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To the Editor:

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We read with great interest the article “Maternal Vitamin K Deficient Embryopathy: Association with Hyperemesis Gravidarum and Crohn Disease” by Toriello et al. [2013]. We have been following a 16-year-old female with multiple medical issues including chondrodysplasia punctata, Binder phenotype (Fig. 1), brachytelephalangy, partial complex seizures secondary to cortical dysplasia, Chiari Type II malformation, and tethered cord. Her mother had hyperemesis gravidarum requiring partial parenteral therapy and we believe that her constellation of symptoms can be explained by a similar vitamin K deficiency embryopathy. This is the first report outside of infancy of a patient with symptomatic cortical dysplasia as a result of the syndrome.

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Figure 1. The patient at age 3 years (AC) and age 13 years (DF), note the Binder phenotype of flat nasal bridge, and brachytelephalangy.

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The patient was a 2,190 g (10th centile) product of a 37-week pregnancy to a G2P2 mother whose pregnancy was complicated by hyperemesis gravidarum starting at 6 weeks past her last menstrual period and requiring total parenteral therapy with indwelling catheter from week 8 to week 27 of pregnancy. Only routine blood work was performed; no vitamin or mineral levels, including vitamin K, were performed. Family history was noncontributory. The patient was originally seen by genetics at birth for her small nasal bridge, and short and asymmetric limbs. Stippling of multiple bones was also noted on X-rays after birth and a diagnosis of chondrodysplasia punctata was presumptively made. Testing for mutations in arylsulfatase E at that time was negative [Nino et al., 2008]. Plasmalogen levels from red blood cells were also normal.

Our patient walked at 13 months, began talking at 12 months and spoke two-word sentences at 18 months. She had recurrent sinus infections in childhood, thought to be secondary to her abnormal craniofacial profile, which improved after an adenoidectomy at age 5. Starting in Kindergarten she was found to have a learning disability, but was able to maintain As and Bs in an age-appropriate classroom with extra resources. When she was 7 she was found to have stable mild conductive hearing loss in the left ear. After a sport-related concussion she was found to have progressed to moderate hearing loss in the left ear and mild right-sided loss, for which she uses hearing aids.

An MRI performed for persistent headaches identified a Chiari type II malformation that was decompressed at age 9 (Fig. 2). She was also found to have a tethered cord and syrinx at T3–T10, which was released at age 10 and again a year later. At age 11 she began to have periods of confusion, where she would wander or walk in place for about 30 seconds, then belch or vomit. This was followed by a headache and 2–4 hr of tiredness. She reported three to four episodes a week with no known triggers or prodrome. A brain MRI at that time showed mildly prominent ventricles with right parietal and occipital cortical dysplasia. A routine awake EEG showed right temporal theta bursts. She was eventually diagnosed with complex partial seizures secondary to the cortical dysplasia seen on MRI. These seizures were refractory to eight different antiepileptic medications, and eventually the patient underwent thermal ablation of the dysplastic tissue at age 15. She continued to have seizures, so a second thermal ablation was performed at age 16. She has now been seizure-free for almost a year after the second ablation. Due to short stature and low IGRF-1 levels the patient was started on growth hormone therapy starting at age 12 for 3 years, with which she reached a final height of 4′10.5″ and it was discontinued. A SNP microarray performed at age 13 showed a normal 46,XX result.

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Figure 2. T1 weighted MRI image of patient's brain at age 14 before thermal ablation showing right occipital cortical heterotopias likely secondary to a neuronal migration defect.

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She was recently re-evaluated by genetics at age 16. Her exam was notable for a height of 149 cm (<3rd centile, 50th centile for 11.5 years), weight of 39 kg (<3rd centile, 50th centile for 11.5 years), head circumference of 54.5 cm (75th centile), and interpupillary distance of 6.25cm (75th centile). Hand length bilaterally was 15.5 cm (<3rd centile, 50th centile for 10 years) with a bilateral middle finger length of 6.5 cm (<3rd centile, 50th centile for 10 years) and bilateral foot length of 21.5 cm (<3rd centile, 50th centile for 10 years) Additionally she had a distinctive facial appearance with bilateral epicanthus tarsalis with a depressed nasal bridge resulting in a saddle-type nose. Her distal phalanges were also noted to be broad and short and great toes were noted to be broad. She is doing well in a normal 11th grade classroom and plans on attending a 4-year college after graduation.

There have been two previously reported patients with likely hyperemesis gravidarum-induced vitamin K-deficient embryopathy leading to chondrodysplasia punctata and cortical heterotopias [Brunetti-Pierri et al., 2007; Toriello et al., 2013]. However, the patient reported by Toriello et al. [2012] was lost to follow up at age 6 months, and the patient reported by Brunetti-Pierri et al. [2007] was 7 months old. This is the first report of the natural history of cortical dysplasias secondary to hyperemesis gravidarum induced vitamin K deficient embryopathy, and emphasizes that epilepsy may be a later finding and more consistent finding than previously recognized.

As reviewed by Toriello et al. [2013], there can be multiple causes for maternal vitamin K deficiency that appear to lead to similar fetal phenotypes, including warfarin exposure, autoimmune disease, hyperemesis, alcoholism, antiepileptic drug exposure, hepatic and renal disease. It is thought that 8 weeks after LMP is the most critical period of embryonic development affected by vitamin K deficiency and previous studies have shown deleterious effects on brain formation leading to Chiari type II malformations, Dandy–Walker malformations, microcephaly, and cerebellar atrophy [Ferland, 2012]. Cortical dysplasias result from incomplete neuronal migration during development. The Gas6/Axl signaling pathway has been implicated in neuronal migration of certain areas of the cortex [Allen et al., 2002]. Gas6 requires post-translational processing by the vitamin K-dependent enzyme GGCX [Varnum et al., 1995]. Therefore there is a plausible mechanism by which vitamin K deficiency could lead to impaired neuronal migration and cortical dysplasia. We agree with the conclusions of Toriello et al. [2013] in increased recognition and treatment of women at risk for Vitamin K deficiency during pregnancy, and surveillance among affected offspring for cortical dysplasia and epilepsy.

REFERENCES

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  2. To the Editor:
  3. REFERENCES
  • Allen MP, Linseman DA, Udo H, Xu M, Schaack JB, Varnum B, Kandel ER, Heidenreich KA, Wierman ME. 2002. Novel mechanism for gonadotropinreleasing hormone neuronal migration involving Gas6/Ark signaling to p38 mitogen-activated protein kinase. Mol Cell Biol 22:599613.
  • Brunetti-Pierri N, Hunter JV, Boerkel CF. 2007. Gray matter heterotopias and brachytelephalangic chondrodysplasia punctata: A complication of hyperemesis gravidarum induced vitamin K deficiency? Am J Med Genet Part A 143A:200204.
  • Ferland G. 2012. Vitamin K and the nervous system: An overview of its actions. Adv Nutr 3:204212.
  • Nino M, Matos-Miranda C, Maeda M, Chen L, Allanson J, Armour C, Greene C, Kamaluddeen M, Rita D, Medne L, Zackai E, Mansour S, Superti-Furga A, Lewanda A, Bober M, Rosenbaum K, Braverman N. 2008. Clincal and molecular analysis of arylsulfatase E in patients with brachytelephalangic chondrodysplasia punctata. Am J Med Genet Part A 146A:9971008.
  • Toriello HV, Erick M, Alessandri JL, Bailey D, Brunetti-Pierri N, Cox H, Fryer A, Marty D, McCurdy C, Mulliken JB, Murphy H, Omlor J, Pauli RM, Ranells JD, Sanchez-Valle A, Tobiasz A, Van Maldergem L, Lin AE. 2013. Maternal vitamin K deficient embryopathy: Association with hyperemesis gravidarum and crohn disease. Am J Med Genet Part A 161A:417429.
  • Varnum BC, Young C, Elliott G, Garcia A, Bartley TD, Fridell YW, Hunt RW, Trail G, Clogston C, Toso RJ, et al. 1995. Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6. Nature. 373:623626.