatory for prenatal diagnosis of X-linked hydrocephalus in early second trimester. Taiwan J Obstet Gynecol. 2022;61(2):353–55.6. Fetology. Chapter 16: Hydrocephalus. McGraw-Hill; pp134–141.7. Kuller JA, et al. Cesarean delivery for fetal malformations. Obstet Gynecol Surv. 1996;51(6):371–75.8. Yamasaki M, et al. CRASH syndrome: mutations in L1CAM correlate with severity of the disease. Neuropediatrics. 1997;28(3):175–78.9. Michaelis RC, et al. Site of a missense mutation in L1CAM influences infant mortality and severity of X-linked hydrocephalus. J Med Genet. 1998;35(11):901–4.10. Richards S, et al. Standards and guidelines for interpretation of sequence variants: a joint consensus recommendation of ACMG and AMP. Genet Med. 2015;17(5):405–24.11. Serikawa T, et al. Prenatal molecular diagnosis of X-linked hydrocephalus via a silent C924T mutation in the L1CAM gene. Congenit Anom (Kyoto). 2014;54(4):243–45.
