Ultrasound Obstet Gynecol 2014; 44: 365–368 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.13359
Prenatal ultrasound and MRI findings of temporal and occipital lobe dysplasia in a twin with achondroplasia D. PUGASH*, A. M. LEHMAN† and S. LANGLOIS† *Department of Radiology, British Columbia Women’s Hospital and University of British Columbia, Vancouver, Canada; †Department of Medical Genetics, British Columbia Women’s Hospital and University of British Columbia, Vancouver, Canada
K E Y W O R D S: achondroplasia; fetal MRI; FGFR3 mutations; hypochondroplasia; prenatal ultrasound; temporal lobe; twin
CASE REPORT A 39-year-old woman in her sixth pregnancy was seen at 24 + 4 weeks’ gestation for possible brain abnormalities in Twin B of a dichorionic diamniotic pregnancy. Maternal medical history included a diagnosis of melanoma and antiphospholipid antibody syndrome. Paternal age was 43 years. Obstetric history included three miscarriages. In her fourth pregnancy, the mother was treated with heparin and acetylsalicylic acid (ASA). The pregnancy was complicated by vaginal bleeding at 24 weeks’ gestation and again at 27 weeks, with premature rupture of membranes and delivery at 27 weeks. The newborn female had an uncomplicated course, undergoing 1 day of ventilation and
subsequent continuous positive airway pressure. Cranial magnetic resonance imaging (MRI) at 8 days postpartum as part of a research study revealed findings consistent with periventricular leukomalacia. At the age of 3 years, the child had mild cerebral palsy with left hemiplegia. The current pregnancy was conceived under treatment with clomiphene citrate. ASA and heparin were started at 5 weeks’ gestation. A dichorionic diamniotic gestation was found at a dating scan at 8 + 3 weeks’ gestation. Nuchal translucency at 12 + 3 weeks’ gestation and integrated first- and second-trimester serum screenings were negative for trisomy 21, trisomy 18 and neural tube defect. Routine ultrasound examination was performed at 20 weeks’ gestation and normal biometry and anatomy were confirmed in both male twins. Biometry of Twin A showed the head at the 90th centile, with the abdomen and the femur at the 75th centile. Biometry of Twin B showed the head at the 93rd centile, the abdomen at the 85th centile and the femur at the 60th centile. At follow-up ultrasound examination at 24 + 4 weeks’ gestation biometry and anatomy of Twin A were normal. Biometry of Twin B was normal, apart from head circumference on the 99th centile. However, mild unilateral ventriculomegaly (10–11 mm) and subtle asymmetry of the calcarine sulci and the mesial temporal and occipital lobes were observed (Figures 1a and b). Ultrasound examination was repeated at 28 weeks’ gestation and biometry and anatomy of Twin A were normal. Twin B had moderate polyhydramnios, macrocephaly and a prominent forehead. In Twin B, biometry of the femora and humeri was below the 1st centile, and asymmetrical abnormal sulcation, involving both mesial temporal and occipital lobes, with abnormal configuration of the calcar avis, was observed (Figure 1c). At ultrasound examination at 31 + 5 weeks’ gestation biometry and anatomy of Twin A were normal. Twin B
Correspondence to: Dr D. Pugash, Ultrasound Department - 1T48, British Columbia Women’s Hospital, 4500 Oak Street, Vancouver, B.C., Canada V6H 3N1 (e-mail: [email protected]) Accepted: 26 February 2014
Figure 1 Sagittal (a) and coronal (b) ultrasound images at 24 + 4 weeks’ and coronal image at 28 weeks’ gestation (c), showing abnormal deep clefting involving the mesial temporal lobe (a, arrow) and asymmetrical sulcation involving the medial aspect of the temporal lobes (b, c, arrowheads).
had moderate polyhydramnios, macrocephaly, frontal bossing and femoral and humeral biometry below the 1st centile. Ultrasound findings were suggestive of achondroplasia. Fetal MRI was performed at 32 + 5 weeks’ gestation. MRI anatomy in Twin B included macrocephaly, frontal bossing and short femora. In contrast to normal findings in Twin A, the findings in Twin B included abnormal sagittal clefting in the mesial temporal lobe (Figure 2a), abnormal configuration of the temporal horns with deep transverse clefts of the mesial temporal lobes (Figure 3a), enlargement of the lateral temporal lobes (Figure 4a) and oversulcation extending to the calcar avis (Figures S1 and S2). Based on reports of similar imaging results in children1 – 3 , a tentative diagnosis of hypochondroplasia was made, although the degree of limb shortening
at that gestational age was more in keeping with achondroplasia. Elective Cesarean delivery was performed at 38 weeks’ gestation because of breech presentation. On postnatal examination, Twin A was normal and Twin B had macrocephaly, frontal bossing, rhizomelic limb shortening relative to a long trunk and trident configuration of the fingers. DNA testing was performed postnatally and showed that Twin B was heterozygous for FGFR3 (fibroblast growth factor receptor 3) c.1138G>A (p.Gly380Arg) mutation, diagnostic of achondroplasia. At 2 months of age, macrocephaly (2.8 SD above the mean) and mild truncal hypotonia were present, but otherwise neurodevelopmental assessment was normal. At 7 months of age, neurodevelopment was normal and the infant had not experienced seizures.
Figure 2 Parasagittal T2-weighted magnetic resonance images at 32 + 5 weeks’ gestation in twin with achondroplasia showing abnormal vertical clefting in the mesial temporal lobe (a, arrow), compared with appearance of the temporal lobe in the normal twin (b, arrowhead). Also note frontal bossing in the affected twin (a).
Figure 3 Axial T2-weighted magnetic resonance images at 32 + 5 weeks’ gestation showing abnormal configuration of temporal horns and deep transverse clefts of mesial temporal lobes (a, arrow) in the twin with achondroplasia. (b) Normal configuration of temporal horns and mesial temporal lobes is shown in the normal twin.
Figure 4 Enlargement of temporal lobes in twin with achondroplasia (a), in which the surface of the temporal lobe bulges beyond the contour of the frontoparietal lobe, in contrast with normal twin (b). Arrows indicate frontoparietal lobes; lateral border of the temporal lobes is indicated by dashed lines.
DISCUSSION Thanatophoric dysplasia, achondroplasia and hypochondroplasia are all caused by FGFR3 gene mutations4 – 6 . Temporal lobe dysplasia has been well described in cases of thanatophoric dysplasia7 – 10 . Philpott et al. described brain imaging studies in nine children with hypochondroplasia3 . The FGFR3 Asn540Lys mutation was confirmed in three of the nine cases. All children had enlarged temporal lobes, abnormally shaped temporal horns, deep transverse fissures of the inferior temporal lobe surface and oversulcation of the mesial temporal and occipital lobes with abnormal inferomedial orientation of redundant gyri. Linnankivi et al. reported neurological findings in 13 children with hypochondroplasia and
FGFR3 Asn540Lys mutations2 . MRI was performed in eight of these children, all of whom had bilateral temporal lobe dysgenesis. The role of Fgfr3 in brain development has been studied in murine models, which have shown that mice expressing a constitutively active mutant Fgfr3 allele display an enlarged cerebral cortex, mostly due to increased progenitor proliferation11,12 . The increase in progenitor proliferation in the ventricular zone was graded along the rostrocaudal axis, with the greatest effect seen in the caudal region11 . Activation of Fgfr3 selectively promotes growth of the occipitotemporal cortex13 . This may explain the premature sulcation of the occipital cortex in fetuses with FGFR3 mutations, resulting in thanatophoric dysplasia (TD), hypochondroplasia and, as in this case,
Ultrasound Obstet Gynecol 2014; 44: 365–368.
Pugash et al.
achondroplasia. Ultrasound findings as well as prenatal and postnatal MRI findings are typical of hypochondroplasia but differ substantially from those obtained in the case of TD. In TD, abnormal sulcation is typically found in the inferior aspect of the temporal lobes, whereas, in this case, abnormal sulcation primarily involved the medial aspect of the temporal and occipital lobes. In the case presented here, prenatal recognition of central nervous system anomalies was assisted by comparison of the abnormal findings in the affected twin with those in the normal cotwin. Fetal ultrasound and MRI findings in the affected twin were virtually identical to those reported in children with hypochondroplasia. Published case reports describe antenatal ultrasound findings of short long bones and subsequent postnatal, postmortem or retrospective genetic confirmation of hypochondroplasia14,15 . We are unaware of reports of similar findings in cases of achondroplasia. In the present case, intracranial findings were not identified by postnatal ultrasound examination. However, in conjunction with fetal MRI, postnatal MRI confirmed the antenatally diagnosed abnormalities (Figure S3). We believe that this is the first report of the prenatal temporal lobe abnormalities typical of hypochondroplasia in a fetus with a confirmed postnatal clinical and genetic diagnosis of achondroplasia.
The authors would like to thank the family who gave their consent to this publication, as well as the RAFT (Research in Advanced Fetal diagnosis and Therapy) Group at BC Women’s Hospital and Health Centre.
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hypochondroplasia and FGFR3 N540K mutation. Am J Med Genet A 2012; 158A: 3119–3125. Philpott CM, Widjaja E, Raybaud C, Branson HM, Kannu P, Blaser S. Temporal and occipital lobe features in children with hypochondroplasia/FGFR3 gene mutation. Pediatr Radiol 2013; 43: 1190–1195. Prinos P, Costa T, Sommer A, Kilpatrick MW, Tsipouras P. A common FGFR3 gene mutation in hypochondroplasia. Hum Mol Genet 1995; 4: 2097–2101. Tsai FJ, Tsai CH, Chang JG, Wu JY. Mutations in the fibroblast growth factor receptor 3 (FGFR3) cause achondroplasia, hypochondroplasia, and thanatophoric dysplasia: Taiwanese data. Am J Med Genet 1999; 86: 300–3001. Winterpacht A, Hilbert K, Stelzer C, Schweikardt T, Decker H, Segerer H, Spranger J, Zabel B. A novel mutation in FGFR-3 disrupts a putative N-glycosylation site and results in hypochondroplasia. Physiol Genomics 2000; 2: 9–12. Knisely AS, Ambler MW. Temporal-lobe abnormalities in thanatophoric dysplasia. Pediatr Neurosci 1988; 14: 169–176. Kannu P, Hayes IM, Mandelstam S, Donnan L, Savarirayan R. Medial temporal lobe dysgenesis in hypochondroplasia. Am J Med Genet A 2005; 138A: 389–391. Fink AM, Hingston T, Sampson A, Ng J, Palma-Dias R. Malformation of the fetal brain in thanatophoric dysplasia: US and MRI findings. Pediatr Radiol 2010; 40 (Suppl 1) 134–137. Blaas HG, Vogt C, Eik-Nes SH. Abnormal gyration of the temporal lobe and megalencephaly are typical features of thanatophoric dysplasia and can be visualized prenatally by ultrasound. Ultrasound Obstet Gynecol 2012; 40: 230–234. Thomson RE, Pellicano F, Iwata T. Fibroblast growth factor receptor 3 kinase domain mutation increases cortical progenitor proliferation via mitogen-activated protein kinase activation. J Neurochem 2007; 100: 1565–1578. Inglis-Broadgate SL, Thomson RE, Pellicano F, Tartaglia MA, Pontikis CC, Cooper JD, Iwata T. FGFR3 regulates brain size by controlling progenitor cell proliferation and apoptosis during embryonic development. Dev Biol 2005; 279: 73–85. Thomson RE, Kind PC, Graham NA, Etherson ML, Kennedy J, Fernandes AC, Marques CS, Hevner RF, Iwata T. Fgf receptor 3 activation promotes selective growth and expansion of occipitotemporal cortex. Neural Dev 2009; 4: 4. Huggins MJ, Mernagh JR, Steele L, Smith JR, Nowaczyk MJ. Prenatal sonographic diagnosis of hypochondroplasia in a high-risk fetus. Am J Med Genet 1999; 87: 226–229. Karadimas C, Sifakis S, Valsamopoulos P, Makatsoris C, Velissariou V, Nasioulas G, Petersen MB, Koumantakis E, Hatzaki A. Prenatal diagnosis of hypochondroplasia: report of two cases. Am J Med Genet A 2006; 140A: 998–1003.
SUPPORTING INFORMATION ON THE INTERNET The following supporting information may be found in the online version of this article: Figure S1 Axial T2-weighted magnetic resonance images demonstrating oversulcation of the mesial temporal lobes in twin with achondroplasia compared with normal cotwin. Figure S2 Coronal T2-weighted magnetic resonance images showing abnormal sulcation in the region of the calcar avis in twin with achondroplasia compared with normal appearance in normal twin. Figure S3 Antenatal compared with postnatal T2-weighted magnetic resonance images of the twin with achondroplasia.
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